1

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

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.

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

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

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

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

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

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

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,

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

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

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

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

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

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.

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

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,

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

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

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

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.

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

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

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

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

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

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,

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

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

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

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

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

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

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

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

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,

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

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

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,

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

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

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

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

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

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

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

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

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

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

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

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

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

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,

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

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

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

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

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

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

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

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

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

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

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

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?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

101

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

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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

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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

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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

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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

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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

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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,

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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