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

                                                                 2

 

                              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.

                                                                 3

 

                            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

                                                                 4

 

                      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

 

                                                                 5

 

                         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

 

                                                                 6

 

      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

 

                                                                 7

 

      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

 

                                                                 8

 

      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

 

                                                                 9

 

      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,

 

                                                                10

 

      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

 

                                                                11

 

      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

 

                                                                12

 

      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

 

                                                                13

 

      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

 

                                                                14

 

      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

 

                                                                15

 

      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.

 

                                                                16

 

                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

 

                                                                17

 

      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,

 

                                                                18

 

      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

 

                                                                19

 

      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

 

                                                                20

 

      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

 

                                                                21

 

      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.

 

                                                                22

 

      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

 

                                                                23

 

      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

 

                                                                24

 

      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

 

                                                                25

 

      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

 

                                                                26

 

      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

 

                                                                27

 

      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,

 

                                                                28

 

      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

 

                                                                29

 

      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

 

                                                                30

 

      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

 

                                                                31

 

      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

 

                                                                32

 

      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

 

                                                                33

 

      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

 

                                                                34

 

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

 

      percent reduction in the risk of death in never

 

      smoking patients treated with Iressa compared to

 

      placebo.  There was no significant difference in

 

      ever smokers.

 

                Similarly, this slide shows survival

 

      curves by ethnic origin.  Again, you can see there

 

      was a 34 percent reduction in the risk of death in

 

      Asian patients treated with Iressa compared to

 

      placebo, and there was no significant difference in

 

      non-Asian patients.

 

                I would like to move on now to look

 

      briefly at the safety data in Trial 709.  I should

 

      note these data have become available since we

 

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

 

      your papers.

 

                The adverse event profile in Trial 709 is

 

      consistent with the established safety profile for

 

      Iressa with the most common adverse events being

 

      rash and diarrhea.

 

                Notably, there was little difference

 

      between the treatments in terms of serious adverse

 

                                                                35

 

      events, adverse events leading to withdrawal, and

 

      the incidence of interstitial lung disease.

 

                Here is a summary of the most common

 

      adverse events in the trial ordered from highest to

 

      lowest frequency in Iressa-treated subjects.

 

                As you can see, with the exception of rash

 

      and diarrhea, which I just mentioned, there is

 

      little difference between Iressa and

 

      placebo-treated patients in terms of the adverse

 

      event reporting.  In particular, there were

 

      relatively few Grade 3/4 adverse events in

 

      Iressa-treated subjects.

 

                This list of adverse events continues on

 

      this slide where again it can be seen there is

 

      little difference between Iressa and

 

      placebo-treated subjects.

 

                As I mentioned at the outset, the

 

      preliminary data we saw on December 16th were

 

      validated and finalized as of the 2nd of February

 

      2005.  These final data confirmed a total of 976

 

      deaths occurring on or before the October 2004 data

 

      cutoff.  With only 7 additional deaths, it is

 

                                                                36

 

      obviously not surprising that the findings based on

 

      the preliminary data remain unchanged.

 

                On reviewing the data in December, the

 

      Independent Data Monitoring Committee recommended

 

      that further follow-up of Trial 709 should be

 

      obtained.  Having seen somewhat late separation in

 

      the Kaplan-Meier curve, they were unwilling to rule

 

      out that further separation could occur with more

 

      follow-up.

 

                Hence, survival data were updated as of

 

      the end of January, which provided for a further 3

 

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

 

      months and overall mortality in the trial to 70

 

      percent.

 

                As you can see, these further data are

 

      consistent with the planned protocol analysis, and

 

      despite increased crossover in the placebo arm to

 

      Iressa, variability in survival outcomes continues

 

      to be seen.

 

                To briefly summarize what we have shared

 

      today, the data seen on December 16 showed some

 

      improvement in survival in Iressa-treated patients,

 

                                                                37

 

      but the magnitude of that improvement was not

 

      sufficient to reach statistical significance in the

 

      primary stratified log-rank test.

 

                Overall, however, considering both primary

 

      and secondary endpoints, these data showed that

 

      Iressa was efficacious in the population study, but

 

      there was marked variability in survival outcomes.

 

                So, with that, I would like to thank you

 

      for your attention and hand over to my colleague,

 

      Dr. Ochs.  Judy.

 

                   Clinical Actions and Implications

 

                DR. OCHS:  Thank you, Kevin.

 

                In this part of our presentation, I would

 

      like to briefly summarize AstraZeneca's actions to

 

      communicate the results of Trial 709 to the

 

      oncology community.  Following this, I would like

 

      to give an overview of the clinical implications of

 

      the Trial 709 data, review some of the immediately

 

      relevant emerging science, and conclude with our

 

      proposed or ongoing development proposals.

 

                In agreement with the FDA, AstraZeneca

 

      concluded that it was in the best interest of

 

                                                                38

 

      patients that the information on Trial 709 be

 

      rapidly, extensively, and clearly communicated.

 

                On December 17th, a Dear Doctor letter

 

      approved by the FDA was distributed by AstraZeneca.

 

      This communication provided physicians with the

 

      needed information to enable them to make the most

 

      appropriate treatment decisions.  The expectation

 

      was that this communication would greatly reduce

 

      the number of patients receiving Iressa for the

 

      first time.

 

                In addition, AstraZeneca would provide to

 

      the FDA, prescription data every two weeks to be

 

      able to assess the continuing impact of the

 

      communications.

 

                It was also agreed that a key goal was to

 

      maintain Iressa availability to those patients

 

      already benefiting who would wish to continue and

 

      had concerns about possible Iressa availability.

 

                A commitment was given to the FDA that

 

      AstraZeneca would rapidly provide them with all of

 

      the data as it became available to allow them a

 

      thorough and informed analysis.

 

                Upon public release of the top line Trial

 

      709 survival results a series of extensive

 

      communications were simultaneously begun and are

 

                                                                39

 

      listed on this slide, and were previously mentioned

 

      by Dr. Pazdur.

 

                Taken as a whole these actions were

 

      designed to ensure that relevant physicians would

 

      be aware of the results and be reminded that

 

      alternative therapeutic options with proven

 

      survival benefits should be considered.

 

                On January 6, the FDA and AstraZeneca met

 

      and agreed upon the following steps for continuing

 

      communication of the Trial 709 data.  A public

 

      disclosure of the then available results would be

 

      made at the first available scheduled ODAC meeting,

 

      today, acknowledging that the further trial data

 

      would still be pending.

 

                Ongoing communication of the Dear Doctor

 

      letter was to be done using journal placement and

 

      the full clinical data would be submitted and

 

      presented at scientific meetings and published in

 

      refereed scientific journals as soon as possible.

 

                Abstracts have been submitted to the AACR

 

      meeting, as well as the World Lung Cancer

 

      Conference.  A full publication submission is

 

      planed in the May-June time frame.

 

                Here is a copy of the Dear Doctor letter,

 

      which I realize you cannot read.  The letter,

 

                                                                40

 

      however, does include the survival results in the

 

      overall and adenocarcinoma subpopulation along with

 

      median survival and respective hazard ratios.

 

                The sentence highlighted in red above is

 

      included in the body of the letter and urges

 

      physicians to consider other treatment options.

 

      This is how the letter is being displayed in the 10

 

      most widely read oncology journals, and a list of

 

      these journals is shown in the next slide.

 

                The impact on Iressa usage has been marked

 

      in the 10 weeks since the Dear Doctor letter was

 

      first sent out. There has already been a

 

      significant reduction in the prescriptions written

 

      for Iressa, and our internal AZ usage data also

 

      indicates marked reduction.

 

                Market research, that we have just

 

                                                                41

 

      obtained from 100 community oncologists, indicates

 

      that the great majority are aware of the data

 

      contained in the Dear Doctor letter and have

 

      modified their treatment practice accordingly.

 

                Thus, all of the agreed upon communication

 

      actions have been set in motion, and the available

 

      information suggests that the oncology community is

 

      aware of and acting on the information.

 

                The larger question is now being asked:

 

      What are the clinical implications of the Trial 709

 

      data, and what are the next steps?  These are

 

      clearly important questions for oncologists and

 

      patients since Iressa possesses significant durable

 

      anti-tumor activity which has greatly benefited

 

      some patients and some patient subsets.

 

                Yet, in Trial 709, Iressa did not meet the

 

      statistically defined survival endpoint in an

 

      unselected patient population.

 

                Advances in understanding of the molecular

 

      biology in this area of EGFR inhibition, as well as

 

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

 

      occurring rapidly and have the potential to better

 

                                                                42

 

      select or predict those patients who would benefit

 

      beyond, or in addition to, clinical

 

      characteristics.

 

                What are the questions that we are asking

 

      as we seek to understand the Trial 709 outcomes,

 

      and not wrongly or prematurely make conclusions

 

      about the actual role or place of Iressa, an agent

 

      with anti-tumor activity in the treatment of a

 

      disease with a continuing poor prognosis?  Why did

 

      this result occur?

 

                How does this result compare with our

 

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

 

      findings in our trial due to play of chance?  Was

 

      the dose selection appropriate?  Were there

 

      methodologic issues, such as the trial population

 

      and where the trial was conducted of any potential

 

      impact on the findings?

 

                What biologic data may be available now

 

      and in the future to help better understand the

 

      clinical outcomes, and what further relevant

 

      clinical data in the recurrent non-small cell lung

 

      cancer setting are expected?

 

                Firstly, how does the survival outcome

 

      seen in Trial 709 compare to other data with

 

      Iressa?  As was previously mentioned by Dr. Scott

 

                                                                43

 

      in our Phase II program, a striking and

 

      unanticipated finding was the apparent high rate of

 

      response in patients with certain clinical

 

      characteristics.

 

                It can be seen if one compares these Phase

 

      II response rates with those in Trial 709, and the

 

      Phase II results are in the right-hand column in

 

      yellow, and the 709 results in the middle column in

 

      white, that the same patient groups continued to

 

      show higher response rates.

 

                In addition to these higher response

 

      rates, the subgroups having the highest response

 

      rates experienced the greatest benefit in survival.

 

      The patient subgroup with the highest response rate

 

      were the never smokers, and as previously noted,

 

      the survival in this subgroup was significantly

 

      increased.

 

                Similar trend, although not of the same

 

      magnitude, of survival benefit was seen in women

 

                                                                44

 

      and with the adenocarcinoma group.

 

                Continuing with this line of inquiry,

 

      higher response rates and statistically significant

 

      survival results and benefit were seen in those

 

      patients of Asian descent.

 

                Could chance have played a role as the

 

      defined survival endpoint was so narrowly missed?

 

      Trial 709 and the erlotinib trial BR21 are the only

 

      two Phase III survival trials which compare an oral

 

      EGFR inhibitor with placebo in the recurrent

 

      non-small cell lung cancer patient population.

 

                Both Iressa and erlotinib have similar

 

      overall response rates as can be seen in the

 

      right-hand portion of the slide.  The erlotinib

 

      trial did reach statistical significance for the

 

      overall population.

 

                Juxtaposing overall survival hazard ratios

 

      as we have done in this slide shows that while the

 

      point estimates differ, there is a high degree of

 

      overlap in the confidence intervals.  The small

 

      confidence interval in Trial 709 reflects the

 

      larger trial size in 709, which is almost twice

 

                                                                45

 

      that of the BR21 trial.

 

                Dose selection.  Since there appears to be

 

      a difference in magnitude of survival benefit in

 

      BR21 compared to Trial 709, questions about the

 

      adequacy of the Iressa dose have arisen

 

      irrespective of the data used to support its use in

 

      this trial.

 

                The erlotinib dose used was at the maximal

 

      tolerated dose, while the Iressa dose is one-third

 

      the maximal tolerated dose, reflecting different

 

      development strategies.

 

                As you might guess, we have gone back and

 

      re-evaluated our prior experience in light of the

 

      current data. Our extensive Phase I program had 280

 

      patients, and these patients received doses ranging

 

      from 50 mg to 1,000 mg.

 

                Responses and durable stable disease first

 

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

 

      dose response evident from 150 mg through 1,000 mg

 

      with respect to partial response rates, partial

 

      response rates plus stable disease rates, or the

 

      duration on Iressa therapy.

 

                In our Phase II trials, as previously

 

      mentioned, we formally compared the 250 and 500 mg

 

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

 

                                                                46

 

      minimum dose that we saw responses and stable

 

      disease at, and 500 mg dose was chosen in part

 

      because of minimizing the amount of patient

 

      interruptions of therapy due to toxicity.

 

                We found no difference in efficacy

 

      including survival although the adverse events and

 

      therapy interruptions were more frequent at the

 

      higher 500 mg dose.

 

                Admittedly, however, we have not

 

      rigorously evaluated doses above 500 mg, and it is

 

      unknown if doses above 500 mg would achieve better

 

      overall or patient subset survival outcomes.  Due

 

      to the lack of data, we cannot rule this out

 

      entirely.

 

                Speculatively, can the inability to

 

      achieve statistically significant survival be

 

      explained by too few patients likely to benefit

 

      based on their advanced disease status with

 

      refractoriness as specified in our patient

 

                                                                47

 

      inclusion criteria.

 

                Another area to further explore are the

 

      impact of environmental factors, such as smoking,

 

      as it relates to various geographic regions where

 

      the trial was conducted.

 

                As Mr. Carroll showed, over one-third of

 

      the patients on Trial 709 were from Eastern Europe

 

      where the median pack year exposure was very high.

 

      Patients with the highest smoking exposure appear

 

      less likely to benefit from EGFR inhibitor therapy.

 

                We have looked at our data and found a

 

      continuous spectrum in terms of survival benefit,

 

      with the greatest survival benefit appearing in

 

      never smokings, but it continues with the amount of

 

      exposure to smoke.

 

                So, what can we conclude at this point?

 

      Iressa is an active agent, the response data are

 

      consistent in our Phase II and III trials.  The

 

      patients most likely to benefit are those patients

 

      who never smoked and those of Asian ethnicity.

 

                With these consistent findings, using an

 

      agent that inhibits a specific receptor and

 

                                                                48

 

      pathway, it is logical to assume that there is an

 

      underlying biologic basis.  In the last 10 months,

 

      two areas of translational research have been

 

      fruitful and may be useful in better understanding

 

      the clinical data in our Phase III program in Trial

 

      709, as well as guide therapy in our future

 

      development.

 

                The two biomarkers of most promise

 

      currently are EGFR expression and the EGFR

 

      mutations.  Published Iressa Phase II data did not

 

      appear to show definitive correlation of EGFR

 

      expression with response, but tumor samples were

 

      not available from all patients, and the trials

 

      were not controlled.

 

                Recently, however, results relating EGFR

 

      expression to survival outcomes were included in

 

      the erlotinib label.

 

                The second promising biomarker are

 

      activating mutations.  These were first described

 

      approximately 10 months ago in responding Iressa

 

      patients.  There are other promising, but more

 

      exploratory biomarkers that are included in the

 

                                                                49

 

      Iressa science program including gene copy number

 

      and dimerization patients, but again these remain

 

      more exploratory.

 

                What I would like to do now is show you

 

      from the erlotinib label--and I have included the

 

      three graphs they have relating to EGFR

 

      expression--and to ensure perfect synchronicity and

 

      accuracy, I am going to read the portion for you

 

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

 

      right-hand column.

 

                What we see here are three graphs.  The

 

      graph to the upper far left is the graph of the

 

      patients who had positive EGFR expression in their

 

      tumors, with the lower part of the Kaplan-Meier

 

      showing the patients treated with placebo.

 

                The graph to your far right, on the

 

      upperhand side is the patients who were EGFR

 

      expression-negative compared to placebo.  The lower

 

      lefthand is those patients that they did not have

 

      EGFR expression data on.

 

                As stated in the label, Tarceva prolonged

 

      survival in the EGFR-positive subgroup and the

 

                                                                50

 

      subgroup whose EGFR status was unmeasured, but did

 

      not appear to have an effect on survival in the

 

      EGFR-negative subgroup.  However, the confidence

 

      intervals for the EGFR-positive, negative, and

 

      unmeasured subgroups are wide and overlap, so that

 

      a survival benefit due to Tarceva in the

 

      EGFR-negative subgroup cannot be excluded.

 

                It needs to be said that a positive EGFR

 

      expression status in this study was defined as

 

      having at least 10 percent of cells staining

 

      positive for EGFR in contrast to the 1 percent

 

      cutoff specified in the DAKO EGFR pharmDx kit

 

      instructions.

 

                The use of the pharmDx kit has not been

 

      validated for use in non-small cell.  Accordingly,

 

      the data to date are inconclusive, but tantalizing

 

      as to the predictive nature of EGFR testing.

 

                In this trial, as in Trial 709, the tumor

 

      sample collection was not mandatory, and thus the

 

      number of samples is less than the number of

 

      enrolled patients.

 

                This is a busy slide and summarizes a very

 

                                                                51

 

      busy area of research in the 10 months since

 

      mutations were first described.  As noted on this

 

      slide, mutation appears to occur almost exclusively

 

      in non-small cell lung cancer.  The mutation is

 

      activating and in the ATP-binding site, which is

 

      where Iressa's activity occurs.

 

                I mentioned that the mutation was first

 

      described in patients with rapid, dramatic and

 

      prolonged responses to Iressa.  The increased

 

      frequency of the mutation occurs in patient subsets

 

      where Iressa responses are most frequent and where

 

      the survival benefit is most likely to be seen,

 

      that is, those patients who were never smokers,

 

      patients of Asian descent, women, and

 

      adenocarcinoma histology.

 

                There are actually two papers out this

 

      week looking at smoking status in relationship to

 

      the presence of these activating mutations, and

 

      depending on the paper, a minimum of 25 percent to

 

      75 percent of patients in different geographic

 

      regions who were never smokers have the mutation

 

      present.

 

                While patients whose tumors possess this

 

      type of somatic mutation appeared to be much more

 

      likely to have a response, all patients with

 

                                                                52

 

      mutations do not have a response.  We have recently

 

      looked at our IDEAL II data, and in the small

 

      subset with 14 mutations that we detected, 6 of

 

      these patients had prolonged partial responses.

 

                Again, where are we?  EGFR expression

 

      appears to be associated with increased survival.

 

      EGFR mutations appear to explain some, but not all,

 

      of the responses to Iressa.

 

                Outcomes in Trial 709, comparing Iressa to

 

      placebo, will be explored in terms of EGFR

 

      expression, activating mutation, and other

 

      biomarkers.

 

                We anticipate that this data will be

 

      available in June 2005.  We have collected close to

 

      600 tumor samples.  Approximately 400 of them we

 

      estimated based on our past experience will be

 

      fully evaluable for EGFR expression, and 200 for

 

      mutation status.

 

                It is hoped that these results may provide

 

                                                                53

 

      further insight into the clinical outcomes that we

 

      have seen in Trial 709.

 

                Thus, with these current clinical and

 

      translational data, what prospective studies are

 

      underway or could be considered?

 

                One proposal would be to evaluate patients

 

      with metastatic disease and compare the outcomes of

 

      Iressa with chemotherapy.  Mandatory tissue

 

      collection is an obvious requirement to evaluate

 

      the utility of biomarkers with respect to both

 

      outcomes in both the chemotherapy-treated patients

 

      and in patients with EGFR expression or

 

      overexpression.

 

                Targeted studies in patient populations is

 

      another obvious way to proceed.  We have an ongoing

 

      Phase II trial which is enrolling patients who are

 

      mutation-positive, another trial that is a trial

 

      that should be considered is that in patients who

 

      are never smokers.

 

                Never smokers represent 20 percent of the

 

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

 

      patients.

 

                Finally, specific trials in the Asian

 

      populations to define the role of Iressa in the

 

      first line setting appear warranted.  Here, too,

 

                                                                54

 

      translational studies would be integral to the

 

      trial.  There are already several trials being

 

      conducted in Asia, as you might anticipate.

 

                A clinical question of increasing

 

      relevance that hasn't been answered to date is that

 

      of comparing both survival outcome and toxicities

 

      of Iressa or any EGFR inhibitor with single agent

 

      chemotherapy.

 

                Trial 721, as previously noted by Dr.

 

      Scott, is a randomized Phase III post-approval

 

      commitment trial which compares Iressa to

 

      docetaxel.  This trial will complete patient

 

      enrollment by the end of the summer, and an interim

 

      survival analysis is expected this May or June.

 

                Trial 721's principal investigators and

 

      steering committees have reviewed the Trial 709

 

      data and continue to support this trial.  Another

 

      similar trial is being conducted entirely in Japan.

 

                Some clinical support to continue at this

 

                                                                55

 

      dose is mature Phase II data in a Caucasian and

 

      Hispanic patient population, which has recently

 

      matured and become available. In addition to

 

      showing comparability with the primary symptom

 

      endpoint, comparable outcomes were seen with

 

      response rates, time to progression, and overall

 

      survival.

 

                The next slide is a Kaplan-Meier survival

 

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

 

      comparability of these trial results.  With a

 

      median follow-up of 9 months and 55 percent overall

 

      mortality, there are no differences between Iressa

 

      and docetaxel.

 

                The overall survival with docetaxel is

 

      consistent with that previously reported with this

 

      agent and in this clinical setting.  Although the

 

      trial is small, if Iressa was behaving as a

 

      placebo, then, one would have expected Iressa to

 

      have performed substantially worse in both time to

 

      progression, as well as overall survival.

 

                Back to our original question:  Where are

 

      we now?

 

                Well tolerated agents in the EGFR

 

      inhibitor class of agents are now an accepted

 

      addition to the therapeutic armamentarium of

 

                                                                56

 

      practicing oncologists and clinical trial

 

      investigators.

 

                Clinical and translational data are

 

      pointing the way to the most appropriate and

 

      optimal use of Iressa.  AstraZeneca and our

 

      clinical investigators remain committed to this and

 

      other biologically targeted agents as the way to

 

      the future.

 

                Thank you.

 

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

 

      realize there was more from AstraZeneca, but if we

 

      want to have some discussion or clarification

 

      before the open public hearing, that would be

 

      appropriate.

 

                                Summary

 

                DR. SCOTT:  Thank you, Dr. Ochs.

 

                As you have heard from both Mr. Carroll

 

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

 

      fully understand Trial 709, and there are other

 

                                                                57

 

      trials, such as Trial 503, that provide supportive

 

      information, and Trial 721, which is also part of

 

      our Subpart H commitment to the FDA.

 

                This slide summarizes some key milestones

 

      that will be occurring.  It is expected that the

 

      complete data from Trial 709 and Trial 503 will be

 

      with the FDA in June for their review.  After that

 

      time, we expect to discuss labeling updates as

 

      appropriate based on the final data findings.

 

                It is expected that the Subpart H

 

      commitment trial, Trial 721, will deliver its final

 

      survival data in November of 2006.

 

                While the drug development road for Iressa

 

      has not been straightforward or without its

 

      surprises, the development program for this agent

 

      has provided a great deal of valuable information

 

      about non-small cell lung cancer and the EGFR

 

      target.

 

                Iressa is an active and well tolerated

 

      agent, and the lung cancer community has urged us

 

      to continue the development of this drug, and we

 

      are committed to doing so.

 

                Trial 709 has provided important patient

 

      selection information in a controlled randomized

 

      setting that may in the future help us write

 

                                                                58

 

      appropriate labeling to guide the clinical use of

 

      Iressa.

 

                You have also heard today the critical

 

      information regarding EGFR expression and mutation

 

      status is yet to be delivered from this trial.

 

                Trial 721, the head-to-head trial versus

 

      docetaxel can provide confirmatory evidence of the

 

      effectiveness of Iressa.  As outlined, the

 

      development program for Iressa will help in

 

      identifying those patients who are most likely to

 

      benefit from Iressa.

 

                AstraZeneca rapidly and thoroughly

 

      disseminated information to oncologists about Trial

 

      709 to ensure informed treatment decisions would be

 

      made while further analysis were underway.

 

                As the patients responsive to Iressa will

 

      tell us, and their physicians will support, Iressa

 

      remains an important treatment option for non-small

 

      cell lung cancer.

 

                We thank the committee for their attention

 

      and welcome any questions at this time.

 

                          Committee Questions

 

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

 

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

 

      Ochs actually had the slide up--where you

 

                                                                59

 

      demonstrated what has been done to disseminate this

 

      information, if you would just flash that one more

 

      time.

 

                I will allow the committee to ask

 

      questions.  We actually have no time allotted for

 

      that, so please keep your questions pertinent to

 

      today's issue, which really is has this information

 

      been appropriately disseminated.

 

                The slide that I want you all to just

 

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

 

      to disseminate this information.  Rick, can you

 

      simultaneously just remind the group what the FDA

 

      has done from its side in terms of disseminating

 

      the information, so that everyone is sort of up to

 

      date.

 

                DR. PAZDUR:  We have notified shortly when

 

                                                                60

 

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

 

      went out from the FDA to ASCO members notifying

 

      them on that day that we received the information

 

      of the study results and alternative treatment.

 

                We have a letter posted on our website

 

      that is included in your packet.

 

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

 

      side, the information has gone out to physicians

 

      primarily, as well as the website.

 

                DR. PAZDUR:  Correct.

 

                DR. MARTINO:  And from AstraZeneca,

 

      information has been provided to physicians, as

 

      well as to the lay public.

 

                DR. OCHS:  Yes.

 

                DR. MARTINO:  At this point, I will take

 

      some questions, but please keep them brief and

 

      succinct.

 

                Dr. Hussain, you are first.

 

                DR. HUSSAIN:  It is a question to either

 

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

 

      you are possibly thinking about targeted

 

      population, I saw that there were no women

 

                                                                61

 

      mentioned and no adenocarcinoma.

 

                Does that mean if you were a smoker and a

 

      woman, that the smoker component takes over as far

 

      as your potential benefit, or that if you are an

 

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

 

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

 

      discuss that particular issue since there is a lot

 

      of interconnection and interplay.

 

                MR. CARROLL:  Thank you for your question.

 

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

 

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

 

      interplay between the factors of interest, be they

 

      Asians, be adenocarcinoma, gender.

 

                The data, as I said, were finalized

 

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

 

      kind of analysis requires multivariate analysis to

 

      actually see which factors are contributing, which

 

      are the ones that are predicting the treatment

 

      effect.

 

                That is something that we do plan to do in

 

      the next coming weeks and months to provide that

 

      data to the FDA, so we can answer the very

 

                                                                62

 

      important question that you have raised, because I

 

      am not sure we have the answer to that today.

 

                DR. MARTINO:  Dr. Perry.

 

                DR. PERRY:  I am not sure who gets this

 

      question, but I have been under the impression that

 

      in Europe particularly, the incidence of squamous

 

      cell carcinoma was considerably higher than in the

 

      United States, so I am somewhat surprised of a 48

 

      percent incidence of adenocarcinoma histology

 

      worldwide, particularly when two-thirds of the

 

      patients seem to be from Europe.

 

                How do you know that these are

 

      adenocarcinomas, is this the local pathologist's

 

      interpretation, and are they inclined to overread

 

      them as adenocarcinomas rather than as non-small

 

      cell carcinomas not otherwise specified?

 

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

 

      come and speak to that point.

 

                DR. BARGE:  Thank you.  Alan Barge,

 

      AstraZeneca.

 

                We have not done central pathology review.

 

      All of the diagnoses were the ones that were

 

                                                                63

 

      confirmed by the hospital pathologists, so we

 

      couldn't answer your question directly, I am

 

      afraid.

 

                DR. MARTINO:  Dr. Rodriguez.

 

                DR. RODRIGUEZ:  I just wanted some

 

      clarification about the actual trial design, and

 

      just have a few questions which might be relevant

 

      because this was done by a variety of cultural

 

      groups.

 

                Were the patients and the investigators

 

      both blinded to the assignment to placebo?

 

                DR. SCOTT:  Yes, it was a randomized

 

      double-blind trial.

 

                DR. RODRIGUEZ:  How was compliance

 

      confirmed in the participants?

 

                DR. SCOTT:  Nick Botwood will come to the

 

      stand.

 

                DR. BOTWOOD:  Thank you.  Nick Botwood,

 

      AstraZeneca.  We did look at compliance on this

 

      trial and found that over 90 percent of the

 

      patients were compliant and had taken at least 95

 

      percent of their medication.

 

                This was based primarily on data that we

 

      collected in the CRF in terms of any documented

 

      dose interruptions for whatever reason, and then we

 

                                                                64

 

      went on to further validate that, to actually look

 

      at the number of tablets that were returned and

 

      looked at the number of tablets that had actually

 

      been prescribed to validate that what was in the

 

      CRF was actually the correct information.

 

                DR. RODRIGUEZ:  Along those lines, was

 

      there a required or concurrent diarrhea prophylaxis

 

      program, and was compliance to that also monitored?

 

                DR. BOTWOOD:  That wasn't, no.

 

                DR. RODRIGUEZ:  It is interesting because

 

      your failure to treatment has a significantly

 

      different profile with regards to symptoms and

 

      adverse events.  It seems that the patients on the

 

      Iressa arm, a higher proportion were taken off

 

      study because of those problems, is that correct?

 

      That is what your bar graph seemed to show.

 

                DR. BOTWOOD:  Kevin Carroll can answer

 

      that question, please.

 

                MR. CARROLL:  If I am correct, you are

 

                                                                65

 

      asking whether there was a difference in withdrawal

 

      due to--

 

                DR. RODRIGUEZ:  Yes, side effects.

 

                MR. CARROLL:  Side effects.  As I showed

 

      when we went through the adverse event data, there

 

      was very little difference between the two

 

      treatments in terms of withdrawal due to adverse

 

      events, and in terms of the data that we obtained

 

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

 

      fewer--Iressa failed fewer patients due to

 

      progression than placebo, so I don't think the

 

      difference was there in the way that perhaps you

 

      think.

 

                DR. MARTINO:  Dr. Levine.

 

                DR. LEVINE:  I also have several

 

      questions.  First, you mentioned crossover.  How

 

      many of these placebo patients did cross over to

 

      Iressa?

 

                DR. SCOTT:  Dr. Botwood.

 

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

 

      crossover from placebo to Iressa in this trial was

 

      only 3 percent.

 

                DR. LEVINE:  Three.  Do you have data on

 

      other treatment beyond, you know, crossover to

 

      anything?

 

                                                                66

 

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

 

      patients that went on to receive any subsequent

 

      chemotherapy was 10 percent, and this was balanced

 

      between the Iressa and placebo arm.

 

                DR. LEVINE:  Just to further that a little

 

      bit, even complementary therapies in Asia, and so

 

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

 

                DR. BOTWOOD:  It was extremely small.

 

                DR. LEVINE:  My other question related to

 

      the concept of secondary smoke.  In Eastern Europe

 

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

 

      even individuals who say that they weren't smokers

 

      may have been exposed, and therefore, did you look

 

      at cotinine levels or anything?  That might be

 

      something to explore, or did you look at that?

 

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

 

      at that. When we looked at the smoking demography

 

      of the patients from Eastern Europe, approximately

 

      85 percent of the patients from Eastern Europe were

 

                                                                67

 

      heavy smokers, and they had a higher median year

 

      exposure than the patients from other regions, but

 

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

 

                DR. MARTINO:  Dr. D'Agostino?

 

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

 

      time keeping my questions solely to the material

 

      that has been circulated as opposed to asking a

 

      million questions about the study, but the question

 

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

 

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

 

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

 

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

 

                I understand that the study did run its

 

      course, and then you did an analysis with unclean

 

      data or not completely clean data, and then later

 

      on had clean data, or was the analysis you are

 

      reporting an interim analysis?

 

                DR. SCOTT:  The analysis that we reported

 

      on in December was not an interim analysis.  It was

 

      based on final survival data, but it had been yet

 

      to be validated.

 

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

 

                                                                68

 

      validation. Thank you.

 

                DR. MARTINO:  Dr. Proschan.

 

                DR. PROSCHAN:  You mentioned that the

 

      Phase II trials identified subgroups, and ethnicity

 

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

 

      you specifically decided to break it into Asian

 

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

 

      difference?

 

                DR. SCOTT:  We can have Mr. Carroll talk

 

      about the rationale behind the subgroups that we

 

      planned for Trial 709, and then perhaps have Alan

 

      Barge talk about why we think so.

 

                MR. CARROLL:  The subsets that we have

 

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

 

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

 

      subsets, of course, and they were determined

 

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

 

      also information that came out in June of this year

 

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

 

                There, there was an evaluation of Asians

 

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

 

      findings in the IDEAL trials where our Japanese

 

                                                                69

 

      patients had a much higher response rate was a

 

      motivation to look at that subset amongst others

 

      that were deemed to be clinically relevant.

 

                Perhaps I can now turn to my colleague,

 

      Dr. Barge, to answer the second part of your

 

      question.

 

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

 

      good deal of speculation as to why patients of

 

      Asian ethnic origin appear to do better on this

 

      class of drug.  There have been some quite

 

      interesting publications very recently.  In fact,

 

      this week there was a publication from Dr. Gazda

 

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

 

      frequency of activating mutations of the kind that

 

      Dr. Ochs described is much higher in Asian

 

      populations, particularly female Asians, and

 

      particularly female Asians with adenocarcinoma.

 

                The Phase II studies that we conducted in

 

      various Asian countries all show that the frequency

 

      of responses are much higher in those populations,

 

      and we have seen response rates as high as 60 or

 

      even 80 percent in selected populations of Asian

 

                                                                70

 

      nonsmoking females.

 

                Whether or not that is all driven by

 

      activating mutations we don't know, but that is

 

      certainly a very strong hypothesis at the moment.

 

                DR. MARTINO:  Mrs. Ross.

 

                MRS. ROSS:  Thank you, Madam Chair.

 

                If I understand correctly, the primary

 

      purpose of this hearing is to evaluate or just to

 

      discuss the transparency of the post-approval

 

      process and the adequacy of the notifications.

 

                In that regard, I would like to advise the

 

      rest of the panel of other steps that were indeed

 

      taken by both AstraZeneca and the FDA, and I would

 

      like to thank Dr. Pazdur in particular for his help

 

      on this.

 

                As the only lung cancer advocacy

 

      organization nationwide, we started receiving many

 

      phone calls from patients who were somewhat

 

      panicked when they heard the news in the press that

 

      Iressa might be pulled.  The press always leaps to

 

      the worst possible conclusion, as you all know.

 

                These people were discussing stockpiling

 

                                                                71

 

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

 

      panic out there. Dr. Pazdur responded, and

 

      AstraZeneca did, by helping us draft more

 

      information, more plain English information to put

 

      up on our website and to tell people over the phone

 

      when they called in a state of panic about Iressa.

 

                I think that should be noted.  I think

 

      that overall, the process was extraordinarily

 

      transparent and more than adequate in dealing with

 

      the situation.  Again, I would just like to thank

 

      FDA and AstraZeneca for all they did.

 

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

 

      make a comment?

 

                DR. TEMPLE:  Just one question.  We

 

      certainly never at any time thought that someone

 

      who had apparently responded to the drug should

 

      lose access to it.  That was never in doubt.

 

                But I wanted to ask you about where

 

      AstraZeneca is at the moment.  This was, shall we

 

      say, an optimistic presentation.  The study, after

 

      all, failed.  You had opportunities to identify

 

      subsets before the study that would be your primary

 

                                                                72

 

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

 

      enough to do that.

 

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

 

      distinction, Ralph may want to comment more--these

 

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

 

      did not win.  That is different from subset

 

      analyses in a study that did win.

 

                But what I really want to know is where do

 

      you come out on the question of new patients with

 

      non-small cell lung cancer being started on Iressa

 

      now.  The material you put out says you should

 

      consider other drugs.  Fine.

 

                But would it be your view that at the

 

      present time, optimism about the future and data

 

      that might come forward notwithstanding, a person

 

      with this disease should really not be started on

 

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

 

      your view anymore?

 

                DR. SCOTT:  Our view is that what was

 

      stated in the Dear Doctor letter then is what is

 

      today, that physicians should consider other

 

      options armed with the information from this

 

                                                                73

 

      particular trial.

 

                If I could ask Dr. Kris to come up and

 

      talk about how this has played out in his practice,

 

      maybe Dr. Burris, as well.

 

                DR. KRIS:  To answer your question, Dr.

 

      Temple, I think the most important thing is to put

 

      this into a context of what is available for a

 

      patient with advanced non-small cell lung cancer

 

      particularly after the failure of initial therapy.

 

                I think that the information that we have

 

      today is that there are some patients, those with

 

      an EGFR mutation, that have, and the literature

 

      today says that they have an 89 percent chance of

 

      having a response, and in those patients, when you

 

      look at their duration of response and survival, it

 

      is clearly prolonged.  In the trials that looked at

 

      survival in mutation positive and negative people

 

      being treated, it is much better with treatment.

 

                So, as a clinician, my first point is to

 

      find those people that have that extraordinary

 

      chance of benefit, that is, mutation-positive

 

      people, and the two surrogates for positive

 

                                                                74

 

      mutation we have today, that is, never smoking

 

      status for U.S. population and worldwide, is

 

      probably Asian, and it is not simply Japanese.

 

      There are reports now from Taiwan, from China,

 

      Singapore.

 

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

 

      are looking at the mutation status of the people

 

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

 

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

 

      overwhelming and knock everybody's eyes out.

 

                But at the moment you have no prospective

 

      data on that subgroup for survival.

 

                DR. KRIS:  The only prospective data that

 

      exists on the treatment of mutation-positive

 

      patients is, frankly, an extrapolation to the never

 

      smoking patients.

 

                DR. TEMPLE:  I understand.

 

                DR. KRIS:  But those are

 

      placebo-controlled trials.

 

                DR. TEMPLE:  But what I am really asking

 

      is what you really mean, and we will probably have

 

      to have subsequent discussions, one might say that

 

                                                                75

 

      you should use the drug with very similar

 

      properties, similar mechanism, et cetera, that has

 

      actually been shown to improve survival.

 

                Are you saying something to the contrary

 

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

 

      thought it was clear, but from your presentation, I

 

      don't.

 

                DR. KRIS:  Well, I frankly think that the

 

      most critical slide there was looking at the hazard

 

      ratios for the two substances, for gefitinib and

 

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

 

      not an AstraZeneca hat right now, and that

 

      clinician's hat is that there is effect there.

 

                You can argue the p value of 0.04 versus

 

      0.07, and there are people here that can do that

 

      much better than I, but from the clinician

 

      standpoint, you have to make that choice.  But you

 

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

 

      patient, you have a man with a squamous cancer

 

      sitting in your office that is smoking today, and

 

      his likelihood of benefit by the literature is

 

      extraordinarily small, well under 5 percent.

 

                So, for that patient, you are going to

 

      make another choice, so that the choice for the

 

      patient is not going to be decided by this trial as

 

                                                                76

 

      a clinician.

 

                DR. TEMPLE:  I am really asking about what

 

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

 

      for an EGFR order of treatment now based on

 

      available data.  I actually thought you thought

 

      that for the moment, one should use the drug that

 

      actually won, but I no longer perceive that in your

 

      presentation.

 

                DR. KRIS:  I am talking about from a

 

      clinician's standpoint, and I interpret the whole

 

      of the data as unbelievably consistent.  I mean I

 

      think it is extraordinary that when you look at the

 

      mutations, when you look at the response rates

 

      across country, across drug, it is how consistent

 

      it is, particularly the smoking observation.

 

                DR. TEMPLE:  The pattern may be the same.

 

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

 

      as the other one even though the pattern is the

 

      same.  It is possible.

 

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

 

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

 

      data in my estimation, and this is one piece of

 

      data today.

 

                DR. PAZDUR:  But Mark, you pointed out

 

      that you may look at the mutational status in

 

                                                                77

 

      making a decision, but really, in the United

 

      States, only a small number of people really have

 

      that available to them.

 

                DR. KRIS:  Rick, from a practical

 

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

 

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

 

      limited availability right now.  The decision is

 

      made on clinical grounds, and the surrogates for

 

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

 

      never smoking status and Asian birth, and that is

 

      how we make our decision.

 

                DR. PAZDUR:  I have another question for

 

      AstraZeneca.  In your presentation, you noted a

 

      decrease in new prescriptions.  Could you tell us

 

      what you mean by new prescriptions for Iressa, does

 

      that mean new patients or simply renewal of

 

                                                                78

 

      prescriptions of existing patients that are already

 

      on it, or can you distinguish between that?

 

                DR. SCOTT:  The new prescriptions are not

 

      new patients, they are a mixture of patients that

 

      are getting a refill of prescriptions, because

 

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

 

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

 

      be for new patients, but I will ask Carolyn

 

      Fitzsimons to talk about that data, how we are

 

      interpreting it with the availability of other

 

      information that is indicative of most--

 

                DR. PAZDUR:  Because we are very much

 

      interested, following up on Bob's question, how

 

      many new patients--

 

                DR. SCOTT:  Right, and I will ask Carolyn

 

      Fitzsimons to come and speak to that.

 

                MS. FITZSIMONS:  Thank you.  Carolyn

 

      Fitzsimons, AstraZeneca.

 

                If I can just show the slide as to what is

 

      happening with the prescription data and try and

 

      answer your question, Dr. Pazdur, in terms of

 

      specifically new patients.

 

                We have not been able to secure a source

 

      to actually define new patients, so we have to take

 

      the new prescription data as indicative of what is

 

                                                                79

 

      happening in the marketplace.

 

                The new prescription data, as Mark has

 

      just explained, is not wholly attributed for by new

 

      patients.  It encompasses every time a new

 

      prescription is written, so a repeat prescription.

 

                From the data that we have and is shown

 

      here, on the significant decrease that we have seen

 

      in new prescriptions, a 58 percent decrease since

 

      the announcements of Trial 709.

 

                It is our belief, based upon the duration

 

      of therapy of an Iressa patient who is currently

 

      receiving the product, that the majority of these

 

      prescriptions are now being written for patients

 

      who were prescribed Iressa prior to the

 

      announcements of Trial 709, and are receiving

 

      ongoing therapy from consultations with their

 

      physician, therefore, we assume they are deemed to

 

      be benefiting.

 

                We have conducted some market research

 

                                                                80

 

      earlier in February to try and further establish

 

      what is happening with new patients, and from that

 

      data, we have established that physicians are aware

 

      of the Trial 709 results, and are not longer

 

      choosing Iressa as their EGFR inhibitor of choice,

 

      they are choosing erlotinib, and 86 percent of them

 

      indicated that from the market research.

 

                DR. SCOTT:  If I could ask Skip Burris to

 

      come up and talk about what has happened at

 

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

 

      is reflective.

 

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

 

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

 

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

 

      and he and Mark were certainly talking about one

 

      issue, but we felt the need to issue some

 

      guidelines.

 

                Certainly those guidelines were that those

 

      patients that were being treated with Iressa,

 

      should be continued on Iressa, that those patients

 

      who fit into a class where it is felt it

 

      appropriate that an EGFR inhibitor should be

 

                                                                81

 

      utilized, that erlotinib or Tarceva would, in fact,

 

      be the preferred agent in the short term, that

 

      there should be consideration given based on the

 

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

 

      patients were intolerant of one or the other, to

 

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

 

      has occurred in at least several patients.

 

                Lastly, and maybe most importantly, is the

 

      fact that as a conscious decision, analyzing the

 

      data within our group, we have continued to accrue

 

      and randomize patients on a count done quickly

 

      yesterday, 9 patients, in fact, randomized to

 

      Iressa in a controlled Phase III trial in patients

 

      with refractory lung cancer.

 

                So, the believe of the group, as Mark

 

      alluded to, certainly subsets that will benefit,

 

      but we have continued to accrue to trials comparing

 

      a new agent with Iressa in this setting, so that

 

      accounts for some of the new prescriptions written

 

      in our group, as well.

 

                While the comment, and I certainly agree

 

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

 

                                                                82

 

      have a winner here in the sense that there is not

 

      randomized data between erlotinib and gefitinib to

 

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

 

      this class is heading into what subsets will

 

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

 

      head the differences in the two.

 

                Certainly there are small differences in

 

      terms of mechanism of action, pharmacology and

 

      toxicity.

 

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

 

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

 

      public forum.

 

                MRS. ROSS:  Thank you very much, Madam

 

      Chair.

 

                I just had a quick question actually for

 

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

 

      are you, that doctors should not be allowed to

 

      write new prescriptions for Iressa?

 

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

 

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

 

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

 

      prescription--a new prescription for Iressa in

 

                                                                83

 

      someone who is already on the drug and responding

 

      to it is not an issue.

 

                MRS. ROSS:  New patient new to the drug.

 

                DR. TEMPLE:  I am more worried about what

 

      AstraZeneca is telling people.  I thought it was

 

      fairly clear they thought, given a choice, for

 

      someone who wants that mechanism, they would use

 

      the drug that actually showed a benefit, not the

 

      drug that didn't.

 

                I no longer am clear that that is their

 

      goal after this presentation today.  It sounds much

 

      more ambiguous than that, and I am just trying to

 

      find out what it is.  I thought the comment about

 

      what is being done in Tennessee makes a lot of

 

      sense, if you think that therapy is appropriate,

 

      use the drug that won.

 

                Look, we have been pushing, if anything,

 

      the idea that there are subsets of the population

 

      that are more likely to respond than others, and

 

      that has been I think apparent from the earliest

 

      data with Iressa.  There undoubtedly are

 

      differences among subsets of the population.

 

                But Ralph can comment on this.  All of

 

      those differences in a trial are much more credible

 

      when the trial wins overall or when you have

 

                                                                84

 

      specified that as the primary endpoint.  It remains

 

      somewhat after the fact, not implausible given the

 

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

 

      are much more likely to respond.

 

                All those things are probably true, but

 

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

 

      which has a quite successful overall clinical

 

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

 

      time people would suggest that you use the one that

 

      actually had the favorable result.

 

                I thought that was the direction

 

      AstraZeneca was urging people to go.  I am not as

 

      sure of that after hearing the presentation today.

 

                DR. SCOTT:  Could I--

 

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

 

      question here.

 

                Has the FDA had the opportunity to review

 

      the materials that have been prepared by

 

      AstraZeneca?

 

                DR. TEMPLE:  Yes.

 

                DR. MARTINO:  You have.  So, you have

 

      seen, in fact, the written materials?

 

                DR. PAZDUR:  The written materials, yes.

 

                DR. MARTINO:  Okay.  And can I trust that

 

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

 

                                                                85

 

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

 

      decided that they are okay with you?  I

 

      understand--

 

                DR. TEMPLE:  We did.  I am now slightly

 

      nervous about them.

 

                DR. MARTINO:  I understand the concept of

 

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

 

      a committee, can judge is the steps that they have

 

      taken, the material that they have supplied, and

 

      the content, the written content in that material,

 

      is it fair, appropriate, and informative.

 

                What their intent might be in their gut

 

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

 

      understand your question, but it is not really what

 

      this committee can deal with.

 

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

 

                                                                86

 

      question?  I mean I thought that what we were

 

      looking at was basically this letter, and that I

 

      think is fine, and I think it reflects what the

 

      data shows.

 

                I am bothered by the presentation that

 

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

 

      and then showing this presentation, because the

 

      presentation has a completely different bent to it,

 

      and my question was going to be, what is their

 

      presentation to the field, is it just this letter,

 

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

 

      than the people who are running the studies.

 

                The ones who are running the studies

 

      obviously have to see this, but what is the

 

      collection of M.D.'s being told?

 

                DR. MARTINO:  That is an important

 

      question, that, I would like the company to answer

 

      to.

 

                DR. SCOTT:  If I could respond first and

 

      have Judy Ochs talk about the intent of the letter.

 

      Again, the intent of the letter in December is the

 

      intent today, and I will have Judy Ochs talk about

 

                                                                87

 

      the intent, please.

 

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

 

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

 

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

 

      letter is true.  It is no less true today.

 

                The presentation today, however, reflects

 

      some time, now that we have the full totality of

 

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

 

      be submitted to you.  The FDA will review it.

 

      Again, many times when one goes through protocols

 

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

 

      be some aspects to the interpretation.

 

                The bottom line, that the trial did not

 

      meet statistical significance has not changed.

 

                DR. MARTINO:  One more question and then I

 

      will turn to the open forum, please.

 

                DR. REAMAN:  You did show data today about

 

      a particular subgroup or subgroups that do appear

 

      to potentially have more of a benefit than others,

 

      the corollary being that there is a large group

 

      that don't appear to have any benefit.

 

                Is that data that has only been made

 

                                                                88

 

      available to you since the letter went out in

 

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

 

      of that in the communication?

 

                DR. OCHS:  When the letter went out, that

 

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

 

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

 

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

 

      people, on Tuesday, and the data went out Friday

 

      morning, it was that quick a happening.

 

                Again, I think as we are looking at the

 

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

 

      say is that as Kevin presented in his presentation,

 

      all of the patients, if you look at the hazard

 

      ratios, it is to the left in terms of potential

 

      benefit for Iressa.

 

                There obviously are, as Kevin pointed out,

 

      variability, but nonetheless, we are looking at a

 

      trial that barely missed reaching statistical

 

      significance, so it is not like there wasn't

 

      benefit, it did not meet a statistically defined

 

      endpoint to which we all agree, and to which we

 

      would not change our recommendation to physicians

 

                                                                89

 

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

 

      Kris and Dr. Burris have brought up other things,

 

      other data that is out there, other information.

 

                And I think one of the things that has

 

      happened is that Iressa has been around for a

 

      while, people have had some experience, so people

 

      will be looking at the literature.  Certainly, the

 

      first opportunity for the data as a whole to be

 

      seen is today.

 

                We submitted it to a scientific forum

 

      where it will be presented.  There will be

 

      questions asked.  It will be questioned, and it

 

      will be submitted to peer-reviewed journals.

 

                          Open Public Hearing

 

                DR. MARTINO:  Thank you.  We will continue

 

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

 

      to turn to the open public hearing.  There are

 

      several of you that have asked to speak, so the

 

      microphone that you will be using is in the center

 

      of the room.

 

                Allow me to read the following in

 

      anticipation of your presentations.

 

                Both the Food and Drug Administration and

 

      the public believe in a transparent process for

 

      information gathering and decisionmaking.  To

 

                                                                90

 

      ensure such transparency at the open public hearing

 

      session of the Advisory Committee meeting, the FDA

 

      believes that it is important to understand the

 

      context of an individual's presentation.

 

                For this reason, FDA encourages you, the

 

      open public hearing speaker, at the beginning of

 

      your written or oral statement to advise the

 

      committee of any financial relationship that you

 

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

 

      known, its direct competitors.

 

                For example, this financial information

 

      may include the sponsor's payment of your travel,

 

      lodging, or other expenses in connection with your

 

      attendance at the meeting.

 

                Likewise, the FDA encourages you at the

 

      beginning of your statement to advise the committee

 

      if you do not have any such financial relationship.

 

      If you choose not to address this issue of

 

      financial relationship at the beginning of your

 

                                                                91

 

      statement, it will not preclude you from speaking.

 

                Ms. Clifford, if you will announce our

 

      speakers, please.

 

                MS. CLIFFORD:  Peter Lurie is our first

 

      speaker.

 

                DR. LURIE:  Good morning.  Peter Lurie

 

      with Public Citizens Health Research Group.  I am a

 

      physician.  I have no conflicts of interest to

 

      disclose.  We take no money from government or

 

      industry.

 

                As the members of the committee will I

 

      hope have noticed by now, this morning Public

 

      Citizen filed a petition with the FDA to remove

 

      Iressa from the market on the grounds that no less

 

      than three mortality studies have now proved

 

      negative.

 

                We, instead, ask that for those patients

 

      who remain on the drug, and completing courses of

 

      therapy, that they can receive the drug through IND

 

      status.

 

                You will notice, too, that in Europe, the

 

      marketing application for Iressa has been withdrawn

 

                                                                92

 

      and that in Japan, the Ministry is giving serious

 

      consideration to removing the drug from the market.

 

                As you all know, Subpart H is the

 

      mechanism through which this drug was approved, and

 

      to emphasize, that accelerated approval law makes

 

      clear that the FDA may withdraw approval of a fast

 

      track product "if a post-marketing clinical study

 

      fails to verify clinical benefit." That is

 

      certainly the case over here.

 

                In fact, even prior to approval, there

 

      were a couple of studies that showed lack of

 

      clinical benefit, and the two instant studies were,

 

      in the words of the FDA medical officer,

 

      "unambiguously negative," and the medical officer

 

      made the observation that "the FDA has never

 

      received a cancer drug application for accelerated

 

      approval when definitive data in another related

 

      setting showed a lack of efficacy."

 

                Those were first line therapy trials,

 

      which were both negative with respect to mortality,

 

      and the drug on the market for third line therapy,

 

      of course, we will acknowledge the principle in

 

                                                                93

 

      oncology is that a drug is most likely to work as

 

      first line therapy rather than third line therapy,

 

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

 

      the ISEL has confirmed.

 

                So, we have these two negative mortality

 

      studies even going into the approval of this drug.

 

      Now we have the ISEL study, which shows a very

 

      small survival difference, 27 versus 22 percent,

 

      but not statistically significant under the primary

 

      data analysis.

 

                As you will notice from the slides

 

      presented by AstraZeneca this morning, the overall

 

      quality of life was also not benefited by Iressa.

 

                Instead, what we have seen, you have all

 

      heard of rescue chemotherapy, I think what we have

 

      seen here is rescue biostatistics.  A number of

 

      subanalyses that have been done, some of them

 

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

 

      You will notice from your briefing materials that

 

      some subanalyses are described as prespecified, but

 

      the second table is one that implicitly are not

 

      prespecified. The Asian group is among them.

 

                How many of these subanalyses have been

 

      done?  Why is it that the rather simple to conduct

 

      multivariate analysis has not been done, and why is

 

                                                                94

 

      it that conveniently none of them are ready for

 

      this meeting?

 

                In response, we have seen the FDA put out

 

      a letter.  We have seen another letter from

 

      AstraZeneca, which in effect are telling patients

 

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

 

      kind of public health approach is this to have a

 

      letter from a drug company that, in effect,

 

      suggests that patients not take their drug?

 

                That doesn't seem like an adequate public

 

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

 

      still taking the drug, 331 new prescriptions in the

 

      week of February 18th. The company may claim that

 

      these are not new patients, but there is no

 

      evidence for that either.

 

                The fact is that there is a drug on the

 

      market which has clear, proven mortality benefit,

 

      and patients can easily be diverted from the

 

      effective therapy to this one for which there is no

 

                                                                95

 

      benefit.

 

                As Dr. Temple said, if there are two drugs

 

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

 

                There are also dangers from this drug, and

 

      we have outlined these in prior letters to FDA,

 

      particularly in the area of interstitial lung

 

      disease, 588 deaths now in Japan, and our analysis

 

      of the adverse drug reaction data from FDA show 144

 

      reports of interstitial lung disease including 87

 

      deaths in this country just since the time that the

 

      drug was approved.

 

                What really we are seeing over here is an

 

      elaborate dragging out of this process, a drug that

 

      probably should not have been approved in the first

 

      place, and now, even while empowered by Subpart H

 

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

 

      happened.

 

                How ironic this is.  A company gets a drug

 

      on the market through an accelerated approval

 

      process and then when the data turn out to be

 

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

 

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

 

                                                                96

 

      multivariate analysis that we haven't done, and the

 

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

 

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

 

      in time for this meeting.

 

                These EGFR analyses should be thought

 

      about in the following context.  In the Phase II

 

      trial, there was no relationship between the

 

      expression of EGFR and outcomes. There is no

 

      calculation of a positive predictive value for

 

      these mutations.

 

                Clearly, people without them are

 

      responding and vice versa.  We really don't know

 

      the positive predictive value, and as was also

 

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

 

      something--and even AstraZeneca admits this--that

 

      can be used to distinguish patients at present, and

 

      therefore, decide whether or not to provide them

 

      with therapy.

 

                If this is important enough a question, it

 

      should be researched, and the IND is the

 

      appropriate mechanism to do that.

 

                Finally, to close, with Subpart H, if ever

 

                                                                97

 

      there was a drug that was slated for and eligible

 

      for removal from the market under Subpart H, this

 

      is it, a drug, which even for the

 

      indirect--sorry--for the surrogate marker had

 

      minimal benefit in the Phase II uncontrolled,

 

      non-placebo-controlled, even unblinded trial,

 

      minimal benefit on the surrogate markers, clear

 

      dangers, proven effective therapy in terms of

 

      reducing mortality, and now patients continue to be

 

      placed on the drug, and three negative mortality

 

      studies.

 

                If this drug is not taken off the market

 

      on these grounds, it will make an absolutely

 

      mockery of Subpart H.

 

                Thank you.

 

                MS. CLIFFORD:  Thank you, Mr. Lurie.

 

                Our next speaker is Laurie Fenton.

 

                MS. FENTON:  Good morning.  I am Laurie

 

      Fenton and I am President of The Lung Cancer

 

      Alliance, the only national organization that is

 

      dedicated exclusively to advocating on behalf of

 

      lung cancer patients and their caregivers and

 

                                                                98

 

      survivors.

 

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

 

                MS. FENTON:  Okay.  How is that?

 

                Again, Laurie Fenton, the President of The

 

      Lung Cancer Alliance.  We are the only national

 

      organization that is dedicated exclusively to

 

      advocating on behalf of lung cancer patients, their

 

      caregivers and survivors.

 

                I believe you have my statement, so I will

 

      condense what I would like to present today.

 

                AstraZeneca has provided grants in the

 

      past for educational programs, but they have not

 

      compensated me in any way today to present what we

 

      are here to share.

 

                The Lung Cancer Alliance understands that

 

      the FDA is required by statute to evaluate drugs by

 

      looking at safety and efficacy data in large

 

      populations of patients to determine whether

 

      benefits outweigh the risks.

 

                Interestingly, we have discovered that

 

      Iressa does not fit neatly into this protocol, and

 

      while Iressa's current clinical trial data has not

 

                                                                99

 

      revealed dramatic survival benefits overall, it has

 

      shown striking benefits for a small subset of the

 

      larger population, with less side effects and

 

      quicker response rates.

 

                As was shared earlier, we received many

 

      phone calls from patients who were extremely

 

      concerned that Iressa could be pulled from the

 

      market, particularly a drug that had helped them so

 

      dramatically.

 

                Patients spoke of stockpiling the drug and

 

      beginning to take Iressa every other day to make

 

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

 

      able to hear from patients directly on this point.

 

                The reality is that we have an unmet

 

      public health need.  Lung cancer's mortality

 

      statistics can no longer be ignored.  Beyond

 

      demanding that government redirect its own

 

      resources to effect change, we as advocates also

 

      want to nurture responsible drug development to

 

      help in our fight to eradicate this number one

 

      cancer killer.

 

                Alimta and Tarceva, recently approved for

 

                                                               100

 

      the treatment of lung cancer, are important arrows

 

      in our treatment quiver, but Iressa must also be

 

      recognized as an important weapon in this battle.

 

                Even if unable to meet the broad

 

      population standard, we cannot ignore the fact that

 

      Iressa has shown striking benefits within a subset

 

      of the population, and to this effect, lung cancer

 

      patients and their doctors need all, not limited,

 

      choices now.

 

                It is our hope that both the FDA and

 

      AstraZeneca find a way to allow doctors and lung

 

      cancer patients access to Iressa while, at the same

 

      time, agreeing upon a way to further study and

 

      evaluate the drug.

 

                It could provide a window of opportunity

 

      to better understand the horrible disease that lung

 

      cancer is, who will benefit most from the drug

 

      treatments and why.

 

                I again thank you for allowing us to be

 

      represented here today.

 

                MS. CLIFFORD:  Thank you for your

 

      comments, Ms. Fenton.

 

                Our next speaker is Selma Schimmel.

 

                MS. SCHIMMEL:  Good morning.  My name is

 

      Selma Schimmel.  I am the CEO and founder of Vital

 

                                                               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

 

                                                               102

 

      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

 

                                                               103

 

      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

 

                                                               104

 

      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

 

                                                               105

 

      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

 

                                                               106

 

      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.

 

                                                               107

 

                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

 

                                                               108

 

      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

 

                                                               109

 

      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

 

                                                               110

 

      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. 

 

                                                               111

 

      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,

 

                                                               112

 

      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

 

                                                               113

 

      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

 

                                                               114

 

      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

 

                                                               115

 

      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

 

                                                               116

 

      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

 

                                                               117

 

      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

 

                                                               118

 

      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

 

                                                               120

 

      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

 

                                                               121

 

      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

 

                                                               122

 

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

 

      things that come before this committee are those

 

      that are bathed in shades of gray.

 

                So, I think it is clear that we have

 

      varying viewpoints, that we have very different

 

      interpretations of the evidence before us, and I

 

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

 

      expect that we are going to walk away with a clear

 

      black or white decision.

 

                When I raised my hand half an hour ago, I

 

      was trying to address--

 

                DR. MARTINO:  I do apologize.

 

                DR. PERRY:  Yes, I understand.  You are

 

      doing a wonderful job in a difficult circumstance,

 

      particularly when all of us love to hear our own

 

      voices, they resonate so well.

 

                I was going to address Question No. 2,

 

      which is whether target audiences have been

 

      addressed selectively.  I have to say, to give

 

      credit to AstraZeneca, I have got more notice about

 

      this drug than I have credit card applications, so

 

      they have clearly done a good job in saturating the

 

                                                               123

 

      medical community, at least the lung cancer

 

      doctors.

 

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

 

      have clearly I think gone over and above their

 

      obligation to communicate with doctors.  I can't

 

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

 

      have been so inundated with information about the

 

      adverse effects of a drug.

 

                DR. MARTINO:  I do apologize officially

 

      and personally, and thank you.

 

                Dr. Brawley.

 

                DR. BRAWLEY:  Run down your list, Madam

 

      Chairman. My first thought is I must say to the

 

      advocates I appreciate all four of their comments

 

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

 

      just leave it that I got something positive and

 

      something to think about from every advocate's

 

      statement this morning.

 

                I wonder why so many patients were

 

      concerned that Iressa might be pulled, and was

 

      there some press, did anyone do something to

 

      frighten patients into believing that this drug

 

                                                               124

 

      that they are on is going to be pulled away from

 

      them.

 

                Next, going into Questions 3 and 4, and

 

      actually addressing the advocates and the

 

      survivors, I think we all owe them an apology

 

      because the development of this drug has been

 

      mishandled.  It has been mishandled by AstraZeneca,

 

      it has been mishandled by this committee.

 

                I, myself, take some blame for that,

 

      because I voted for approval of it two years ago.

 

      The fact remains that this drug has been available

 

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

 

      exactly how this drug should be used in the

 

      treatment of lung cancer.

 

                Perhaps if we had held off in getting it

 

      available to people two, three years ago, those

 

      studies would have been done.  There are a number

 

      of studies that have done a number of subset

 

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

 

      saying we should not do subset analysis based on

 

      race, because race or ethnicity is not a biological

 

      categorization of populations, it's non-scientific.

 

                I actually think I was quoted in the press

 

      when I voted for this drug two years ago saying

 

      that this is lung cancer's tamoxifen in search of

 

                                                               125

 

      its estrogen receptor.  Unfortunately, the failure

 

      to totally find and totally categorize that

 

      estrogen receptor is the reason why we are in the

 

      pickle that we are in today.

 

                It may very well be that people--Asian is

 

      a way of racial profiling, and the best way to

 

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

 

      scientifically profile is people who happen to have

 

      that receptor, which may very well be of a higher

 

      prevalence in people who were originally born in

 

      Japan or China, or maybe even Iraq.

 

                That is what we have got to start doing,

 

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

 

      in partial defense of everybody who mishandled the

 

      development of this drug, including myself, this is

 

      one of the first of the targeted therapies to come

 

      along, and none of us really had developed target

 

      therapies a lot before this one came along, so we

 

      need to learn from our mistakes and go forward.

 

                With that, I will relinquish the

 

      microphone.

 

                DR. MARTINO:  Dr. Levine.

 

                DR. LEVINE:  Several comments.  First, I

 

      will agree, I mean there is not winning and not

 

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

 

                                                               126

 

      honestly believe in my soul that there is no

 

      efficacy of this drug.  I think the company have

 

      shown data to suggest that there may be something

 

      there.

 

                The other thing that bothers me a little,

 

      I wasn't on the committee either for Tarceva or

 

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

 

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

 

      drug.

 

                So, my question is, by chance, how many

 

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

 

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

 

      fair to compare one drug to another when those very

 

      important issues have not been presented to us, and

 

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

 

      comment I have.  I feel disquiet about it.

 

                The second is an administrative question.

 

      The company was asked, after accelerated approval,

 

      to do three studies.  One study was agreed upon

 

      that should be dropped, but my question to the FDA

 

      is, if you are going to base everything on one

 

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

 

      three, and what is the administrative concept here,

 

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

 

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

 

                                                               127

 

      them in making our decisions.

 

                That's it.

 

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

 

      to comment on that?

 

                DR. TEMPLE:  Rick has to remind me what

 

      the second study is, but I think the short answer

 

      is this was a very large study.  You would expect

 

      it to be able to detect an overall survival effect

 

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

 

      you something.

 

                It absolutely, as people have said, it

 

      doesn't prove the negative.  A negative study never

 

      proves the negative almost.  Maybe if it's

 

                                                               128

 

      significantly worse than no treatment, but that

 

      hardly ever happens, but it doesn't support the

 

      positive.

 

                Not to get too far apart, but we are

 

      learning in more and more cases that there are

 

      subsets of the overall population that respond, and

 

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

 

      overall effect on survival, that is inevitable.

 

      That doesn't mean the drug is useless.

 

                So, there are obviously people who respond

 

      dramatically, and if you could identify them ahead

 

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

 

      survival benefit in that subset we were sort of

 

      talking about this yesterday, but this is a

 

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

 

      do that.

 

                Just for what it's worth, in the Tarceva

 

      data, there are some very intriguing things.  For

 

      example, if you look at the subsets of people who

 

      do particularly well, like nonsmokers, it's the

 

      nonsmokers who are EGFR-positive who do

 

      spectacularly well, it's not the nonsmokers who are

 

                                                               129

 

      EGFR-negative who do spectacularly well, and that

 

      is true for women and all those subsets.

 

                So, you know, we are not declaring any of

 

      that definitive, the number of patients in the

 

      negative subsets are too small to be definitive,

 

      and the confidence intervals overlap, but you are

 

      starting to get the impression that these data are

 

      telling you something, but it is still early.

 

                But one of my problems with survival data

 

      in general is that if the response rate is low

 

      enough, you can't bring the whole study along

 

      unless you have a population of a million or

 

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

 

      so we have got to get better at identifying who the

 

      potential responders are, so you can study them and

 

      identify them as the people to be responders.

 

                Anyway, the new study even without the

 

      additional study, gives you more information than

 

      you had before, and I think the view would

 

      generally be that that should be reflected in

 

      labeling, and if you learn something else in

 

      addition, you add that.

 

                DR. PAZDUR:  We generally do ask for other

 

      than just one confirmatory trial.  We are

 

      interested for the development of the drug, and we

 

                                                               130

 

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

 

      chance alone obviously.

 

                Given the fact there are other trials, the

 

      docetaxel trial, it was a difficult trial, and we

 

      brought this same question to the committee several

 

      months ago when we looked at Alimta.

 

                One cannot do a non-inferiority trial

 

      here, they have to beat this drug.  A

 

      non-inferiority is impossible to do in this setting

 

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

 

      you with, on this whole issue of non-inferiority

 

      with docetaxel.

 

                But there are problems here, and that was

 

      specifically stated by us, had to be a superiority

 

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

 

      about as clean as you could get here, and

 

      obviously, this is bothersome or we wouldn't be

 

      here to bring this to people's attention.

 

                DR. MARTINO:  Mrs. Ross.

 

                MRS. ROSS:  Thank you, Madam Chair.

 

                First, just an administrative technical

 

      question and then one other question.  I didn't

 

      hear properly the start of the testimony of Ralph

 

      Nader's group.  Did they file a financial

 

      disclaimer on this, or were they testifying on

 

                                                               131

 

      behalf of someone?

 

                DR. TEMPLE:  He stated that he had no

 

      conflict.

 

                MR. LURIE:  I made it perfectly clear that

 

      we have no conflict of interest whatsoever.  We

 

      take no money from AstraZeneca or any other drug

 

      company, or any other corporation, nor from the

 

      government.

 

                MRS. ROSS:  Thank you.  I just wanted to

 

      clarify, I didn't hear that.

 

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

 

      audience the day you voted in favor of accelerated

 

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

 

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

 

      members from FDA, however--

 

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

 

                                                               132

 

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

 

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

 

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

 

      the benefits that have come from this.  First of

 

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

 

      significant number of people who have, in fact,

 

      benefited from Iressa.  Their quality of life, as

 

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

 

      University of Wisconsin, was greatly improved.

 

                Now, they might not be living five years

 

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

 

      what the data is from Japan on longer term survival

 

      with Iressa, but the fact is that there are people

 

      surviving.

 

                Secondly, the other enormous benefit to

 

      come from this is that it is focusing attention,

 

      large populations, on these targeted therapies, and

 

      who knows, maybe Iressa in combination with a VEGF,

 

      or in combination with something else, might be the

 

      real answer to a lot of these recalcitrant late

 

      stage lung cancer, but please, please keep in mind

 

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

 

                                                               133

 

      window, we have another place to go to look and

 

      help these late stage lung cancer patients.

 

                Late stage lung cancer patients only have

 

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

 

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

 

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

 

      you that we need to do more research on these

 

      receptors, in determining who will respond to these

 

      drugs, and we will do anything we can to support

 

      that research.

 

                Perhaps if this committee makes a clamor

 

      for that, we might get the attention of other

 

      government agencies who are charged with that

 

      research and get them talking, too.

 

                DR. MARTINO:  Ladies and gentlemen, this

 

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

 

      group that you have gotten off track here.  Okay?

 

      Even though I keep reminding you, the point today

 

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

 

      the issue here, and some of you refuse to

 

      understand that.

 

                The issue here was have we sufficiently

 

                                                               134

 

      informed the necessary people.  So, I realize there

 

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

 

      satisfaction, would like to hear an answer to that

 

      question, and I am going to start with Dr.

 

      Doroshow.  Are you satisfied that the public and

 

      the physicians have been appropriately informed or

 

      not?

 

                DR. DOROSHOW:  Yes.

 

                DR. BRAWLEY:  No.

 

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

 

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

 

      move quickly on making a resolution about this

 

      particular study, but I think they are informed.

 

                DR. PROSCHAN:  Yes.

 

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

 

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

 

      because as a physician, I have been receiving the

 

      same number of communications by e-mail, letters,

 

      et cetera, that Dr. Perry has.

 

                DR. MORTIMER:  Yes, on the basis of the

 

      e-mails and mail.

 

                DR. PERRY:  Yes.

 

                DR. HUSSAIN:  Yes.

 

                DR. MARTINO:  Yes.

 

                DR. REAMAN:  I will give a conditional yes

 

                                                               135

 

      for the constituency of the medical community, but

 

      I don't think we have actually seen anything that

 

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

 

      be asked to comment or vote on something that we

 

      have never seen.

 

                DR. MARTINO:  I actually think that is a

 

      very fair statement.  I mean we have been told that

 

      the FDA has seen what has been put in the public

 

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

 

      right now we have to kind of trust that.

 

                DR. BRAWLEY:  Madam Chairman--

 

                DR. PAZDUR:  We have examples in your

 

      packet of the letter and their ad.

 

                DR. REAMAN:  The only thing I have in my

 

      packet is a copy of the Dear Doctor letter.

 

                DR. WILLIAMS:  But I do think we should

 

      mention it has been limited, I believe, to the

 

      patients AstraZeneca has access to, which

 

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

 

                                                               136

 

      another way to reach those others.  Certainly, the

 

      advocates have been helpful.

 

                DR. REAMAN:  We heard that there is

 

      announcements on websites.  We have not seen that,

 

      we could have seen that, that could have been

 

      provided, and it wasn't.

 

                DR. BRAWLEY:  Madam Chairman, the basis of

 

      my no vote is I do think the physicians have been

 

      well informed, but I am concerned when I hear

 

      advocates say they are afraid that they are going

 

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

 

      taken away from them while they are on therapy.

 

                DR. RODRIGUEZ:  I concur with the

 

      previously stated comments.  I actually don't know

 

      what the public has heard.  Obviously, the public

 

      heard some negative statements from the press,

 

      otherwise, there would not have been this fear in

 

      the patients about the drug being removed, which

 

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

 

                DR. MARTINO:  Perhaps we can infer the

 

      very fact that the public was so concerned that the

 

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

 

                                                               137

 

      the word that the results are negative must have

 

      gotten out.

 

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

 

      For them to be worried, that is the message that

 

      they heard, however they heard it.

 

                DR. LEVINE:  I agree that the medical

 

      community has been well informed, and I am

 

      respectful for the company of having done a very

 

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

 

      what the committee is asking them to do as far as

 

      the patient community.

 

                I don't think we are saying that they

 

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

 

      this is all wonderful, the drug is available.  We

 

      can't go in that direction.

 

                I would be in favor of a label change, and

 

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

 

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

 

      has directly advertised to the community of

 

      patients on TV and radio, they should be asked to

 

      directly advertise that the drug has difficulties

 

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

 

                MS. HAYLOCK:  I am an oncology nurse and a

 

      member of the Oncology Nursing Society, and I would

 

      just like to add that the Oncology Nursing Society

 

                                                               138

 

      was involved in distribution of information, and we

 

      have a membership of over 30,000 nurses.

 

                So, I think the nursing community, and for

 

      those of you who have been through treatment, I

 

      think you realize that the oncology nurses are the

 

      ones who are oftentimes involved in informed

 

      consent and also patient and family information,

 

      and teaching, and for caregivers, as well.

 

                So, I think the nursing community was also

 

      involved in the dissemination of information to

 

      recipients and patients and caregivers.

 

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

 

      sent out to ASCO simultaneously goes out to ONS

 

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

 

                MRS. ROSS:  Yes, we are quite satisfied

 

      with the information disseminated to the patients

 

      and particularly in the follow-up, as I mentioned

 

      before, we did speak with FDA regarding the calls

 

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

 

                                                               139

 

      crafting a statement that we could put on our

 

      website that would allay people's fears.

 

                Their main concern was they were afraid

 

      the drug was going to be pulled immediately, and

 

      that came about because of the press and certain

 

      other citizens organizations that were crying wolf.

 

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

 

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

 

      and we, at the Lung Cancer Alliance, immediately

 

      notified every other lung cancer group we knew plus

 

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

 

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

 

                DR. MARTINO:  Last question from me to Dr.

 

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

 

      considering revising the package insert, or where

 

      are you in that process?

 

                DR. PAZDUR:  Yes, we will be discussing

 

      that internally.

 

                DR. MARTINO:  Ladies and gentlemen, that

 

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

 

      second topic and I am going to ask you to return

 

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

 

                                                               140

 

      part of this meeting.

 

                [Break.]

 

                                                               141

 

                    Call to Order and Introductions

 

                DR. MARTINO:  Good morning, ladies and

 

      gentlemen.

 

                The topic for this morning's meeting and

 

      discussion relates to a safety concern with the

 

      agents Aredia and Zometa, specifically

 

      osteonecrosis of the jaw.

 

                Before we start into the topic, I would

 

      like the committee members, as well as the members

 

      from the FDA, to introduce themselves, and I think

 

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

 

      would introduce yourself, please.

 

                DR. DOROSHOW:  Jim Doroshow, NCI.

 

                DR. BRAWLEY:  Otis Brawley, Medical

 

      Oncology and Epidemiology, Emory University.

 

                DR. D'AGOSTINO:  Ralph D'Agostino,

 

      Biostatistician, Boston University.

 

                DR. PROSCHAN:  Mike Proschan,

 

      Statistician, National Heart, Lung, and Blood

 

      Institute.

 

                DR. GRILLO-LOPEZ:  Antonio Grillo-Lopez,

 

      Industry Representative.

 

                DR. MORTIMER:  Joanne Mortimer, Medical

 

      Oncology, University of California at San Diego.

 

                DR. PERRY:  Michael Perry, Medical

 

                                                               142

 

      Oncology, University of Missouri, Ellis Fischel

 

      Cancer Center.

 

                DR. HUSSAIN:  Maha Hussain, Medical

 

      Oncology, University of Michigan.

 

                DR. MARTINO:  Silvana Martino, Medical

 

      Oncology, Cancer Institute Medical Group, Santa

 

      Monica.

 

                DR. REAMAN:  Gregory Reaman, Pediatric

 

      Oncology, George Washington University.

 

                DR. RODRIGUEZ:  Maria Rodriguez, Medical

 

      Oncology, M.D. Anderson Cancer Center.

 

                DR. LEVINE:  Alexandra Levine,

 

      Hematology/Oncology, University of Southern

 

      California.

 

                MS. HAYLOCK:  Pam Haylock, Oncology Nurse,

 

      University of Texas Medical Branch in Galveston,

 

      and I am the Consumer Representative.

 

                DR. IBRAHIM:  Amna Ibrahim, Medical

 

      Officer, FDA.

 

                DR. SCHER:  Nancy Scher, Medical Officer,

 

      FDA.

 

                DR. COLMAN:  Eric Colman, Medical Officer,

 

      FDA.

 

                DR. AVIGAN:  Mark Avigan, Office of Drug

 

      Safety.

 

                                                               143

 

                DR. TEMPLE:  Bob Temple, Office Director,

 

      OD-I.

 

                DR. PAZDUR:  Richard Pazdur, FDA.

 

                DR. MARTINO:  Thank you.

 

                Next, the Conflict of Interest Statement

 

      by Ms. Clifford.

 

                     Conflict of Interest Statement

 

                MS. CLIFFORD:  Thank you.  The following

 

      announcement addresses the issue of conflict of

 

      interest and is made a part of the record to

 

      preclude even the appearance of such at this

 

      meeting.

 

                Based on the submitted agenda and all

 

      financial interests reported by the committee

 

      participants, it has been determined that all

 

      interests in firms regulated by the Center for Drug

 

                                                               144

 

      Evaluation and Research present no potential for

 

      appearance of a conflict of interest with the

 

      following exceptions:

 

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

 

      full waivers have been granted for the following

 

      participants. Please note that the following

 

      interests waived are unrelated to Zometa, Aredia,

 

      and its competing products.

 

                Dr. Otis Brawley has been granted waivers

 

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

 

      stock in a competitor, valued between 25,000 and

 

      50,000 per firm.

 

                Dr. Michael Perry has been granted a

 

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

 

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

 

      Because his stock interests fall below the de

 

      minimis exception allowed under 5 CFR

 

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

 

      required.

 

                A copy of the waiver statements may be

 

      obtained by submitting a written request to the

 

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

 

                                                               145

 

      of the Parklawn Building.

 

                With respect to the FDA's invited industry

 

      representative, we would like to disclose that Dr.

 

      Antonio Grillo-Lopez is participating in this

 

      meeting as an acting industry representative acting

 

      on behalf of regulated industry.  Dr. Grillo-Lopez

 

      is employed by Neoplastic and Autoimmune Disease

 

      Research.

 

                In the event that the discussions involve

 

      any other products or firms not already on the

 

      agenda for which an FDA participant has a financial

 

      interest, the participants are aware of the need to

 

      exclude themselves from such involvement, and their

 

      exclusion will be noted for the record.

 

                With respect to all other participants, we

 

      ask in the interest of fairness that they address

 

      any current or previous financial involvement with

 

      any firm whose products they may wish to comment

 

      upon.

 

                Thank you.

 

                DR. MARTINO:  Thank you.

 

                Dr. Pazdur will now address the group and

 

                                                               146

 

      give us some guidance as to the nature of this

 

      problem and what our agenda is.

 

                            Opening Remarks

 

                DR. PAZDUR:  Pamidronate and Zometa are

 

      potent intravenous bisphosphonates.  Aredia

 

      received approval for hypercalcemia malignancy in

 

      1991, for multiple myeloma in 1995, and for

 

      osteolytic bone metastases from breast cancer in

 

      1996.  Zometa was approved for hypercalcemia

 

      malignancy in August of 2001 and for a broad bone

 

      metastasis indication in February of 2002.

 

                In 2002, the FDA received 9 spontaneous

 

      reports for osteonecrosis of the jaw in patients

 

      with malignancy whose treatment regimens included

 

      intravenous bisphosphonates.

 

                In 2003, the first published reports of

 

      ONJ in patients treated with intravenous

 

      bisphosphonates appeared in the literature.

 

                In a high proportion of cases, there was

 

      an association with a recent dental procedure.

 

      These patients had no history of radiation therapy

 

      to the head and neck.

 

                The Zometa package insert was updated in

 

      September 2003 to include information about

 

      osteonecrosis of the jaw in the Adverse Events

 

                                                               147

 

      section.  The Aredia package insert was also

 

      updated in November of 2003.

 

                In August 2004, changes were made to the

 

      Precautions section of the Zometa label, followed

 

      by a parallel change to the Aredia label, regarding

 

      osteonecrosis of the jaw.  Novartis issued a Dear

 

      Doctor letter in September 2004 regarding

 

      osteonecrosis of the jaw.

 

                The purpose of bringing to ODAC the

 

      problem of osteonecrosis of the jaw in association

 

      with intravenous bisphosphonates is to highlight a

 

      drug safety issue in oncology and stimulate

 

      consideration of how post-marketing safety issues

 

      in oncology should be addressed.

 

                Although there have been anecdotal reports

 

      of ONJ in association with oral bisphosphonates

 

      administered for osteoporosis, we wish to limit

 

      today's discussion to osteonecrosis of the jaw in

 

      association with Zometa and pamidronate.  Less data

 

                                                               148

 

      is available for the oral bisphosphonates, and the

 

      risk-benefit considerations are different for

 

      patients with malignancy compared to patients being

 

      treated for benign bone diseases.

 

                Thank you.

 

                DR. MARTINO:  Thank you, Dr. Pazdur.

 

                Dr. Nancy Scher will now describe the

 

      history of Zometa and Aredia and its regulatory

 

      process.

 

                            FDA Presentation

 

                Regulatory History of Zometa and Aredia

 

                DR. SCHER:  Good morning.  I shall provide

 

      an overview of the regulatory history of the

 

      approval of Zometa and Aredia, and also provide

 

      some chronology regarding the recognition of an

 

      unusual adverse event occurring in some patients

 

      treated with intravenous bisphosphonates.

 

                Aredia is approved for treatment of

 

      patients with osteolytic bone metastases of breast

 

      cancer and osteolytic lesions of multiple myeloma

 

      in conjunction with standard antineoplastic

 

      therapy.

 

                It is also approved for hypercalcemia of

 

      malignancy and Paget's Disease of bone.

 

                You have heard the Aredia approval dates.

 

                                                               149

 

      Again, in 1995, there was an approval for

 

      osteolytic lesions of multiple myeloma, and in

 

      1996, for breast cancer.

 

                The approval of Aredia represents a

 

      regulatory precedent.  Skeletal related events, or

 

      SRE, were defined and used as a basis for the

 

      approvals in the bone metastases indications for

 

      Aredia and subsequently for Zometa.

 

                This slide shows you the four components

 

      that define that composite endpoint - pathologic

 

      fractures, radiation therapy to bone, surgery to

 

      bone, and spinal cord compression.

 

                The multiple myeloma indication for Aredia

 

      was based on a single double-blind, randomized,

 

      placebo-controlled trial, where Aredia 90 mg

 

      monthly intravenously was given for 9 months.

 

                Aredia demonstrated superiority to placebo

 

      for several SRE endpoints.

 

                For breast cancer, there were two

 

                                                               150

 

      licensing trials for Aredia.  They were

 

      double-blind, randomized, placebo-controlled,

 

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

 

      months.

 

                Patients were required to have at least 1

 

      osteolytic lesion.  In one study, patients were

 

      receiving chemotherapy, and in the other study,

 

      patients were receiving hormonal therapy.

 

                Together, the trial results supported the

 

      indication for Aredia in patients with metastatic

 

      breast cancer.

 

                Zometa is approved for treatment of

 

      patients with multiple myeloma and patients with

 

      documented bone metastases from solid tumors, in

 

      conjunction with standard antineoplastic therapy.

 

      Prostate cancer should have progressed after

 

      treatment with at least one hormonal therapy.

 

      Zometa is also approved for hypercalcemia of

 

      malignancy.

 

                Zometa was approved for hypercalcemia of

 

      malignancy in August of 2001.  At that time,

 

      Novartis submitted a supplemental NDA for the bone

 

                                                               151

 

      metastases indications to FDA.  FDA reviewed this

 

      application as a priority NDA.

 

                In February 2002, Zometa was approved for

 

      the bone metastases indications.  This approval for

 

      Zometa expanded the indications for

 

      bisphosphonates.

 

                Zometa was approved for a broad range of

 

      solid tumors, not limited to breast cancer as

 

      Aredia had been.  Furthermore the lesion type was

 

      not limited to osteolytic lesions.  However, the

 

      optimal duration of therapy could not be defined

 

      from the trial design.

 

                The oncology indication for Zometa was

 

      based on 3 randomized trials.  The multiple

 

      myeloma/metastatic breast cancer trial randomized

 

      patients to an active control of Aredia 90 mg, for

 

      Zometa 4 mg.

 

                The remaining 2 trials were

 

      placebo-controlled, 1 in prostate cancer and 1 in

 

      other solid tumors.

 

                The primary endpoints were time to first

 

      SRE and proportion of patients with SRE.

 

                This slide provides some additional detail

 

      about the Zometa registration trials.  You can see

 

      the multiple myeloma/breast cancer trial was

 

                                                               152

 

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

 

      and it had a non-inferiority design.

 

                Time to first SRE was the preferred FDA

 

      endpoint. You see information about that presented.

 

      For prostate cancer and other solid tumors, Zometa

 

      4 mg demonstrated superiority to placebo.  For

 

      multiple myeloma or breast cancer, Zometa 4 mg was

 

      non-inferior to Aredia 90 mg.

 

                This slide shows the number of cases of

 

      osteonecrosis of the jaw reported to the FDA by

 

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

 

      2002, there were 9 cases reported of patients with

 

      osteonecrosis of the jaw who were receiving

 

      intravenous bisphosphonates as part of their

 

      treatment regimen.

 

                There were additional cases in 2003, and

 

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

 

      numbers were provided to me by the Office of Drug

 

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

 

                                                               153

 

      subsequent presentations, the number of reports is

 

      in excess of 600.

 

                This slide lists a fairly comprehensive

 

      review of the literature of reports of

 

      osteonecrosis of the jaw associated with

 

      bisphosphonates.  You will see the chronology is

 

      somewhat similar to the chronology of the adverse

 

      events reported to the FDA.

 

                I want to point out that this literature

 

      pretty much starts in 2003.  Most of the reports

 

      are abstracts or very brief reports, and

 

      particularly earlier on, we are limited to the oral

 

      surgery literature.

 

                The most detailed report that I am aware<