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DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ONCOLOGIC DRUGS ADVISORY COMMITTEE

VOLUME II

Friday, March 4, 2005

8:00 a.m.

Gaithersberg Hilton

620 Perry Parkway

Gaithersburg, Maryland

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PARTICIPANTS

Silvana Martino, D.O., Acting Chair

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

COMMITTEE MEMBERS

Otis W. Brawley, M.D.

James H. Doroshow, M.D.

Antonio J. Grillo-Lopez, M.D., Industry

Representative

Pamela J. Haylock, RN, Consumer Representative

Maha H.A. Hussain, M.D.

Alexandra M. Levine, M.D.

Joanne E. Mortimer, M.D.

Michael C. Perry, M.D.

Gregory H. Reaman, M.D.

Maria Rodriguez, M.D.

CONSULTANTS (VOTING)

Ralph D\'Agostino, Ph.D.

Michael Proschan, Ph.D.

PATIENT REPRESENTATIVE (VOTING)

Sheila Ross - For Iressa

FDA

Martin Cohen, M.D. (a.m. session)

Grant Williams, M.D. (a.m. session)

Amna Ibrahim, M.D.

Nancy Scher, M.D.

Eric Colman, M.D.

Mark Avigan, M.D.

Richard Pazdur, M.D.

Robert Temple, M.D.

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C O N T E N T S

Page

Call to Order and Introductions

Silvana Martino, D.O. 5

Conflict of Interest Statement

Johanna Clifford, M.S., RN 7

Opening Remarks

Richard Pazdur, M.D. 10

Sponsor Presentation

AstraZeneca L.P.

Introduction and Regulatory History

Mark Scott, Ph.D. 15

Trial 709

Kevin Carroll, MSc 24

Clinical Actions and Implications

Judith Ochs, M.D. 37

Summary

Mark Scott, Ph.D. 56

Committee Questions 59

Open Public Hearing 89

Committee Discussion 107

\- - -

Call to Order and Introductions

Silvana Martino, D.O. 140

Conflict of Interest Statement

Johanna Clifford, M.S., RN 142

Opening Remarks

Richard Pazdur, M.D. 145

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C O N T E N T S (Continued)

Page

FDA Presentation

Regulatory History of Zometa and Aredia

Nancy Scher, M.D. 147

Post-Marketing Safety Assessment of

Osteonecrosis of the Jaw: Pamidronate

and Zoledronic Acid

Carol Palmer, R.Ph. 155

Osteonecrosis of the Jaws in Myeloma:

Time Dependent Correlation with Zometa

and Zometa use

Brian Durie, M.D. 173

Sponsor Presentation

Novartis Pharmaceuticals

ONJ Reported in Bisphosphonates Treated

Patients - An Overview

Diane Young, M.D. 188

Clinical Benefit of Bisphosphonates in Cancer

Patients with Metastatic Bone Disease

James Berenson, M.D. 222

Open Public Hearing 229

Committee Discussion 252

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P R O C E E D I N G S

Call to Order and Introductions

DR. MARTINO: Good morning, ladies and

gentlemen.

The topic before us this morning is some

additional new data that has arisen relative to the

agent Iressa. Before we start with the topic

itself, I am going to ask the committee to

introduce itself, and we will start on my left with

Dr. Pazdur, please.

DR. PAZDUR: Richard Pazdur, FDA.

DR. WILLIAMS: Grant Williams, FDA.

DR. COHEN: Martin Cohen, FDA.

MRS. ROSS: Sheila Ross, Lung Cancer

Alliance formerly ALCASE.

MS. HAYLOCK: Pam Haylock, Oncology Nurse,

University of Texas Medical Branch in Galveston.

DR. LEVINE: Alexandra Levine, University

of Southern California, Chief of Heme.

DR. RODRIGUEZ: Maria Rodriguez, M.D.

Anderson Cancer Center.

DR. REAMAN: Gregory Reaman, Pediatric

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Oncologist, Children\'s Hospital, Washington, D.C.

DR. MARTINO: Silvana Martino, Medical

Oncology, Cancer Institute Medical Group in Santa

Monica.

MS. CLIFFORD: Johanna Clifford, Executive

Secretary to the Oncologic Drugs Advisory

Committee.

DR. HUSSAIN: Maha Hussain, Medical

Oncology, University of Michigan.

DR. PERRY: Michael Perry, Medical

Oncology, University of Missouri, Ellis Fischel

Cancer Center.

DR. MORTIMER: Joanne Mortimer, Medical

Oncology, University of California at San Diego.

DR. GRILLO-LOPEZ: Antonio Grillo-Lopez.

I am a hematologist/oncologist, a five-year cancer

survivor, and I am here as the industry

representative on this committee. I would like to

state that although I am the industry

representative, I receive no support whatsoever

from industry for my presence here.

DR. PROSCHAN: Mike Proschan. I am from

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the National Heart, Lung, and Blood Institute.

DR. D\'AGOSTINO: Ralph D\'Agostino, Boston

University, Biostatistician.

DR. BRAWLEY: Otis Brawley, Medical

Oncology and Epidemiology, Emory University.

DR. DOROSHOW: Jim Doroshow, National

Cancer Institute.

DR. MARTINO: Thank you.

Next, I would like Ms. Clifford to read

the Conflict of Interest Statement for the group.

Conflict of Interest Statement

MS. CLIFFORD: The following announcement

addresses the issue of conflict of interest and is

made a part of the record to preclude even the

appearance of such at this meeting.

Based on the submitted agenda and all

financial interests reported by the committee

participants, it has been determined that all

interests in firms regulated by the Center for Drug

Evaluation and Research present no potential for an

appearance of a conflict of interest with the

following exceptions:

In accordance with 18 U.S.C. 208(b)(3),

full waivers have been granted to the following

participants. Please note that the following

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consulting activities waived are unrelated to

Iressa and its competing products.

Dr. Silvana Martino for consulting for a

competitor, which her employer receives less than

10,001 per year.

Dr. Michael Perry for consulting with a

competitor which he receives less than 10,001 per

year. In addition, Dr. Perry has been granted a

waiver under 21 U.S.C. 505(n) for owning stock in a

competitor, valued between \$5,001 to \$25,000.

Because his stock interest falls below the de

minimis exception allowed under 5 CFR(b)(2), a

waiver under 18 U.S.C. 208 is not required.

Dr. Maha Hussain has been granted waivers

under 208(b)(3) and 21 U.S.C. 505(n) for owning

stock in a sponsor and a competitor. These stocks

are valued from 25,000 to 50,000 per firm.

A copy of the waiver statements may be

obtained by submitting a written request to the

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Agency\'s Freedom of Information Office, Room 12A-30

of the Parklawn Building.

With respect to the FDA\'s invited industry

representative, we would like to disclose that Dr.

Antonio Grillo-Lopez is participating in this

meeting as an acting industry representative acting

on behalf of regulated industry. Dr. Grillo-Lopez

is employed by Neoplastic and Autoimmune Disease

Research.

In the event that the discussions involve

any other products or firms not related on the

agenda for which an FDA participant has a financial

interest, the participants are aware of the need to

exclude themselves from such involvement, and their

exclusion will be noted for the record.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firm whose products they may wish to comment

upon.

DR. MARTINO: Thank you.

Next on our agenda is Dr. Richard Pazdur,

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who will address the committee and give us some

direction for this morning\'s meeting, please.

Opening Remarks

DR. PAZDUR: Thank you, Dr. Martino.

Iressa was originally approved by the FDA

on May 5th, 2003, as a monotherapy for the

treatment of patients with locally advanced or

metastatic non-small cell lung cancer after failure

of both platinum-based and docetaxel

chemotherapies.

Partial tumor responses occurred in

approximately 10 percent of patients. Iressa was

approved under the accelerated approval

regulations. As discussed yesterday, these

regulations allow approval based on a surrogate

endpoint reasonably likely to predict clinical

benefit and require subsequent studies to verify

and define its clinical benefit.

As an approval condition, AstraZeneca

committed to conduct a randomized trial examining

the Iressa effect on survival in patients with

advanced non-small cell lung cancer who had

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received 1 to 2 prior chemotherapies. This is

defined as Trial 0709.

The primary endpoint of this trial was

overall survival and improved survival for

Iressa-treated patients was to satisfy the

requirement for the demonstration of clinical

benefit. For drugs approved under accelerated

approval, the FDA may withdraw approval for the

failure of a post-marketing study to verify

clinical benefit. I should note that there were

several studies that were included in their Phase

IV commitment.

The withdrawal procedure requires a formal

hearing whose composition and procedures are

defined in the Code of Federal Regulations. This

meeting is not that formal hearing.

AstraZeneca notified the United States

Food and Drug Administration on December 17th,

2004, that a large randomized study comparing

Iressa plus best supportive care to placebo plus

best supportive care failed to demonstrate a

survival advantage for Iressa in the treatment of

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non-small cell lung cancer.

The results will be reported in detail by

AstraZeneca during this meeting.

The FDA has not received the complete data

set for this trial, especially data that would

allow pharmacogenetic or immunohistochemistry

subset analysis. The FDA management plan is rapid

communication of the above trial results to health

care professionals and patients concurrent with the

expeditious completion of the trial analysis by

AstraZeneca, including the effects of EGFR status

determined by immunohistochemistry and EGFR

mutational status on survival.

We are interested in reviewing the

immunohistochemistry subset analysis since

interesting exploratory findings were included in

the Tarceva label that was recently approved this

year.

The FDA will not make a regulatory

decision on Iressa until the data regarding subset

analysis and the study results are received and

reviewed. In the interim, AstraZeneca has

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suspended promotion of Iressa, but will continue to

make the drug available to patients who appear to

be benefiting from Iressa treatment.

Actions have been taken to communicate the

most recent Iressa information to health care

professionals and patients.

These are delineated in the preamble to

the discussion points and include: AstraZeneca

press release of the ISEL study results, Dear

Doctor letters notifying physicians of the study

results and alternative therapies available,

AstraZeneca sales force distribution of Dear Doctor

letters, other Dear Doctor letters being posted on

the AstraZeneca website, patient advocate groups

being notified, AstraZeneca communications to known

patients, information being posted on the FDA

website, abstracts at meetings, journal placements

of the Dear Doctor letters, advertisements on a

continuing basis in all issues of the 10 most

widely read oncology journals urging physicians to

consider options other than Iressa.

A copy of this advertisement is attached

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in today\'s Discussion Points.

AstraZeneca is also tracking total and new

Iressa prescriptions every two weeks to ensure that

the above communications are resulting in decreased

Iressa use.

We are not here today to vote on the

ultimate regulatory fate of this drug. We may be

bringing this question back to future ODAC meetings

after the FDA reviews this study and additional

subset analysis.

The purpose of this ODAC meeting is to

provide transparency of the process that we have

undertaken and to obtain your input on the adequacy

of these steps to date to ensure that patients and

prescribing physicians are aware of the study

results and treatment options other than Iressa

while allowing the drug to be available to patients

who may be benefiting from it.

Thank you.

DR. MARTINO: Thank you, Dr. Pazdur.

A new member has joined us. Dr. Temple,

if you would be so kind as to introduce yourself.

DR. TEMPLE: Good morning. Bob Temple,

Office Director.

DR. MARTINO: Thank you. For the

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audience, as well as the committee, I want to

remind everyone that this morning\'s purpose is not

to decide the fate of this drug, so those of you

who are here thinking that that is what we are

going to do, please relax, that is not the point.

The point this morning is realizing that

there is some new information that needs to be

properly disseminated to the public, both the

medical public as well as the lay public, has that

process taken place and what is that process.

So, those really are the issues before

this committee.

At this point, I would like AstraZeneca to

approach the podium and introduce your speakers, as

well as give us some understanding of what they

will be speaking on please.

Sponsor Presentation - AstraZeneca L.P.

Introduction and Regulatory History

DR. SCOTT: Thank you, Dr. Martino.

My name is Mark Scott and I am the U.S.

Development Leader for Iressa.

As Dr. Pazdur just mentioned, Iressa was

granted an accelerated approval under Subpart H in

May of 2003 to treat advanced non-small cell lung

cancer after failure of two types of chemotherapy.

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Subsequent to Iressa\'s approval, this

committee has discussed in general the terms of the

Subpart H approval guidelines and the need for

rapid completion by sponsors of their

post-marketing trials that are required as part of

such an approval.

During these discussions, an important

question was raised by ODAC, what should be done if

a confirmatory trial does not meet its primary

objective. The ODAC discussion at the time

acknowledged that there would probably be no quick

and easy answer if this situation were to arise.

We are here today because this

hypothetical situation is now real and it applies

to Iressa. The study we are here to discuss is

Trial 709, one of the confirmatory trials for

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Iressa which did not achieve statistical

significance for its primary endpoint of overall

survival.

We will describe for you the actions

AstraZeneca has undertaken to communicate the

results of Trial 709 to physicians, so that

informed decisions can be made regarding the

clinical use of Iressa.

Today, we will describe important findings

from Trial 709, how the data from Trial 709 is

actually quite similar to prior clinical data on

Iressa and additional analyses, and clinical trials

that are being conducted or planned to better

understand which patients are most likely to

benefit from Iressa.

We will also outline the timings of

availability for data for FDA review, what has

occurred and the future direction for Iressa,

provide important lessons about drug development,

and accelerated approval in the era of targeted

oncology therapies.

After I cover a brief regulatory history,

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Mr. Kevin Carroll will speak more on Trial 709,

then, Dr. Judy Ochs will present the actions

AstraZeneca has taken to inform the oncology

community and the implications for the development

of Iressa. I will then review the timelines that

we have to provide data to FDA.

As posed to the committee by FDA, we look

forward to hearing the Committee\'s thoughts on the

appropriateness of the communications taken

regarding Trial 709.

Today, we have two experts on lung cancer,

Howard Burris from Sarah Cannon and Mark Kris from

Memorial Sloan- Kettering, and they will be

supporting the AstraZeneca staff here to answer any

questions the Committee may have.

Lung cancer is the most common cancer and

the leading cause of cancer mortality in both men

and women with over 170,000 new patients being seen

each year in the United States.

The disease is complex, most patients are

diagnosed with advanced disease, symptoms are

common, and the prognosis is poor.

Standard first line therapy for advanced

disease was, and continues to be, platinum-based

doublet chemotherapy. Prior to 2003, after failure

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of first line therapy, only docetaxel had been

demonstrated to improve overall survival. No

therapy had been approved for use after failure of

both first and second line therapy.

Standard chemotherapies do offer benefits,

but with significant toxicity. Therefore, there

are many lung cancer patients who cannot tolerate

any chemotherapy.

There was a great demand for new, active,

less toxic agents for non-small cell lung cancer.

Now, Iressa is a small molecule inhibitor of the

epidermal growth factor inhibitor tyrosine kinase.

EGFR expression plays a role in angiogenesis,

apoptosis, proliferation in many tumors. Iressa is

thought to mitigate against these factors.

The Iressa Phase I program began in 1998

and doses up to 1,000 mg/day were studied. Among

the 289 subjects enrolled, the most common

toxicities were low-grade diarrhea and rash, and

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the dose-limiting toxicity was reversible Grade 3

diarrhea, and this dose-limiting toxicity occurred

at doses beyond 800 mg/day.

Marked anti-tumor activity was seen in

non-small cell lung cancer population that

participated in the Phase I program, and there were

actually 10 of 100 patients where responses were

noted, and these responses occurred across the dose

range.

Because of the safety findings and the

activity findings in Phase I, we chose the doses of

250 and 500 mg/day to be further investigated in

the third line monotherapy setting, as well as in

first line trials in combination with

platinum-based chemotherapy.

I will now focus on the data relevant to

the accelerated approval of Iressa.

IDEAL I and II were trials conducted among

patients where chemotherapy had failed. Both

trials randomized patients between 250 mg and 500

mg of Iressa per day. The primary endpoint in each

trial was objective response, the requirement for

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response was at least a 50 percent reduction in

measurable tumor area, or significant reduction in

non-measurable disease, and these decreases needed

to persist for at least one month.

Across doses, response rates seen in IDEAL

I and IDEAL II were 19 and 10.6 percent. Responses

were durable with ranges of 13 months and 7 months

for IDEAL I and II respectively.

Also of note was the variability that was

seen in response across some subgroups. Higher

rates were seen in females, never smokers, those

with adenocarcinoma histology, and of those of

Asian ethnicity.

As you will see in a few minutes, this

same variability in response is suggested for

survival, as well, when Trial 709 was further

analyzed. There were no differences in efficacy

between the two doses, and the survival curves are

presented on this slide where we have collapsed

IDEAL I and II together and looked at 250 versus

500, and the survival curves were completely

overlapping.

As for safety, the most drug-related

adverse events were of low grade, while the most

common adverse events were rash and diarrhea.

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There were a greater number of events at the 500 mg

dose. On the basis of these data, the 250 mg dose

was chosen on the basis of its efficacy and

tolerability as part of our application for

accelerated approval as a monotherapy in refractory

disease.

As Dr. Pazdur mentioned, Iressa was the

subject of the ODAC in September of 2002. These

response rate and safety data were reviewed, and

the committee voted in favor of accelerated

approval.

The FDA granted accelerated approval in

May of 2003 in patients refractory to both

docetaxel and a platinum-containing regimen. The

post-approval commitment trial started in July of

2003\.

We agreed to conduct and analyze and

report on three additional clinical trials, to

examine the effects of Iressa as a monotherapy in

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patient with advanced non-small cell lung cancer

where chemotherapy had failed.

These included Trial 709 where an

improvement in survival was sought, and the

preliminary results will be the focus of Mr.

Carroll\'s presentation today.

Trial 721 examines whether the survival

seen with Iressa is not inferior to survival seen

with docetaxel. There is a planned interim

analysis of this trial with complete data for this

to be available in June of this year, and with

survival data from this trial available in November

of next year. The results from this trial can

confirm the effectiveness of Iressa.

Trial 710, the third Subpart H commitment,

was a placebo-controlled trial where an improvement

in symptoms was sought. However, the early

availability of results from Trial 709 in December

of last year compromised the ability to recruit

patients.

As a consequence, the independent Data

Safety Monitoring Committee recommended that

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further recruitment was not justified because the

trial was unlikely to be completed. In agreement

with FDA, this trial was stopped in September of

last year.

Two other trials featured as additional

commitments that were not linked to the accelerated

approval, we were asked to provide reports on the

SWOG 0023 and BR19 trials.

These placebo-controlled trials seek to

demonstrate a survival improvement for Iressa after

definitive therapy in two settings of non-small

cell lung cancer. Both trials continue to recruit.

In summary, there were three Subpart H

confirmatory trials and two additional trials. One

has been closed, three are ongoing, and I will like

to ask Mr. Kevin Carroll, the statistician for

Iressa, to come and share with you the fifth trial,

Trial 709.

Trial 709

MR. CARROLL: Thank you, Mark.

Today, I will be presenting to you

preliminary data from Trial 709, which is a large

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randomized Phase III trial comparing Iressa to

placebo in advanced chemotherapy-failed non-small

cell lung cancer.

The data I will be sharing with you today

are as we saw them for the first time on December

16, 2004, and so are consistent with the materials

in your briefing document.

Since then, the data have been further

validated, in fact, were finalized on the 2nd of

February 2005. There have been few changes to

these data and none that materially affect the

results I will be showing you today.

In Trial 709, 1,692 patients were

randomized to Iressa or placebo on a 2 to 1 basis

in 210 centers across 28 countries. In light of

the approval of Iressa in the U.S.A. in May 2003,

no U.S. sites were included in this trial, as

randomization to placebo was considered infeasible.

Further, to ensure balance between the

treatments at baseline, the randomization was

stratified for histology, gender, reason for

failure to prior chemotherapy, and smoking history.

In terms of key eligibility criteria, the

patients randomized into Trial 709 had advanced

non-small cell lung cancer and had failed 1 to 2

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prior chemotherapy regimens.

Furthermore, the patient population

entered into Trial 709 was highly refractory since

the patients had either to be intolerant to their

most recent chemotherapy or had to have progressed

on or within 90 days of their last chemotherapy

cycle.

In Trial 709, as has been said, the

primary endpoint was overall survival. As stated

in the protocol, the primary analysis method was a

stratified log-rank test. As is common in oncology

trials, the protocol also stated that a supportive

Cox regression analysis would be conducted.

There were 2 co-primary populations for

analysis, the overall population and a subset of

patients with adenocarcinoma histology. At least

900 deaths were required overall to provide 90

percent power.

The secondary endpoints are listed on this

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slide, being time to treatment failure, objective

response, quality of life, symptoms, and safety.

Several subgroup analyses were pre-planned

with the aim being to examine outcomes in relation

to important clinical and biologic factors, such as

EGFR expression and EGFR mutations, and my

colleague, Dr. Ochs, will say more about this later

in our presentation.

The data I will be presenting today are

all those that accrued up to and including the end

of October 2004. This date was chosen because it

was estimated by this time the 900 deaths we needed

for analysis would have occurred on the database.

So, following data collection, preliminary

data became available for the first time in

mid-December 2004. At this time, median follow up

was 7 months, and we knew of 969 patient deaths.

As can be seen on this slide, patients in

Trial 709 were recruited mainly from Central and

Eastern Europe and then Asia. As I mentioned

before, there were no U.S. sites in Trial 709, and

due to the approval of Iressa in December 2003,

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only 1 percent of patients were recruited in

Canada.

This slide shows the baseline

characteristics of the patients in Trial 709. The

median age was 62 years, about two-thirds were

male, one-fifth were never smokers, one-fifth were

of Asian descent, about half had adenocarcinoma

histology, and about half had received one prior

chemotherapy.

In line with our intent to recruit a

highly refractory patient population, 90 percent of

the patients in 709 had progressed on or within 90

days of their most recent chemotherapy. Finally,

as you would expect in a large randomized clinical

trial, the treatment groups were well balanced at

baseline.

I would like to move on now to look at

survival in the overall population. As you can

see, there was some improvement in overall survival

in Iressa-treated patients with the Kaplan-Meier

curves separating after about 4 months. However,

the magnitude of that improvement was not

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sufficient to reach statistical significance in the

primary stratified log-rank test, however, the

supportive Cox regression analysis did suggest

statistical significance.

Here are the survival curves for the

co-primary population of patients with

adenocarcinoma histology. Again, there was some

improvement in overall survival in Iressa-treated

patients, but the magnitude of that improvement was

not sufficient to reach statistical significance on

the primary stratified log-rank test.

Again, here, the supportive Cox regression

analysis did suggest statistical significance.

Moving on now to secondary endpoint data,

tumor shrinkage in terms of response rates was

significantly greater in Iressa-treated patients

compared to placebo.

In terms of the time to treatment failure

being the time from randomization to the first

event that led to the cessation of randomized

treatment, there was a statistically significant

difference between the treatments with the risk of

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treatment failure being 18 percent lower in

Iressa-treated patients compared to placebo.

The reasons for treatment failure are

shown on this slide. As can be seen, the primary

driver for treatment failure was progression be it

either symptomatic or radiographic, with

approximately 56 percent progressing on Iressa

compared to 70 percent progressing on placebo.

As you would expect, Iressa failed more

often due to adverse events than placebo, and Other

on this slide refers to a number of items including

lost to follow-up, noncompliance, and withdrawal of

consent. As you can see, there was no difference

between the two treatments in this regard.

Turning now to quality-of-life data, the

analyses of these data is currently ongoing, but I

can share with you some initial results. As you

can see, the primary quality of life endpoints

being symptoms, overall quality of life, and trial

outcome index, all tended to favor Iressa-treated

patients although the treatment differences were

relatively small.

As I mentioned before, several subgroup

analyses were pre-planned. Now, before I run

through these data with you, it is important to

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emphasize that these analyses are not

retrospective, nor are they data driven.

The subsets were identified in advance

based on what we saw in our Phase II trials and

based upon findings on other drugs in the same

class.

Furthermore, in analyzing these subsets,

we have applied a rigorous statistical approach

whereby we looked first for evidence of a subset by

treatment interaction to give us confidence that

the subsets are truly behaving differently, and if

evidence exists, then, we go on to look at detail

at the subsets.

It is important to recognize that this is

a harder test to pass than simply having a list of

subsets and looking for p less than 0.05. So, if

we do see differences in Trial 709, we can be

reasonably confident that they are more likely due

to a real drug effect than due to chance alone.

This is the first of two slides that show

subset analyses. For each subset analyzed, you can

see the hazard ratio and its confidence limits and

the response rate in Iressa-treated patients.

As you will recall, the hazard ratio

measures the risk of death on Iressa-treated

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patients to placebo-treated patients, and

therefore, a hazard ratio of less than 1 to the

left of the vertical line shows a treatment effect

in favor of Iressa, and a hazard ratio to the right

of the vertical line shows a treatment effect in

favor of placebo.

So, now while no subgroup favored placebo,

there was clearly some variability in survival

outcome. This was most marked in terms of smoking

history where outcomes in never smokers was

statistically different than outcomes in ever

smokers.

This is the second slide showing data in

subsets, the same format as the previous slide.

Again, you can see there was variability in

outcomes with, in this instance, it being most

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marked in terms of ethnicity where patients of

Asian ethnic origin have statistically different

outcomes to patients of non-Asian ethnic origin.

Now, while the credibility of subset

analyses is always a matter of debate in any

clinical trial, in 709, the rigorous approach we

have taken provides us with confidence that the

differences we have seen are most likely due to a

real effect of the drug, and less likely due to

chance.

So, the findings we have seen in Asians

and on smokers are therefore supported

statistically by the presence of subset by

treatment interactions and also clinically by prior

Phase II data that have consistently shown

increased response rates in these populations.

Furthermore, Trial 709 is internally

consistent with respect to these subsets, with

better time to treatment failure and a two-fold

improvement in quality of life in Iressa-treated

patients.

This slide shows survival curves for never

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and ever smokers. As you can see, there was a 33

percent reduction in the risk of death in never

smoking patients treated with Iressa compared to

placebo. There was no significant difference in

ever smokers.

Similarly, this slide shows survival

curves by ethnic origin. Again, you can see there

was a 34 percent reduction in the risk of death in

Asian patients treated with Iressa compared to

placebo, and there was no significant difference in

non-Asian patients.

I would like to move on now to look

briefly at the safety data in Trial 709. I should

note these data have become available since we

compiled the briefing document, so they won\'t be in

your papers.

The adverse event profile in Trial 709 is

consistent with the established safety profile for

Iressa with the most common adverse events being

rash and diarrhea.

Notably, there was little difference

between the treatments in terms of serious adverse

35

events, adverse events leading to withdrawal, and

the incidence of interstitial lung disease.

Here is a summary of the most common

adverse events in the trial ordered from highest to

lowest frequency in Iressa-treated subjects.

As you can see, with the exception of rash

and diarrhea, which I just mentioned, there is

little difference between Iressa and

placebo-treated patients in terms of the adverse

event reporting. In particular, there were

relatively few Grade 3/4 adverse events in

Iressa-treated subjects.

This list of adverse events continues on

this slide where again it can be seen there is

little difference between Iressa and

placebo-treated subjects.

As I mentioned at the outset, the

preliminary data we saw on December 16th were

validated and finalized as of the 2nd of February

2005\. These final data confirmed a total of 976

deaths occurring on or before the October 2004 data

cutoff. With only 7 additional deaths, it is

36

obviously not surprising that the findings based on

the preliminary data remain unchanged.

On reviewing the data in December, the

Independent Data Monitoring Committee recommended

that further follow-up of Trial 709 should be

obtained. Having seen somewhat late separation in

the Kaplan-Meier curve, they were unwilling to rule

out that further separation could occur with more

follow-up.

Hence, survival data were updated as of

the end of January, which provided for a further 3

months of follow-up, taking median follow-up to 10

months and overall mortality in the trial to 70

percent.

As you can see, these further data are

consistent with the planned protocol analysis, and

despite increased crossover in the placebo arm to

Iressa, variability in survival outcomes continues

to be seen.

To briefly summarize what we have shared

today, the data seen on December 16 showed some

improvement in survival in Iressa-treated patients,

37

but the magnitude of that improvement was not

sufficient to reach statistical significance in the

primary stratified log-rank test.

Overall, however, considering both primary

and secondary endpoints, these data showed that

Iressa was efficacious in the population study, but

there was marked variability in survival outcomes.

So, with that, I would like to thank you

for your attention and hand over to my colleague,

Dr. Ochs. Judy.

Clinical Actions and Implications

DR. OCHS: Thank you, Kevin.

In this part of our presentation, I would

like to briefly summarize AstraZeneca\'s actions to

communicate the results of Trial 709 to the

oncology community. Following this, I would like

to give an overview of the clinical implications of

the Trial 709 data, review some of the immediately

relevant emerging science, and conclude with our

proposed or ongoing development proposals.

In agreement with the FDA, AstraZeneca

concluded that it was in the best interest of

38

patients that the information on Trial 709 be

rapidly, extensively, and clearly communicated.

On December 17th, a Dear Doctor letter

approved by the FDA was distributed by AstraZeneca.

This communication provided physicians with the

needed information to enable them to make the most

appropriate treatment decisions. The expectation

was that this communication would greatly reduce

the number of patients receiving Iressa for the

first time.

In addition, AstraZeneca would provide to

the FDA, prescription data every two weeks to be

able to assess the continuing impact of the

communications.

It was also agreed that a key goal was to

maintain Iressa availability to those patients

already benefiting who would wish to continue and

had concerns about possible Iressa availability.

A commitment was given to the FDA that

AstraZeneca would rapidly provide them with all of

the data as it became available to allow them a

thorough and informed analysis.

Upon public release of the top line Trial

709 survival results a series of extensive

communications were simultaneously begun and are

39

listed on this slide, and were previously mentioned

by Dr. Pazdur.

Taken as a whole these actions were

designed to ensure that relevant physicians would

be aware of the results and be reminded that

alternative therapeutic options with proven

survival benefits should be considered.

On January 6, the FDA and AstraZeneca met

and agreed upon the following steps for continuing

communication of the Trial 709 data. A public

disclosure of the then available results would be

made at the first available scheduled ODAC meeting,

today, acknowledging that the further trial data

would still be pending.

Ongoing communication of the Dear Doctor

letter was to be done using journal placement and

the full clinical data would be submitted and

presented at scientific meetings and published in

refereed scientific journals as soon as possible.

Abstracts have been submitted to the AACR

meeting, as well as the World Lung Cancer

Conference. A full publication submission is

planed in the May-June time frame.

Here is a copy of the Dear Doctor letter,

which I realize you cannot read. The letter,

40

however, does include the survival results in the

overall and adenocarcinoma subpopulation along with

median survival and respective hazard ratios.

The sentence highlighted in red above is

included in the body of the letter and urges

physicians to consider other treatment options.

This is how the letter is being displayed in the 10

most widely read oncology journals, and a list of

these journals is shown in the next slide.

The impact on Iressa usage has been marked

in the 10 weeks since the Dear Doctor letter was

first sent out. There has already been a

significant reduction in the prescriptions written

for Iressa, and our internal AZ usage data also

indicates marked reduction.

Market research, that we have just

41

obtained from 100 community oncologists, indicates

that the great majority are aware of the data

contained in the Dear Doctor letter and have

modified their treatment practice accordingly.

Thus, all of the agreed upon communication

actions have been set in motion, and the available

information suggests that the oncology community is

aware of and acting on the information.

The larger question is now being asked:

What are the clinical implications of the Trial 709

data, and what are the next steps? These are

clearly important questions for oncologists and

patients since Iressa possesses significant durable

anti-tumor activity which has greatly benefited

some patients and some patient subsets.

Yet, in Trial 709, Iressa did not meet the

statistically defined survival endpoint in an

unselected patient population.

Advances in understanding of the molecular

biology in this area of EGFR inhibition, as well as

in the area of non-small cell lung cancer, are

occurring rapidly and have the potential to better

42

select or predict those patients who would benefit

beyond, or in addition to, clinical

characteristics.

What are the questions that we are asking

as we seek to understand the Trial 709 outcomes,

and not wrongly or prematurely make conclusions

about the actual role or place of Iressa, an agent

with anti-tumor activity in the treatment of a

disease with a continuing poor prognosis? Why did

this result occur?

How does this result compare with our

other data on Iressa in non-small cell? Were the

findings in our trial due to play of chance? Was

the dose selection appropriate? Were there

methodologic issues, such as the trial population

and where the trial was conducted of any potential

impact on the findings?

What biologic data may be available now

and in the future to help better understand the

clinical outcomes, and what further relevant

clinical data in the recurrent non-small cell lung

cancer setting are expected?

Firstly, how does the survival outcome

seen in Trial 709 compare to other data with

Iressa? As was previously mentioned by Dr. Scott

43

in our Phase II program, a striking and

unanticipated finding was the apparent high rate of

response in patients with certain clinical

characteristics.

It can be seen if one compares these Phase

II response rates with those in Trial 709, and the

Phase II results are in the right-hand column in

yellow, and the 709 results in the middle column in

white, that the same patient groups continued to

show higher response rates.

In addition to these higher response

rates, the subgroups having the highest response

rates experienced the greatest benefit in survival.

The patient subgroup with the highest response rate

were the never smokers, and as previously noted,

the survival in this subgroup was significantly

increased.

Similar trend, although not of the same

magnitude, of survival benefit was seen in women

44

and with the adenocarcinoma group.

Continuing with this line of inquiry,

higher response rates and statistically significant

survival results and benefit were seen in those

patients of Asian descent.

Could chance have played a role as the

defined survival endpoint was so narrowly missed?

Trial 709 and the erlotinib trial BR21 are the only

two Phase III survival trials which compare an oral

EGFR inhibitor with placebo in the recurrent

non-small cell lung cancer patient population.

Both Iressa and erlotinib have similar

overall response rates as can be seen in the

right-hand portion of the slide. The erlotinib

trial did reach statistical significance for the

overall population.

Juxtaposing overall survival hazard ratios

as we have done in this slide shows that while the

point estimates differ, there is a high degree of

overlap in the confidence intervals. The small

confidence interval in Trial 709 reflects the

larger trial size in 709, which is almost twice

45

that of the BR21 trial.

Dose selection. Since there appears to be

a difference in magnitude of survival benefit in

BR21 compared to Trial 709, questions about the

adequacy of the Iressa dose have arisen

irrespective of the data used to support its use in

this trial.

The erlotinib dose used was at the maximal

tolerated dose, while the Iressa dose is one-third

the maximal tolerated dose, reflecting different

development strategies.

As you might guess, we have gone back and

re-evaluated our prior experience in light of the

current data. Our extensive Phase I program had 280

patients, and these patients received doses ranging

from 50 mg to 1,000 mg.

Responses and durable stable disease first

were seen at the 150 mg dose level. There was no

dose response evident from 150 mg through 1,000 mg

with respect to partial response rates, partial

response rates plus stable disease rates, or the

duration on Iressa therapy.

In our Phase II trials, as previously

mentioned, we formally compared the 250 and 500 mg

dosage. 250 mg was chosen as it was above the 150

46

minimum dose that we saw responses and stable

disease at, and 500 mg dose was chosen in part

because of minimizing the amount of patient

interruptions of therapy due to toxicity.

We found no difference in efficacy

including survival although the adverse events and

therapy interruptions were more frequent at the

higher 500 mg dose.

Admittedly, however, we have not

rigorously evaluated doses above 500 mg, and it is

unknown if doses above 500 mg would achieve better

overall or patient subset survival outcomes. Due

to the lack of data, we cannot rule this out

entirely.

Speculatively, can the inability to

achieve statistically significant survival be

explained by too few patients likely to benefit

based on their advanced disease status with

refractoriness as specified in our patient

47

inclusion criteria.

Another area to further explore are the

impact of environmental factors, such as smoking,

as it relates to various geographic regions where

the trial was conducted.

As Mr. Carroll showed, over one-third of

the patients on Trial 709 were from Eastern Europe

where the median pack year exposure was very high.

Patients with the highest smoking exposure appear

less likely to benefit from EGFR inhibitor therapy.

We have looked at our data and found a

continuous spectrum in terms of survival benefit,

with the greatest survival benefit appearing in

never smokings, but it continues with the amount of

exposure to smoke.

So, what can we conclude at this point?

Iressa is an active agent, the response data are

consistent in our Phase II and III trials. The

patients most likely to benefit are those patients

who never smoked and those of Asian ethnicity.

With these consistent findings, using an

agent that inhibits a specific receptor and

48

pathway, it is logical to assume that there is an

underlying biologic basis. In the last 10 months,

two areas of translational research have been

fruitful and may be useful in better understanding

the clinical data in our Phase III program in Trial

709, as well as guide therapy in our future

development.

The two biomarkers of most promise

currently are EGFR expression and the EGFR

mutations. Published Iressa Phase II data did not

appear to show definitive correlation of EGFR

expression with response, but tumor samples were

not available from all patients, and the trials

were not controlled.

Recently, however, results relating EGFR

expression to survival outcomes were included in

the erlotinib label.

The second promising biomarker are

activating mutations. These were first described

approximately 10 months ago in responding Iressa

patients. There are other promising, but more

exploratory biomarkers that are included in the

49

Iressa science program including gene copy number

and dimerization patients, but again these remain

more exploratory.

What I would like to do now is show you

from the erlotinib label\--and I have included the

three graphs they have relating to EGFR

expression\--and to ensure perfect synchronicity and

accuracy, I am going to read the portion for you

for all of those of you who can\'t read the lower

right-hand column.

What we see here are three graphs. The

graph to the upper far left is the graph of the

patients who had positive EGFR expression in their

tumors, with the lower part of the Kaplan-Meier

showing the patients treated with placebo.

The graph to your far right, on the

upperhand side is the patients who were EGFR

expression-negative compared to placebo. The lower

lefthand is those patients that they did not have

EGFR expression data on.

As stated in the label, Tarceva prolonged

survival in the EGFR-positive subgroup and the

50

subgroup whose EGFR status was unmeasured, but did

not appear to have an effect on survival in the

EGFR-negative subgroup. However, the confidence

intervals for the EGFR-positive, negative, and

unmeasured subgroups are wide and overlap, so that

a survival benefit due to Tarceva in the

EGFR-negative subgroup cannot be excluded.

It needs to be said that a positive EGFR

expression status in this study was defined as

having at least 10 percent of cells staining

positive for EGFR in contrast to the 1 percent

cutoff specified in the DAKO EGFR pharmDx kit

instructions.

The use of the pharmDx kit has not been

validated for use in non-small cell. Accordingly,

the data to date are inconclusive, but tantalizing

as to the predictive nature of EGFR testing.

In this trial, as in Trial 709, the tumor

sample collection was not mandatory, and thus the

number of samples is less than the number of

enrolled patients.

This is a busy slide and summarizes a very

51

busy area of research in the 10 months since

mutations were first described. As noted on this

slide, mutation appears to occur almost exclusively

in non-small cell lung cancer. The mutation is

activating and in the ATP-binding site, which is

where Iressa\'s activity occurs.

I mentioned that the mutation was first

described in patients with rapid, dramatic and

prolonged responses to Iressa. The increased

frequency of the mutation occurs in patient subsets

where Iressa responses are most frequent and where

the survival benefit is most likely to be seen,

that is, those patients who were never smokers,

patients of Asian descent, women, and

adenocarcinoma histology.

There are actually two papers out this

week looking at smoking status in relationship to

the presence of these activating mutations, and

depending on the paper, a minimum of 25 percent to

75 percent of patients in different geographic

regions who were never smokers have the mutation

present.

While patients whose tumors possess this

type of somatic mutation appeared to be much more

likely to have a response, all patients with

52

mutations do not have a response. We have recently

looked at our IDEAL II data, and in the small

subset with 14 mutations that we detected, 6 of

these patients had prolonged partial responses.

Again, where are we? EGFR expression

appears to be associated with increased survival.

EGFR mutations appear to explain some, but not all,

of the responses to Iressa.

Outcomes in Trial 709, comparing Iressa to

placebo, will be explored in terms of EGFR

expression, activating mutation, and other

biomarkers.

We anticipate that this data will be

available in June 2005. We have collected close to

600 tumor samples. Approximately 400 of them we

estimated based on our past experience will be

fully evaluable for EGFR expression, and 200 for

mutation status.

It is hoped that these results may provide

53

further insight into the clinical outcomes that we

have seen in Trial 709.

Thus, with these current clinical and

translational data, what prospective studies are

underway or could be considered?

One proposal would be to evaluate patients

with metastatic disease and compare the outcomes of

Iressa with chemotherapy. Mandatory tissue

collection is an obvious requirement to evaluate

the utility of biomarkers with respect to both

outcomes in both the chemotherapy-treated patients

and in patients with EGFR expression or

overexpression.

Targeted studies in patient populations is

another obvious way to proceed. We have an ongoing

Phase II trial which is enrolling patients who are

mutation-positive, another trial that is a trial

that should be considered is that in patients who

are never smokers.

Never smokers represent 20 percent of the

U.S. population of non-small cell lung cancer

patients.

Finally, specific trials in the Asian

populations to define the role of Iressa in the

first line setting appear warranted. Here, too,

54

translational studies would be integral to the

trial. There are already several trials being

conducted in Asia, as you might anticipate.

A clinical question of increasing

relevance that hasn\'t been answered to date is that

of comparing both survival outcome and toxicities

of Iressa or any EGFR inhibitor with single agent

chemotherapy.

Trial 721, as previously noted by Dr.

Scott, is a randomized Phase III post-approval

commitment trial which compares Iressa to

docetaxel. This trial will complete patient

enrollment by the end of the summer, and an interim

survival analysis is expected this May or June.

Trial 721\'s principal investigators and

steering committees have reviewed the Trial 709

data and continue to support this trial. Another

similar trial is being conducted entirely in Japan.

Some clinical support to continue at this

55

dose is mature Phase II data in a Caucasian and

Hispanic patient population, which has recently

matured and become available. In addition to

showing comparability with the primary symptom

endpoint, comparable outcomes were seen with

response rates, time to progression, and overall

survival.

The next slide is a Kaplan-Meier survival

curve from this trial, and it is easy to see the

comparability of these trial results. With a

median follow-up of 9 months and 55 percent overall

mortality, there are no differences between Iressa

and docetaxel.

The overall survival with docetaxel is

consistent with that previously reported with this

agent and in this clinical setting. Although the

trial is small, if Iressa was behaving as a

placebo, then, one would have expected Iressa to

have performed substantially worse in both time to

progression, as well as overall survival.

Back to our original question: Where are

we now?

Well tolerated agents in the EGFR

inhibitor class of agents are now an accepted

addition to the therapeutic armamentarium of

56

practicing oncologists and clinical trial

investigators.

Clinical and translational data are

pointing the way to the most appropriate and

optimal use of Iressa. AstraZeneca and our

clinical investigators remain committed to this and

other biologically targeted agents as the way to

the future.

Thank you.

DR. PAZDUR: Silvana, I am sorry, I didn\'t

realize there was more from AstraZeneca, but if we

want to have some discussion or clarification

before the open public hearing, that would be

appropriate.

Summary

DR. SCOTT: Thank you, Dr. Ochs.

As you have heard from both Mr. Carroll

and Dr. Ochs, there is a lot of work ongoing to

fully understand Trial 709, and there are other

57

trials, such as Trial 503, that provide supportive

information, and Trial 721, which is also part of

our Subpart H commitment to the FDA.

This slide summarizes some key milestones

that will be occurring. It is expected that the

complete data from Trial 709 and Trial 503 will be

with the FDA in June for their review. After that

time, we expect to discuss labeling updates as

appropriate based on the final data findings.

It is expected that the Subpart H

commitment trial, Trial 721, will deliver its final

survival data in November of 2006.

While the drug development road for Iressa

has not been straightforward or without its

surprises, the development program for this agent

has provided a great deal of valuable information

about non-small cell lung cancer and the EGFR

target.

Iressa is an active and well tolerated

agent, and the lung cancer community has urged us

to continue the development of this drug, and we

are committed to doing so.

Trial 709 has provided important patient

selection information in a controlled randomized

setting that may in the future help us write

58

appropriate labeling to guide the clinical use of

Iressa.

You have also heard today the critical

information regarding EGFR expression and mutation

status is yet to be delivered from this trial.

Trial 721, the head-to-head trial versus

docetaxel can provide confirmatory evidence of the

effectiveness of Iressa. As outlined, the

development program for Iressa will help in

identifying those patients who are most likely to

benefit from Iressa.

AstraZeneca rapidly and thoroughly

disseminated information to oncologists about Trial

709 to ensure informed treatment decisions would be

made while further analysis were underway.

As the patients responsive to Iressa will

tell us, and their physicians will support, Iressa

remains an important treatment option for non-small

cell lung cancer.

We thank the committee for their attention

and welcome any questions at this time.

Committee Questions

DR. MARTINO: Dr. Ochs, do one thing for

me before you leave. A slide was shown by\--Dr.

Ochs actually had the slide up\--where you

59

demonstrated what has been done to disseminate this

information, if you would just flash that one more

time.

I will allow the committee to ask

questions. We actually have no time allotted for

that, so please keep your questions pertinent to

today\'s issue, which really is has this information

been appropriately disseminated.

The slide that I want you all to just

notice are the things that they have, in fact, done

to disseminate this information. Rick, can you

simultaneously just remind the group what the FDA

has done from its side in terms of disseminating

the information, so that everyone is sort of up to

date.

DR. PAZDUR: We have notified shortly when

60

we were in receipt of this information, an e-mail

went out from the FDA to ASCO members notifying

them on that day that we received the information

of the study results and alternative treatment.

We have a letter posted on our website

that is included in your packet.

DR. MARTINO: So, then, from the FDA\'s

side, the information has gone out to physicians

primarily, as well as the website.

DR. PAZDUR: Correct.

DR. MARTINO: And from AstraZeneca,

information has been provided to physicians, as

well as to the lay public.

DR. OCHS: Yes.

DR. MARTINO: At this point, I will take

some questions, but please keep them brief and

succinct.

Dr. Hussain, you are first.

DR. HUSSAIN: It is a question to either

Dr. Mark or Dr. Ochs. When you pointed out that

you are possibly thinking about targeted

population, I saw that there were no women

61

mentioned and no adenocarcinoma.

Does that mean if you were a smoker and a

woman, that the smoker component takes over as far

as your potential benefit, or that if you are an

Asian and a smoker, then, the smoker takes over?

DR. OCHS: I think I will let Dr. Carroll

discuss that particular issue since there is a lot

of interconnection and interplay.

MR. CARROLL: Thank you for your question.

Of course, it is very important, I mean it is one

that we need to look at more closely, what is the

interplay between the factors of interest, be they

Asians, be adenocarcinoma, gender.

The data, as I said, were finalized

only\--I am not sure\--four or so weeks ago, and that

kind of analysis requires multivariate analysis to

actually see which factors are contributing, which

are the ones that are predicting the treatment

effect.

That is something that we do plan to do in

the next coming weeks and months to provide that

data to the FDA, so we can answer the very

62

important question that you have raised, because I

am not sure we have the answer to that today.

DR. MARTINO: Dr. Perry.

DR. PERRY: I am not sure who gets this

question, but I have been under the impression that

in Europe particularly, the incidence of squamous

cell carcinoma was considerably higher than in the

United States, so I am somewhat surprised of a 48

percent incidence of adenocarcinoma histology

worldwide, particularly when two-thirds of the

patients seem to be from Europe.

How do you know that these are

adenocarcinomas, is this the local pathologist\'s

interpretation, and are they inclined to overread

them as adenocarcinomas rather than as non-small

cell carcinomas not otherwise specified?

DR. SCOTT: I will ask Dr. Alan Barge to

come and speak to that point.

DR. BARGE: Thank you. Alan Barge,

AstraZeneca.

We have not done central pathology review.

All of the diagnoses were the ones that were

63

confirmed by the hospital pathologists, so we

couldn\'t answer your question directly, I am

afraid.

DR. MARTINO: Dr. Rodriguez.

DR. RODRIGUEZ: I just wanted some

clarification about the actual trial design, and

just have a few questions which might be relevant

because this was done by a variety of cultural

groups.

Were the patients and the investigators

both blinded to the assignment to placebo?

DR. SCOTT: Yes, it was a randomized

double-blind trial.

DR. RODRIGUEZ: How was compliance

confirmed in the participants?

DR. SCOTT: Nick Botwood will come to the

stand.

DR. BOTWOOD: Thank you. Nick Botwood,

AstraZeneca. We did look at compliance on this

trial and found that over 90 percent of the

patients were compliant and had taken at least 95

percent of their medication.

This was based primarily on data that we

collected in the CRF in terms of any documented

dose interruptions for whatever reason, and then we

64

went on to further validate that, to actually look

at the number of tablets that were returned and

looked at the number of tablets that had actually

been prescribed to validate that what was in the

CRF was actually the correct information.

DR. RODRIGUEZ: Along those lines, was

there a required or concurrent diarrhea prophylaxis

program, and was compliance to that also monitored?

DR. BOTWOOD: That wasn\'t, no.

DR. RODRIGUEZ: It is interesting because

your failure to treatment has a significantly

different profile with regards to symptoms and

adverse events. It seems that the patients on the

Iressa arm, a higher proportion were taken off

study because of those problems, is that correct?

That is what your bar graph seemed to show.

DR. BOTWOOD: Kevin Carroll can answer

that question, please.

MR. CARROLL: If I am correct, you are

65

asking whether there was a difference in withdrawal

due to\--

DR. RODRIGUEZ: Yes, side effects.

MR. CARROLL: Side effects. As I showed

when we went through the adverse event data, there

was very little difference between the two

treatments in terms of withdrawal due to adverse

events, and in terms of the data that we obtained

on time to treatment failure, there were, in fact,

fewer\--Iressa failed fewer patients due to

progression than placebo, so I don\'t think the

difference was there in the way that perhaps you

think.

DR. MARTINO: Dr. Levine.

DR. LEVINE: I also have several

questions. First, you mentioned crossover. How

many of these placebo patients did cross over to

Iressa?

DR. SCOTT: Dr. Botwood.

DR. BOTWOOD: Yes, thank you. The rate of

crossover from placebo to Iressa in this trial was

only 3 percent.

DR. LEVINE: Three. Do you have data on

other treatment beyond, you know, crossover to

anything?

66

DR. BOTWOOD: Yes, we do. The number of

patients that went on to receive any subsequent

chemotherapy was 10 percent, and this was balanced

between the Iressa and placebo arm.

DR. LEVINE: Just to further that a little

bit, even complementary therapies in Asia, and so

forth, do you have data on that, green tea?

DR. BOTWOOD: It was extremely small.

DR. LEVINE: My other question related to

the concept of secondary smoke. In Eastern Europe

and in Asia, where so many of the population smoke,

even individuals who say that they weren\'t smokers

may have been exposed, and therefore, did you look

at cotinine levels or anything? That might be

something to explore, or did you look at that?

DR. BARGE: I am afraid we haven\'t looked

at that. When we looked at the smoking demography

of the patients from Eastern Europe, approximately

85 percent of the patients from Eastern Europe were

67

heavy smokers, and they had a higher median year

exposure than the patients from other regions, but

that is as far as we got, I am afraid.

DR. MARTINO: Dr. D\'Agostino?

DR. D\'AGOSTINO: Yes. I am having a hard

time keeping my questions solely to the material

that has been circulated as opposed to asking a

million questions about the study, but the question

I do have in terms of the reporting of the data,

you may have said it, and I am sorry if I missed

it, you did have the expected number of deaths, you

wanted 690 or whatever, 960, and you got more.

I understand that the study did run its

course, and then you did an analysis with unclean

data or not completely clean data, and then later

on had clean data, or was the analysis you are

reporting an interim analysis?

DR. SCOTT: The analysis that we reported

on in December was not an interim analysis. It was

based on final survival data, but it had been yet

to be validated.

DR. D\'AGOSTINO: Okay. So, it was the

68

validation. Thank you.

DR. MARTINO: Dr. Proschan.

DR. PROSCHAN: You mentioned that the

Phase II trials identified subgroups, and ethnicity

was one of them. I am wondering if, at that time,

you specifically decided to break it into Asian

versus non-Asian, and why do you think there is a

difference?

DR. SCOTT: We can have Mr. Carroll talk

about the rationale behind the subgroups that we

planned for Trial 709, and then perhaps have Alan

Barge talk about why we think so.

MR. CARROLL: The subsets that we have

looked at in Trial 709, all of them we have shared

with you today, I have not shared a subset of the

subsets, of course, and they were determined

primarily by what we saw in our Phase II data, and

also information that came out in June of this year

on the BR21 trial, as described by Dr. Ochs.

There, there was an evaluation of Asians

and non-Asians, and that, in addition to our

findings in the IDEAL trials where our Japanese

69

patients had a much higher response rate was a

motivation to look at that subset amongst others

that were deemed to be clinically relevant.

Perhaps I can now turn to my colleague,

Dr. Barge, to answer the second part of your

question.

DR. BARGE: Yes, thank you. There is a

good deal of speculation as to why patients of

Asian ethnic origin appear to do better on this

class of drug. There have been some quite

interesting publications very recently. In fact,

this week there was a publication from Dr. Gazda

\[ph\] at UT-Southwestern. His group showed that the

frequency of activating mutations of the kind that

Dr. Ochs described is much higher in Asian

populations, particularly female Asians, and

particularly female Asians with adenocarcinoma.

The Phase II studies that we conducted in

various Asian countries all show that the frequency

of responses are much higher in those populations,

and we have seen response rates as high as 60 or

even 80 percent in selected populations of Asian

70

nonsmoking females.

Whether or not that is all driven by

activating mutations we don\'t know, but that is

certainly a very strong hypothesis at the moment.

DR. MARTINO: Mrs. Ross.

MRS. ROSS: Thank you, Madam Chair.

If I understand correctly, the primary

purpose of this hearing is to evaluate or just to

discuss the transparency of the post-approval

process and the adequacy of the notifications.

In that regard, I would like to advise the

rest of the panel of other steps that were indeed

taken by both AstraZeneca and the FDA, and I would

like to thank Dr. Pazdur in particular for his help

on this.

As the only lung cancer advocacy

organization nationwide, we started receiving many

phone calls from patients who were somewhat

panicked when they heard the news in the press that

Iressa might be pulled. The press always leaps to

the worst possible conclusion, as you all know.

These people were discussing stockpiling

71

drugs, buying them in Japan. There was a lot of

panic out there. Dr. Pazdur responded, and

AstraZeneca did, by helping us draft more

information, more plain English information to put

up on our website and to tell people over the phone

when they called in a state of panic about Iressa.

I think that should be noted. I think

that overall, the process was extraordinarily

transparent and more than adequate in dealing with

the situation. Again, I would just like to thank

FDA and AstraZeneca for all they did.

DR. MARTINO: Dr. Temple, did you want to

make a comment?

DR. TEMPLE: Just one question. We

certainly never at any time thought that someone

who had apparently responded to the drug should

lose access to it. That was never in doubt.

But I wanted to ask you about where

AstraZeneca is at the moment. This was, shall we

say, an optimistic presentation. The study, after

all, failed. You had opportunities to identify

subsets before the study that would be your primary

72

analysis, but you didn\'t think that they were good

enough to do that.

So, these are now\--it\'s an important

distinction, Ralph may want to comment more\--these

are after-the-fact subset analyses in a study that

did not win. That is different from subset

analyses in a study that did win.

But what I really want to know is where do

you come out on the question of new patients with

non-small cell lung cancer being started on Iressa

now. The material you put out says you should

consider other drugs. Fine.

But would it be your view that at the

present time, optimism about the future and data

that might come forward notwithstanding, a person

with this disease should really not be started on

Iressa, would that be your view, or is that not

your view anymore?

DR. SCOTT: Our view is that what was

stated in the Dear Doctor letter then is what is

today, that physicians should consider other

options armed with the information from this

73

particular trial.

If I could ask Dr. Kris to come up and

talk about how this has played out in his practice,

maybe Dr. Burris, as well.

DR. KRIS: To answer your question, Dr.

Temple, I think the most important thing is to put

this into a context of what is available for a

patient with advanced non-small cell lung cancer

particularly after the failure of initial therapy.

I think that the information that we have

today is that there are some patients, those with

an EGFR mutation, that have, and the literature

today says that they have an 89 percent chance of

having a response, and in those patients, when you

look at their duration of response and survival, it

is clearly prolonged. In the trials that looked at

survival in mutation positive and negative people

being treated, it is much better with treatment.

So, as a clinician, my first point is to

find those people that have that extraordinary

chance of benefit, that is, mutation-positive

people, and the two surrogates for positive

74

mutation we have today, that is, never smoking

status for U.S. population and worldwide, is

probably Asian, and it is not simply Japanese.

There are reports now from Taiwan, from China,

Singapore.

DR. TEMPLE: Let me be clear, though. You

are looking at the mutation status of the people

in\--some of the people anyway, about 200 you

said\--in the trial, and maybe that will be

overwhelming and knock everybody\'s eyes out.

But at the moment you have no prospective

data on that subgroup for survival.

DR. KRIS: The only prospective data that

exists on the treatment of mutation-positive

patients is, frankly, an extrapolation to the never

smoking patients.

DR. TEMPLE: I understand.

DR. KRIS: But those are

placebo-controlled trials.

DR. TEMPLE: But what I am really asking

is what you really mean, and we will probably have

to have subsequent discussions, one might say that

75

you should use the drug with very similar

properties, similar mechanism, et cetera, that has

actually been shown to improve survival.

Are you saying something to the contrary

or not? I don\'t think it is clear yet. I sort of

thought it was clear, but from your presentation, I

don\'t.

DR. KRIS: Well, I frankly think that the

most critical slide there was looking at the hazard

ratios for the two substances, for gefitinib and

erlotinib. I am putting my clinician hat on, it is

not an AstraZeneca hat right now, and that

clinician\'s hat is that there is effect there.

You can argue the p value of 0.04 versus

0.07, and there are people here that can do that

much better than I, but from the clinician

standpoint, you have to make that choice. But you

must remember that this isn\'t\--you also have a

patient, you have a man with a squamous cancer

sitting in your office that is smoking today, and

his likelihood of benefit by the literature is

extraordinarily small, well under 5 percent.

So, for that patient, you are going to

make another choice, so that the choice for the

patient is not going to be decided by this trial as

76

a clinician.

DR. TEMPLE: I am really asking about what

is your view now, is on a person who is a candidate

for an EGFR order of treatment now based on

available data. I actually thought you thought

that for the moment, one should use the drug that

actually won, but I no longer perceive that in your

presentation.

DR. KRIS: I am talking about from a

clinician\'s standpoint, and I interpret the whole

of the data as unbelievably consistent. I mean I

think it is extraordinary that when you look at the

mutations, when you look at the response rates

across country, across drug, it is how consistent

it is, particularly the smoking observation.

DR. TEMPLE: The pattern may be the same.

It may just be that this drug doesn\'t work as well

as the other one even though the pattern is the

same. It is possible.

DR. KRIS: Again, I can\'t rule out that

possibility, but you can\'t look at any one piece of

data in my estimation, and this is one piece of

data today.

DR. PAZDUR: But Mark, you pointed out

that you may look at the mutational status in

77

making a decision, but really, in the United

States, only a small number of people really have

that available to them.

DR. KRIS: Rick, from a practical

standpoint, I don\'t look at the mutation status.

We can do that at our institution, but it is a very

limited availability right now. The decision is

made on clinical grounds, and the surrogates for

mutation we have today, and they are two. They are

never smoking status and Asian birth, and that is

how we make our decision.

DR. PAZDUR: I have another question for

AstraZeneca. In your presentation, you noted a

decrease in new prescriptions. Could you tell us

what you mean by new prescriptions for Iressa, does

that mean new patients or simply renewal of

78

prescriptions of existing patients that are already

on it, or can you distinguish between that?

DR. SCOTT: The new prescriptions are not

new patients, they are a mixture of patients that

are getting a refill of prescriptions, because

every time a new script is written, it could be for

a patient that didn\'t have a refill, and it could

be for new patients, but I will ask Carolyn

Fitzsimons to talk about that data, how we are

interpreting it with the availability of other

information that is indicative of most\--

DR. PAZDUR: Because we are very much

interested, following up on Bob\'s question, how

many new patients\--

DR. SCOTT: Right, and I will ask Carolyn

Fitzsimons to come and speak to that.

MS. FITZSIMONS: Thank you. Carolyn

Fitzsimons, AstraZeneca.

If I can just show the slide as to what is

happening with the prescription data and try and

answer your question, Dr. Pazdur, in terms of

specifically new patients.

We have not been able to secure a source

to actually define new patients, so we have to take

the new prescription data as indicative of what is

79

happening in the marketplace.

The new prescription data, as Mark has

just explained, is not wholly attributed for by new

patients. It encompasses every time a new

prescription is written, so a repeat prescription.

From the data that we have and is shown

here, on the significant decrease that we have seen

in new prescriptions, a 58 percent decrease since

the announcements of Trial 709.

It is our belief, based upon the duration

of therapy of an Iressa patient who is currently

receiving the product, that the majority of these

prescriptions are now being written for patients

who were prescribed Iressa prior to the

announcements of Trial 709, and are receiving

ongoing therapy from consultations with their

physician, therefore, we assume they are deemed to

be benefiting.

We have conducted some market research

80

earlier in February to try and further establish

what is happening with new patients, and from that

data, we have established that physicians are aware

of the Trial 709 results, and are not longer

choosing Iressa as their EGFR inhibitor of choice,

they are choosing erlotinib, and 86 percent of them

indicated that from the market research.

DR. SCOTT: If I could ask Skip Burris to

come up and talk about what has happened at

Tennessee Oncology. Although it is an n of 1, it

is reflective.

DR. BURRIS: Thank you, Mark. It is an n

of 1, but it is a large group of 36 practicing

oncologists, and it gets to Dr. Temple\'s questions,

and he and Mark were certainly talking about one

issue, but we felt the need to issue some

guidelines.

Certainly those guidelines were that those

patients that were being treated with Iressa,

should be continued on Iressa, that those patients

who fit into a class where it is felt it

appropriate that an EGFR inhibitor should be

81

utilized, that erlotinib or Tarceva would, in fact,

be the preferred agent in the short term, that

there should be consideration given based on the

data between the two agents, that, in fact, if

patients were intolerant of one or the other, to

switch to the other in the class. If fact, that

has occurred in at least several patients.

Lastly, and maybe most importantly, is the

fact that as a conscious decision, analyzing the

data within our group, we have continued to accrue

and randomize patients on a count done quickly

yesterday, 9 patients, in fact, randomized to

Iressa in a controlled Phase III trial in patients

with refractory lung cancer.

So, the believe of the group, as Mark

alluded to, certainly subsets that will benefit,

but we have continued to accrue to trials comparing

a new agent with Iressa in this setting, so that

accounts for some of the new prescriptions written

in our group, as well.

While the comment, and I certainly agree

with most of what Dr. Temple said, I mean we don\'t

82

have a winner here in the sense that there is not

randomized data between erlotinib and gefitinib to

date, so I think for many of us, the direction of

this class is heading into what subsets will

benefit, and for now we don\'t know direct head to

head the differences in the two.

Certainly there are small differences in

terms of mechanism of action, pharmacology and

toxicity.

DR. MARTINO: Mrs. Ross, you will have the

last comment, and then I am going to turn to the

public forum.

MRS. ROSS: Thank you very much, Madam

Chair.

I just had a quick question actually for

Dr. Pazdur and Dr. Temple. You are not suggesting,

are you, that doctors should not be allowed to

write new prescriptions for Iressa?

DR. TEMPLE: Well, no. First of all, we

don\'t control what doctors write, but there isn\'t

any doubt that\--I don\'t know what you mean by a new

prescription\--a new prescription for Iressa in

83

someone who is already on the drug and responding

to it is not an issue.

MRS. ROSS: New patient new to the drug.

DR. TEMPLE: I am more worried about what

AstraZeneca is telling people. I thought it was

fairly clear they thought, given a choice, for

someone who wants that mechanism, they would use

the drug that actually showed a benefit, not the

drug that didn\'t.

I no longer am clear that that is their

goal after this presentation today. It sounds much

more ambiguous than that, and I am just trying to

find out what it is. I thought the comment about

what is being done in Tennessee makes a lot of

sense, if you think that therapy is appropriate,

use the drug that won.

Look, we have been pushing, if anything,

the idea that there are subsets of the population

that are more likely to respond than others, and

that has been I think apparent from the earliest

data with Iressa. There undoubtedly are

differences among subsets of the population.

But Ralph can comment on this. All of

those differences in a trial are much more credible

when the trial wins overall or when you have

84

specified that as the primary endpoint. It remains

somewhat after the fact, not implausible given the

other data, that people who never smoked, you know,

are much more likely to respond.

All those things are probably true, but

still, given a choice of two drugs now, one of

which has a quite successful overall clinical

result, and the other of which doesn\'t, most of the

time people would suggest that you use the one that

actually had the favorable result.

I thought that was the direction

AstraZeneca was urging people to go. I am not as

sure of that after hearing the presentation today.

DR. SCOTT: Could I\--

DR. MARTINO: I am sorry, I need to ask a

question here.

Has the FDA had the opportunity to review

the materials that have been prepared by

AstraZeneca?

DR. TEMPLE: Yes.

DR. MARTINO: You have. So, you have

seen, in fact, the written materials?

DR. PAZDUR: The written materials, yes.

DR. MARTINO: Okay. And can I trust that

since they are in the public media now, that, in

85

fact, you have agreed or approved, or in some way

decided that they are okay with you? I

understand\--

DR. TEMPLE: We did. I am now slightly

nervous about them.

DR. MARTINO: I understand the concept of

what is their intent, however, I think what we, as

a committee, can judge is the steps that they have

taken, the material that they have supplied, and

the content, the written content in that material,

is it fair, appropriate, and informative.

What their intent might be in their gut

and in their heart, in all fairness, I think I

understand your question, but it is not really what

this committee can deal with.

DR. D\'AGOSTINO: Can I go to Bob\'s

86

question? I mean I thought that what we were

looking at was basically this letter, and that I

think is fine, and I think it reflects what the

data shows.

I am bothered by the presentation that

if\--are they also, are they putting this letter out

and then showing this presentation, because the

presentation has a completely different bent to it,

and my question was going to be, what is their

presentation to the field, is it just this letter,

or are they throwing this\--now, that is different

than the people who are running the studies.

The ones who are running the studies

obviously have to see this, but what is the

collection of M.D.\'s being told?

DR. MARTINO: That is an important

question, that, I would like the company to answer

to.

DR. SCOTT: If I could respond first and

have Judy Ochs talk about the intent of the letter.

Again, the intent of the letter in December is the

intent today, and I will have Judy Ochs talk about

87

the intent, please.

DR. OCHS: Yes, I did send the letter, and

my signature is on it, and I stand by it. That was

the letter that we sent out. What we said in that

letter is true. It is no less true today.

The presentation today, however, reflects

some time, now that we have the full totality of

the data, we are beginning to look at it, it will

be submitted to you. The FDA will review it.

Again, many times when one goes through protocols

and through data, there will be the data, there may

be some aspects to the interpretation.

The bottom line, that the trial did not

meet statistical significance has not changed.

DR. MARTINO: One more question and then I

will turn to the open forum, please.

DR. REAMAN: You did show data today about

a particular subgroup or subgroups that do appear

to potentially have more of a benefit than others,

the corollary being that there is a large group

that don\'t appear to have any benefit.

Is that data that has only been made

88

available to you since the letter went out in

December, and, if not, why wasn\'t there any mention

of that in the communication?

DR. OCHS: When the letter went out, that

is all we had. We didn\'t have the rest of the data

to a large degree. We hadn\'t had any opportunity

to look at it. We literally saw the data, about 10

people, on Tuesday, and the data went out Friday

morning, it was that quick a happening.

Again, I think as we are looking at the

data ourselves, it is clear. The one thing I would

say is that as Kevin presented in his presentation,

all of the patients, if you look at the hazard

ratios, it is to the left in terms of potential

benefit for Iressa.

There obviously are, as Kevin pointed out,

variability, but nonetheless, we are looking at a

trial that barely missed reaching statistical

significance, so it is not like there wasn\'t

benefit, it did not meet a statistically defined

endpoint to which we all agree, and to which we

would not change our recommendation to physicians

89

that solely based on the data, but I think that Dr.

Kris and Dr. Burris have brought up other things,

other data that is out there, other information.

And I think one of the things that has

happened is that Iressa has been around for a

while, people have had some experience, so people

will be looking at the literature. Certainly, the

first opportunity for the data as a whole to be

seen is today.

We submitted it to a scientific forum

where it will be presented. There will be

questions asked. It will be questioned, and it

will be submitted to peer-reviewed journals.

Open Public Hearing

DR. MARTINO: Thank you. We will continue

this in a few moments, but at this point I do want

to turn to the open public hearing. There are

several of you that have asked to speak, so the

microphone that you will be using is in the center

of the room.

Allow me to read the following in

anticipation of your presentations.

Both the Food and Drug Administration and

the public believe in a transparent process for

information gathering and decisionmaking. To

90

ensure such transparency at the open public hearing

session of the Advisory Committee meeting, the FDA

believes that it is important to understand the

context of an individual\'s presentation.

For this reason, FDA encourages you, the

open public hearing speaker, at the beginning of

your written or oral statement to advise the

committee of any financial relationship that you

may have with the sponsor, its products, and, if

known, its direct competitors.

For example, this financial information

may include the sponsor\'s payment of your travel,

lodging, or other expenses in connection with your

attendance at the meeting.

Likewise, the FDA encourages you at the

beginning of your statement to advise the committee

if you do not have any such financial relationship.

If you choose not to address this issue of

financial relationship at the beginning of your

91

statement, it will not preclude you from speaking.

Ms. Clifford, if you will announce our

speakers, please.

MS. CLIFFORD: Peter Lurie is our first

speaker.

DR. LURIE: Good morning. Peter Lurie

with Public Citizens Health Research Group. I am a

physician. I have no conflicts of interest to

disclose. We take no money from government or

industry.

As the members of the committee will I

hope have noticed by now, this morning Public

Citizen filed a petition with the FDA to remove

Iressa from the market on the grounds that no less

than three mortality studies have now proved

negative.

We, instead, ask that for those patients

who remain on the drug, and completing courses of

therapy, that they can receive the drug through IND

status.

You will notice, too, that in Europe, the

marketing application for Iressa has been withdrawn

92

and that in Japan, the Ministry is giving serious

consideration to removing the drug from the market.

As you all know, Subpart H is the

mechanism through which this drug was approved, and

to emphasize, that accelerated approval law makes

clear that the FDA may withdraw approval of a fast

track product \"if a post-marketing clinical study

fails to verify clinical benefit.\" That is

certainly the case over here.

In fact, even prior to approval, there

were a couple of studies that showed lack of

clinical benefit, and the two instant studies were,

in the words of the FDA medical officer,

\"unambiguously negative,\" and the medical officer

made the observation that \"the FDA has never

received a cancer drug application for accelerated

approval when definitive data in another related

setting showed a lack of efficacy.\"

Those were first line therapy trials,

which were both negative with respect to mortality,

and the drug on the market for third line therapy,

of course, we will acknowledge the principle in

93

oncology is that a drug is most likely to work as

first line therapy rather than third line therapy,

and, of course, in the end, that is exactly what

the ISEL has confirmed.

So, we have these two negative mortality

studies even going into the approval of this drug.

Now we have the ISEL study, which shows a very

small survival difference, 27 versus 22 percent,

but not statistically significant under the primary

data analysis.

As you will notice from the slides

presented by AstraZeneca this morning, the overall

quality of life was also not benefited by Iressa.

Instead, what we have seen, you have all

heard of rescue chemotherapy, I think what we have

seen here is rescue biostatistics. A number of

subanalyses that have been done, some of them

aren\'t clearly post-hoc, especially the Asian one.

You will notice from your briefing materials that

some subanalyses are described as prespecified, but

the second table is one that implicitly are not

prespecified. The Asian group is among them.

How many of these subanalyses have been

done? Why is it that the rather simple to conduct

multivariate analysis has not been done, and why is

94

it that conveniently none of them are ready for

this meeting?

In response, we have seen the FDA put out

a letter. We have seen another letter from

AstraZeneca, which in effect are telling patients

to think about not to take the drug. I mean what

kind of public health approach is this to have a

letter from a drug company that, in effect,

suggests that patients not take their drug?

That doesn\'t seem like an adequate public

health response to us, and, in fact, patients are

still taking the drug, 331 new prescriptions in the

week of February 18th. The company may claim that

these are not new patients, but there is no

evidence for that either.

The fact is that there is a drug on the

market which has clear, proven mortality benefit,

and patients can easily be diverted from the

effective therapy to this one for which there is no

95

benefit.

As Dr. Temple said, if there are two drugs

that are available, why not use the one that won.

There are also dangers from this drug, and

we have outlined these in prior letters to FDA,

particularly in the area of interstitial lung

disease, 588 deaths now in Japan, and our analysis

of the adverse drug reaction data from FDA show 144

reports of interstitial lung disease including 87

deaths in this country just since the time that the

drug was approved.

What really we are seeing over here is an

elaborate dragging out of this process, a drug that

probably should not have been approved in the first

place, and now, even while empowered by Subpart H

to remove the drug from the market, it still hasn\'t

happened.

How ironic this is. A company gets a drug

on the market through an accelerated approval

process and then when the data turn out to be

negative, suddenly it goes slow - let\'s wait for

the EGFR data, let\'s wait for the easy-to-do

96

multivariate analysis that we haven\'t done, and the

EGFR data will be ready, would you believe it, in

two to three weeks from now, it couldn\'t be ready

in time for this meeting.

These EGFR analyses should be thought

about in the following context. In the Phase II

trial, there was no relationship between the

expression of EGFR and outcomes. There is no

calculation of a positive predictive value for

these mutations.

Clearly, people without them are

responding and vice versa. We really don\'t know

the positive predictive value, and as was also

pointed out, this is a research tool. It is not

something\--and even AstraZeneca admits this\--that

can be used to distinguish patients at present, and

therefore, decide whether or not to provide them

with therapy.

If this is important enough a question, it

should be researched, and the IND is the

appropriate mechanism to do that.

Finally, to close, with Subpart H, if ever

97

there was a drug that was slated for and eligible

for removal from the market under Subpart H, this

is it, a drug, which even for the

indirect\--sorry\--for the surrogate marker had

minimal benefit in the Phase II uncontrolled,

non-placebo-controlled, even unblinded trial,

minimal benefit on the surrogate markers, clear

dangers, proven effective therapy in terms of

reducing mortality, and now patients continue to be

placed on the drug, and three negative mortality

studies.

If this drug is not taken off the market

on these grounds, it will make an absolutely

mockery of Subpart H.

Thank you.

MS. CLIFFORD: Thank you, Mr. Lurie.

Our next speaker is Laurie Fenton.

MS. FENTON: Good morning. I am Laurie

Fenton and I am President of The Lung Cancer

Alliance, the only national organization that is

dedicated exclusively to advocating on behalf of

lung cancer patients and their caregivers and

98

survivors.

DR. PERRY: We can\'t hear you very well.

MS. FENTON: Okay. How is that?

Again, Laurie Fenton, the President of The

Lung Cancer Alliance. We are the only national

organization that is dedicated exclusively to

advocating on behalf of lung cancer patients, their

caregivers and survivors.

I believe you have my statement, so I will

condense what I would like to present today.

AstraZeneca has provided grants in the

past for educational programs, but they have not

compensated me in any way today to present what we

are here to share.

The Lung Cancer Alliance understands that

the FDA is required by statute to evaluate drugs by

looking at safety and efficacy data in large

populations of patients to determine whether

benefits outweigh the risks.

Interestingly, we have discovered that

Iressa does not fit neatly into this protocol, and

while Iressa\'s current clinical trial data has not

99

revealed dramatic survival benefits overall, it has

shown striking benefits for a small subset of the

larger population, with less side effects and

quicker response rates.

As was shared earlier, we received many

phone calls from patients who were extremely

concerned that Iressa could be pulled from the

market, particularly a drug that had helped them so

dramatically.

Patients spoke of stockpiling the drug and

beginning to take Iressa every other day to make

their supply last longer, and I am glad you will be

able to hear from patients directly on this point.

The reality is that we have an unmet

public health need. Lung cancer\'s mortality

statistics can no longer be ignored. Beyond

demanding that government redirect its own

resources to effect change, we as advocates also

want to nurture responsible drug development to

help in our fight to eradicate this number one

cancer killer.

Alimta and Tarceva, recently approved for

100

the treatment of lung cancer, are important arrows

in our treatment quiver, but Iressa must also be

recognized as an important weapon in this battle.

Even if unable to meet the broad

population standard, we cannot ignore the fact that

Iressa has shown striking benefits within a subset

of the population, and to this effect, lung cancer

patients and their doctors need all, not limited,

choices now.

It is our hope that both the FDA and

AstraZeneca find a way to allow doctors and lung

cancer patients access to Iressa while, at the same

time, agreeing upon a way to further study and

evaluate the drug.

It could provide a window of opportunity

to better understand the horrible disease that lung

cancer is, who will benefit most from the drug

treatments and why.

I again thank you for allowing us to be

represented here today.

MS. CLIFFORD: Thank you for your

comments, Ms. Fenton.

Our next speaker is Selma Schimmel.

MS. SCHIMMEL: Good morning. My name is

Selma Schimmel. I am the CEO and founder of Vital

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Options International. It is a nonprofit cancer

communications and advocacy organization that also

produces the Group Room Cancer talk radio show,

which weekly gives me an opportunity to speak with

a great many cancer patients.

While I am not a lung cancer survivor, I

have survived both breast and ovarian cancer. I

want to clarify that I have no financial interest,

investment, or gain associated with my presence

here today, but I am here to help lung cancer

patients, their loved ones dealing with non-small

cell lung cancer, and because I really believe that

we are at a crossroads and a convergence of

technology that necessitates a new dialogue and

opportunity for positive change.

Patients and medical consumers deserve

choice, but most importantly, they need and expect

full disclosure and rational explanations to help

them make informed choices, and what patients

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especially need are adequate safeguards to protect

them from erroneous choice.

As advocates, we thank and rely upon our

partners at the FDA and the NCI. We also applaud

AstraZeneca\'s prompt and open disclosure regarding

its top line Iressa data results on December 17th,

2004\. It was a respected and valued action and of

particular importance at a time when the general

public has such a lack of trust and expresses

hostility towards the pharmaceutical industry and

the regulatory and approval process.

So, I bring a question to the forefront,

because it is really at the core of today\'s

proceedings, and because the process and the course

of action being taken now sets a tone and a

precedent for our future.

How am I to respond to the man who tells

me that he has read that Iressa has no survival

advantage, that it is not being used in Europe, yet

he will begin receiving it here? I find I have no

reasonable and satisfactory answer.

But what the patient is really asking is

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how many patients are being harmed by not receiving

the most effective and safest product for their

disease. How can patients advocate for themselves

when they are receiving conflicting information and

double messages?

Finally, how can patients trust the

system? While Iressa should remain available to a

defined patient population who might benefit, as

well as for the subset of patients who are already

responding favorably or for whom there is no other

option, a labeling change is needed now, not months

from now, to reflect the current indications and

information, so patients are not mistakenly

deprived of their best treatment option and to

avoid further patient confusion and misperceptions,

a labeling change allows for the full circle of

information disclosure to be complete, as well as

implemented.

Iressa has paved the way for a deeper

understanding of the differences between EGFR

agents. There is much yet to be understood about

Iressa and the scope of who may and may not

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benefit, as well as which patient groups may derive

comparable or perhaps even greater benefit from

Iressa than other proven therapies.

One of the great hopes is the development

of proper screening assays, but since none have

been scientifically validated, patients are in need

of additional security and safeguards.

So, as we face a new world in medical

technology, we must also try to bridge the

communication and comprehension gap between

patients and providers. It is hoped the decisions

coming out of this meeting are made in context to

today\'s fragmented medical culture and evaluated in

its entirety for the much broader and significant

implications that will impact the oncology

community in general, color public perception and

attitudes associated with clinical trials,

confidence when trials are negative or halted

early, and drugs that are developed under an FDA

fast track application.

Advancing and widening technology requires

a mechanism to teach the public and to instill

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trust.

Thank you very much. I have copies of my

statement at request.

MS. CLIFFORD: Thank you, Ms. Schimmel.

Our next speaker is Rosalind Brannigan.

MS. BRANNIGAN: Good morning. My name is

Rosalind Brannigan and I have no financial

relationship with AstraZeneca except that I am

buying its drug.

Recently I have had two profound shocks.

First, in November of 2003, I broke my arm

at my health club and was diagnosed with Stage IV

non-small cell lung cancer. This was a major shock

to someone who had not smoked in 38 years, who

exercised an hour a day, and who has spent their

life working in public health.

I underwent six months of weekly

chemotherapy, platinum and Taxotere. Three months

later, my cancer had come back and had metastasized

to my liver, and I was put back on weekly

chemotherapy.

Shortly after that, I learned from the

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Massachusetts General Hospital that I had the

genetic mutation to be a candidate for Iressa, and

I was put on Iressa in October of 2004.

By December, when I had a PET and CT scan,

it showed that my tumor in my lung and my liver had

both reduced significantly in size and that my CEA

tumor marker had plummeted by 90 percent.

However, this good news was immediately

followed by having me open the New York Times on

December 20th and to read that FDA was reviewing

its approval of Iressa and that it might take this

drug off the market.

Just last Friday I had another PET/CT

scan, and it showed that the tumors in my liver are

completely gone, and that the tumor in my lung

continues to shrink.

Iressa is working for me. When I asked my

oncologist if I should switch to Tarceva, he said,

\"Absolutely not.\" He was adamant that I stay on

Iressa because it\'s working for me, and he thinks

it\'s a wonderful drug for all of his patients in

his practice who are responding to the drug.

Iressa should remain available.

Thank you very much.

MS. CLIFFORD: Thank you, Ms. Brannigan.

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DR. MARTINO: Thank you, ladies and

gentlemen.

Committee Discussion

We will now return to the committee\'s

proceedings in terms of if there are additional

questions, but as I let you do that, let me read

for you the questions that I really want you to

discuss and to think about.

1\. Discuss whether the content of the

information communicated by the FDA and AstraZeneca

on Iressa is satisfactory. Should any other

information be communicated?

2\. Further, discuss whether the target

audience and the selected means of communication

are satisfactory. Should any other audiences or

means of communication be used?

Now, in your packet, you each have a

letter from the FDA, and there is also the Dear

Doctor letter that AstraZeneca has provided. What

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I, myself, have not seen is what has been provided

to the lay public. It sounds like there has been

information provided in various magazines, et

cetera.

Can someone from the company review that

for us and tell us what the content of that

information is, because providing information to

physicians is critical, but with this drug I am

concerned that unless we communicate properly to

the lay population, we may be confusing them rather

than helping them as I think our last speaker made

clear to us.

DR. SCOTT: I will ask Carolyn Fitzsimons

to come and talk about the patient communications.

MS. FITZSIMONS: Thank you. Can I just

clarify the question you are asking, you want to

know about the content of the communications

directly to patients and the public?

DR. MARTINO: Correct.

MS. FITZSIMONS: On December the 17th, as

was shown on the original presentation by Dr. Ochs,

we immediately informed the patient advocate

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groups. We had a teleconference with them, gave

them the information about the top line results

with the guidance that should they have any

concerns, that they should go at their first

opportunity to consult with their physicians about

what the most appropriate treatment options would

be.

We did say that they should not stop

taking their Iressa until they had spoken to their

physicians and deemed what was the most appropriate

action in consultation with their physicians.

We also put out similar information on the

AstraZeneca website and also on the specific Iressa

websites also.

Subsequent to December 17th, we then went

back to our own records where we had got

information from patients who had contacted

AstraZeneca directly to gain information about

Iressa or were on our patient assistance program

for Iressa.

So, any known patients to AstraZeneca, we

went out a mailing, either postal or on e-mail to

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inform them of the information, provide them with

the Dear Doctor letter, and give them the guidance

that at the first opportunity, they should consult

with their physicians about their ongoing

treatments and what would be the best choices for

them.

DR. MARTINO: Has the FDA seen any of the

written material for the public, and are you

satisfied with it? Is that a yes or a no?

DR. PAZDUR: Yes.

DR. MARTINO: Generally yes? Okay.

Dr. Hussain, you had a question?

DR. HUSSAIN: I want to thank the members

of the public that presented, and I thought that

their comments were very thoughtful, to be honest

with you. It kind of encapsulated everything that

this committee is facing at this moment.

But I want to go back to the presentation

that Ms. Schimmel had done and Ms. Brannigan.

Before coming here I talked to my lung colleagues

who deal with lung cancer and have worked with

Iressa and Tarceva, and a variety of other agents.

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I have myself not used it in the setting of lung

cancer.

What I was impressed by is their

impression from their own patients that there is

clearly subsets of patients that benefit, and I

think Ms. Brannigan is a perfect example of that.

So, there is no question as doctors, ethically, it

is going to be very hard to say to a patient who is

on it and is responding, or is likely to respond

when there is nothing else that you can\'t get it.

That, to me, doesn\'t make a lot of sense.

On the other hand, I think it is also

unethical to keep it available for people who we

know are not likely to benefit and to allow that

part to happen, because there is an ethical issue

of side effects and cost, and these things are not

cheap, and there may be, by giving them something

of this sort, will take them away from stuff that

works.

I have to get back to the clinicians in

the group, and I do agree with Dr. Temple, when you

are starting a new patient and you have two drugs,

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one that stood the test, and the other one did not

stand the test, to me, it, from a clinical sense,

doesn\'t make sense to use a drug that didn\'t stand

the test when you are starting a new patient, but

that is where the art of medicine comes in, and I

am not sure that I could argue that way too much.

So, my point is to go back to Ms.

Schimmel\'s recommendation, which I think the

package insert and the labeling has to change,

reflecting the fact that the definitive trial did

not work, and that perhaps\--and I don\'t know if

that is allowed\--that there are some subsets that

seem to benefit, and that if one is to use the

drug, perhaps they could consider using them in

that subset to give some guidance to the

physicians.

The other thing, to the patients, I think

that considering that industry uses the media to

advertise their drugs, perhaps to ensure that every

patient had heard about it, is to use the media to

indirectly say something, so that they can contact

their doctors as another means of assuring that

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people have heard about it.

The other concern I had, had to do with

the labeling of people as Asian. We live in the

United States and have certain definition of

ethnicity, which I am not sure that are clear. I,

myself, was born in Baghdad. I consider myself

Asian. So, does that drug apply to me?

I think when we talk about benefits in

general, and I wouldn\'t consider a Japanese person

equal to Vietnamese, equal to Chinese, equal to

Indian, Pakistan, Afghanistan, and on. I think

those populations have to be very clearly defined

beyond this Asian ethnicity thing, because I don\'t

really know what it means.

DR. TEMPLE: It\'s actually, I mean I am

not saying this is fully worked out, it\'s actually

non-Caucasian who seem to do best. It is not

entirely\--it was actually some mixture of Japanese,

some mixture of other people, but non-Caucasian was

the subgroup.

DR. HUSSAIN: I think we get wrapped up in

these ethnicity race issues. To be honest with

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you, I don\'t even know what I would even describe

myself, so we have to be very clear about those

definitions.

DR. TEMPLE: You are right, and it is

totally after the fact, and I doubt if you probed,

you would always get a good answer on who it was.

I do want to remind everybody that the same subsets

that seemed to be responding better here are the

same subsets that respond better to Tarceva, too,

except there you have some EGFR data that helps

shed light on it.

DR. PAZDUR: Perhaps that\'s an area that I

would like to focus on in the discussion and get

several people\'s opinion on, in this fact of new

patients, and that is what we feel very

uncomfortable with here, basically, what should be

the option for new patients that would be looking

at an EGFR receptor drug.

Here again, you have two drugs here, very

similar, similar response rates, similar facts,

that if you take a look at their development

program, they have had failed trials in first line

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settings when combined with chemotherapy, however,

in the Registration study for Tarceva, there was a

survival advantage seen and secondary endpoints

were positive in this trial, so we are quite

comfortable that that was a win for this drug.

Given the information, given the fact that

there are similar subsets also that we see in the

patients between Iressa and Tarceva, and remember

the Iressa data is somewhat subject to questions

about these subsets, because they did not win on

their primary endpoint, so looking at these subsets

could be statistically ambiguous or criticized.

Given that fact, given a new patient, what

should be the treatment option if you are looking

at a EGFR receptor drug?

DR. MARTINO: I am having a hard time with

all of this, Rick, which is we are now getting to

issues of as a physician in my own office, okay,

how do I practice medicine, and I practice medicine

based on everything that I know at that moment, so

any of you, be it the drug company, be it the FDA,

be it anyone, the only thing that you can do is

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provide me the opportunity for me to know

something. That is all you can do for me.

You cannot be in a position where you are

looking over my shoulder saying, but, Dr. Martino,

did you actually consider that your patient was

male or female, that they were Asian, whatever in

the hell\--excuse me\--that means. That is not the

position that I think either of you can take.

The issue at hand, as I think I understand

it, is have both sides communicated that there is a

problem with this drug, and that people have to

recognize that there are alternatives, the

alternatives are not unknown, so it is not for you

to do anything more than I think to make people

aware, that you are reminding them that there are

alternatives, and that you are reminding them that

they have to think.

I kind of have the feeling like now we are

moving into, you know, how do you sit in my office

and look over my shoulder. I don\'t mean to be

unkind, but that is what I am sensing here, and I

don\'t know that any of you can do that on either

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side of this table.

DR. TEMPLE: There is labeling that, for

one reason or another, sometimes suggests that

another drug be used before this drug. There is a

calcium channel blocker called deprenyl that has

pronounced effects on the Q-T interval. It is

recommended for people who don\'t respond to other

calcium channel blockers for angina.

So, labeling can do that if there is a

good case for it. This isn\'t done lightly, of

course. That doesn\'t force the doctor to do that,

it encourages them, shall we say. Clozapine, a

granulocytosis-causing antipsychotic drug is

explicitly second line therapy because it is

thought that you should fail first on something

that doesn\'t have that liability.

So, there are examples of that if that is

appropriate. I should emphasize we don\'t do that

lightly because, you know, you are not in the

office, you don\'t know the exact circumstances,

that is fair, but sometimes you can conclude, and

the sponsor concludes with us, that the right

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recommendation is this should be reserved for

someone who fails on the other one, or you should

try that one first.

That is something labeling does sometimes

say.

DR. MARTINO: But that is an issue whether

you are ready now to change the labeling, and I

don\'t know that that is again the discussion from

today\'s meeting. I appreciate you have that

responsibility.

Who is next on my list here? Dr.

Mortimer.

DR. MORTIMER: I think the issue from an

evidence-based standpoint, in answer to the FDA, is

clearly that the data support the use of erlotinib

as first line therapy.

I think where the gray zone happens is a

statistical one, and what do we do when there are

overlapping confidence limits, when the difference

in response is 8 and 9 percent, but the confidence

limits overlap.

I think the third issue that is concerning

119

that we don\'t know the answer to until crossover

data is available, is are the same patients

responding to Tarceva, the same patients that

respond to erlotinib, and I guess we don\'t know

that yet. So, the statistical question I think is

at the heart of this.

DR. D\'AGOSTINO: I guess I just didn\'t

think we were going to be talking statistics, I

thought we were going to be talking what is the

material that is being presented, and I am very

concerned that we have an accelerated approval

product here, it has been approved, and you can\'t

ask the sponsor to sit on the data, and not get it

out in the literature.

So, what I am concerned about is that I

think these letters are fine, and I understand the

letters for the public seems to be fine, but if

tomorrow we go to professional meetings and we

start hearing a lot about these subsets, then, I

think there is going to be an awful lot of

confusion.

So, maybe we need an accelerated review of

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this material, so that we can have the statistics

question, because again I did not come here

thinking we were going to have a statistics review,

but rather is the public being made aware of the

fact that the study was negative on the overall,

and then what else might be needed, and I think

what needs to be needed is a quick review of the

actual data, so we can answer your question.

DR. MARTINO: Dr. Proschan.

DR. PROSCHAN: I think the statistical

issues, it is not clear cut. I mean this trial

really is about as close to being a positive one as

you can get in the sense that if they had used a

Cox model, which people feel is fine, you know,

they would have gotten a significant effect, so it

is not just the subgroups, it\'s other issues as

well.

I had problems with some of the

presentation. In particular, the graph showing the

comparison of Iressa to docetaxel, you know, and

the claim that, well, we are not seeing much of a

difference there, and we would have if it were a

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placebo. I have a problem with that.

That is a small sample size and I am not

convinced at all that there is not a difference

there that would be seen with a larger sample size.

So, I have problems with some of the presentation

this morning, but it is very thorny.

I disagree with the classification that

this is a negative trial. There is negative and

there is negative. This is a negative trial, but

there are extenuating circumstances, as well.

DR. D\'AGOSTINO: But, again, we don\'t

really want to get into this, but the Cox analysis

has some assumptions carry to it. These curves are

sticking together and then they separate, so the

assumption may not be met of proportionality, and I

am not going to say another word about statistics.

\[Laughter.\]

DR. MARTINO: Thank you. Dr. Perry.

DR. PERRY: I would like to point out that

during the brief time I have been on the committee,

the FDA has approved several drugs without my help,

and I am sure they have also turned down several

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without my help, so it seems to me that the only

things that come before this committee are those

that are bathed in shades of gray.

So, I think it is clear that we have

varying viewpoints, that we have very different

interpretations of the evidence before us, and I

expect that is why we are here, and so I don\'t

expect that we are going to walk away with a clear

black or white decision.

When I raised my hand half an hour ago, I

was trying to address\--

DR. MARTINO: I do apologize.

DR. PERRY: Yes, I understand. You are

doing a wonderful job in a difficult circumstance,

particularly when all of us love to hear our own

voices, they resonate so well.

I was going to address Question No. 2,

which is whether target audiences have been

addressed selectively. I have to say, to give

credit to AstraZeneca, I have got more notice about

this drug than I have credit card applications, so

they have clearly done a good job in saturating the

123

medical community, at least the lung cancer

doctors.

I can\'t speak to the lay public, but they

have clearly I think gone over and above their

obligation to communicate with doctors. I can\'t

think of another time in which, in my practice, I

have been so inundated with information about the

adverse effects of a drug.

DR. MARTINO: I do apologize officially

and personally, and thank you.

Dr. Brawley.

DR. BRAWLEY: Run down your list, Madam

Chairman. My first thought is I must say to the

advocates I appreciate all four of their comments

this morning, because so frequently\--well, let\'s

just leave it that I got something positive and

something to think about from every advocate\'s

statement this morning.

I wonder why so many patients were

concerned that Iressa might be pulled, and was

there some press, did anyone do something to

frighten patients into believing that this drug

124

that they are on is going to be pulled away from

them.

Next, going into Questions 3 and 4, and

actually addressing the advocates and the

survivors, I think we all owe them an apology

because the development of this drug has been

mishandled. It has been mishandled by AstraZeneca,

it has been mishandled by this committee.

I, myself, take some blame for that,

because I voted for approval of it two years ago.

The fact remains that this drug has been available

for 7 years, and we still haven\'t figured out

exactly how this drug should be used in the

treatment of lung cancer.

Perhaps if we had held off in getting it

available to people two, three years ago, those

studies would have been done. There are a number

of studies that have done a number of subset

analysis, and I have made my career, by the way, by

saying we should not do subset analysis based on

race, because race or ethnicity is not a biological

categorization of populations, it\'s non-scientific.

I actually think I was quoted in the press

when I voted for this drug two years ago saying

that this is lung cancer\'s tamoxifen in search of

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its estrogen receptor. Unfortunately, the failure

to totally find and totally categorize that

estrogen receptor is the reason why we are in the

pickle that we are in today.

It may very well be that people\--Asian is

a way of racial profiling, and the best way to

politically\--I am sorry\--the best way to

scientifically profile is people who happen to have

that receptor, which may very well be of a higher

prevalence in people who were originally born in

Japan or China, or maybe even Iraq.

That is what we have got to start doing,

and we have got to be much more scientific. Now,

in partial defense of everybody who mishandled the

development of this drug, including myself, this is

one of the first of the targeted therapies to come

along, and none of us really had developed target

therapies a lot before this one came along, so we

need to learn from our mistakes and go forward.

With that, I will relinquish the

microphone.

DR. MARTINO: Dr. Levine.

DR. LEVINE: Several comments. First, I

will agree, I mean there is not winning and not

winning, and this is on the edge, and I don\'t

126

honestly believe in my soul that there is no

efficacy of this drug. I think the company have

shown data to suggest that there may be something

there.

The other thing that bothers me a little,

I wasn\'t on the committee either for Tarceva or

Iressa, and I don\'t know the data, but we are

hearing or I am hearing that Tarceva is a \"better\"

drug.

So, my question is, by chance, how many

women were on that trial, how many non-Caucasians,

how many non-smokers, and I don\'t know if it is

fair to compare one drug to another when those very

important issues have not been presented to us, and

I know we aren\'t asked to do that, but that is a

comment I have. I feel disquiet about it.

The second is an administrative question.

The company was asked, after accelerated approval,

to do three studies. One study was agreed upon

that should be dropped, but my question to the FDA

is, if you are going to base everything on one

study out of two, why were they asked to do two or

three, and what is the administrative concept here,

if the company is asked to do two or three studies,

aren\'t we, in fact, obligated to look at all of

127

them in making our decisions.

That\'s it.

DR. MARTINO: Dr. Temple, Rick, you want

to comment on that?

DR. TEMPLE: Rick has to remind me what

the second study is, but I think the short answer

is this was a very large study. You would expect

it to be able to detect an overall survival effect

if there was one, and the fact that it didn\'t tells

you something.

It absolutely, as people have said, it

doesn\'t prove the negative. A negative study never

proves the negative almost. Maybe if it\'s

128

significantly worse than no treatment, but that

hardly ever happens, but it doesn\'t support the

positive.

Not to get too far apart, but we are

learning in more and more cases that there are

subsets of the overall population that respond, and

if the subset is too small, you will not have an

overall effect on survival, that is inevitable.

That doesn\'t mean the drug is useless.

So, there are obviously people who respond

dramatically, and if you could identify them ahead

of time, you might be able to show there is a

survival benefit in that subset we were sort of

talking about this yesterday, but this is a

developing area and we don\'t yet quite know how to

do that.

Just for what it\'s worth, in the Tarceva

data, there are some very intriguing things. For

example, if you look at the subsets of people who

do particularly well, like nonsmokers, it\'s the

nonsmokers who are EGFR-positive who do

spectacularly well, it\'s not the nonsmokers who are

129

EGFR-negative who do spectacularly well, and that

is true for women and all those subsets.

So, you know, we are not declaring any of

that definitive, the number of patients in the

negative subsets are too small to be definitive,

and the confidence intervals overlap, but you are

starting to get the impression that these data are

telling you something, but it is still early.

But one of my problems with survival data

in general is that if the response rate is low

enough, you can\'t bring the whole study along

unless you have a population of a million or

something, and that doesn\'t mean it doesn\'t work,

so we have got to get better at identifying who the

potential responders are, so you can study them and

identify them as the people to be responders.

Anyway, the new study even without the

additional study, gives you more information than

you had before, and I think the view would

generally be that that should be reflected in

labeling, and if you learn something else in

addition, you add that.

DR. PAZDUR: We generally do ask for other

than just one confirmatory trial. We are

interested for the development of the drug, and we

130

are realistic that a trial can fail, in quotes, by

chance alone obviously.

Given the fact there are other trials, the

docetaxel trial, it was a difficult trial, and we

brought this same question to the committee several

months ago when we looked at Alimta.

One cannot do a non-inferiority trial

here, they have to beat this drug. A

non-inferiority is impossible to do in this setting

and we had lengthy discussions, which I won\'t bore

you with, on this whole issue of non-inferiority

with docetaxel.

But there are problems here, and that was

specifically stated by us, had to be a superiority

trial. This is a placebo-controlled trial. It is

about as clean as you could get here, and

obviously, this is bothersome or we wouldn\'t be

here to bring this to people\'s attention.

DR. MARTINO: Mrs. Ross.

MRS. ROSS: Thank you, Madam Chair.

First, just an administrative technical

question and then one other question. I didn\'t

hear properly the start of the testimony of Ralph

Nader\'s group. Did they file a financial

disclaimer on this, or were they testifying on

131

behalf of someone?

DR. TEMPLE: He stated that he had no

conflict.

MR. LURIE: I made it perfectly clear that

we have no conflict of interest whatsoever. We

take no money from AstraZeneca or any other drug

company, or any other corporation, nor from the

government.

MRS. ROSS: Thank you. I just wanted to

clarify, I didn\'t hear that.

To Dr. Brawley\'s comments, I was in the

audience the day you voted in favor of accelerated

approval, and frankly, I am so glad you did. I

know that Dr. Pazdur was not in favor, and other

members from FDA, however\--

DR. PAZDUR: You don\'t know that, you do

132

not know that, ma\'am, you are not a mind reader.

MRS. ROSS: In any event, it was approved,

we don\'t erase that, but I think we have to look at

the benefits that have come from this. First of

all, and let\'s not forget this, there are a

significant number of people who have, in fact,

benefited from Iressa. Their quality of life, as

the study done by Dr. Joan Shold \[ph\] at the

University of Wisconsin, was greatly improved.

Now, they might not be living five years

out, we don\'t even know that. I don\'t even know

what the data is from Japan on longer term survival

with Iressa, but the fact is that there are people

surviving.

Secondly, the other enormous benefit to

come from this is that it is focusing attention,

large populations, on these targeted therapies, and

who knows, maybe Iressa in combination with a VEGF,

or in combination with something else, might be the

real answer to a lot of these recalcitrant late

stage lung cancer, but please, please keep in mind

it has opened, like Laurie says, it has opened a

133

window, we have another place to go to look and

help these late stage lung cancer patients.

Late stage lung cancer patients only have

a 5 percent chance of survival. We can\'t cut down

on what is available to them to survive, and it is

not just that it is not fair. I wholly agree with

you that we need to do more research on these

receptors, in determining who will respond to these

drugs, and we will do anything we can to support

that research.

Perhaps if this committee makes a clamor

for that, we might get the attention of other

government agencies who are charged with that

research and get them talking, too.

DR. MARTINO: Ladies and gentlemen, this

meeting is coming to a close. I need to remind the

group that you have gotten off track here. Okay?

Even though I keep reminding you, the point today

is not whether this drug dies or lives, that is not

the issue here, and some of you refuse to

understand that.

The issue here was have we sufficiently

134

informed the necessary people. So, I realize there

is no vote to be taken, but I, for my own

satisfaction, would like to hear an answer to that

question, and I am going to start with Dr.

Doroshow. Are you satisfied that the public and

the physicians have been appropriately informed or

not?

DR. DOROSHOW: Yes.

DR. BRAWLEY: No.

DR. D\'AGOSTINO: Yes, but I am concerned

that we have to move, the FDA, the sponsor has to

move quickly on making a resolution about this

particular study, but I think they are informed.

DR. PROSCHAN: Yes.

DR. GRILLO-LOPEZ: I don\'t have a vote,

but I do have an opinion, and I would say yes,

because as a physician, I have been receiving the

same number of communications by e-mail, letters,

et cetera, that Dr. Perry has.

DR. MORTIMER: Yes, on the basis of the

e-mails and mail.

DR. PERRY: Yes.

DR. HUSSAIN: Yes.

DR. MARTINO: Yes.

DR. REAMAN: I will give a conditional yes

135

for the constituency of the medical community, but

I don\'t think we have actually seen anything that

has gone to the public, so I don\'t know how we can

be asked to comment or vote on something that we

have never seen.

DR. MARTINO: I actually think that is a

very fair statement. I mean we have been told that

the FDA has seen what has been put in the public

media, and it is to their satisfaction, so I guess

right now we have to kind of trust that.

DR. BRAWLEY: Madam Chairman\--

DR. PAZDUR: We have examples in your

packet of the letter and their ad.

DR. REAMAN: The only thing I have in my

packet is a copy of the Dear Doctor letter.

DR. WILLIAMS: But I do think we should

mention it has been limited, I believe, to the

patients AstraZeneca has access to, which

represents a subset, and I don\'t know if there is

136

another way to reach those others. Certainly, the

advocates have been helpful.

DR. REAMAN: We heard that there is

announcements on websites. We have not seen that,

we could have seen that, that could have been

provided, and it wasn\'t.

DR. BRAWLEY: Madam Chairman, the basis of

my no vote is I do think the physicians have been

well informed, but I am concerned when I hear

advocates say they are afraid that they are going

to run out of their drug, and it is going to be

taken away from them while they are on therapy.

DR. RODRIGUEZ: I concur with the

previously stated comments. I actually don\'t know

what the public has heard. Obviously, the public

heard some negative statements from the press,

otherwise, there would not have been this fear in

the patients about the drug being removed, which

isn\'t even an issue at this stage, as I understand.

DR. MARTINO: Perhaps we can infer the

very fact that the public was so concerned that the

drug is coming off of the market, that, in fact,

137

the word that the results are negative must have

gotten out.

That really is the issue here, isn\'t it?

For them to be worried, that is the message that

they heard, however they heard it.

DR. LEVINE: I agree that the medical

community has been well informed, and I am

respectful for the company of having done a very

good job in that regard, but I am unclear as to

what the committee is asking them to do as far as

the patient community.

I don\'t think we are saying that they

should be going out there and saying don\'t worry,

this is all wonderful, the drug is available. We

can\'t go in that direction.

I would be in favor of a label change, and

I would also say to the company, in all fairness,

and I don\'t know whether they did, if the company

has directly advertised to the community of

patients on TV and radio, they should be asked to

directly advertise that the drug has difficulties

here. If they have not done that, then, fine.

MS. HAYLOCK: I am an oncology nurse and a

member of the Oncology Nursing Society, and I would

just like to add that the Oncology Nursing Society

138

was involved in distribution of information, and we

have a membership of over 30,000 nurses.

So, I think the nursing community, and for

those of you who have been through treatment, I

think you realize that the oncology nurses are the

ones who are oftentimes involved in informed

consent and also patient and family information,

and teaching, and for caregivers, as well.

So, I think the nursing community was also

involved in the dissemination of information to

recipients and patients and caregivers.

DR. PAZDUR: In fact, the e-mail that we

sent out to ASCO simultaneously goes out to ONS

membership, as well as is put on the NCI website.

MRS. ROSS: Yes, we are quite satisfied

with the information disseminated to the patients

and particularly in the follow-up, as I mentioned

before, we did speak with FDA regarding the calls

we were getting, and Dr. Pazdur was very helpful in

139

crafting a statement that we could put on our

website that would allay people\'s fears.

Their main concern was they were afraid

the drug was going to be pulled immediately, and

that came about because of the press and certain

other citizens organizations that were crying wolf.

Also, there is a vast network, an on-line

e-mail list among patients, sub rosa, so to speak,

and we, at the Lung Cancer Alliance, immediately

notified every other lung cancer group we knew plus

got Dr. Pazdur\'s statement up on those e-mail

lists, so I think it was a very widespread net.

DR. MARTINO: Last question from me to Dr.

Temple and Dr. Pazdur, at this point, are you

considering revising the package insert, or where

are you in that process?

DR. PAZDUR: Yes, we will be discussing

that internally.

DR. MARTINO: Ladies and gentlemen, that

is the end of this morning\'s meeting. There is a

second topic and I am going to ask you to return

here at 20 to 11:00, please, to start the second

140

part of this meeting.

\[Break.\]

141

Call to Order and Introductions

DR. MARTINO: Good morning, ladies and

gentlemen.

The topic for this morning\'s meeting and

discussion relates to a safety concern with the

agents Aredia and Zometa, specifically

osteonecrosis of the jaw.

Before we start into the topic, I would

like the committee members, as well as the members

from the FDA, to introduce themselves, and I think

we will start on my right, Dr. Doroshow, if you

would introduce yourself, please.

DR. DOROSHOW: Jim Doroshow, NCI.

DR. BRAWLEY: Otis Brawley, Medical

Oncology and Epidemiology, Emory University.

DR. D\'AGOSTINO: Ralph D\'Agostino,

Biostatistician, Boston University.

DR. PROSCHAN: Mike Proschan,

Statistician, National Heart, Lung, and Blood

Institute.

DR. GRILLO-LOPEZ: Antonio Grillo-Lopez,

Industry Representative.

DR. MORTIMER: Joanne Mortimer, Medical

Oncology, University of California at San Diego.

DR. PERRY: Michael Perry, Medical

142

Oncology, University of Missouri, Ellis Fischel

Cancer Center.

DR. HUSSAIN: Maha Hussain, Medical

Oncology, University of Michigan.

DR. MARTINO: Silvana Martino, Medical

Oncology, Cancer Institute Medical Group, Santa

Monica.

DR. REAMAN: Gregory Reaman, Pediatric

Oncology, George Washington University.

DR. RODRIGUEZ: Maria Rodriguez, Medical

Oncology, M.D. Anderson Cancer Center.

DR. LEVINE: Alexandra Levine,

Hematology/Oncology, University of Southern

California.

MS. HAYLOCK: Pam Haylock, Oncology Nurse,

University of Texas Medical Branch in Galveston,

and I am the Consumer Representative.

DR. IBRAHIM: Amna Ibrahim, Medical

Officer, FDA.

DR. SCHER: Nancy Scher, Medical Officer,

FDA.

DR. COLMAN: Eric Colman, Medical Officer,

FDA.

DR. AVIGAN: Mark Avigan, Office of Drug

Safety.

143

DR. TEMPLE: Bob Temple, Office Director,

OD-I.

DR. PAZDUR: Richard Pazdur, FDA.

DR. MARTINO: Thank you.

Next, the Conflict of Interest Statement

by Ms. Clifford.

Conflict of Interest Statement

MS. CLIFFORD: Thank you. The following

announcement addresses the issue of conflict of

interest and is made a part of the record to

preclude even the appearance of such at this

meeting.

Based on the submitted agenda and all

financial interests reported by the committee

participants, it has been determined that all

interests in firms regulated by the Center for Drug

144

Evaluation and Research present no potential for

appearance of a conflict of interest with the

following exceptions:

In accordance with 18 U.S.C. 208(b)(3),

full waivers have been granted for the following

participants. Please note that the following

interests waived are unrelated to Zometa, Aredia,

and its competing products.

Dr. Otis Brawley has been granted waivers

under 208(b)(3) and 21 U.S.C. 505(n) for owning

stock in a competitor, valued between 25,000 and

50,000 per firm.

Dr. Michael Perry has been granted a

waiver under 21 U.S.C. 505(n) for owning stock in

two competitors, valued between 5,001 to \$25,000.

Because his stock interests fall below the de

minimis exception allowed under 5 CFR

2640.202(b)(2), a waiver under 18 U.S.C. 208 is not

required.

A copy of the waiver statements may be

obtained by submitting a written request to the

Agency\'s Freedom of Information Office, Room 12A-30

145

of the Parklawn Building.

With respect to the FDA\'s invited industry

representative, we would like to disclose that Dr.

Antonio Grillo-Lopez is participating in this

meeting as an acting industry representative acting

on behalf of regulated industry. Dr. Grillo-Lopez

is employed by Neoplastic and Autoimmune Disease

Research.

In the event that the discussions involve

any other products or firms not already on the

agenda for which an FDA participant has a financial

interest, the participants are aware of the need to

exclude themselves from such involvement, and their

exclusion will be noted for the record.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firm whose products they may wish to comment

upon.

Thank you.

DR. MARTINO: Thank you.

Dr. Pazdur will now address the group and

146

give us some guidance as to the nature of this

problem and what our agenda is.

Opening Remarks

DR. PAZDUR: Pamidronate and Zometa are

potent intravenous bisphosphonates. Aredia

received approval for hypercalcemia malignancy in

1991, for multiple myeloma in 1995, and for

osteolytic bone metastases from breast cancer in

1996\. Zometa was approved for hypercalcemia

malignancy in August of 2001 and for a broad bone

metastasis indication in February of 2002.

In 2002, the FDA received 9 spontaneous

reports for osteonecrosis of the jaw in patients

with malignancy whose treatment regimens included

intravenous bisphosphonates.

In 2003, the first published reports of

ONJ in patients treated with intravenous

bisphosphonates appeared in the literature.

In a high proportion of cases, there was

an association with a recent dental procedure.

These patients had no history of radiation therapy

to the head and neck.

The Zometa package insert was updated in

September 2003 to include information about

osteonecrosis of the jaw in the Adverse Events

147

section. The Aredia package insert was also

updated in November of 2003.

In August 2004, changes were made to the

Precautions section of the Zometa label, followed

by a parallel change to the Aredia label, regarding

osteonecrosis of the jaw. Novartis issued a Dear

Doctor letter in September 2004 regarding

osteonecrosis of the jaw.

The purpose of bringing to ODAC the

problem of osteonecrosis of the jaw in association

with intravenous bisphosphonates is to highlight a

drug safety issue in oncology and stimulate

consideration of how post-marketing safety issues

in oncology should be addressed.

Although there have been anecdotal reports

of ONJ in association with oral bisphosphonates

administered for osteoporosis, we wish to limit

today\'s discussion to osteonecrosis of the jaw in

association with Zometa and pamidronate. Less data

148

is available for the oral bisphosphonates, and the

risk-benefit considerations are different for

patients with malignancy compared to patients being

treated for benign bone diseases.

Thank you.

DR. MARTINO: Thank you, Dr. Pazdur.

Dr. Nancy Scher will now describe the

history of Zometa and Aredia and its regulatory

process.

FDA Presentation

Regulatory History of Zometa and Aredia

DR. SCHER: Good morning. I shall provide

an overview of the regulatory history of the

approval of Zometa and Aredia, and also provide

some chronology regarding the recognition of an

unusual adverse event occurring in some patients

treated with intravenous bisphosphonates.

Aredia is approved for treatment of

patients with osteolytic bone metastases of breast

cancer and osteolytic lesions of multiple myeloma

in conjunction with standard antineoplastic

therapy.

It is also approved for hypercalcemia of

malignancy and Paget\'s Disease of bone.

You have heard the Aredia approval dates.

149

Again, in 1995, there was an approval for

osteolytic lesions of multiple myeloma, and in

1996, for breast cancer.

The approval of Aredia represents a

regulatory precedent. Skeletal related events, or

SRE, were defined and used as a basis for the

approvals in the bone metastases indications for

Aredia and subsequently for Zometa.

This slide shows you the four components

that define that composite endpoint - pathologic

fractures, radiation therapy to bone, surgery to

bone, and spinal cord compression.

The multiple myeloma indication for Aredia

was based on a single double-blind, randomized,

placebo-controlled trial, where Aredia 90 mg

monthly intravenously was given for 9 months.

Aredia demonstrated superiority to placebo

for several SRE endpoints.

For breast cancer, there were two

150

licensing trials for Aredia. They were

double-blind, randomized, placebo-controlled,

Aredia 90 mg IV every 3 to 4 weeks was given for 24

months.

Patients were required to have at least 1

osteolytic lesion. In one study, patients were

receiving chemotherapy, and in the other study,

patients were receiving hormonal therapy.

Together, the trial results supported the

indication for Aredia in patients with metastatic

breast cancer.

Zometa is approved for treatment of

patients with multiple myeloma and patients with

documented bone metastases from solid tumors, in

conjunction with standard antineoplastic therapy.

Prostate cancer should have progressed after

treatment with at least one hormonal therapy.

Zometa is also approved for hypercalcemia of

malignancy.

Zometa was approved for hypercalcemia of

malignancy in August of 2001. At that time,

Novartis submitted a supplemental NDA for the bone

151

metastases indications to FDA. FDA reviewed this

application as a priority NDA.

In February 2002, Zometa was approved for

the bone metastases indications. This approval for

Zometa expanded the indications for

bisphosphonates.

Zometa was approved for a broad range of

solid tumors, not limited to breast cancer as

Aredia had been. Furthermore the lesion type was

not limited to osteolytic lesions. However, the

optimal duration of therapy could not be defined

from the trial design.

The oncology indication for Zometa was

based on 3 randomized trials. The multiple

myeloma/metastatic breast cancer trial randomized

patients to an active control of Aredia 90 mg, for

Zometa 4 mg.

The remaining 2 trials were

placebo-controlled, 1 in prostate cancer and 1 in

other solid tumors.

The primary endpoints were time to first

SRE and proportion of patients with SRE.

This slide provides some additional detail

about the Zometa registration trials. You can see

the multiple myeloma/breast cancer trial was

152

relative large, greater than 1,600-patient trial,

and it had a non-inferiority design.

Time to first SRE was the preferred FDA

endpoint. You see information about that presented.

For prostate cancer and other solid tumors, Zometa

4 mg demonstrated superiority to placebo. For

multiple myeloma or breast cancer, Zometa 4 mg was

non-inferior to Aredia 90 mg.

This slide shows the number of cases of

osteonecrosis of the jaw reported to the FDA by

year. In 2001, there were no such reports. In

2002, there were 9 cases reported of patients with

osteonecrosis of the jaw who were receiving

intravenous bisphosphonates as part of their

treatment regimen.

There were additional cases in 2003, and

more cases in the first half of May of 2004. These

numbers were provided to me by the Office of Drug

Safety. As of this time, as you will hear in

153

subsequent presentations, the number of reports is

in excess of 600.

This slide lists a fairly comprehensive

review of the literature of reports of

osteonecrosis of the jaw associated with

bisphosphonates. You will see the chronology is

somewhat similar to the chronology of the adverse

events reported to the FDA.

I want to point out that this literature

pretty much starts in 2003. Most of the reports

are abstracts or very brief reports, and

particularly earlier on, we are limited to the oral

surgery literature.

The most detailed report that I am aware

of was Dr. Ruggiero\'s paper in May of 2004,

reporting 63 cases of osteonecrosis of the jaw in

patients taking bisphosphonates. Again, this was in

the oral surgery literature.

Subsequent speakers will provide you with

details of the clinical manifestations of this

adverse event. This is just a very brief and

limited description of some of the features

154

characterizing these patients.

The patients with ONJ had diagnoses of

malignancy. They had not received head and neck

radiotherapy. Their treatment regimens included

intravenous bisphosphonates. A high proportion of

these patients had recent invasive dental

procedures.

In response to reports of ONJ in cancer

patients treated with IV bisphosphonates, changes

were made to the labels of Zometa and Aredia.

The Adverse Events section was updated to

include ONJ in September of 2003 for Zometa, and

then Aredia in October. The Precautions section

for both drugs were updated in August 2004.

The next two slides paraphrase the

contents of the current Zometa label. For

reference, the actual language from these sections

of the labels is included in the document which

contains discussion points distributed this

morning, and it was also in the Committee\'s

background documents if you would like to refer to

the label information.

I think I need to go back.

The Adverse Events section reported that

ONJ had been seen in patients treated with

155

bisphosphonates. The majority of cases were

associated with a recent invasive dental procedure.

It stated there were multiple risk factors for ONJ,

including cancer, chemotherapy, radiotherapy,

corticosteroids, et cetera.

It stated that although causality cannot

be determined, it would be prudent to avoid dental

surgery as recovery may be prolonged.

The Precautions section reiterates some of

the previous information, is placed in a more

prominent section of the label, and provides some

new information, as well.

Osteonecrosis of the jaw is seen in cancer

patients, many of whom were also receiving

chemotherapy and corticosteroids, the majority of

cases associated with dental procedures. Many

patients had signs of local infection including

osteomyelitis.

Baseline dental exam should be considered

156

if there are risk factors such as cancer,

chemotherapy, corticosteroids, poor oral hygiene.

While on treatment, avoid invasive dental

procedures. If a dental procedure is required,

there is no data to say if discontinuing therapy

reduces the risk of ONJ.

In summary, Zometa and Aredia are

effective drugs for the bone metastasis indication.

An unusual adverse event has been

identified in some patients treated with

intravenous bisphosphonates.

The true incidence of osteonecrosis of the

jaw is unknown.

Thank you very much for your attention,

and you will hear a lot more about this from

subsequent speakers.

DR. MARTINO: Thank you, Dr. Scher.

Our next speaker is Ms. Carol Pamer from

the Office of Drug Safety. She will speak on

Post-Marketing Safety Assessment of Osteonecrosis

of the Jaw with Pamidronate and Zoledronic Acid.

Post-Marketing Safety Assessment of Osteonecrosis

of the Jaw: Pamidronate and Zoledronic Acid

MS. PAMER: Good morning. My name is

Carol Pamer and I am a safety evaluator in the

157

Office of Drug Safety.

I will be presenting a brief overview of

the FDA\'s spontaneous reporting system named AERS,

including its strengths and limitations. I also

will provide a high-level summary of case reports

of ONJ that have been reported with pamidronate and

Zometa.

I am going to discuss specific

difficulties in assessing the case reports, and

finally, our epidemiologist, Carolyn McCloskey, has

prepared some comments concerning the

epidemiological issues concerning the study of this

event, and I will present those remarks on her

behalf.

Generally speaking, a spontaneous

reporting system is a mechanism for clinicians and

patients to report adverse events that occur after

a drug has been marketed in a larger and more

diverse group of patients after the clinical trials

158

are over.

In the U.S., these case reports are known

as Med Watch reports, and the database which houses

them is the AERS database. FDA has maintained a

reporting system since 1969. Over time,

modifications have been made to the system and the

database primarily as computer capabilities have

increased.

There are a number of factors which affect

reporting patterns and quality of case reports that

FDA receives. Some types of adverse events are

more or less likely to be reported than others, and

some examples of that are cases with a fatal

outcome or severe outcome, special populations,

such as children, or adverse events that are

usually suspected to be related to drug use.

The type of product and condition for use

can affect reporting. Prescription drug products

require patient interaction with the health care

system, so those events related to the products may

be detected more frequently.

Reporting for a drug tends to be heaviest

159

in the first few years after marketing, and then it

tapers off over time. Media attention or medical

publishing will affect that. Finally, the quality

and extent of reporting varies by pharmaceutical

company, and regulations affect that directly, as

well.

AERS is an uncontrolled means for

gathering information about a marketed drug, so

some case reports are better documented and more

convincing of a possible relationship than others.

Critical elements of a case report, which

are evaluated, include the time to onset or

temporal relationship of the adverse event to the

drug, assessment of whether the patient has any

symptoms of the adverse event prior to starting a

product, and a baseline health status can help in

documenting that.

Evaluating drug dechallenge is drug safety

jargon for evaluating whether the symptoms of the

adverse event went away after the drug is stopped.

Drug rechallenge refers to testing whether

the adverse event recurs if the drug is restarted.

160

If both dechallenge and rechallenge are positive,

that can be a pretty strong indicator that an

adverse event is related to a drug.

Another critical issue in evaluating the

strength of a case report is determining whether

there are other explanations for the events.

Typically, these are other medical conditions or

other drugs.

The other items, consistency with

pharmacologic effects, known effects in the class,

and controlled trials attempt to make an argument

that the drug caused the events rather than they

were simply associated with it.

There are some limitations of using

spontaneous reports for investigating drug safety.

The system is passive or voluntary in the U.S., so

in many cases, are not reported. This will also

vary from drug to drug and over time.

Reporting bias exists in that some events

are more likely to be reported than others. The

quality of cases is highly variable. You have many

reporters and reports are often incomplete.

161

Duplicated cases can be submitted and this requires

a case review to sort those out.

Very importantly, we don\'t know what

proportion of the true number of cases of an

adverse event in the population are reported to

AERS, which is the numerator of an incidence rate,

and we don\'t know the true counts of how many

people take the drug. That is usually estimated by

drug usage data at this point and that is the

denominator of an incidence rate.

So, with these limitations in mind, there

are adverse events for which AERS is best applied.

Its best functionality is for detecting safety

signals, the early warnings that there might be a

problem with the drug.

The best documented convincing cases can

be used to develop a descriptive case series. The

more well established a diagnosis is for an adverse

event, the more likely it will be noted by a

clinician and also be readily identified in AERS.

Events with a low background rate in the

general population or that are rare can be more

162

readily detected with AERS, and events with a

shorter latency period lend themselves to detect

signal detection more readily.

Now, I will just present a quick summary

of the reports of osteonecrosis and osteomyelitis

that have been reported for the two IV

bisphosphonates.

An in-depth review of 139 cases was

previously conducted by Jenny Chang of the Office

of Drug Safety, and a copy of that review was

included in the background package for this

meeting, and my tables just provide a brief status

update to that review, which my numbers are

cumulative though.

Novartis Pharmaceuticals will be

presenting a more detailed overview of the cases.

This slide lists the details of the search

used for this update, and there are two important

differences to point out. The case series by Jenny

Chang included cases of osteonecrosis at other

sites, although most cases involved the jaw, and

the Novartis data differ due to slight differences

163

in search terms, different cutoff date, and they

don\'t have reports from other manufacturers.

It is probably not very visible all the

way back there, so I will go through it.

This slide summarizes which of the two

drugs was indicated as being prescribed in the

reports. There are a total of 654 in which the two

drugs are mentioned. The first listing is

pamidronate only, which was 136 or 21 percent of

the reports.

Pamidronate or Zometa, its sequential use

was defined in this way as any history of use

primarily to keep the solo use cleaner and the

drugs persist in bone, so it was just neater to

keep solo therapies separate, and then if there was

any mention of a history of the two, then, this is

in this category, and that constituted 28 percent

of these reports.

Then, zoledronic acid were 49 percent, and

then one of the two drugs, oral history again of

another bisphosphonate, that was about 2 percent of

the 654. The numbers just grossly seem to be in

164

proportion to the use of the products.

This table summarizes the primary

indication for use listed in the report. Most

patients were being treated for cancer. Multiple

myeloma was approximately 34 percent either with or

without another. Most of them were alone. Some

mentioned a history of other cancer, so those were

just tallied separately. Breast cancer,

approximately 27 percent if you consider other

cancers mentioned. Prostate cancer, around 7

percent.

There were 16 percent cancer unspecified

or other type. Most of those were unspecified.

Osteoporosis, osteopenia, and osteolysis, which is

probably a cancer, that was 1 percent, and then 15

percent of the cases didn\'t have an indication

listed at this point.

At this point, I will discuss specific

difficulties encountered in evaluating these cases

reported with the two drugs.

One of these is the increased rate of

reporting due to publicity makes the assessment of

165

the usual pattern of reporting difficult.

Confounding factors were present in many of the

cases.

Assessment of drug dechallenge is

confounded. I will explain that later.

Establishing a pattern in the time to onset after

the drug was started is also difficult.

Confounding factors were present in many

of the case reports primarily due to the nature of

the underlying disease being treated.

This list includes the various drugs,

procedures, and medical conditions which

theoretically could have some effect on bone and

increase the risk of ONJ.

Spontaneous reports, as frequently

happens, had missing information, which was also

true in this case series.

A clear assessment of the drug dechallenge

was limited by the fact that these drugs persist in

bone, and the duration of action is prolonged, so

even though the drug is stopped, the actions

persist, and a prolonged period would be required

166

to determine whether the patient completely

recovered.

Many patients required therapeutic

interventions, so this confounds evaluating whether

the only factor in the patient recovering was, in

fact, stopping the drug.

Time to onset was also difficult to

evaluate in that the detection of ONJ was often at

a later stage, for example, when a dental

extraction was conducted, but failed to heal.

We didn\'t search for cases where possible

early symptoms were present, such as jaw pain or

tooth loss, but no definitive diagnosis had been

made. That was beyond the scope of the search.

Information on the early symptoms was missing in a

number of cases.

Now, I will present Carolyn\'s remarks on

the epidemiological perspective of studying this

condition.

Studying osteonecrosis of the jaw is the

challenge and even more so with these drugs. It is

a rare event and obtaining a population background

167

rate for comparison is difficult, and it is

especially difficult for multiple myeloma and

breast cancer patients.

The difficulty in identifying ONJ cases in

existing databases is that ONJ does not have a

specific code for searching a database. For

example, there is no specific ICD-9 code for ONJ.

It is also difficult to determine an

accurate number of patients exposed to IV

bisphosphonates due to the fact that many are given

in free-standing clinics.

Finally, it will be difficult to identify

an equivalent cancer control or comparison group

for study of ONJ associated with the IV

bisphosphonates.

Some potential sources of data include

oncology clinics, which could provide a cohort of

patients exposed to IV bisphosphonates. A

potential source for determining a more accurate

count of cases could be dentists and oral surgeons.

Dentists could provide cases of dental or jaw

infections, jaw pain, or osteomyelitis of the jaw

168

regardless of drug exposure.

A national registry could provide a means

to collect all cases of ONJ identified in different

settings.

To summarize the epi perspective, there

are limitations in identifying and capturing cases

and quantifying IV bisphosphonate exposure in

electronic, pharmacoepidemiological and

post-marketing surveillance data including HMOs and

passive reporting databases.

Chart review studies at major medical or

cancer centers have their own limitations in

capturing all ONJ cases with these products.

Obviously, a randomized, controlled

clinical trial would be superior to studying this

in currently available databases, however, there

are limitations to controlled clinical trials

especially since this condition is rare.

A national registry of ONJ cases should be

considered.

To conclude, in spite of the limitations

of the available drug safety tools, we believe that

169

these cases present a highly plausible safety

signal. Some of the reasons for this are most of

the cases that have been reported affect the jaw,

lending plausibility to a specific or common

mechanism.

A large number of reports of a generally

rare event have been received. The duration of use

of the drug relative to diagnosis of a chronic

condition is fairly short, and serious adverse

event reports tend to be captured well in AERS.

We would suggest that other studies be

conducted to attempt to identify which patients may

be most susceptible or if modification to treatment

regimens would reduce the risk.

Thank you.

DR. MARTINO: Ms. Pamer, on behalf of the

committee, I need to ask you to clarify some things

for me.

Can you give me a better understanding of

who tends to report or who has the ability to

report toxicities to the FDA system? I am assuming

it\'s patients, I am assuming it\'s physicians. Are

170

pharmaceutical data also incorporated into that?

MS. PAMER: Many of the reports we

received are reports that have come to the company,

and then the company is required to send those to

FDA, and patients, there are means through the

Internet. You can also report directly to FDA

through Med Watch. So, this is the Med Watch data

collection system.

DR. MARTINO: So, anyone is able to access

the system. In general, where does most of the

information come from, is it physicians, is it

pharmaceuticals, or is it individual patients? In

general, I am asking you, not specific to this

toxicity.

MS. PAMER: Most of reports are, and in

this case series, most of them were dentists,

M.D.\'s, or oral surgeons. They might have reported

first to the company, but they come to us, but they

are mostly health care providers.

DR. MARTINO: So, a patient would be the

least likely person to report directly to you, do I

understand that correctly?

MS. PAMER: Less frequently they do, but

it depends. There are some issues where they

report a lot through the Internet.

171

DR. MARTINO: So, once someone initiates a

report, I am assuming that there is information

that is requested from them, that gives you certain

details. Is there any human interaction to then

get additional data, or what is the extent of what

is obtained from such a report?

MS. PAMER: Probably the company could

give you an idea of how they collect the

information on how their system works.

DR. MARTINO: My question\--I may ask the

same question of them\--but my question of you is,

the FDA system is really the one I am interested

in, once I, as a human being, report that I have

had a toxicity, I am assuming there is some

questions I will be asked to answer, who are you\--

DR. AVIGAN: Can I just participate?

DR. MARTINO: Can someone help me?

DR. AVIGAN: Yes.

DR. MARTINO: Thank you.

DR. AVIGAN: We actually have a number of

avenues by which we can address those issues, when

a signal is seen and there are questions that are

raised that require follow-up, we have the

opportunity to ask the manufacturer, the company,

to go and do sort of specified follow-ups through

172

discussions that we would have with them.

Another approach is that on particular

issues, we can contact the reporter, the reporters

are listed in our Med Watch form, and get direct

follow-ups from them. So, I would say that there

are a number of possibilities, and these are

generally conceived of based on the case at hand.

The retrospective look at safety problems

typically is limited, because you don\'t get

information in real time, and there is a general

problem of getting a full plate of information on

particular cases when you are going retrospectively

to cases that have been reported about previous

events.

DR. MARTINO: That does answer my

question. Help me to understand what would

173

stimulate the system to recognize that there is a

potential problem. I am assuming that all kinds of

things get reported to you and somehow someone has

to sift through what is noise and what do you sort

of focus in on. Answer that for me, please.

DR. AVIGAN: Right. It really is on a

case-by-case basis, and I think Carol has outlined

some of the points that would raise our concerns

about a signal being truly linked to a risk and a

causally related event.

Some of the points are that the event that

is being reported has a low background rate or

would not be necessarily expected to occur in the

kind of cluster that it is being reported at. So

the background effect, the temporal association,

and then the quality of the cases themselves.

In addition to the counting of the total

aggregate of cases, we actually with specificity

look at individual cases, and some cases based upon

the information that is provided allow us to create

a kind of probability analysis of causality, so

that it is a different dimension of looking at the

174

question of is the drug going to the specific

adverse event.

In this case, one of the features of this

particular adverse event is that the anatomical

site specificities are quite striking, that is, the

osteonecrosis search is not anatomically specific,

but when we pull the cases and look at what these

reports are, they are very, very strongly, well,

biased.

Most of the cases actually are of the jaw,

which would be different than, let\'s say, an

osteonecrosis search for the general background

population or for other medications. As an

example, that would point towards a signal, for

example.

DR. MARTINO: Thank you.

Next, Dr. Brian Durie from Cedars-Sinai

will discuss Osteonecrosis of the Jaw in Myeloma:

Time Dependent Correlation with Zometa and Zometa

Use.

Osteonecrosis of the Jaw in Myeloma: Time

Dependent Correlation with Zometa and Zometa Use

DR. DURIE: Members of the Committee,

ladies and gentlemen, I appreciate the opportunity

to present these data to you today. These data

175

were presented at the American Society of

Hematology in oral session in December and will be

published shortly.

The basis for these studies feeds in

exactly with the discussion that was just being

held. This is a study that was conducted as a

collaboration between the International Myeloma

Foundation, which is a nonprofit entity based in

California, and Cancer and Research and

Biostatistics, which is the research entity run by

John Crowley. Many of you will know that that is

the stat center for the Southwest Oncology Group.

So, this is a collaboration between the

IMF and a rather well-known statistical group.

The International Myeloma Foundation

provides a number of functions. One of them

relates to patients, and that is an educational

function, and that is serviced by an 800 hot line,

and it is serviced by a variety of seminars that

176

are held across the country, as well as help to

support groups.

So, in terms of receiving a signal, if

something unusual is happening, and patients want

to find out, they are quite likely to call our 800

number. So, we are one of the first people who

might hear about a new problem that is emerging.

In this particular study, I would like to

emphasize one other point, and that is that the

purpose here was to try to identify individuals

with osteonecrosis of the jaw, and so we could

evaluate and understand these cases.

We were not in a position to evaluate the

denominator for these studies, so this is not a

study related to the incidence. It is a study

related to an analysis of patients who actually

have this problem.

So, just to show you visually, well, what

is osteonecrosis of the jaw, and these pictures on

the left were provided by Sal Ruggiero, who is

present here today on my right, and was the first

person to report a case series of 63 patients in

177

the Journal of Oral and Maxillofacial Surgery.

So, it covers a spectrum. The first part

of the spectrum is exposed bones, bone spicules.

The end of the spectrum is where there has been

significant underlying osteonecrosis of the jaw,

which can indeed be a substantial problem which

involves poor healing, secondary infection, and

loss of teeth, and in some cases, significant parts

of the jaw.

There are several mechanisms that have

been proposed linked in with this related to the

disruption of the bone remodeling cycle.

So, how frequent is osteonecrosis? As you

have heard, we do not really know the true

incidence of this except that it was rare in the

past, and it is very clear that it was rare in the

past and now we are seeing it.

Our 800 number is ringing. Patients are

coming in to see dentists and oral surgeons. This

was not happening before for myeloma patients. Dr.

Marx reported his first 36 cases in 2003. Dr.

Ruggiero, who is right here, reported his patients

178

in 2004. Those were 63 patients that were

diagnosed between 2001, February, and 2003.

Of note, there are two aspects about his

patients. They did include some patients that had

been treated with oral bisphosphonates, the

majority with IV bisphosphonates. They did include

a few patients who did not have cancer, patient who

had osteoporosis only.

Here, more recently, in myeloma groups

around the country, clearly, we are seeing many

more of those patients. At the patient seminars

that I mentioned earlier, these are seminars where

1- or 200 patients would be present at a time.

Consistently now, there are 5, 10,

sometimes more patients in the audience who have

osteonecrosis, and this translates in that setting

to maybe 2 to 5 percent of the people who are in

that setting. How that translates to the wider

population, I don\'t know.

For me, this was a very important

opportunity because it allowed me to structure the

questionnaire that I am going to show you today. I

179

had met a lot of patients who had osteonecrosis of

the jaw. I understood how it had come to

attention, how it manifested.

I knew, for example, that most of them

knew that they did, in fact, have osteonecrosis of

the jaw. They had seen a dentist, they had seen an

oral surgeon. They knew what that was, so they

could answer that question yes or no.

So, was this a diagnosis missed prior to

2001? I think not. Certainly from the bottom

picture that I showed you, this is not something

that would go unnoticed.

What has caused the increased frequency?

Well, both Dr. Marx and Dr. Ruggiero certainly drew

attention to the bisphosphonates.

So, what are the questions right now?

From our perspective in this questionnaire, we

looked at is the likelihood of osteonecrosis ONJ

linked to the use of the Aredia and Zometa in the

patients that responded to our survey, to what

extent were other therapies impacting the frequency

and the likelihood, were there identifiable risk

180

factors, what was the magnitude or severity of the

problem, and what we thought was quite important

was is this a problem confined to myeloma, is it

more common in myeloma versus, for example, breast

cancer.

So, we surveyed both myeloma patients and

breast cancer patients, which is important in one

particular aspect, and that is that the treatment,

the other treatments for breast cancer and myeloma

are obviously quite different. For example breast

cancer patients are not frequently treated with

thalidomide and high-dose dexamethasone.

So, this was an anonymous web-based survey

that was conducted in August of 2004. It included

1,203 patients, of which 904 had myeloma, 299 had

breast cancer. They were recruited by a variety of

electronic means - through the IMF web site,

through ACOR, but also through a number of

established listservs, Nexcura and Y-Me, National

Breast Cancer Organization.

A number of very, very specific questions

were asked with pop-downs where it was possible to

181

select a variety of answers.

The setting for this, in structuring the

questions, was the treatments that are available

for myeloma. The therapies have mostly been

available for several decades, and you can see

here, starting at the bottom, Melphalen and

prednisone, radiation therapy including sometimes

to the head and neck available for a long time.

Steroids have been used for several decades, stem

cell for two, three decades now.

At the top here, you see really three

types of agents that have been available more

recently: the bisphosphonates, thalidomide, and

Valcade. Valcade has been available sufficiently

recently that it is not really an issue. So, we

focused on thalidomide, bisphosphonates, and

steroids primarily as potential risk factors, but

we looked at all of these therapies.

Of 1,203 patients, 904 myeloma, there were

62 myeloma patients who had osteonecrosis of the

jaw. There were 54 who, in addition, these are 54

additional patients who had suspicious findings.

182

These were patients who had not been given a

diagnosis of osteonecrosis of the jaw, but had

suspicious findings that we identified as bone

erosions, bone spurs, or exposed bone. These were

specific questions that were asked.

For breast cancer, 13 with a diagnosis of

osteonecrosis, 23 with 1 or more of the suspicious

findings.

The first thing that we noticed was that

it was more likely for osteonecrosis to occur over

time. In this case, it was from the time of

diagnosis. You will see I used different time

markers here. This one is time from diagnosis. We

also looked at the time from the start of

bisphosphonate therapy, for example.

You will see this curve has got two parts

to it, a very shallow curve here, and then a

sharper part to the curve here. So, this is what

we decided to investigate in more detail.

The first thing that we looked at was the

time frequency over the last few years, 57 patients

where we had data. These are the number of cases

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in 2004, 321. There were cases in the past. There

were patients related to head and neck irradiation.

The same pattern for breast cancer. You can see a

striking increase in the last 2 1/2, 3 years.

This shows you the frequency of use of

other therapies in addition to the bisphosphonates.

You can see here the 62 patients, myeloma,

osteonecrosis of the jaw, 57 had been taking

bisphosphonates, 3 had head and neck irradiation,

so there are actually 2 patients who had not had

head and neck irradiation or were taking

bisphosphonates.

You can see there was a pattern of Aredia

and Zometa use as listed here. We are going to go

into that in more detail. A majority of patients

had obviously used steroids, some prednisone, some

dexamethasone, and about half the patients had

taken thalidomide at some point.

This shows you the increasing incidence of

osteonecrosis among the respondents from the date

of diagnosis, looking at the use of Zometa, Aredia

alone, patients who had been taking Aredia, but

184

switched over to Zometa when it became available,

and those who had not taken any bisphosphonate.

You can see the little blue one over here.

We are going to look at that in more detail. That

is Zometa, which represented 22 percent of the

patients, 28 percent to Aredia alone, 45 percent

had actually switched over from Aredia to Zometa.

So, interestingly, this occurred more frequently in

this series and patients who had switched from

Aredia to Zometa.

We were quite interested in the time to

the onset in the two major groups there, and this

was quite striking. Patients who had been taking

Zometa, the average time, the mean time 18 months

to the onset of osteonecrosis, 19 months to the

onset of suspicious findings. Aredia, 6 years, 72

months, somewhat shorter, to the onset of

suspicious findings.

Now, obviously, we realized that these

drugs have not been on the market the same length

of time, so we have done some corrections related

to that, that you will see in a moment. This is

185

obviously statistically different.

This just shows you visually, the blue is

Zometa, the red is Aredia, for myeloma and for

breast cancer. The patients were more frequently

either taking Zometa or switched over to Zometa at

the time that they developed the osteonecrosis or

the suspicious findings.

In this case, we looked at the exact

length of the treatment with Aredia or Zometa with

respect to the likelihood of getting osteonecrosis

of the jaw. Again, you can see there is a

difference related to Zometa or those who switched

from Aredia to Zometa versus Aredia alone.

In all three cases, obviously, it is going

up over time, of course.

Now, to compensate for the fact that the

Zometa has only been on the market for three years

at the time of our study, we censored the data at

three years and compared Aredia with Zometa with

three-year censoring and looked at the log rank p

value estimates at 36 months.

Zometa is in blue, and you can see here

186

that it occurred more frequently. I think that

what caught our attention, and our concern

actually, was this is 12 months right here. You

can see that there were clearly patients having

osteonecrosis of the jaw within the first year of

therapy, the mean value was 18 months but certainly

cases occurring within the first 6 to 12 months.

We looked at other factors. This compares

patients who had been taking prednisone and not

taking prednisone. You can see that these are the

events here. No difference in the likelihood with

and without prednisone, although in a variety of

other studies, there was some increased risk in

patients concomitantly taking steroids, but this

did not play out over time.

We also looked at thalidomide and

dexamethasone, and again there were some

suggestions that patients taking thalidomide and

dexamethasone were at higher risk, however, this

did not play out in the time dependent regression

analyses, so that both for thalidomide and

dexamethasone, there was no difference using the

187

log rank method.

So, what suddenly occurred to me was,

well, why did we start to see this problem in 2001,

and I suddenly realized when I was looking at the

statistics that 6 years is the average time to the

onset with Aredia, well, 6 years is the time since

Aredia came on the market, 18 months is the time

for Zometa. Well, that is the time since Zometa

has been on the market.

So, there is a coincidence of time frames

here related to the time since these agents have

been in the marketplace.

There is one other very important point,

and that is that 6 years of Aredia, how many

patients with myeloma are alive and could be taking

Aredia for 6 years. Well, obviously, that is less

than 20 percent of the patients. So, the number of

patients at risk taking Aredia at 6 years is much,

much lower.

Just to compare the data with myeloma and

breast cancer, since the therapies are so much

different, there was no difference in the

188

likelihood with censoring at 3 years between the

breast cancer patients who responded and the

myeloma patients who responded.

However, if you looked at Zometa and

Aredia, the difference persisted. It was much more

likely that Zometa could be associated with

osteonecrosis or suspicious findings early in both

myeloma and breast cancer.

What were predisposing factors? It was

quite striking and has been emphasized by several

speakers that the predisposing factor is prior

dental problems including surgery and all kinds of

dental issues, and here a very striking difference.

Patients likely to get this problem are highly more

likely, with myeloma and breast cancer, to have had

underlying dental problems.

So, among the respondents, duration of

therapy is clearly an increased risk factor. With

the 36-month estimates, Zometa is more likely than

Aredia to be associated with osteonecrosis.

None of the other therapies in the time

dependent analyses impacted this likelihood.

189

Patients with prior dental problems were much more

likely to develop osteonecrosis of the jaw.

Our preliminary working conclusions, and

people are going to be able to discuss elements

that might derive from this, but clearly,

precautions related to dental care could impact the

likelihood of this disease, and obviously,

precautions related to bisphosphonates could impact

the likelihood of this problem.

I would like to thank the groups and

individuals who participated in this project,

particularly the organizations who contributed

patients, the statistical center, and particularly

Vanessa Bolejack, who did the statistical analysis.

Thank you.

DR. MARTINO: Thank you, Dr. Durie.

I would now like to turn to Novartis and

ask Dr. Young to present their data.

Sponsor Presentation - Novartis Pharmaceuticals

ONJ Reported in Bisphosphonates Treated

Patients - An Overview

DR. YOUNG: Good morning. I am Dr. Diane

190

Young, Vice President of Clinical

Development-Oncology at Novartis. I am an

oncologist by training.

I would like to start by thanking the

Chair, ODAC panel members, as well as the FDA today

for the opportunity to share our current

understanding of an important clinical entity,

osteonecrosis of the jaw. There has been an recent

increase in awareness and interest in this

condition due in part to the efforts of Drs.

Ruggiero, Marx, and Durie, as well as the FDA and

Novartis.

In this presentation, I will provide an

overview of the ONJ cases reported in

bisphosphonate-treated patients. This will be

followed by a perspective on the benefit-risk of

bisphosphonates in patients with metastatic bone

disease by Dr. James Berenson.

Allow me to recognize the advisors that

are here with us today to help answer questions

that may come up during the discussion. It is

important to note that while these external

191

advisors have been invited by Novartis, the views

that they express here are their own views, and not

those of the company.

Dr. Ana Hoff from the M.D. Anderson Cancer

Center is the principal investigator on a chart

review that is ongoing in cases of ONJ in

bisphosphonate-treated patients. Dr. James Berenson

from the Institute for Myeloma and Bone Cancer

Research.

Dr. Regina Landesberg, Assistant Professor

of Oral and Maxillofacial Surgery at Columbia

University. Dr. Lloyd Fisher, Professor Emeritus

of Biostatistics from the University of Washington.

Dr. Salvatore Ruggiero, Chief, Division of Oral and

Maxillofacial Surgery at Long Island Jewish Medical

Center.

This is an overview of my presentation.

Importantly, Zometa and Aredia have delivered

significant benefits for patients with multiple

myeloma and metastatic disease from solid tumors,

reducing significant morbidity from the serious

complications that these patients experience

192

related to bone involvement from their tumors.

Novartis has actively examined cases of

osteonecrosis of the jaw since we received the

first spontaneous reports in December of 2002.

In spite of this, ONJ remains a poorly

understood entity. Frequency estimates vary wide,

however, based on available data it appears to be

infrequent in cancer patients on bisphosphonates.

Additionally, the anecdotal and limited

nature of the available data makes it hard to draw

conclusions about causation or any difference

between Aredia and Zometa.

Novartis takes reports of ONJ very

seriously and we are committed to ensuring patient

safety. We will do this through conducting further

studies to increase our understanding of the

condition, communicating our findings, and

identifying strategies to prevent and optimally

manage this problem.

The benefits of Zometa and Aredia in

reducing the significant morbidity associated with

complications of bone disease in cancer patients

193

remain highly favorable when considering the risk

of ONJ.

As the panelists are aware, metastatic

bone involvement by cancer is a prevalent condition

and causes serious consequences for patients with

advanced cancer. The complications of bone

metastases cause considerable morbidity including

pain, impaired mobility, pathologic fracture,

spinal cord or nerve compression, and hypercalcemia

of malignancy.

Zometa and Aredia help people living with

cancer avoid or delay painful and debilitating

complications of metastatic bone disease. As Dr.

Scher noted in her presentation, Aredia and Zometa

have been both shown to be effective in the

treatment of bone metastases in multiple myeloma

and breast cancer.

Zometa has been further shown to be

effective in prostate cancer, where Aredia was not

effective, and in other solid tumors, such as lung,

renal, colorectal, and bladder cancer. The

benefit-risk of IV bisphosphonates is well

194

established. Risk of renal impairment is

manageable in most cases by monitoring creatinine.

Based on this profile, Zometa and Aredia

have become the standard of care and are

recommended in ASCO guidelines for the management

of multiple myeloma and metastatic breast cancer

patients with bone lesions.

I will begin my review with osteonecrosis

as a general clinical condition before focusing on

the jaw. Osteonecrosis is a better known clinical

entity most commonly seen in the hip. The etiology

and pathogenesis are not well understood.

The common precedent is impaired blood

supply leading to ischemia of bone. Osteonecrosis

has been associated with a variety of risk factors,

and is generally felt to be a multifactorial

process. Cancer patients are at particular risk of

developing osteonecrosis.

In a search of the general practice

research database in the UK, the incidence of

osteonecrosis in cancer patients was 4 times higher

than in the general population. Coagulopathy is

195

another risk factor as are treatments, such as

corticosteroids, radiation therapy, and

chemotherapy.

Interestingly, there are preclinical data

and clinical data to suggest a role for

bisphosphonates in treatment of osteonecrosis of

long bones. There is a series of 16 patients with

osteonecrosis of the hip who had improvement after

12 weeks of alendronate by Agarwala, et al.

Osteonecrosis of the jaw has been less

frequently described and the incidence in the

general population is not known. The pathogenesis

is not well understood, although similar risk

factors to osteonecrosis have been suggested in the

literature.

It is important to note that there may be

risk factors that are specific to jaw bones that

may play a role of pathogenesis of osteonecrosis of

the jaw. Exposure to the external environment and

particularly infectious agents through the teeth is

one issue. In addition, there is repeated trauma

from dental procedures, and lastly, the oral cavity

196

is an area where the bone is covered by a

relatively thin mucosal layer, which is subject to

trauma.

ONJ in cancer patients is a condition of

which there is limited awareness until recently.

The incidence of ONJ in cancer patients is unknown.

There were a few case reports of ONJ in

cancer patients that occurred with chemotherapy,

and not with bisphosphonates, in the literature

prior to 2003. Another condition,

osteoradionecrosis, related to head and neck

radiation has been frequently described with a

reported incidence rate of 8.2 percent.

Novartis received the first spontaneous

report of ONJ in an IV bisphosphonate-treated

cancer patient in December 2002. The first series

of such cases were published in 2003 by oral

surgeons who were treating these patients.

Since these reports, we have been

investigating these cases to better understand this

clinical problem.

There are four data sources available

197

regarding ONJ that I will briefly review today -

the Novartis clinical trials, spontaneous reports

that have been made to Novartis, literature, and a

retrospective chart review that is ongoing at M.D.

Anderson.

Before reviewing the data, I want to point

out that there are significant limitations in these

data sets which make it difficult to draw

conclusions about many aspects of ONJ.

Controlled clinical trials offer generally

reliable, quality assured, source verified data.

The Novartis clinical trials which I will discuss

were conducted prior to 2001, at a time when there

was little awareness of ONJ. In addition, the

median follow-up for these trials is about 5 to 13

months, and we plan to update this follow-up as

part of the investigation.

The spontaneous report database, as

expected and as explained well by Dr. Pamer, may

have incomplete information, as well as diagnostic

selection and reporting biases.

The existing literature is mostly case

198

series. In many cases, the data are incomplete.

In addition, there was the web-based survey

presented today, which does have some methodologic

limitations which I will discuss later.

The M.D. Anderson Cancer Center study is a

retrospective chart review of over 4,000 charts of

patients who have received bisphosphonate therapy,

looking for cases of ONJ at a single center. It is

ongoing at the present time.

In addition, there are a number of issues

which may confound interpretation of all these data

sets. The impact of a recent increase in awareness

may affect the numbers and types of reports

received, the lack of consistency across these data

sets in terms of case definition, and there have

been other changes in treatment of cancers that may

have a possible impact during the same time period.

Let us look first at our clinical trials.

We did a retrospective search of the clinical trial

database to identify cases of ONJ, since this had

not been identified as any sort of adverse event

that we noticed during the study conduct.

The lack of clear definition of ONJ poses

a challenge to identifying these cases in a

clinical trial database. This shows the process

199

that Novartis uses to identify potential cases of

ONJ from the clinical trials database and the

spontaneous reports database.

There is no current MedDRA term for ONJ,

so in order to screen for potential ONJ cases,

Novartis used a wide net of 18 MedDRA terms as

shown. Cases that resulted from this screening

were medically reviewed to identify cases of ONJ.

This is the current working definition

that Novartis uses to identify potential ONJ cases,

any of the findings shown here with a suggestion of

maxillofacial area involvement. This is a fairly

broad range of terms because we want to err on the

conservative side and attempt to capture as many

cases as we can.

The next two slides show, in summary,

pivotal trials that have been screened for ONJ, and

also shows the trials where the ONJ cases were

identified, because we actually did identify 6

200

cases consistent with this definition in this

search.

The first 3 trials are the

placebo-controlled Aredia trials in the bone

metastases indication. The median duration of

follow-up for these trials was 10 to 18 months. One

case was identified in the multiple myeloma trial

on an Aredia arm.

007 was a dose-finding study for Zometa in

bone metastases that had an extension phase\--I am

sorry, that is with Aredia. Two cases of ONJ were

identified in the study in multiple myeloma

patients, one in the Zometa arm and one in the

Aredia arm.

036 and 037 were hypercalcemia malignancy

studies comparing Zometa to Aredia. A single case

was identified in this study on the Zometa arm.

Study 10, 11, and 39 were the pivotal bone

metastases studies for Zometa. The median

follow-up was 5 to 14 months in these studies. 10

was the study that was mentioned, a non-inferiority

study in breast cancer and myeloma comparing Zometa

201

to Aredia. A single case was identified in the

Zometa 4 mg arm of the study.

704 was a placebo-controlled study

evaluating prevention of metastases in

hormone-refractory prostate cancer without bone

metastases. A single case of possible ONJ was

identified in the Zometa arm.

The 6 cases are for simplicity displayed

by treatment received. Please note that the dose

groups shown reflected the trials previously. It

is a variety of trials with different follow-up

periods, and these are not balanced per se for

tumor type or indication on bone mets versus

hypercalcemia, but, in general, if we are looking

at it, we did not see any cases in 1,347 patients

treated with placebo.

We saw 2 cases of ONJ out of 1,334

patients treated with Aredia, and 4 cases of ONJ

out of 2,730 patients treated with Zometa. It is

important to note that all of these cases were

described as non-serious by the investigators.

The next two slides show clinical findings

202

in these 6 cases. In the first column, we show the

tumor type, and then the diagnosis, and the site,

as well as the year that the case occurred, the

drug, the time to event, risk factors, and the

severity grade and outcome.

Note that when we look at the case

description, that 2 cases were called osteomyelitis

and 1 was aseptic necrosis. Because of lack of

definition, it is really not clear if all the time

these represent the same clinical entity, but we

capture all these cases.

Interestingly, there were clearly cases

similar to ONJ that occurred prior to 2002 in these

clinical trials, one in 1992, 1999, so they are

rare, but I mean there were cases that were similar

that did occur.

The 2 Aredia cases shown here had a time

to onset to ONJ of 28 months and 14 months. The

time to onset of Zometa cases shown here and on the

following slide were 14, 22, and 22 months.

Also noted is that spectrum of severity is

seen in these cases. All events were initially

203

graded mild to moderate. Two cases of out of these

6 progressed to Grade 3 and had more severe

outcomes, such as mandibular fracture and a

mandibular excision reported on the next page.

The others were listed as stable or

unknown at the end of the study.

Case No. 4 is a head and neck patient who

reportedly developed ONJ 13 days after a single

dose of Zometa for hypercalcemia malignancy. These

was no information in the case report on whether

this patient had radiotherapy, but that is

something that we are looking into since it seems

likely given the history of this patient.

We used the same method described to

search all completed trials for cases of ONJ. We

did not identify any cases in 3,217 patients

treated with Zometa or any cases in 1,214 patients

treated with Aredia. There are more than 10,000

patients enrolled in ongoing studies, and to date,

4 cases of ONJ have been reported in these trials,

all with a dose of 4 mg of Zometa. These cases are

shown on the next slide.

These cases have occurred in 2 patients

with breast cancer, 1 patient with prostate cancer,

and 1 patient with multiple myeloma. All of these

204

cases reported pre-existing dental problems

including pre-existing osteomyelitis of the jaw.

The next data category we will review is

from the spontaneous reports received by Novartis.

These are the total number of spontaneous reports

that Novartis had received as of the cutoff date

for our report of December 7, 2004, at the top.

These include both cases that have been

reported, as well as the reportable cases from the

literature, and there can be duplication at times.

As of the December 7th cutoff, there were 610

cases, 119 in Aredia-treated patients, 248 in

Zometa-treated patients, and 243 who were treated

with both agents, generally Aredia followed by

Zometa.

Most of these cases have been reported in

the U.S. There have been 218 reports in multiple

myeloma patients, and 125 reports in breast cancer

patients. To put these numbers into context, there

205

have been 1.9 million patients treated with Aredia

since 1991 and 1 million patients treated with

Zometa since 2001.

It should be noted that almost no Aredia

is currently used in the U.S., having been replaced

largely by pamidronate generic, and also the Zometa

use has been increasing recently since the

approval.

All analyses that are subsequently

presented are related to the 610 cases. For

completeness, we wanted to include the current

number of case reports as of February 22nd, which

number 875.

We believe that the increase in cases is

due to the increased awareness related to

communications on ONJ during the fourth quarter

last year, such as the Dear Doctor letter, there

was press coverage. There were reports at

scientific meetings, and we believe that is what

this is related to, but we have to watch the

pattern closely.

We looked at all these cases. This is the

206

610 cases for known risk factors of osteonecrosis.

While available data can be limited in many of

these case reports, 74 percent reported at least 1

risk factor in addition to cancer diagnosis,

corticosteroids in 38 percent, chemotherapy in 52

percent, thalidomide in 15 percent.

Twenty-eight cases had radiotherapy to the

head and neck area, and probably have

osteoradionecrosis instead of this condition of

ONJ. Three cases had reported herpesvirus

infection of the maxillofacial area, a reported

cause of ONJ in non-bisphosphonate treated patients

in the literature, and 4 percent of reports had

documented actinomyces infection.

In 50 percent of the cases, dental events

were reported to precede the diagnosis of ONJ, with

tooth extraction being the most common. Many of

the reports were incomplete for this kind of

information.

This shows the limited information that is

available from the spontaneous report database

regarding reported outcomes of ONJ, and relates

207

this to whether or not the patient continued

bisphosphonate therapy. I present this although it

really is difficult to draw conclusions from this

data.

There were only 224 cases which had

sufficient information. If you look at the last

column, which is the total number of accessible

cases, about 20 percent of these cases are reported

as recovered or improved. Forty-one percent are

reported as no change, 8 percent reported as

deteriorated, with 30 percent being unknown, a

category which includes recovered with sequelae.

When we look at the impact of changes in

bisphosphonate therapy, whether it is continued or

discontinued, there are really not major

differences in the groups that stand out. Of those

who continued bisphosphonates, 26 percent were

reported to have recovered and 14 percent had

worsened, while for those who had discontinued

bisphosphonate, 18 percent recovered, and 6 percent

deteriorated.

Unfortunately, this data does not really

208

allow us to conclude whether continuing

bisphosphonate therapy has an impact on the course

of ONJ, and further study of this question will be

needed.

In the spontaneous report database, it

appears that the mean time of onset, defined as the

time from initiation of bisphosphonate therapy

until the onset of ONJ, is longer for Aredia than

for Zometa.

We believe that a direct comparison of the

time to onset for Zometa and Aredia is not feasible

in this data set. Some of the problems have been

talked about already. We don\'t have a common

definition of ONJ or onset of ONJ.

There is this different pattern of product

usage. Aredia has been available for a much longer

time, while Zometa has only been available for

2001\.

The utilization of Aredia has declined

significantly, while utilization of Zometa is

increasing, and the recent increase in awareness

could have accelerated the diagnosis of ONJ. In

209

addition, concurrent therapy has changed

significantly over time with the contribution of

this unknown.

I will now comment on literature reports

of ONJ. This chart summarizes the reports of ONJ

that have appeared in the literature and which Dr.

Scher has already mentioned. I just wanted to

highlight two of these reports.

First, as Dr. Ruggiero has the largest

series of these cases reported, I wanted to briefly

mention his findings. He describes 63 cases of

patients who had received bisphosphonate therapy

and developed osteonecrosis of the jaw.

His results as far as a description of

these cases are generally consistent with what I

have reported from the spontaneous report database

in terms of demographics and reported risk factors.

The bisphosphonate use reported in his

series was 57 percent Aredia, 31 percent Zometa,

and 12 percent others, which included 7

alendronate, and 1 resedronate. The majority of

his cases required surgical removal of involved

210

bone in this series.

I also wanted to comment on the study by

Dr. Durie and his colleagues which was presented

today. This was a web-based survey, which has

underscored the clinical issue of ONJ in patients

taking bisphosphonate, and raised a number of

interesting questions.

There are a number of methodologic issues

inherent in the type of survey which limit the

ability to draw conclusions. First, the survey

participants were anonymous and therefore data

cannot be source verified.

In addition, there are biases with the

survey methodology. Patients who have an event are

more likely to respond as are patients with more

recent events, and lastly, as discussed with our

own post-marketing database, calendar time is

really a confounding factor because of the

different durations that Aredia and Zometa have

been on the market.

The analyses were not adjusted for

calendar time, so caution needs to be used in

211

interpreting these.

Lastly, I would like to review early data

from the M.D. Anderson Cancer Center chart review.

To obtain more information about the incidence,

clinical features, and natural history of ONJ,

Novartis is supporting a retrospective chart review

at M.D. Anderson Cancer Center with Dr. Ana Hoff as

the principal investigator, and Dr. Hoff is with us

today.

M.D. Anderson Cancer Center is a large

institution with access to complete pharmacy,

clinical and dental records. In this study, all IV

bisphosphonate users have been identified by the

pharmacy, as well as all charts with a diagnostic

code consistent with ONJ in the past 10 years,

4,032 charts have been identified.

Dr. Hoff provided us with the results of

the review of the first 25 percent of the charts

because we were coming to this meeting today, and

this was non-random review at this time.

Because of the way that the charts were

sorted by the pharmacy, patients with the greatest

212

number of bisphosphonate infusions were reviewed

first, and, in addition, there were 7 cases that

were reviewed out of sequence because they were

suspected to have ONJ.

There were 18 cases of ONJ identified in

the first 963 charts reviewed. Out of 631 patients

with breast cancer, 11 ONJ cases were identified.

ONJ cases were identified in 6 out of 148 of charts

with multiple myeloma. Another case was seen in a

medullary thyroid cancer patient.

The time from the first bisphosphonate to

ONJ was a broad range, from 4 months, which was an

Aredia-treated patient, to 57 months, Aredia

followed by Zometa in this case.

In these 18 cases, 4 patients received

Aredia only, 3 received Zometa only, 1 received

alendronate followed by Zometa, and 10 received

Aredia followed by Zometa.

We look forward to getting additional

results of this study, and Dr. Hoff may be able to

comment on her opinions of the findings.

We wanted to look at what is the frequency

213

of ONJ, what do we know about this right now. The

background incidence of ONJ in

bisphosphonate-treated patients is not know, nor is

the incidence in cancer-treated patients in

general.

The estimates of frequency from the

various data sets vary significantly, and as we

have discussed, there are many caveats, so we

really don\'t know what the incidence is. The

spontaneous report database, which is certainly

underreported, provides a reporting rate of 0.03

percent if we consider the current patient numbers.

This is certainly an underestimate.

At the other extreme is the web-based

survey, which is most likely an overestimate in

which 6.2 percent reportedly had ONJ.

In the controlled clinical trials, 0.15

percent of patients had suspected ONJ cases. The

median follow-up of these trials is 5 to 18 months,

and they were conducted in a time when there was no

awareness of ONJ.

It is too early to assess the incidence

214

from the M.D. Anderson study as the review is not

yet complete, but in the current data, the rate is

1.9 percent.

ONJ and bisphosphonate-treated patients is

not yet well understood due to the significant

limitations in the data sets that are available.

There is no common definition of ONJ in the various

reports, nor are there common staging or severity

measures to allow objective evaluation across

different series of cases. Diagnostic criteria are

not yet established, and information on the natural

history of disease is not available.

It would be very interesting to know how

long it takes the clinical picture to develop, are

there any early changes that precede the

development of ONJ that could guide prevention

strategies. These are really critical questions.

There is no common treatment algorithm

either how to manage ONJ or what to do with the

bisphosphonate therapy, and lastly, we do not have

an understanding of what factors are causing this

to happen in a small number of cancer patients

215

receiving bisphosphonates. Further investigation

is needed to answer these questions.

Novartis has taken these reports

seriously, and we have undertaken a number of

initiatives to better understand ONJ and to

communicate findings to physicians and patients.

This slide summarizes activities since the

first spontaneous reports were received. Our

activities have focused in three areas. First, was

to ensure patient safety by making sure that the

package insert reflected the evolving information

on this newly-described event. The first update to

the label occurred in August 03, a second update in

March 04, and the precaution was added in September

of 2004.

Secondly, it was to learn more about the

cases. We have actively followed up on many of the

cases that have come into the spontaneous report

data set. We can talk about our methodology, if

you like, and we have been actively trying to

collect additional information.

This is extremely challenging as many of

216

the cases are recognized and treated and reported

by oral surgeons and dentists, while some of the

patient records with information about cancer and

therapies are with the oncologists. This is

critical for this type of adverse event.

We have also initiated two

multi-disciplinary advisory boards to evaluate

these cases and to make some preliminary

recommendations on management. We also initiated

the M.D. Anderson Cancer Center to try and get more

detailed information on frequency and

characteristics of ONJ.

Our third goal was to communicate the new

information. We distributed a Dear Doctor letter

describing the label changes to over 17,000

hematologists, oncologists, urologists who treat

prostate cancer, and oral surgeons.

The results of our advisory panels have

been distributed as a white paper beginning at the

ASCO meeting last year, and this information is

planned to be submitted for publication.

We have also worked with patient advocacy

217

groups, both to share information and to discuss

patient education initiatives.

This summarizes some of the key findings

of the advisory panel that met regarding the care

of patients with ONJ that are reflected in the

white paper that has been distributed.

This describes some of the recommendations

related to diagnosis and treatment of ONJ, an

important learning from the oral surgeons who have

cared for these patients is that aggressive surgery

can often exacerbate the condition and that

conservative management approaches are recommended.

Some patients can be managed with topical

treatments, rinses, and antimicrobial treatments.

Most critical is to understand strategies

to prevent ONJ, and there were a number of

recommendations from the panel. Routine dental

exams were recommended prior to bisphosphonate

therapy, particularly to identify dental problems

that should be addressed.

Patient education regarding good dental

hygiene was considered very important and good

218

communication between dentists and oral surgeons

and oncologists was thought to be essential to

manage these patients.

We have incorporated the recommendations

of this panel into the recent package insert in the

Precaution section that you are reviewing today.

Novartis has also reached out to patient

advocacy groups to share information about ONJ and

to discuss patient education initiatives. We

intend to meet regularly with these groups as they

represent an important way to communicate with the

patients that have these diseases.

We have developed and made available a

patient education brochure starting in August of

04, and have distributed 65,000 copies to our field

representatives. Physicians and nurses can use

these materials to educate patients who are

receiving bisphosphonate therapy.

This brochure describes ONJ, instructs

patients on good dental hygiene practices while

undergoing cancer treatment, and urges patients to

talk to their dentists and their oncologists if

219

symptoms arise.

We are also currently implementing

clinical programs to learn more about ONJ.

Critical as a first step is to develop a consistent

case definition, staging system, and severity

assessment. We are in the process of developing

consensus definitions with experts.

In addition, we will obtain additional

information from our pivotal trials by attempting

to follow up on completed clinical studies to see

if any cases of ONJ have occurred beyond the study

period.

We also plan to capture specific data on

ONJ in ongoing and planned studies. We plan

several new studies. We are going to do a

retrospective chart review specifically in myeloma

patients at the University of Arkansas.

We also plan to incorporate ONJ

assessments into trials that have been planned for

other reasons, to try and get some other

information. We, in particular, are planning a

large randomized prospective study, which includes

220

breast cancer and myeloma patients, and will being

the fourth quarter of this year.

In addition, an ONJ assessment is going to

be incorporated into a study that is under

discussion and being planned by SWOG in adjuvant

breast cancer patients, and the details are under

discussion.

We would also like to initiate a

prospective study to understand the natural history

of ONJ in patients newly receiving bisphosphonates.

We are considering whether we should do a natural

history study or some sort of registry study.

This shows our large randomized study that

we are planning to conduct. The objective of this

study is actually to look at therapy with Zometa

beyond the one-year treatment period, and looks at

Zometa 4 mg weekly every 3 months and placebo.

This is a large study in 3,500 patients,

and we are going to incorporate ONJ assessment in

this study.

This is the SWOG study design. This is a

6,000 patient study randomized to three arms with

221

different bisphosphonates, and this again is a very

large study where we could look, incorporate ONJ

assessment, and get some additional information.

This just shows the ONJ surveillance plan

that is incorporated into the SWOG study.

This is our current proposal for ONJ

monitoring in our clinical trials going forward.

This is being discussed with experts. It includes

physical evaluation and dental evaluation, as well

as imaging with panoramic radiographs, and we plan

to develop specific CRFs to capture details of

dental exam and ONJ assessment including criteria

for staging and severity. We will evaluate at a

minimum of every 6 months.

In conclusion, Zometa and Aredia are

important medications which have significant

benefits for patients with multiple myeloma and

metastatic disease from solid tumors, reducing the

morbidity from the serious complications that these

patients have related to bone involvement of

tumors.

Novartis has actively investigated cases

222

of ONJ since we received the first reports, and we

continue to investigate, however, ONJ remains a

poorly understood entity. Frequency estimates are

variable. Based on available data, it appears to

be infrequent in cancer patients, but we need

additional information.

There is insufficient evidence to

demonstrate a difference between Aredia and Zometa

in terms of risk of ONJ at this time.

Novartis takes these cases seriously and

we are committed to ensuring patient safety, to

increasing our understanding, communicating our

findings, and identifying strategies to prevent and

manage this problem.

The clear benefits of Zometa and Aredia in

reducing the significant morbidity associated with

complications of bone disease in cancer patients

remain highly favorable when considering the risk

of ONJ.

DR. MARTINO: Thank you, Doctor.

I now have a bit of a problem, which is

that we are going to run overtime, and I want to

223

give as much time as possible to the questions and

dealing with the issues amongst the committee.

Dr. Berenson, where are you? Now, with

all kindness and love from me to you, can you

summarize what you are going to say in a few

moments? I would be most grateful. Thank you.

Clinical Benefit of Bisphosphonates in

Cancer Patients with Metastatic Bone Disease

DR. BERENSON: I guess that is why my

mother made me take impromptu speech in high

school.

Let me be brief. What I want to do is

summarize the benefit of bisphosphonates for cancer

patients with metastatic bone disease.

This is an extremely common problem. More

than 500,000 Americans are afflicted with it. Most

myeloma patients develop metastatic bone disease or

myelomatous bone disease, most patients with

breast, prostate, and a significant number of lung

cancer, as well.

The median survival importantly of these

patients is measured in years, unlike other

224

metastatic sites in which patients succumb often

within weeks to months. These have major clinical

consequences, not only for the patient, the

families, but society in general, and the reason

for that is shown here.

That is because these lead to

consequences, and in the top four, in yellow, you

see where they care considered skeletal-related

events from the studies that have been done by

Novartis with Aredia and Zometa.

These are the placebo arms. Commonly,

patients fracture. These are the number of

patients or percentage of patients per year who

develop these complications. Less commonly they

develop cord compression of collapse, often leading

to the requirement for radiotherapy or surgery to

bone, hypercalcemia less common, bone pain frequent

before bisphosphonates, often leading to the use of

analgesics with quality of life effects, of course,

ultimately impacting the patient\'s survival.

Now, here is the overall results of

bisphosphonates that have been done. First, in the

225

nineties, that we did with Aredia, that is, the

myeloma trial showing a marked reduction, as you

see, in both the percentage of patients with an

event by 21 percent, the endpoint, and more

impressive on the right side is halving from 2 to 1

of the number of events per year.

Similar data from the breast cancer data

led by Hortobagyi shows a nice reduction in both

the percentage of patients with an event and about

a third reduction in the number of events per year.

As one can see in the trials that have

been similarly conducted with prostate cancer,

Kohno, a recent Japanese study, and Lee Rosen\'s

study, marked reductions not only in the percentage

of patients with an event, but impressive and

important, the number of events per year is halved,

from a third to a half, huge reductions when one

thinks about the 500,000 of Americans who have this

problem.

Now, the only head-to-head comparison of

Zometa and Aredia, which led to the approval of

this drug, as you know, for breast and myeloma,

226

this was a non-inferiority comparison trial, of

course, but one can see the four major endpoints

all favored Zometa, less patients with an event, a

delay in time to first event, reducing the number

of events per year by approximately a third, and on

the right side, the multiple event analysis taking

into account not only the time to first event, but

time between subsequent events, a 16 percent

relative risk reduction and statistically

significant in favor of Zometa.

So, what does this all mean? Well, first

of all, it means that Aredia has been shown to

definitively reduce skeletal complications in

breast and cancer patients with lytic disease only.

Two studies showed it to be ineffective in

prostate cancer that were randomized I did not

mention. It has not been evaluated in other tumor

types. In addition to breast cancer and myeloma,

Zometa has been shown to dramatically reduce the

skeletal complications in patients with prostate

cancer, that is, metastatic to bone, as well as

other solid tumors that are metastatic to bone.

Data I did not present, these drugs have

been shown to markedly reduce bone pain and the

requirement for analgesics, and, indeed, in trials

227

done with both Zometa and in the past with Aredia,

preventing the deterioration in the quality of

life, most important to our patients with

metastatic cancer to bone.

In our own experience, we have had 6 cases

of ONJ, and by the way, we have had more than that

number of patients who were referring to our oral

surgeon with a presumptive diagnosis from the

dentist who did not have it.

There has been an important range of

severity. Three patients required only

intermittent antibiotics were on Aredia and Zometa

in one case, and Zometa only in the other two.

They remain on ongoing bisphosphonate treatment,

and their symptoms have all improved.

One patient was only diagnosed last month.

She remains on treatment, her symptoms largely

resolved with several weeks of clarithromycin

orally. Two other patients, one on Aredia followed

228

by Zometa, one on long-term Zometa on a clinical

trial initially, discontinued bisphosphonates

secondary to significant effects on chewing.

Importantly, both of these patients have markedly

improved by being off the bisphosphonate and are

chewing normally in one case, and almost normally

in the other.

Equally importantly is the bottom bullet,

the status of these patients\' myeloma. One of

these patients has had a skeletal-related event, 3

are in long-term complete remission, 1 following a

transplant, 1 simply on VAD alone, and 1 on

thalidomide alone.

One is in near complete remission, and

impressive to me is the last sub-bullet. Two

patients on long-term therapy are still indolent,

and both patients have received no other treatment,

and, in fact, 1 patient had a 40 percent reduction

in M-protein, which is ongoing 5 years later.

So, skeletal complications have profound

effects on the lives of patients with metastatic

bone. We have seen data that shows that the IV

229

bisphosphonates markedly reduce the risk of bony

complications.

Both then number of events per year are

reduced by about a third to a half, and the percent

of patients with any event by 15 to 40 percent.

These drugs have profoundly reduced bone pain, the

requirement for pain medication, and prevented the

deterioration in the quality of life.

As you have seen, patients receiving IV

bisphosphonates may infrequently develop ONJ. What

the frequency is, we don\'t know. We have seen a

range of numbers I put up here. Equally important

is the severity, it varies markedly, and in all of

our cases, it has improved even on patients who

continue on therapy with oral antibiotics and

Peridex washes.

Thus, the risk of ONJ is a minor one, it

is rarely clinically significant in our own

practice compared with the major problems that

would result if patients did not continue these

important medications. That is the high risk of

fracture you have seen that is reduced, the risk of

230

cord compression, the requirement for radiotherapy

or surgery to bone.

Thus, the benefits, the reduction in

fractures, the requirement for radiotherapy,

reduction in bone pain, and ultimately the impact

on quality of life far outweigh the putative small

risk of ONJ and the renal deterioration that

infrequently occurs, and with good management, is

even less frequent, and I will stop there. Thank

you.

DR. MARTINO: Thank you, Doctor, I most

appreciate your succinctness.

Open Public Hearing

The next part is the public portion of our

program. There are several of you that have asked

to address this committee. The microphone you are

going to use is the one that is in the center of

the room, and as you get ready for that, I need to

read a statement to you that relates to your

presentations.

Both the Food and Drug Administration and

the public believe in a transparent process for

231

information gathering and decisionmaking. To

ensure such transparency at the public hearing

session of the Advisory Committee meeting, FDA

believes that it is important to understand the

context of an individual\'s presentation.

For this reason, the FDA encourages you,

the open public hearing speaker, at the beginning

of your written or oral statement to advise the

committee of any financial relationship that you

may have with the sponsor, its product, and, if

known, its direct competitors.

For example, this financial information

may include the sponsor\'s payment of your travel,

lodging, or other expenses in connection with your

attendance at today\'s meeting.

Likewise, the FDA encourages you at the

beginning of your statement to advise the committee

if you do not have any such financial relationship.

If you choose not to address this issue of

financial relationship at the beginning of your

statement, it will not preclude you from speaking.

MS. CLIFFORD: Felice.

DR. O\'RYAN: Felice O\'Ryan. I am an oral

and maxillofacial surgeon at Kaiser Permanente in

Northern California, and after hearing in 2003, Dr.

232

Sal Ruggiero\'s wonderful presentation about

osteonecrosis in bisphosphonate patients, I finally

found what I thought was at least some sort of

beginning answer to what I had been seeing.

In Kaiser Permanente, we have 3.2 million

members in Northern California, and 4 million

members in Southern California, therefore, we have

a huge and well-documented database.

My colleagues in Southern California have

also noticed some of the problems we have been

seeing and after looking at some of the clinical

problems, I am looking to you today to present some

cases, show you the spectrum. I do not consider

these problems minor or insignificant, nor do my

patients, and to ask for guidance.

I also feel that the FDA and Novartis has

done a very poor job of informing people about this

potential risk. I have informed our oncologists at

Kaiser Permanente via e-mails and attached clinical

233

photos about the risk of this.

Unfortunately, the oncologists are not

particularly comfortable doing oral exams, and so

some of this has been missed.

I won\'t go through the pathophysiology, I

think that is pretty well known to people. I am

just going to show you the spectrum of cases that I

see from what I would consider minor and

insignificant.

This is a 65-year-old woman with breast

cancer. She has been on\--all my patients have been

on, first, Aredia, followed by Zometa. The

earliest has been 6 months after the initiation of

Zometa treatment.

I have at least 30 patients, and these are

unsolicited patients, in other words, patients that

have been referred to me with this complaint.

She did undergo a dental extraction and on

your right you can see that she has teeth, and just

behind the teeth, around the mucosa, is a small

bone defect that has been chronically present, not

responsive to oral antibiotic therapy, nor oral

234

rinses.

This is another patient of mine, a

68-year-old male, multiple myeloma, been on both

Aredia and Zometa. He does have some bad teeth, I

admit it.

However, unfortunately, you can\'t see this

particularly well. The necrotic areas in his

mandible are up on the right corner and look like

some food debris. That is not food, that\'s his

jaw. These are how my patients have all begun.

The tissue on the lingual surface of the

mandible initially sloughs off, and then, like the

jaw is on fire, it continues, at least in my small

patient group, from the back end of the mandible up

to the front end, and can involve teeth.

The majority of my patients have not had

dental extractions, dental trauma, dental treatment

before presenting.

Again, this is not responsive to

antibiotics or local oral therapy.

This case concerns me the very most. She

is a 60-year-old delightful woman with multiple

235

myeloma, been on both Aredia and Zometa,

thalidomide, and, of course, all these patients

have been on corticosteroids.

She came to me with a small lesion in her

mandible that began as the size of maybe a small

split pea in the back. What you are looking at is

6 months or progression. This is her mandible.

This is dead bone. She has had a draining fistula

on the outside of her face that now she has been\--I

have had her on a PIC line, I have had for

hyperbaric oxygen.

It is continuing to spread. I have

nothing to offer her. I have no treatment. I

can\'t resect this because the rest of the bone is

dead and there is nothing normal to resect to. She

is looking at a possible free fibula flap, which is

a 20-hour operation, and a really hard hit for

these people who are already medically compromised.

So, I don\'t think anybody can stand here

and tell me that that is an insignificant problem.

These patients are in pain, they smell bad, they

can\'t eat, and nothing helps fix them.

So, the question about tooth extraction,

poor oral hygiene and possible associated

medications are totally legitimate. I may have a

236

unique subset of patients who have not had dental

extractions in the majority of the cases. Poor

oral hygiene, possibly, but again many of my

patients are edentulous, so poor oral hygiene or

tooth extraction has nothing to do with it.

Associated therapies, you know, possibly.

We don\'t know. All I can say is that I have never

seen this until recently.

What is the prevalence? Who do we prevent

it, and what do I do to treat these patients? I

think we have databases that are available to us to

look at. We are just in the process of looking

into this at Kaiser Permanente.

I don\'t know the prevention, and I

certainly don\'t know the treatment, but I would

love to know what the treatment could be. We have

had our patients discontinue the bisphosphonates.

I have not had a single lesion heal. I have not

seen a single lesion regress. I have only seen

237

them become worse.

So, I don\'t know if I have a unique subset

of patients or what.

Thank you.

MS. CLIFFORD: The next speaker is Scott

Santarella and Bruce Holmberg.

MR. SANTARELLA: Good afternoon. My name

is Scott Santarella. I am the Executive Director

of the Multiple Myeloma Research Foundation located

in New Canaan, Connecticut. Personally, I receive

no financial support from Novartis, however, our

organization has received unrestricted educational

grants for educational programs relative to

multiple myeloma disease.

The MMRF is a nationally recognized

501(c)(3) nonprofit. We are the world\'s largest

nonprofit funder of myeloma research, and I thank

you for providing me a few moments to speak today.

On behalf of the nearly 200,000 patients,

family members, and caregivers associated with our

organization and the issue of osteonecrosis of the

jaw and bisphosphonate use, I would like to just

238

say a few words.

As an organization that devotes 80 percent

of the funds we raise to support research efforts,

we have access to and committed partnerships with

the world\'s leading myeloma experts.

In addition, our secondary focus of

providing the myeloma community with educational

and informational programs relative to the latest

treatment options and therapies, we have become a

well-respected resource with more than 500,000

visitors to our website annually.

In addition, our focus for the last eight

years has been providing patients, clinicians,

caregivers, and nurses with the most current

information on treatment options and clinical

trials available, as well as educating patients on

supportive care therapy like the use of

bisphosphonates in treating multiple myeloma.

With this information as a backdrop, it

has been our experience in working with the

hundreds of the world\'s leading myeloma researchers

and local hematologists, as well as the tens of

239

thousands of patients who rely on bisphosphonates

in the treatment of bone disease suffered by those

patients, that bisphosphonates are considered an

essential part of supportive care for this disease

community.

As an organization, we feel the relatively

small number of cases of osteonecrosis of the jaw,

although worthy of note and attention, are minimal

in comparison to the benefits bisphosphonates

provide the majority of the patients.

In addition, it has been our experience

that the information available on bisphosphonates

use provided by companies like Novartis have always

been presented in a very detailed format with

explanation of dosing levels, as well as

preventative measures one would undertake to avoid

possible risk factors associated with the use of

these compounds.

It is our hope that ODAC will undertake a

complete review of not just the incidence of

osteonecrosis of the jaw, but the overall research,

both historically and currently, that shows the

240

treatment value and benefit of bisphosphonates in

the care of multiple myeloma patients, as well as

other cancer patients relying on these compounds to

help them in the treatment of their disease, and

recognize it as an essential to their care and

quality of life.

MR. HOLMBERG: Good afternoon. My name is

Bruce Holmberg. I have absolutely no financial

connection with Novartis.

I live nearby in Rockville and I am

multiple myeloma patient, diagnosed with Stage I

IgA multiple myeloma in May of 2000 when I was 61

years old. I am treated here at the National Naval

Medical Center in Bethesda.

I am here today to give you a brief

experience or a brief view of my experiences with

bisphosphonates as it relates to my multiple

myeloma.

When I was diagnosed, like so many, I had

never heard of this blood cancer. My only signs

were anemia, and at the results of my first

skeletal survey, which occurred a month after I was

241

diagnosed, showed only some slight lesions in my

skull.

When I heard my diagnosis, I asked the

hematologist two questions, what was my prognosis

and what is my treatment. To the first, he said,

\"Well, statistically, three to five years, but you

may be one of these patients who goes on for many,

many years.\"

To the second, he said, \"There is none,

your disease is not bad enough yet to treat, and we

just watch your disease as it progresses until the

treatment is less harmful to you than the cancer,

then, we do something.\"

That answer thoroughly baffled me until I

went home and researched multiple myeloma on the

website. What I saw were terms like immune system

failure, kidney failure, incurable, fatal, and bone

destruction.

The treatments were chemo and stem cell

transplants primarily, and neither did more than

buy much time, or buy time, and not much at that.

I changed doctors to one who was more

242

proactive. At my second appointment, he related a

conversation he had with a prominent myeloma

researcher at the association, at a recent Ash

meeting, where he had asked if Aredia could be

given as a prophylactic before the onset of bone

destruction to suppress the effects of the myeloma.

The answer was yes, that there was a good

possibility that Aredia had a suppressive effect on

the development of the myeloma cells themselves.

I began a monthly Aredia treatment

immediately. My disease progressed very slowly, so

that Aredia, and then Zometa, when it became

available, and I did make that switch, was my only

treatment for three years.

In 2003, it got bad enough to warrant the

addition of low-dose thalidomide and later the

steroid dexamethasone. Thalidomide and Zometa alone

helped, but I had an immediately and near complete

response to these combined treatments of Zometa,

thalidomide, and dex.

While I know this treatment is likely

temporary, that sooner or later the cancer will

243

mutate around the treatment, I am incredibly

grateful for this respite.

My quality of life is really important to

me. I am very physically active. I hike, bike,

work out daily, ski. I am still an active

patrolling member of the National Ski Patrol. So,

bone health is at the very top of my list.

Despite the progress of my disease, my

bone structure remains as it was when I was

diagnosed, only slight skull lesions that have

never gotten any worse, probably damage that was

done before I was diagnosed and started on

bisphosphonates.

My hematologist, my dentist, and I

understand the potential issues with jaw

osteonecrosis. If I need a dental procedure that

might pose a risk, we plan to suspend the use of

Zometa for a period in advance of the procedure.

I acknowledge that as more information

becomes available, more precautions may be

necessary, but the benefits of bisphosphonates to

us multiple myeloma patients significantly outweigh

244

any known down sides.

Let me add one more point. None of the

treatment options we myeloma patients have

available are without side effects, some of them

serious, but we take them and we tolerate the side

effects and mitigate them when we can because the

alternative is so unsatisfactory.

I have no side effects or have had no side

effects in the five years of taking Aredia and now

Zometa, no bone pain, no kidney issues, and no jaw

problems.

I urge you to weigh all of the benefits,

as well as the potential risks as you make your

deliberations.

Thank you.

MS. CLIFFORD: Thank you, Mr. Holmberg.

Our next speaker is Michael Katz.

MR. KATZ: My name is Michael Katz and I

am a Vice President of the International Myeloma

Foundation. This is an uncompensated volunteer

position. The organization receives unrestricted

educational grants from Novartis, I receive none,

245

no compensation from either the IMF or Novartis,

and I have paid my own way to come to this meeting.

As an advocate, I am in constant contact

with patients and caregivers with multiple myeloma.

With the IMF, I have helped conduct over two dozen

patient and family seminars across the country, I

lead two in-person myeloma support groups, and

moderate an on-line myeloma-specific listserv with

over 1,300 members, hosted by the Association of

Cancer On-Line Resources.

I also do phone counseling as part of the

IMF hot line. I am here today to speak to you as a

patient. I was diagnosed with multiple myeloma in

1990\. Over the past 15 years, the disease has

relentlessly attacked my bones, causing serious

damage to my pelvis, both hips, multiple ribs, two

vertebrae, my skull, and my shoulders.

I have had various systemic therapies

including steroids, Melphalen, thalidomide, 8

courses of radiation including radiation therapy to

the jaw. I began taking Aredia in January of 1995,

over 10 years ago, and I have since had over 120

246

infusions.

As such, I am very concerned about the

rapid rise in reports of osteonecrosis of the jaw

in patients with myeloma and other cancers. I

applaud the FDA and ODAC for taking the initiative

to have a public dialogue on this very serious

safety issue.

Even with the potential risk of ONJ,

bisphosphonates are an important part of therapy in

minimizing bone damage to patients with myeloma and

other cancers that threaten the bone.

ONJ is preferable to a collapsed vertebrae

or broken femurs. It is important that

bisphosphonates are made available to patients who

can benefit from them, but we also need to make

sure that we can protect our bones from destruction

by cancer, and at the same time, minimize the risk

that we will develop serious problems like ONJ.

Dr. Durie and I had met with

representatives of Novartis at last spring\'s ASCO

meeting to understand what could be done to better

understand this issue and provide more practical

247

information to both patients and physicians.

The idea for the web-based survey that was

discussed earlier initially came up at this

meeting.

As Dr. Durie said, we were able to recruit

over 1,200 respondents within 30 days.

Participants completed an extensive survey

detailing diagnosis, treatment history, dental care

habits, and any dental issues including both

explicit diagnosis of ONJ, as well as symptoms that

would be indicative of undiagnosed ONJ.

The results of this survey, which Dr.

Durie presented earlier, were dramatic, showing

increased time dependent risk associated with

Aredia and Zometa, and no statistical association

with any of the other treatments reported including

steroids, thalidomide, or Valcade, radiation or

alkylating agents.

As Dr. Durie stated, the time dependent

risk associated with Zometa was dramatically higher

than that associated with Aredia. People this

morning and outside this forum have characterized

248

osteonecrosis of the jaw as a long-standing issue

in oncology patients. They call it rare. They

raise issues about the condition being imprecisely

defined and standardized criteria for diagnosis not

being established.

They cite the many other risk factors that

could contribute to or cause the problem. The fact

remains, though, that almost all of these risk

factors have been facts of life for decades in

myeloma and other cancers. Why, one must ask, has

this problem become so much more pronounced in

these few short years.

They also point out the limitations of

anonymous surveys and of patients and caregivers

self-reporting medical information. Are there

limitations with this type of survey? Certainly,

there are. Indisputably, prospective clinical

trials are the gold standard for efficacy and

safety data.

Having said all of this, though, I must

ask if these same people had cancer and had to make

the decision to put the IV in their arm every month

249

and hang that bag of bisphosphonates, I wonder if

they would be so dismissive of data provided by

1,200 concerned fellow patients.

Would they ignore this data and wait two,

three, four, or more years until these studies

could be completed and better data is available? I

doubt it.

It is clear that osteonecrosis of the jaw

is a problem that has mushroomed in the past few

years. To quote Dr. Robert Kyle of the Mayo

Clinic, who chairs the IMF Scientific Advisory

Board, I quote, \"In my 40-plus years of caring for

patients with multiple myeloma, I had not seen or

heard of osteonecrosis of the jaw in this disease

until one to two years ago.\"

Prospective trials take years to design

and execute. When dealing with serious safety

issues like ONJ, we cannot afford to wait years.

These trials should be done, but we need to use the

data that we can acquire more quickly via

retrospective studies and surveys to help patients

and their doctors make better decisions today.

I applaud you for allowing us to share

this data with the scientific community and the

public, and I applaud you for daring to ask the

250

question how can we use this data to help patients

and physicians make better decisions today while we

work to learn more tomorrow.

ONJ is not a stroke, it is not a heart

attack, it is seldom life-threatening although I

must say I did meet a woman last month at our

patient seminar in Dallas whose husband died of

complications resulting from his ONJ.

More commonly, though, ONJ is a painful

condition that can destroy a cancer patient\'s

quality of life. It is painful, the patient\'s

teeth fall out. It can interfere with speech, make

eating difficult. It can also prevent patients

from receiving life-saving treatments like

transplants.

Yet, bisphosphonates are proven to prevent

or lessen the severity of cancer-induced bone

damage and must remain available to the patients

who need them. Having said all of this, what would

251

and my fellow patients ask of the FDA and Novartis?

First, please be more proactive in getting

the word out to patients, caregivers,

hematologists, oral surgeons, and, for God sakes,

the regular dentist, because those are the people

that are pulling teeth out and triggering this

condition.

The labeling changes, the white papers,

the Dear Doctor letters, they are all steps in the

right direction, but they don\'t go far enough in

terms of audience or message.

Second, please provide answers as soon as

possible, and I know these are tough questions, to

the following four questions:

1\. If patients have been on Aredia or

Zometa for a long period of time, is there a point

at which they should consider decreasing the

treatment frequency or dosage?

2\. If there is a dental problem that

requires invasive surgery, to what extent can the

risk of ONJ be reduced by stopping or tapering

Aredia or Zometa therapy?

3\. Given the risks, under what

circumstances is prophylactic use of Aredia

justified?

252

4\. Lastly, given the evidence of

increased risk of ONJ and kidney damage, and the

lack of evidence of any incremental benefit of one

drug over the other, why should any myeloma patient

be given Zometa as opposed to Aredia?

One last thought. In the preapproval

setting, the possibility of harm must be excluded

by proving that a drug is safe. Drugs are guilty

until proven innocent. In the post-marketing

setting, where we now find ourselves with these

drugs, we change our tune, requiring proof of harm

rather than proof of safety. Drugs are innocent

until proven guilty.

As a patient taking these drugs, I find

this difficult to understand.

I than you for the opportunity to speak,

and I thank you for your diligence in investigating

this matter.

MS. CLIFFORD: Thank you, Mr. Katz.

Ron Rogers?

MR. ROGERS: I, too, have multiple

myeloma. It was discovered in 1999. Approximately

two months later, I went on Zometa. I have

continued on Zometa to this day, and live an

extremely active lifestyle, skiing, writing,

253

hiking, hunting, fishing.

In January of 04, I was diagnosed with

osteonecrosis. With antibiotics, it had cleared up

within approximately six months, and I still am on

Zometa, and I am thankful to be able to have the

kind of lifestyle I have.

Thank you.

DR. MARTINO: The Committee is grateful to

all of you who have spoken, and as always, you have

a way of putting all of this in the right context

for those of us that sit here. I am personally

grateful to each of you for this morning\'s

contribution.

Committee Discussion

DR. MARTINO: The next portion and the

final portion of this meeting is actually the

254

discussion amongst the panel. There really are

three sets of questions that I want to focus you

on, and the time is short, so again, please be

succinct, I want your thoughts and not your

ramblings.

The first question really relates to given

that we recognize that there is a potential problem

here, have we appropriately informed the necessary

people.

The second question relates to do we know

what to do, either in terms of preventing this

problem or in terms of treating it once it occurs.

Thirdly, are there additional studies that

need to be done.

I would like to address the first question

first, however. Have we informed the right people

and in the proper manner? To that, can I ask the

company to basically, briefly, summarize what they

have done in terms of informing and who have they

informed.

DR. YOUNG: I am going to invite my

colleague, Peter Tarassoff, to the stand to talk

255

about the communication efforts of Novartis.

DR. TARASSOFF: Good afternoon. My name

is Peter Tarassoff. I am with Novartis Oncology,

Medical Information and Communication. I would

just like to briefly summarize the steps that we

have taken to bring this matter to the attention of

the patient groups.

We maintain an ongoing dialogue, as Dr.

Young had indicated, with a number of patient

advocacy groups. In May of 2004, we hosted a

meeting hear our offices in New Jersey to which we

invited a number of representative patient groups

to come and listen to the discussion that we had in

terms of what we knew about the topic of

osteonecrosis of the jaw.

Again, we had further meetings with

representatives of additional groups at the Ash

Meeting in San Diego in December 2004, and provided

further updates on this information.

At the time that the Dear Doctor letter

was published by Novartis in September 2004, we did

publish this patient brochure that had several

256

topics of pertinent information that would be

useful to patients.

We have distributed, as Dr. Young had

indicated, approximately 55,000 copies of this

brochure to our sales representatives to give to

the health care professionals that they see during

the course of their daily activities, and we have

been very vigorous in instructing them to be

proactive, to be sure that offices where Zometa is

given, that this particular information was given

out.

It contains information for patients to be

able to recognize the signs and symptoms of

osteonecrosis. It calls to their attention the

fact that there are certain items of dental hygiene

that they need to be aware of, and thirdly, it

provides them information that they should share

with their dental professionals in terms of their

cancer treatment and things that a dental

professional should be aware of.

We have this information also available on

the Novartis U.S. Zometa website. This information

257

is here. A number of the patient advocacy groups,

we understand also have this information on their

website, so we try to use as much of the new IT

technology that we have available to us to make

this information available to greater numbers of

patients.

This is the white paper that represents

the two advisory board meetings that we held in

December 2003 and again in March of 2004, to try to

put together in a succinct format information that

could be made available to health care

professionals, to bring to their attention this

topic of osteonecrosis, what might be able to be

done to prevent it, what should be done in terms of

treatment.

We have distributed this initially at the

ASCO meeting in New Orleans in June 2004. Through

our offices, we have distributed an additional

3,000 copies that have gone out to health care

professionals who have questions about the topic of

ONJ. We provided them this information, as well as

a copy of the Dear Doctor letter.

So, we have tried to look at a number of

different avenues by which we can share this

information with both patient communities and also

258

with the oncology and dental communities.

We do have a manuscript that stems from

this white paper that is now undergoing final

review, and our plan for that is to submit it to

journals that will be read by oncologists, as well

as health care providers in the dental fields.

Thank you.

DR. MARTINO: A question on the Dear

Doctor letter. I am assuming those are sent to

oncologists, or are they sent more broadly? I am

particularly concerned with the dental

professionals.

DR. TARASSOFF: The 17,000 copies,

slightly more than 17,000 copies of the Dear Doctor

letter were sent out to hematologists, oncologists,

urologists, and oral surgeons in the ADA database.

We have considered also the idea of sending it to

dentists, and that is something that is under

consideration.

DR. MARTINO: That would strike me as a

key group to whom this should be disseminated since

they are more likely to be the ones who see

patients for these problems.

Dr. Brawley.

DR. BRAWLEY: I am interested in what is

259

being done in terms of promotion of Aredia and

Zometa for usage right now. For a while after

Zometa\'s approval, it was sort of like a freight

train moving toward it being malpractice for those

of us who take care of patients who have metastatic

disease or the threat of metastatic disease, to not

put them on Zometa.

I am wondering what now is the company

doing in terms of promoting the usage of both

Aredia and Zometa.

DR. YOUNG: I am going to invite our

colleague, Dr. Deborah Dunsire, to speak about the

promotion of Zometa and Aredia.

DR. DUNSIRE: Good afternoon. My name is

Dr. Deborah Dunsire from Novartis.

Zometa is actively promoted by the

260

Novartis Oncology Sales Forces at this time.

Aredia is no longer promoted. It has been

generically available since 2001, and at the

present time, there is practically zero Aredia

utilization. Any pamidronate use has moved over to

generic pamidronate, and the promotion is always

within the FDA label and within the OIG guidelines.

If there is anything further I can

clarify, please ask.

DR. BRAWLEY: I am not satisfied with the

answer, but I don\'t know exactly how to ask for a

better answer. You are still promoting Zometa. I

mean literally in Atlanta, virtually everyone with

metastatic disease was donating \$6,000 to Novartis

for Zometa treatment, and that may be an overusage

of the drug.

So, I will just leave it at that. I don\'t

know if you want to respond to that or just leave

it as a comment.

DR. DUNSIRE: I think that the drug is

promoted for patients with bone metastasis because

of the benefits that it provides.

DR. MARTINO: Dr. Perry.

DR. PERRY: I have a comment and a

suggestion, Dr. Pazdur. Richard, this seems to me

261

to be a great topic for dissemination through the

CCOP \[ph\] mechanism, and perhaps a great research

project for them to get cancer control credits

perhaps by first making people, their patient

populations aware of the potential problem, and

then when we get a little bit\--hopefully, a whole

lot smarter, knowing how to identify and treat it

better, then a treatment program.

I take it you still talk to those people

and can convey that suggestion.

DR. PAZDUR: I think that is an excellent

idea and we will bring it back and discuss it with

the CCOP people, but I think that is even an area

to look at, even a registry potentially

incorporating their practices in, because it does

represent perhaps even a more real world type of

usage of these drugs outside of a cancer center,

which may have its own peculiarities about it, as

the M.D. Anderson data is doing.

DR. MARTINO: Dr. Levine.

DR. LEVINE: Several comments. First of

all, one of my problems is that the patients who

are being educated are those who are perhaps more

involved, i.e., they are members of support groups,

they are on the Internet, and so forth, and I am

262

worried about the regular patients out there who

may not be involved in that sense.

I am not sure, so I will defer and ask

you, but I believe the company markets this on

television directly to the patients, and if that is

true, then, I would absolutely ask that you market

something else about this. If you don\'t market, I

would still do that. It needs to go to the general

population.

The reason I feel strongly is that I am

worried that simply by stopping the product for a

month or two, that is not really going to help as

far as what to do, and what you have to do is

prior, I guess, some of the sense I am getting, is

that you may want to advise patients to take care

of dental work prior to ever starting these

263

products.

So, you have to do it in a proactive way.

I also agree with what has been said as far as

educating very carefully the dentists, and when I

go into the dentist, the technician says to me, you

know, any change in your medical health, but I

would want the technician to be saying to me, have

you taken these drugs, and list them right there.

The second thing, and I have to go, so I

am not going to answer this properly in order, but

one of the questions that really needs to be

answered here is what is the appropriate duration

of use of these drugs, is there, in fact, a moment

where the risk outweighs the benefit, and I don\'t

think there are data to address the question. That

would be an extremely important one.

There was a New England Journal article,

not about this at all, but several years ago, using

one of these products for osteoporosis, and I think

the finding was that one dose a year was as good as

once a month or whatever it is. So, those kinds of

questions really have to be addressed.

DR. YOUNG: I would first like Dr. Deborah

Dunsire to address the question about promotion,

and then I will address your question about longer

264

term duration of therapy.

DR. DUNSIRE: Deborah Dunsire from

Novartis clarifying that Zometa is not promoted on

television at all, and that the direct-to-patient

and outreach to the regular patient, who isn\'t

engaged in the Internet, is really through their

physician.

It is the only way we can get to them, and

that was the purpose of the patient brochure around

osteonecrosis of the jaw, and in our regular

patient education materials, which can be given to

a patient when they start Zometa, we have also

added information on osteonecrosis of the jaw,

hoping and encouraging all the professionals,

physicians and nurses, who are in contact with

patients, to give this to the patient, so that they

can become aware. Thank you.

DR. YOUNG: I just wanted to add that I

was kind of rushed at the end of my presentation,

265

but one of the studies that we are undertaking,

which we have actually been in discussions about

the FDA, is a study that takes patients who have

been on treatment for a year with multiple myeloma

and metastatic breast cancer, and then randomizes

them to either Zometa in the label dose very 3

months or placebo, and that is really a large study

that is designed to get at this question about

demonstrating continued benefit and safety of

therapy, and also it is a good setting to be able

to monitor for osteonecrosis of the jaw.

DR. MARTINO: Dr. D\'Agostino.

DR. D\'AGOSTINO: I have a couple of

comments and I am going to jump from the first and

the third question. I think in the first question,

in terms of the information being sent out, I think

there is a lot of information. The program seems

to be moving along well.

My concern is, is there an evaluation

component, how do you know you are actually

reaching anybody, and especially the patient and

the oral surgeon, are they thinking this way, and

266

they get a lot of information, they may just chuck

it in the pail, I don\'t know.

So, I think there should be, and there may

be, but I think there should be an evaluation

component that the FDA may want to insist on.

In terms of the clinical trials, I think

the registry idea is good, and I think the clinical

trial, they have got ongoing clinical trials, which

sound very nice. My concern there is are they long

enough and are they big enough to pick up the

safety issue if they are designed for other things.

So, I think if they embed this question

within a clinical trial, it has to have some hope

of getting at an answer to this particular problem.

DR. MARTINO: Dr. Hussain.

DR. HUSSAIN: I think some of the issues I

wanted to raise was raised by Dr. Levine, but I

want to reiterate the issue that Dr. Brawley had

brought up, and I think maybe I can rephrase what

he said. There is aggressive marketing in areas

where it shouldn\'t be marketed, and I will give you

an example.

I can\'t give you proof, but I can give you

examples. Patients with metastatic

hormone-sensitive prostate cancer, if you look at

267

the absolute indication, there is no indication in

that setting. Yet, under the umbrella of bone

disease, the drug is being marketed to the prostate

cancer patients.

If I saw correctly what is up there, it

seems to me there is almost a relationship to how

long you live, and then osteonecrosis and side

effects, if you don\'t live long enough, you are not

going to get that side effect, because you just

died.

So, in those patients, their average

longevity is three years, some of them live longer.

I think there is a risk in there. There is

multiple trials from Europe that showed no benefit

to the addition of bisphosphonates albeit second

generation in that setting, so I would be very

careful about marketing it indirectly.

Otis, is that about something similar?

The second issue I think is the issue of

268

frequency and the need to start these medications,

and I think it is important\--I can\'t speak about

myeloma, but in looking at the data for prostate

cancer, correct me if I am wrong, but the patients

that the drug was tested in were really far

advanced prostate cancer patients.

This is not the patient whose PSA went

from 0.1 to 0.3, and the unfortunate approval is a

blanket approval, you know, anytime you develop

androgen-dependent disease, you are going to go get

the drug, and yet, if I am not mistaken, again,

correct me if I am wrong, the median PSA for these

patients that went on it is in the several

hundreds.

So, not only I think education needs to be

given about the setting, but actually the timing of

its use, and not the minute the patient becomes

androgen independent.

DR. MARTINO: Dr. Perry.

DR. PERRY: I would like to ask Dr. Young

or someone from the company how many patients get

this product a year?

DR. YOUNG: I am going to have to call on

Dr. Deborah Dunsire again. How many? Do you want

in the U.S.?

269

DR. PERRY: It doesn\'t have to be to three

decimal points. I mean are we talking about 5,000,

50,000, 500,000?

DR. DUNSIRE: It\'s variable by indication.

To be clear, lung cancer patients generally get it

for a shorter period of time. So, overall, we know

that since 2001, about a million patients have been

treated. There are probably several hundred

thousand treated at some point during a year.

DR. PERRY: In the United States?

DR. DUNSIRE: No, that would be global.

DR. PERRY: How many patients in the

United States get this drug per year?

DR. DUNSIRE: I would have to look to get

you exact figures, but it\'s in the tens of

thousands.

DR. PERRY: Tens of thousands, and we have

given out 55,000 booklets. It doesn\'t seem to me

to be enough.

DR. DUNSIRE: Right, there would be less

than 55,000 patients, however, in a year.

DR. PERRY: My assumption is that you have

reached 25 percent or less of the patients.

DR. DUNSIRE: We are actively continuing.

DR. PERRY: I understand that, but I am

270

trying to get a handle on the magnitude of the

problem.

DR. DUNSIRE: Absolutely.

DR. PERRY: It seems to me that there a

lot more patients who get the drug than get the

booklet.

DR. MARTINO: Dr. Proschan.

DR. PROSCHAN: I think that the reaction

of Novartis is somewhat defensive, and I think that

hurts. I am looking at this, the adverse

reactions, and the first sentence is, Osteonecrosis

of the jaw has been reported in patients with

cancer receiving treatment regimens including

bisphosphonates. Now, if you read that just a

little bit differently, I realize there is no comma

in there, but you could read that as Osteonecrosis

271

of the jaw has been reported in patients with

cancer receiving treatment regimens including

bisphosphonates.

In other words, it has been reported with

a number of regimens, and this is one of the

things. That may very well have been accidental,

but I think it comes off as being defensive. Many

of these patients were also receiving chemotherapy,

you know, and I think it would be a lot better to

take those defensive things out.

DR. MARTINO: Is that wording from the

company or is that wording from the FDA?

DR. PAZDUR: This was negotiated, labeling

changes, that we were in discussion and agreed

with, with the sponsor, but we will be more than

willing to renegotiate these if the committee feels

that this is too weak.

DR. MARTINO: I just wanted to make that

clear. I mean it is not really entirely their

choice of wording. I mean it\'s an interaction.

DR. PROSCHAN: Like I said, that first one

may very well have been accidental. I mean even if

272

you changed it to, instead of including

bisphosphonates, if you change it to \"that include

bisphosphonates,\" that is a minor change that

doesn\'t have that potential misinterpretation.

DR. MARTINO: I think for me the issue is,

you know, as time is going on, there are more and

more of these cases, recognizing that we don\'t know

the denominator. So, perhaps what might have been

an appropriate stance to take, you know, a year ago

or 18 months ago, may be not quite appropriate

today, that we know more right now in terms of the

fact that, yes, this does occur.

The other thing I have to say I don\'t have

a real sense of is the severity of this. I mean I

have seen one speaker this morning imply that these

tend to be fairly minor issues, and then I have

seen another speaker with a very different

experience.

So, as a clinician, I am just kind of here

struggling trying to figure out, not only is the

frequency of this problem, but I don\'t feel I

really have an understanding of that.

DR. REAMAN: I would echo the same thing

and again I would also criticize we are being asked

to comment on the materials that have been provided

273

to patients and the public without having had the

opportunity to review them.

But I am totally baffled about this whole

entity, which has been attributed to

bisphosphonates. We have heard people claim that

they have never seen it before in their lives or

rarely saw it, but yet it is associated with a

number of well-established risk factors is what it

says in this.

So, if we know so much about it, that it

is associated with well-established risk factors,

it seems to me a great deal of double talk. As a

physician, I don\'t understand what this statement

says. As I patient, I am certain that I wouldn\'t

have been able to understand.

DR. MARTINO: Rick, did you have something

you wanted to say?

DR. PAZDUR: Well, by no means I don\'t

think it is anyone saying that this is a trivial

274

situation, and with any clinical expression of a

toxicity, there are various manifestations of it

that could be progressive in many patients, but I

want to make sure.

The reason why we are having this meeting

is to bring attention to it. We, at the FDA, are

somewhat limited in what we could do to notify the

public. We change labels, we send out e-mails, we

had advisory committees, and I think is kind of the

apex of what we could do with the toxicity, to

spend time in an open public forum to bring this to

people\'s attention here.

I don\'t think it is well characterized,

and I think the surrounding areas that are

associated with it are areas that are

characteristics of patients that have it, whether

they are causal effects, whether they are casual

associations, I think that is to be further

delineated and to be further examined with more

time.

DR. BERENSON: May I comment briefly on

this? Every patient who is seen in our practice is

275

informed of the renal risks, the osteonecrosis of

the jaw risk, as well as the flu-like symptoms in

detail, and every patient is evaluated by a dentist

now before they actually begin therapy.

In addition, those patients with possible

jaw problems are referred to an expert at UCLA for

further evaluation. The spectrum of patients that

I am seeing are amongst everybody who gets treated

with bisphosphonate for myeloma, so I am not seeing

necessarily the extreme cases, I have seen just

six, but I can only comment on my own experience,

but we are very aggressive about making sure these

patients are informed about this complication.

DR. PAZDUR: Unfortunately, perhaps many

aren\'t, as was pointed out by the oral surgeon from

Kaiser, medical oncologists don\'t get into people\'s

mouth many times. That isn\'t a focus of some of

their examinations, and especially in an

unrecognized problem, they may not be paying

attention to this.

Many patients are started on aggressive

chemotherapy regimens without a visit to the

276

dentist or without a really thorough examination.

Here again, I think this points out not only to a

problem with a drug, but also a problem with our

practice of medicine in oncology, that we need to

pay more attention to, so there is various factors

that go into this.

DR. MARTINO: As a clinician, I am not

sure that I have even a clear understanding of how

I would recognize this. In other words, what would

the patient say to me other than it hurts here,

Doctor, and they would be pointing to their jaw.

I mean I don\'t have an understanding that

if I sent them to a dentist, the dentist will do

anything more than I would do, which is to look in

the mouth and decide if they need a tooth pulled or

some gross basic thing like that.

What I am most at loss of is an

understanding of what is the actual behavior of

this disease, and if the company has the ability to

sort of characterize it, that would be great.

DR. PAZDUR: You have Dr. Ruggiero here, I

believe, and perhaps he would like to address this.

DR. YOUNG: I will invite Dr. Ruggiero. I

just want to say I think this is a critical

condition, and based on the kinds of information

277

that we have now, which is spontaneous reports, it

is very hard to sort out these things.

I mean we have a variety of symptoms and

signs that are reported. You know, we may have a

mixed group of cases at this point, so I think this

is why we really critically want to put together a

definition, a severity system, a grading system, so

that we can prospectively look at this going

forward and get a better idea of the natural

history.

DR. PERRY: Yes, I think that is where the

FDA could really do something instructive is to get

together a group of experts and come up with a

scoring system, so that if what we have seen are

Grade 4\'s on the usual CTC system, we would have a

better idea of what kind of elephant we are dealing

with.

DR. MARTINO: Dr. Brawley, you are next.

DR. BRAWLEY: Dr. Hussain was much more

278

eloquent in describing the question I have. I

remember when Novartis brought this before the ODAC

before, and we suggested that it might be approved,

and I don\'t regret voting for it being approved,

because I think there is some benefit to the drug,

but I recall that of the skeletal-related events

that they talked about, and the decrease in the

skeletal-related events, they increased the number

of events found and increased the number of events,

reduced in the Zometa arm by doing screening of the

spine with x-rays.

So, many of the skeletal-related events

that were prevented with Zometa were asymptomatic

fractures that were here nor there to the patient,

but they were prevented nonetheless.

So, when I see that and I heard about the

advantages of Zometa, I worry about is the

promotion of the drug as accurate as I would like.

DR. MARTINO: Dr. Reaman.

DR. REAMAN: Just a question. Are there

any kind of screening studies that could be done?

I mean when I go to the dentist and say something

279

hurts, the first thing that is done is x-rays. I

mean is there a recommendation for doing some sort

of radiographic studies based on duration of

exposure?

DR. YOUNG: I am going to ask Dr.

Landesberg. I want an oral surgeon to speak about

this.

DR. LANDESBERG: Regina Landesberg from

Columbia University. I believe that as far as a

screening exam, we have documented what we would

recommend for that, and it really just includes

something that should be done by every dental oral

surgical professional, a complete oral exam,

examining the head and neck structure, but it

really requires that you are diligent.

We believe that there will be some

predictive indices and we may be able to see

changes on radiographs, but that has not been

established at this point. I do believe that we

can find some predictive indices that will indicate

who is going to be at risk for this disease.

DR. REAMAN: I think it\'s great that

280

dentists are made aware of this, but are

oncologists who are prescribing this made aware of

this, and are they being told that this is

something that they have to do for patients for

whom they are prescribing this drug.

DR. MARTINO: Actually, that may really be

a very worthwhile thing to do. I mean I will tell

you I have never had the habit of sending my

patients to a dentist prior to this, and I don\'t

know that that would solve the problem, to be

honest with you. I am not sure right now that I

have that feeling, but it is not an unreasonable

thing to do.

DR. PERRY: I was wondering, you know, I

was a little troubled when I first looked at this

by the fact that the same doctor had reported so

many of these cases, I am just wondering whether

this is something that is very easy to see and

confirm, and whether anyone else did confirm those.

DR. MARTINO: I think we have got that

doctor here, and I must admit I had that same

reaction as to was this somehow a selected are we

281

looking for.

DR. RUGGIERO: Well, there are a bunch of

questions that I have to address here.

First, it was, when we first started

seeing these problems, very interesting to me that

we were the only center that was seeing such a

number of cases, we were really were. At the

beginning, we were seeing 10, 20 cases where people

weren\'t seeing this at all.

As of yesterday, I logged the 105th

patient in our local database in my practice alone,

and I don\'t know why we are seeing so much.

Clearly now, because of all the publicity, I am

seeing more and more patients, but a lot of them

are local people.

The spectrum of disease, as you have

mentioned before, there is truly a spectrum from

small, little tiny areas of exposed bone that are

very easy to diagnose. This is not something that

is rocket science to diagnose. It\'s simple, it\'s

easy. You look in the mouth, you see exposed bone,

you have a diagnosis.

So, yes, I don\'t expect the oncologist to

be looking in the mouth, but if an awareness is

sort of made to the patient that this is a possible

282

problem, then, the diagnosis can be easily made.

There is a spectrum, and we have seen that here

today. Dr. Levine showed cases of massive exposure

of bone. I have many cases like that. Likewise, I

have many cases with small, little areas of exposed

bone that remain quiescent over a very long period

of time and respond very well to treatment.

I have a lot of patients who have not

responded to treatment, and have done very poorly

and lost their job over this complication, and it

is very frustrating because we don\'t have any

clinical indices right now to predict who is going

to be the person who loses their job, who is going

to be the person that is going to continue to do

well on rinses alone.

I think one of the things that has to come

out of this meeting and meetings like this, is to

educate the patients, educate the oncologists, and

more importantly, educate the general dentists,

283

because I think the dentists are probably the ones

that are kind of caught in the middle here. They

are looking at things, and they don\'t really know

what they are looking at.

Oftentimes, it winds up in the oral

surgeon\'s office and they are now one of the

professional groups that is probably more aware of

this than any other group, probably oral

pathologists, as well, since they are reading all

these specimens.

The oncologists are a distant third, and I

think that is getting better, but I think the main

focus at this point is to educate the oncologists,

and that is going to be as well as myself, and a

few of my colleagues, to educate the ADA, and we

are doing that in the process of getting some of

this data off to them.

But, if you have any more questions?

DR. MARTINO: Doctor, when you see these

patients, what do you do as a way of managing the

problem, how do you, quote, unquote \"treat\"?

DR. RUGGIERO: It depends upon the

284

symptoms that they have when they present. If they

present with exposed bone, but they are

asymptomatic, they have no pain, they have no

evidence of infection, I do relatively nothing.

The main goal here, in my mind, is to

maintain the highest quality of life possible,

because this problem, if left unchecked, or if it

progresses, can be in many patients\' own testimony

to me, is worse than any other chemotherapy they

have ever gotten, because it can be very painful.

So, if they present and they have exposed

bone, but they are asymptomatic, we leave it alone.

The worst thing to do in my mind, and I have been

through this loop because when we first started

seeing these patients, we thought this was just

exposed necrotic bone, we went after it surgically.

I took jaws off, I took sections of jaws off. They

don\'t heal, and we have made it worse.

So, we have to learn, as a profession, to

put the scalpel in the holster most of the time,

and just follow these patients, and when they are

symptomatic with pain infection, hit them hard with

285

antibiotics.

Now, these are recommendations that have

developed over the course of time based on my

experience and a few other oral surgeons across the

country, and we have come to somewhat of a

consensus.

Is it based on a lot of good data? The

answer is no, it\'s my own personal preference, and

we have had some success with it. It has to be

looked at in a more structured way.

There have to be some prospective studies

looking at why this happens, how to prevent it, how

to identify patients who are at risk of developing

this, and we just don\'t know that right now.

DR. MARTINO: Yes.

DR. AVIGAN: I was just going to emphasize

the importance to distinguish between case

identification criteria where the clinician would

be prepared to identify the case and then

appropriately manage it, and prevention and risk

mitigation, which is really a different arena,

where we clearly from what we have heard today,

286

need more information to determine the relationship

between duration of treatment, cycled therapies,

susceptibility factors, is there a threshold effect

of what the total dose is, and that would then

inform benefit-risk for those patients who might

have a longer course disease.

So, you have to think about the natural

course of the disease that they have, on one side

of the scale, and then the other side is the

natural course of the treatment and its effect on

the hazard and risk over time, which needs to be

studied.

DR. MARTINO: Thank you.

Dr. Pazdur, do you have any other needs

from this committee today? Are there questions you

have that we have not answered for you?

DR. PAZDUR: I think some of the questions

that we have laid out here perhaps don\'t have

answers at this time. I think we have evolve that

data. In my own mind, listening to what has been

said, I think there are several major areas that

Novartis, FDA, the investigator community have to

287

work on, number one, duration, and I think that is

an important issue and how optimally to use this

drug.

The half-life of this drug in bone is

very, very, very long. Do people need the same

dosing schedule over a long period of time?

Greater awareness by the community that treats

this, not only oncologists, oncology nursing

personnel, oral surgeons and dentists.

Is there a preferential bisphosphonate,

Aredia versus Zometa? There some very interesting

data that was presented by the group here. We have

to remember that the basis for approval in multiple

myeloma was on the basis of a non-inferiority for

Zometa.

So, is there a big advantage is we have a

toxicity issue? Here again, we don\'t know this.

This is data that is hypothesis generating that we

heard, but these are I think major questions that

need to be answered and hopefully they can be

answered.

Here again, our reason for bringing this

288

to the committee, we really wanted to highlight the

safety issue. It\'s an important issue. This is

one of the few opportunities that we get to have a

public face to the FDA, and I think that this is

important to illustrate, not only efficacy, but

important safety issue.

So, I thank you and I don\'t have any

questions at this time.

DR. MARTINO: Thank you, and this meeting

is adjourned.

\[Whereupon, at 1:27 p.m., the meeting

adjourned.\]

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