FOOD AND DRUG ADMINISTRATION


















                               VOLUME II

















                         Friday, March 4, 2005


                               8:00 a.m.









                          Gaithersberg Hilton

                           620 Perry Parkway

                         Gaithersburg, Maryland





      Silvana Martino, D.O., Acting Chair

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




      Otis W. Brawley, M.D.

      James H. Doroshow, M.D.

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


      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.




      Ralph D'Agostino, Ph.D.

      Michael Proschan, Ph.D.




      Sheila Ross - For Iressa




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

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

      Amna Ibrahim, M.D.

      Nancy Scher, M.D.

      Eric Colman, M.D.

      Mark Avigan, M.D.

      Richard Pazdur, M.D.

      Robert Temple, M.D.



                            C O N T E N T S




      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



      Mark Scott, Ph.D.                                         56


      Committee Questions                                       59


      Open Public Hearing                                       89


      Committee Discussion                                     107


                                 - - -


      Call to Order and Introductions

      Silvana Martino, D.O.                                    140


      Conflict of Interest Statement

      Johanna Clifford, M.S., RN                               142


      Opening Remarks

      Richard Pazdur, M.D.                                     145



                      C O N T E N T S (Continued)



                            FDA Presentation


      Regulatory History of Zometa and Aredia

      Nancy Scher, M.D.                                        147


      Post-Marketing Safety Assessment of

      Osteonecrosis of the Jaw: Pamidronate

      and Zoledronic Acid

      Carol Palmer, R.Ph.                                      155


      Osteonecrosis of the Jaws in Myeloma:

      Time Dependent Correlation with Zometa

      and Zometa use

      Brian Durie, M.D.                                        173


                          Sponsor Presentation

                        Novartis Pharmaceuticals


      ONJ Reported in Bisphosphonates Treated

      Patients - An Overview

      Diane Young, M.D.                                        188


      Clinical Benefit of Bisphosphonates in Cancer

      Patients with Metastatic Bone Disease

      James Berenson, M.D.                                     222


      Open Public Hearing                                      229


      Committee Discussion                                     252




                         P R O C E E D I N G S


                    Call to Order and Introductions


                DR. MARTINO:  Good morning, ladies and




                The topic before us this morning is some


      additional new data that has arisen relative to the


      agent Iressa.  Before we start with the topic


      itself, I am going to ask the committee to


      introduce itself, and we will start on my left with


      Dr. Pazdur, please.


                DR. PAZDUR:  Richard Pazdur, FDA.


                DR. WILLIAMS:  Grant Williams, FDA.


                DR. COHEN:  Martin Cohen, FDA.


                MRS. ROSS:  Sheila Ross, Lung Cancer


      Alliance formerly ALCASE.


                MS. HAYLOCK:  Pam Haylock, Oncology Nurse,


      University of Texas Medical Branch in Galveston.


                DR. LEVINE:  Alexandra Levine, University


      of Southern California, Chief of Heme.


                DR. RODRIGUEZ:  Maria Rodriguez, M.D.


      Anderson Cancer Center.


                DR. REAMAN:  Gregory Reaman, Pediatric




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


                DR. MARTINO:  Silvana Martino, Medical


      Oncology, Cancer Institute Medical Group in Santa




                MS. CLIFFORD:  Johanna Clifford, Executive


      Secretary to the Oncologic Drugs Advisory




                DR. HUSSAIN:  Maha Hussain, Medical


      Oncology, University of Michigan.


                DR. PERRY:  Michael Perry, Medical


      Oncology, University of Missouri, Ellis Fischel


      Cancer Center.


                DR. MORTIMER:  Joanne Mortimer, Medical


      Oncology, University of California at San Diego.


                DR. GRILLO-LOPEZ:  Antonio Grillo-Lopez.


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


      survivor, and I am here as the industry


      representative on this committee.  I would like to


      state that although I am the industry


      representative, I receive no support whatsoever


      from industry for my presence here.


                DR. PROSCHAN:  Mike Proschan.  I am from




      the National Heart, Lung, and Blood Institute.


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


      University, Biostatistician.


                DR. BRAWLEY:  Otis Brawley, Medical


      Oncology and Epidemiology, Emory University.


                DR. DOROSHOW:  Jim Doroshow, National


      Cancer Institute.


                DR. MARTINO:  Thank you.


                Next, I would like Ms. Clifford to read


      the Conflict of Interest Statement for the group.


                     Conflict of Interest Statement


                MS. CLIFFORD:  The following announcement


      addresses the issue of conflict of interest and is


      made a part of the record to preclude even the


      appearance of such at this meeting.


                Based on the submitted agenda and all


      financial interests reported by the committee


      participants, it has been determined that all


      interests in firms regulated by the Center for Drug


      Evaluation and Research present no potential for an


      appearance of a conflict of interest with the


      following exceptions:


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


      full waivers have been granted to the following


      participants. Please note that the following




      consulting activities waived are unrelated to


      Iressa and its competing products.


                Dr. Silvana Martino for consulting for a


      competitor, which her employer receives less than


      10,001 per year.


                Dr. Michael Perry for consulting with a


      competitor which he receives less than 10,001 per


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


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


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


      Because his stock interest falls below the de


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


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


                Dr. Maha Hussain has been granted waivers


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


      stock in a sponsor and a competitor.  These stocks


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


                A copy of the waiver statements may be


      obtained by submitting a written request to the




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


      of the Parklawn Building.


                With respect to the FDA's invited industry


      representative, we would like to disclose that Dr.


      Antonio Grillo-Lopez is participating in this


      meeting as an acting industry representative acting


      on behalf of regulated industry.  Dr. Grillo-Lopez


      is employed by Neoplastic and Autoimmune Disease




                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




                DR. MARTINO:  Thank you.


                Next on our agenda is Dr. Richard Pazdur,




      who will address the committee and give us some


      direction for this morning's meeting, please.


                            Opening Remarks


                DR. PAZDUR:  Thank you, Dr. Martino.


                Iressa was originally approved by the FDA


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


      treatment of patients with locally advanced or


      metastatic non-small cell lung cancer after failure


      of both platinum-based and docetaxel




                Partial tumor responses occurred in


      approximately 10 percent of patients.  Iressa was


      approved under the accelerated approval


      regulations.  As discussed yesterday, these


      regulations allow approval based on a surrogate


      endpoint reasonably likely to predict clinical


      benefit and require subsequent studies to verify


      and define its clinical benefit.


                As an approval condition, AstraZeneca


      committed to conduct a randomized trial examining


      the Iressa effect on survival in patients with


      advanced non-small cell lung cancer who had




      received 1 to 2 prior chemotherapies.  This is


      defined as Trial 0709.


                The primary endpoint of this trial was


      overall survival and improved survival for


      Iressa-treated patients was to satisfy the


      requirement for the demonstration of clinical


      benefit.  For drugs approved under accelerated


      approval, the FDA may withdraw approval for the


      failure of a post-marketing study to verify


      clinical benefit.  I should note that there were


      several studies that were included in their Phase


      IV commitment.


                The withdrawal procedure requires a formal


      hearing whose composition and procedures are


      defined in the Code of Federal Regulations.  This


      meeting is not that formal hearing.


                AstraZeneca notified the United States


      Food and Drug Administration on December 17th,


      2004, that a large randomized study comparing


      Iressa plus best supportive care to placebo plus


      best supportive care failed to demonstrate a


      survival advantage for Iressa in the treatment of




      non-small cell lung cancer.


                The results will be reported in detail by


      AstraZeneca during this meeting.


                The FDA has not received the complete data


      set for this trial, especially data that would


      allow pharmacogenetic or immunohistochemistry


      subset analysis.  The FDA management plan is rapid


      communication of the above trial results to health


      care professionals and patients concurrent with the


      expeditious completion of the trial analysis by


      AstraZeneca, including the effects of EGFR status


      determined by immunohistochemistry and EGFR


      mutational status on survival.


                We are interested in reviewing the


      immunohistochemistry subset analysis since


      interesting exploratory findings were included in


      the Tarceva label that was recently approved this




                The FDA will not make a regulatory


      decision on Iressa until the data regarding subset


      analysis and the study results are received and


      reviewed.  In the interim, AstraZeneca has




      suspended promotion of Iressa, but will continue to


      make the drug available to patients who appear to


      be benefiting from Iressa treatment.


                Actions have been taken to communicate the


      most recent Iressa information to health care


      professionals and patients.


                These are delineated in the preamble to


      the discussion points and include:  AstraZeneca


      press release of the ISEL study results, Dear


      Doctor letters notifying physicians of the study


      results and alternative therapies available,


      AstraZeneca sales force distribution of Dear Doctor


      letters, other Dear Doctor letters being posted on


      the AstraZeneca website, patient advocate groups


      being notified, AstraZeneca communications to known


      patients, information being posted on the FDA


      website, abstracts at meetings, journal placements


      of the Dear Doctor letters, advertisements on a


      continuing basis in all issues of the 10 most


      widely read oncology journals urging physicians to


      consider options other than Iressa.


                A copy of this advertisement is attached




      in today's Discussion Points.


                AstraZeneca is also tracking total and new


      Iressa prescriptions every two weeks to ensure that


      the above communications are resulting in decreased


      Iressa use.


                We are not here today to vote on the


      ultimate regulatory fate of this drug.  We may be


      bringing this question back to future ODAC meetings


      after the FDA reviews this study and additional


      subset analysis.


                The purpose of this ODAC meeting is to


      provide transparency of the process that we have


      undertaken and to obtain your input on the adequacy


      of these steps to date to ensure that patients and


      prescribing physicians are aware of the study


      results and treatment options other than Iressa


      while allowing the drug to be available to patients


      who may be benefiting from it.


                Thank you.


                DR. MARTINO:  Thank you, Dr. Pazdur.


                A new member has joined us.  Dr. Temple,


      if you would be so kind as to introduce yourself.


                DR. TEMPLE:  Good morning.  Bob Temple,


      Office Director.


                DR. MARTINO:  Thank you.  For the




      audience, as well as the committee, I want to


      remind everyone that this morning's purpose is not


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


      who are here thinking that that is what we are


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


                The point this morning is realizing that


      there is some new information that needs to be


      properly disseminated to the public, both the


      medical public as well as the lay public, has that


      process taken place and what is that process.


                So, those really are the issues before


      this committee.


                At this point, I would like AstraZeneca to


      approach the podium and introduce your speakers, as


      well as give us some understanding of what they


      will be speaking on please.


                Sponsor Presentation - AstraZeneca L.P.


                  Introduction and Regulatory History


                DR. SCOTT:  Thank you, Dr. Martino.


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


      Development Leader for Iressa.


                As Dr. Pazdur just mentioned, Iressa was


      granted an accelerated approval under Subpart H in


      May of 2003 to treat advanced non-small cell lung


      cancer after failure of two types of chemotherapy.




                Subsequent to Iressa's approval, this


      committee has discussed in general the terms of the


      Subpart H approval guidelines and the need for


      rapid completion by sponsors of their


      post-marketing trials that are required as part of


      such an approval.


                During these discussions, an important


      question was raised by ODAC, what should be done if


      a confirmatory trial does not meet its primary


      objective.  The ODAC discussion at the time


      acknowledged that there would probably be no quick


      and easy answer if this situation were to arise.


                We are here today because this


      hypothetical situation is now real and it applies


      to Iressa.  The study we are here to discuss is


      Trial 709, one of the confirmatory trials for




      Iressa which did not achieve statistical


      significance for its primary endpoint of overall




                We will describe for you the actions


      AstraZeneca has undertaken to communicate the


      results of Trial 709 to physicians, so that


      informed decisions can be made regarding the


      clinical use of Iressa.


                Today, we will describe important findings


      from Trial 709, how the data from Trial 709 is


      actually quite similar to prior clinical data on


      Iressa and additional analyses, and clinical trials


      that are being conducted or planned to better


      understand which patients are most likely to


      benefit from Iressa.


                We will also outline the timings of


      availability for data for FDA review, what has


      occurred and the future direction for Iressa,


      provide important lessons about drug development,


      and accelerated approval in the era of targeted


      oncology therapies.


                After I cover a brief regulatory history,




      Mr. Kevin Carroll will speak more on Trial 709,


      then, Dr. Judy Ochs will present the actions


      AstraZeneca has taken to inform the oncology


      community and the implications for the development


      of Iressa.  I will then review the timelines that


      we have to provide data to FDA.


                As posed to the committee by FDA, we look


      forward to hearing the Committee's thoughts on the


      appropriateness of the communications taken


      regarding Trial 709.


                Today, we have two experts on lung cancer,


      Howard Burris from Sarah Cannon and Mark Kris from


      Memorial Sloan- Kettering, and they will be


      supporting the AstraZeneca staff here to answer any


      questions the Committee may have.


                Lung cancer is the most common cancer and


      the leading cause of cancer mortality in both men


      and women with over 170,000 new patients being seen


      each year in the United States.


                The disease is complex, most patients are


      diagnosed with advanced disease, symptoms are


      common, and the prognosis is poor.


                Standard first line therapy for advanced


      disease was, and continues to be, platinum-based


      doublet chemotherapy.  Prior to 2003, after failure




      of first line therapy, only docetaxel had been


      demonstrated to improve overall survival.  No


      therapy had been approved for use after failure of


      both first and second line therapy.


                Standard chemotherapies do offer benefits,


      but with significant toxicity.  Therefore, there


      are many lung cancer patients who cannot tolerate


      any chemotherapy.


                There was a great demand for new, active,


      less toxic agents for non-small cell lung cancer.


      Now, Iressa is a small molecule inhibitor of the


      epidermal growth factor inhibitor tyrosine kinase.


      EGFR expression plays a role in angiogenesis,


      apoptosis, proliferation in many tumors.  Iressa is


      thought to mitigate against these factors.


                The Iressa Phase I program began in 1998


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


      the 289 subjects enrolled, the most common


      toxicities were low-grade diarrhea and rash, and




      the dose-limiting toxicity was reversible Grade 3


      diarrhea, and this dose-limiting toxicity occurred


      at doses beyond 800 mg/day.


                Marked anti-tumor activity was seen in


      non-small cell lung cancer population that


      participated in the Phase I program, and there were


      actually 10 of 100 patients where responses were


      noted, and these responses occurred across the dose




                Because of the safety findings and the


      activity findings in Phase I, we chose the doses of


      250 and 500 mg/day to be further investigated in


      the third line monotherapy setting, as well as in


      first line trials in combination with


      platinum-based chemotherapy.


                I will now focus on the data relevant to


      the accelerated approval of Iressa.


                IDEAL I and II were trials conducted among


      patients where chemotherapy had failed.  Both


      trials randomized patients between 250 mg and 500


      mg of Iressa per day.  The primary endpoint in each


      trial was objective response, the requirement for




      response was at least a 50 percent reduction in


      measurable tumor area, or significant reduction in


      non-measurable disease, and these decreases needed


      to persist for at least one month.


                Across doses, response rates seen in IDEAL


      I and IDEAL II were 19 and 10.6 percent.  Responses


      were durable with ranges of 13 months and 7 months


      for IDEAL I and II respectively.


                Also of note was the variability that was


      seen in response across some subgroups.  Higher


      rates were seen in females, never smokers, those


      with adenocarcinoma histology, and of those of


      Asian ethnicity.


                As you will see in a few minutes, this


      same variability in response is suggested for


      survival, as well, when Trial 709 was further


      analyzed.  There were no differences in efficacy


      between the two doses, and the survival curves are


      presented on this slide where we have collapsed


      IDEAL I and II together and looked at 250 versus


      500, and the survival curves were completely




                As for safety, the most drug-related


      adverse events were of low grade, while the most


      common adverse events were rash and diarrhea.




      There were a greater number of events at the 500 mg


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


      was chosen on the basis of its efficacy and


      tolerability as part of our application for


      accelerated approval as a monotherapy in refractory




                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




                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




                We agreed to conduct and analyze and


      report on three additional clinical trials, to


      examine the effects of Iressa as a monotherapy in




      patient with advanced non-small cell lung cancer


      where chemotherapy had failed.


                These included Trial 709 where an


      improvement in survival was sought, and the


      preliminary results will be the focus of Mr.


      Carroll's presentation today.


                Trial 721 examines whether the survival


      seen with Iressa is not inferior to survival seen


      with docetaxel.  There is a planned interim


      analysis of this trial with complete data for this


      to be available in June of this year, and with


      survival data from this trial available in November


      of next year.  The results from this trial can


      confirm the effectiveness of Iressa.


                Trial 710, the third Subpart H commitment,


      was a placebo-controlled trial where an improvement


      in symptoms was sought.  However, the early


      availability of results from Trial 709 in December


      of last year compromised the ability to recruit




                As a consequence, the independent Data


      Safety Monitoring Committee recommended that




      further recruitment was not justified because the


      trial was unlikely to be completed.  In agreement


      with FDA, this trial was stopped in September of


      last year.


                Two other trials featured as additional


      commitments that were not linked to the accelerated


      approval, we were asked to provide reports on the


      SWOG 0023 and BR19 trials.


                These placebo-controlled trials seek to


      demonstrate a survival improvement for Iressa after


      definitive therapy in two settings of non-small


      cell lung cancer.  Both trials continue to recruit.


                In summary, there were three Subpart H


      confirmatory trials and two additional trials.  One


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


      to ask Mr. Kevin Carroll, the statistician for


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


      Trial 709.


                               Trial 709


                MR. CARROLL:  Thank you, Mark.


                Today, I will be presenting to you


      preliminary data from Trial 709, which is a large




      randomized Phase III trial comparing Iressa to


      placebo in advanced chemotherapy-failed non-small


      cell lung cancer.


                The data I will be sharing with you today


      are as we saw them for the first time on December


      16, 2004, and so are consistent with the materials


      in your briefing document.


                Since then, the data have been further


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


      February 2005.  There have been few changes to


      these data and none that materially affect the


      results I will be showing you today.


                In Trial 709, 1,692 patients were


      randomized to Iressa or placebo on a 2 to 1 basis


      in 210 centers across 28 countries.  In light of


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


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


      randomization to placebo was considered infeasible.


                Further, to ensure balance between the


      treatments at baseline, the randomization was


      stratified for histology, gender, reason for


      failure to prior chemotherapy, and smoking history.


                In terms of key eligibility criteria, the


      patients randomized into Trial 709 had advanced


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




      prior chemotherapy regimens.


                Furthermore, the patient population


      entered into Trial 709 was highly refractory since


      the patients had either to be intolerant to their


      most recent chemotherapy or had to have progressed


      on or within 90 days of their last chemotherapy




                In Trial 709, as has been said, the


      primary endpoint was overall survival.  As stated


      in the protocol, the primary analysis method was a


      stratified log-rank test. As is common in oncology


      trials, the protocol also stated that a supportive


      Cox regression analysis would be conducted.


                There were 2 co-primary populations for


      analysis, the overall population and a subset of


      patients with adenocarcinoma histology.  At least


      900 deaths were required overall to provide 90


      percent power.


                The secondary endpoints are listed on this




      slide, being time to treatment failure, objective


      response, quality of life, symptoms, and safety.


                Several subgroup analyses were pre-planned


      with the aim being to examine outcomes in relation


      to important clinical and biologic factors, such as


      EGFR expression and EGFR mutations, and my


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


      in our presentation.


                The data I will be presenting today are


      all those that accrued up to and including the end


      of October 2004. This date was chosen because it


      was estimated by this time the 900 deaths we needed


      for analysis would have occurred on the database.


                So, following data collection, preliminary


      data became available for the first time in


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


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


                As can be seen on this slide, patients in


      Trial 709 were recruited mainly from Central and


      Eastern Europe and then Asia.  As I mentioned


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


      due to the approval of Iressa in December 2003,




      only 1 percent of patients were recruited in




                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




                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




                I would like to move on now to look at


      survival in the overall population.  As you can


      see, there was some improvement in overall survival


      in Iressa-treated patients with the Kaplan-Meier


      curves separating after about 4 months.  However,


      the magnitude of that improvement was not




      sufficient to reach statistical significance in the


      primary stratified log-rank test, however, the


      supportive Cox regression analysis did suggest


      statistical significance.


                Here are the survival curves for the


      co-primary population of patients with


      adenocarcinoma histology.  Again, there was some


      improvement in overall survival in Iressa-treated


      patients, but the magnitude of that improvement was


      not sufficient to reach statistical significance on


      the primary stratified log-rank test.


                Again, here, the supportive Cox regression


      analysis did suggest statistical significance.


                Moving on now to secondary endpoint data,


      tumor shrinkage in terms of response rates was


      significantly greater in Iressa-treated patients


      compared to placebo.


                In terms of the time to treatment failure


      being the time from randomization to the first


      event that led to the cessation of randomized


      treatment, there was a statistically significant


      difference between the treatments with the risk of




      treatment failure being 18 percent lower in


      Iressa-treated patients compared to placebo.


                The reasons for treatment failure are


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


      driver for treatment failure was progression be it


      either symptomatic or radiographic, with


      approximately 56 percent progressing on Iressa


      compared to 70 percent progressing on placebo.


                As you would expect, Iressa failed more


      often due to adverse events than placebo, and Other


      on this slide refers to a number of items including


      lost to follow-up, noncompliance, and withdrawal of


      consent.  As you can see, there was no difference


      between the two treatments in this regard.


                Turning now to quality-of-life data, the


      analyses of these data is currently ongoing, but I


      can share with you some initial results.  As you


      can see, the primary quality of life endpoints


      being symptoms, overall quality of life, and trial


      outcome index, all tended to favor Iressa-treated


      patients although the treatment differences were


      relatively small.


                As I mentioned before, several subgroup


      analyses were pre-planned.  Now, before I run


      through these data with you, it is important to




      emphasize that these analyses are not


      retrospective, nor are they data driven.


                The subsets were identified in advance


      based on what we saw in our Phase II trials and


      based upon findings on other drugs in the same




                Furthermore, in analyzing these subsets,


      we have applied a rigorous statistical approach


      whereby we looked first for evidence of a subset by


      treatment interaction to give us confidence that


      the subsets are truly behaving differently, and if


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


      at the subsets.


                It is important to recognize that this is


      a harder test to pass than simply having a list of


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


      we do see differences in Trial 709, we can be


      reasonably confident that they are more likely due


      to a real drug effect than due to chance alone.


                This is the first of two slides that show


      subset analyses.  For each subset analyzed, you can


      see the hazard ratio and its confidence limits and


      the response rate in Iressa-treated patients.


                As you will recall, the hazard ratio


      measures the risk of death on Iressa-treated




      patients to placebo-treated patients, and


      therefore, a hazard ratio of less than 1 to the


      left of the vertical line shows a treatment effect


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


      of the vertical line shows a treatment effect in


      favor of placebo.


                So, now while no subgroup favored placebo,


      there was clearly some variability in survival


      outcome.  This was most marked in terms of smoking


      history where outcomes in never smokers was


      statistically different than outcomes in ever




                This is the second slide showing data in


      subsets, the same format as the previous slide.


      Again, you can see there was variability in


      outcomes with, in this instance, it being most




      marked in terms of ethnicity where patients of


      Asian ethnic origin have statistically different


      outcomes to patients of non-Asian ethnic origin.


                Now, while the credibility of subset


      analyses is always a matter of debate in any


      clinical trial, in 709, the rigorous approach we


      have taken provides us with confidence that the


      differences we have seen are most likely due to a


      real effect of the drug, and less likely due to




                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




                This slide shows survival curves for never




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


      percent reduction in the risk of death in never


      smoking patients treated with Iressa compared to


      placebo.  There was no significant difference in


      ever smokers.


                Similarly, this slide shows survival


      curves by ethnic origin.  Again, you can see there


      was a 34 percent reduction in the risk of death in


      Asian patients treated with Iressa compared to


      placebo, and there was no significant difference in


      non-Asian patients.


                I would like to move on now to look


      briefly at the safety data in Trial 709.  I should


      note these data have become available since we


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


      your papers.


                The adverse event profile in Trial 709 is


      consistent with the established safety profile for


      Iressa with the most common adverse events being


      rash and diarrhea.


                Notably, there was little difference


      between the treatments in terms of serious adverse




      events, adverse events leading to withdrawal, and


      the incidence of interstitial lung disease.


                Here is a summary of the most common


      adverse events in the trial ordered from highest to


      lowest frequency in Iressa-treated subjects.


                As you can see, with the exception of rash


      and diarrhea, which I just mentioned, there is


      little difference between Iressa and


      placebo-treated patients in terms of the adverse


      event reporting.  In particular, there were


      relatively few Grade 3/4 adverse events in


      Iressa-treated subjects.


                This list of adverse events continues on


      this slide where again it can be seen there is


      little difference between Iressa and


      placebo-treated subjects.


                As I mentioned at the outset, the


      preliminary data we saw on December 16th were


      validated and finalized as of the 2nd of February


      2005.  These final data confirmed a total of 976


      deaths occurring on or before the October 2004 data


      cutoff.  With only 7 additional deaths, it is




      obviously not surprising that the findings based on


      the preliminary data remain unchanged.


                On reviewing the data in December, the


      Independent Data Monitoring Committee recommended


      that further follow-up of Trial 709 should be


      obtained.  Having seen somewhat late separation in


      the Kaplan-Meier curve, they were unwilling to rule


      out that further separation could occur with more




                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




                As you can see, these further data are


      consistent with the planned protocol analysis, and


      despite increased crossover in the placebo arm to


      Iressa, variability in survival outcomes continues


      to be seen.


                To briefly summarize what we have shared


      today, the data seen on December 16 showed some


      improvement in survival in Iressa-treated patients,




      but the magnitude of that improvement was not


      sufficient to reach statistical significance in the


      primary stratified log-rank test.


                Overall, however, considering both primary


      and secondary endpoints, these data showed that


      Iressa was efficacious in the population study, but


      there was marked variability in survival outcomes.


                So, with that, I would like to thank you


      for your attention and hand over to my colleague,


      Dr. Ochs.  Judy.


                   Clinical Actions and Implications


                DR. OCHS:  Thank you, Kevin.


                In this part of our presentation, I would


      like to briefly summarize AstraZeneca's actions to


      communicate the results of Trial 709 to the


      oncology community.  Following this, I would like


      to give an overview of the clinical implications of


      the Trial 709 data, review some of the immediately


      relevant emerging science, and conclude with our


      proposed or ongoing development proposals.


                In agreement with the FDA, AstraZeneca


      concluded that it was in the best interest of




      patients that the information on Trial 709 be


      rapidly, extensively, and clearly communicated.


                On December 17th, a Dear Doctor letter


      approved by the FDA was distributed by AstraZeneca.


      This communication provided physicians with the


      needed information to enable them to make the most


      appropriate treatment decisions.  The expectation


      was that this communication would greatly reduce


      the number of patients receiving Iressa for the


      first time.


                In addition, AstraZeneca would provide to


      the FDA, prescription data every two weeks to be


      able to assess the continuing impact of the




                It was also agreed that a key goal was to


      maintain Iressa availability to those patients


      already benefiting who would wish to continue and


      had concerns about possible Iressa availability.


                A commitment was given to the FDA that


      AstraZeneca would rapidly provide them with all of


      the data as it became available to allow them a


      thorough and informed analysis.


                Upon public release of the top line Trial


      709 survival results a series of extensive


      communications were simultaneously begun and are




      listed on this slide, and were previously mentioned


      by Dr. Pazdur.


                Taken as a whole these actions were


      designed to ensure that relevant physicians would


      be aware of the results and be reminded that


      alternative therapeutic options with proven


      survival benefits should be considered.


                On January 6, the FDA and AstraZeneca met


      and agreed upon the following steps for continuing


      communication of the Trial 709 data.  A public


      disclosure of the then available results would be


      made at the first available scheduled ODAC meeting,


      today, acknowledging that the further trial data


      would still be pending.


                Ongoing communication of the Dear Doctor


      letter was to be done using journal placement and


      the full clinical data would be submitted and


      presented at scientific meetings and published in


      refereed scientific journals as soon as possible.


                Abstracts have been submitted to the AACR


      meeting, as well as the World Lung Cancer


      Conference.  A full publication submission is


      planed in the May-June time frame.


                Here is a copy of the Dear Doctor letter,


      which I realize you cannot read.  The letter,




      however, does include the survival results in the


      overall and adenocarcinoma subpopulation along with


      median survival and respective hazard ratios.


                The sentence highlighted in red above is


      included in the body of the letter and urges


      physicians to consider other treatment options.


      This is how the letter is being displayed in the 10


      most widely read oncology journals, and a list of


      these journals is shown in the next slide.


                The impact on Iressa usage has been marked


      in the 10 weeks since the Dear Doctor letter was


      first sent out. There has already been a


      significant reduction in the prescriptions written


      for Iressa, and our internal AZ usage data also


      indicates marked reduction.


                Market research, that we have just




      obtained from 100 community oncologists, indicates


      that the great majority are aware of the data


      contained in the Dear Doctor letter and have


      modified their treatment practice accordingly.


                Thus, all of the agreed upon communication


      actions have been set in motion, and the available


      information suggests that the oncology community is


      aware of and acting on the information.


                The larger question is now being asked:


      What are the clinical implications of the Trial 709


      data, and what are the next steps?  These are


      clearly important questions for oncologists and


      patients since Iressa possesses significant durable


      anti-tumor activity which has greatly benefited


      some patients and some patient subsets.


                Yet, in Trial 709, Iressa did not meet the


      statistically defined survival endpoint in an


      unselected patient population.


                Advances in understanding of the molecular


      biology in this area of EGFR inhibition, as well as


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


      occurring rapidly and have the potential to better




      select or predict those patients who would benefit


      beyond, or in addition to, clinical




                What are the questions that we are asking


      as we seek to understand the Trial 709 outcomes,


      and not wrongly or prematurely make conclusions


      about the actual role or place of Iressa, an agent


      with anti-tumor activity in the treatment of a


      disease with a continuing poor prognosis?  Why did


      this result occur?


                How does this result compare with our


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


      findings in our trial due to play of chance?  Was


      the dose selection appropriate?  Were there


      methodologic issues, such as the trial population


      and where the trial was conducted of any potential


      impact on the findings?


                What biologic data may be available now


      and in the future to help better understand the


      clinical outcomes, and what further relevant


      clinical data in the recurrent non-small cell lung


      cancer setting are expected?


                Firstly, how does the survival outcome


      seen in Trial 709 compare to other data with


      Iressa?  As was previously mentioned by Dr. Scott




      in our Phase II program, a striking and


      unanticipated finding was the apparent high rate of


      response in patients with certain clinical




                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




                Similar trend, although not of the same


      magnitude, of survival benefit was seen in women




      and with the adenocarcinoma group.


                Continuing with this line of inquiry,


      higher response rates and statistically significant


      survival results and benefit were seen in those


      patients of Asian descent.


                Could chance have played a role as the


      defined survival endpoint was so narrowly missed?


      Trial 709 and the erlotinib trial BR21 are the only


      two Phase III survival trials which compare an oral


      EGFR inhibitor with placebo in the recurrent


      non-small cell lung cancer patient population.


                Both Iressa and erlotinib have similar


      overall response rates as can be seen in the


      right-hand portion of the slide.  The erlotinib


      trial did reach statistical significance for the


      overall population.


                Juxtaposing overall survival hazard ratios


      as we have done in this slide shows that while the


      point estimates differ, there is a high degree of


      overlap in the confidence intervals.  The small


      confidence interval in Trial 709 reflects the


      larger trial size in 709, which is almost twice




      that of the BR21 trial.


                Dose selection.  Since there appears to be


      a difference in magnitude of survival benefit in


      BR21 compared to Trial 709, questions about the


      adequacy of the Iressa dose have arisen


      irrespective of the data used to support its use in


      this trial.


                The erlotinib dose used was at the maximal


      tolerated dose, while the Iressa dose is one-third


      the maximal tolerated dose, reflecting different


      development strategies.


                As you might guess, we have gone back and


      re-evaluated our prior experience in light of the


      current data. Our extensive Phase I program had 280


      patients, and these patients received doses ranging


      from 50 mg to 1,000 mg.


                Responses and durable stable disease first


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


      dose response evident from 150 mg through 1,000 mg


      with respect to partial response rates, partial


      response rates plus stable disease rates, or the


      duration on Iressa therapy.


                In our Phase II trials, as previously


      mentioned, we formally compared the 250 and 500 mg


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




      minimum dose that we saw responses and stable


      disease at, and 500 mg dose was chosen in part


      because of minimizing the amount of patient


      interruptions of therapy due to toxicity.


                We found no difference in efficacy


      including survival although the adverse events and


      therapy interruptions were more frequent at the


      higher 500 mg dose.


                Admittedly, however, we have not


      rigorously evaluated doses above 500 mg, and it is


      unknown if doses above 500 mg would achieve better


      overall or patient subset survival outcomes.  Due


      to the lack of data, we cannot rule this out




                Speculatively, can the inability to


      achieve statistically significant survival be


      explained by too few patients likely to benefit


      based on their advanced disease status with


      refractoriness as specified in our patient




      inclusion criteria.


                Another area to further explore are the


      impact of environmental factors, such as smoking,


      as it relates to various geographic regions where


      the trial was conducted.


                As Mr. Carroll showed, over one-third of


      the patients on Trial 709 were from Eastern Europe


      where the median pack year exposure was very high.


      Patients with the highest smoking exposure appear


      less likely to benefit from EGFR inhibitor therapy.


                We have looked at our data and found a


      continuous spectrum in terms of survival benefit,


      with the greatest survival benefit appearing in


      never smokings, but it continues with the amount of


      exposure to smoke.


                So, what can we conclude at this point?


      Iressa is an active agent, the response data are


      consistent in our Phase II and III trials.  The


      patients most likely to benefit are those patients


      who never smoked and those of Asian ethnicity.


                With these consistent findings, using an


      agent that inhibits a specific receptor and




      pathway, it is logical to assume that there is an


      underlying biologic basis.  In the last 10 months,


      two areas of translational research have been


      fruitful and may be useful in better understanding


      the clinical data in our Phase III program in Trial


      709, as well as guide therapy in our future




                The two biomarkers of most promise


      currently are EGFR expression and the EGFR


      mutations.  Published Iressa Phase II data did not


      appear to show definitive correlation of EGFR


      expression with response, but tumor samples were


      not available from all patients, and the trials


      were not controlled.


                Recently, however, results relating EGFR


      expression to survival outcomes were included in


      the erlotinib label.


                The second promising biomarker are


      activating mutations.  These were first described


      approximately 10 months ago in responding Iressa


      patients.  There are other promising, but more


      exploratory biomarkers that are included in the




      Iressa science program including gene copy number


      and dimerization patients, but again these remain


      more exploratory.


                What I would like to do now is show you


      from the erlotinib label--and I have included the


      three graphs they have relating to EGFR


      expression--and to ensure perfect synchronicity and


      accuracy, I am going to read the portion for you


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


      right-hand column.


                What we see here are three graphs.  The


      graph to the upper far left is the graph of the


      patients who had positive EGFR expression in their


      tumors, with the lower part of the Kaplan-Meier


      showing the patients treated with placebo.


                The graph to your far right, on the


      upperhand side is the patients who were EGFR


      expression-negative compared to placebo.  The lower


      lefthand is those patients that they did not have


      EGFR expression data on.


                As stated in the label, Tarceva prolonged


      survival in the EGFR-positive subgroup and the




      subgroup whose EGFR status was unmeasured, but did


      not appear to have an effect on survival in the


      EGFR-negative subgroup.  However, the confidence


      intervals for the EGFR-positive, negative, and


      unmeasured subgroups are wide and overlap, so that


      a survival benefit due to Tarceva in the


      EGFR-negative subgroup cannot be excluded.


                It needs to be said that a positive EGFR


      expression status in this study was defined as


      having at least 10 percent of cells staining


      positive for EGFR in contrast to the 1 percent


      cutoff specified in the DAKO EGFR pharmDx kit




                The use of the pharmDx kit has not been


      validated for use in non-small cell.  Accordingly,


      the data to date are inconclusive, but tantalizing


      as to the predictive nature of EGFR testing.


                In this trial, as in Trial 709, the tumor


      sample collection was not mandatory, and thus the


      number of samples is less than the number of


      enrolled patients.


                This is a busy slide and summarizes a very




      busy area of research in the 10 months since


      mutations were first described.  As noted on this


      slide, mutation appears to occur almost exclusively


      in non-small cell lung cancer.  The mutation is


      activating and in the ATP-binding site, which is


      where Iressa's activity occurs.


                I mentioned that the mutation was first


      described in patients with rapid, dramatic and


      prolonged responses to Iressa.  The increased


      frequency of the mutation occurs in patient subsets


      where Iressa responses are most frequent and where


      the survival benefit is most likely to be seen,


      that is, those patients who were never smokers,


      patients of Asian descent, women, and


      adenocarcinoma histology.


                There are actually two papers out this


      week looking at smoking status in relationship to


      the presence of these activating mutations, and


      depending on the paper, a minimum of 25 percent to


      75 percent of patients in different geographic


      regions who were never smokers have the mutation




                While patients whose tumors possess this


      type of somatic mutation appeared to be much more


      likely to have a response, all patients with




      mutations do not have a response.  We have recently


      looked at our IDEAL II data, and in the small


      subset with 14 mutations that we detected, 6 of


      these patients had prolonged partial responses.


                Again, where are we?  EGFR expression


      appears to be associated with increased survival.


      EGFR mutations appear to explain some, but not all,


      of the responses to Iressa.


                Outcomes in Trial 709, comparing Iressa to


      placebo, will be explored in terms of EGFR


      expression, activating mutation, and other




                We anticipate that this data will be


      available in June 2005.  We have collected close to


      600 tumor samples.  Approximately 400 of them we


      estimated based on our past experience will be


      fully evaluable for EGFR expression, and 200 for


      mutation status.


                It is hoped that these results may provide




      further insight into the clinical outcomes that we


      have seen in Trial 709.


                Thus, with these current clinical and


      translational data, what prospective studies are


      underway or could be considered?


                One proposal would be to evaluate patients


      with metastatic disease and compare the outcomes of


      Iressa with chemotherapy.  Mandatory tissue


      collection is an obvious requirement to evaluate


      the utility of biomarkers with respect to both


      outcomes in both the chemotherapy-treated patients


      and in patients with EGFR expression or




                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




                Finally, specific trials in the Asian


      populations to define the role of Iressa in the


      first line setting appear warranted.  Here, too,




      translational studies would be integral to the


      trial.  There are already several trials being


      conducted in Asia, as you might anticipate.


                A clinical question of increasing


      relevance that hasn't been answered to date is that


      of comparing both survival outcome and toxicities


      of Iressa or any EGFR inhibitor with single agent




                Trial 721, as previously noted by Dr.


      Scott, is a randomized Phase III post-approval


      commitment trial which compares Iressa to


      docetaxel.  This trial will complete patient


      enrollment by the end of the summer, and an interim


      survival analysis is expected this May or June.


                Trial 721's principal investigators and


      steering committees have reviewed the Trial 709


      data and continue to support this trial.  Another


      similar trial is being conducted entirely in Japan.


                Some clinical support to continue at this




      dose is mature Phase II data in a Caucasian and


      Hispanic patient population, which has recently


      matured and become available. In addition to


      showing comparability with the primary symptom


      endpoint, comparable outcomes were seen with


      response rates, time to progression, and overall




                The next slide is a Kaplan-Meier survival


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


      comparability of these trial results.  With a


      median follow-up of 9 months and 55 percent overall


      mortality, there are no differences between Iressa


      and docetaxel.


                The overall survival with docetaxel is


      consistent with that previously reported with this


      agent and in this clinical setting.  Although the


      trial is small, if Iressa was behaving as a


      placebo, then, one would have expected Iressa to


      have performed substantially worse in both time to


      progression, as well as overall survival.


                Back to our original question:  Where are


      we now?


                Well tolerated agents in the EGFR


      inhibitor class of agents are now an accepted


      addition to the therapeutic armamentarium of




      practicing oncologists and clinical trial




                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






                DR. SCOTT:  Thank you, Dr. Ochs.


                As you have heard from both Mr. Carroll


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


      fully understand Trial 709, and there are other




      trials, such as Trial 503, that provide supportive


      information, and Trial 721, which is also part of


      our Subpart H commitment to the FDA.


                This slide summarizes some key milestones


      that will be occurring.  It is expected that the


      complete data from Trial 709 and Trial 503 will be


      with the FDA in June for their review.  After that


      time, we expect to discuss labeling updates as


      appropriate based on the final data findings.


                It is expected that the Subpart H


      commitment trial, Trial 721, will deliver its final


      survival data in November of 2006.


                While the drug development road for Iressa


      has not been straightforward or without its


      surprises, the development program for this agent


      has provided a great deal of valuable information


      about non-small cell lung cancer and the EGFR




                Iressa is an active and well tolerated


      agent, and the lung cancer community has urged us


      to continue the development of this drug, and we


      are committed to doing so.


                Trial 709 has provided important patient


      selection information in a controlled randomized


      setting that may in the future help us write




      appropriate labeling to guide the clinical use of




                You have also heard today the critical


      information regarding EGFR expression and mutation


      status is yet to be delivered from this trial.


                Trial 721, the head-to-head trial versus


      docetaxel can provide confirmatory evidence of the


      effectiveness of Iressa.  As outlined, the


      development program for Iressa will help in


      identifying those patients who are most likely to


      benefit from Iressa.


                AstraZeneca rapidly and thoroughly


      disseminated information to oncologists about Trial


      709 to ensure informed treatment decisions would be


      made while further analysis were underway.


                As the patients responsive to Iressa will


      tell us, and their physicians will support, Iressa


      remains an important treatment option for non-small


      cell lung cancer.


                We thank the committee for their attention


      and welcome any questions at this time.


                          Committee Questions


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


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


      Ochs actually had the slide up--where you




      demonstrated what has been done to disseminate this


      information, if you would just flash that one more




                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




                DR. PAZDUR:  We have notified shortly when




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


      went out from the FDA to ASCO members notifying


      them on that day that we received the information


      of the study results and alternative treatment.


                We have a letter posted on our website


      that is included in your packet.


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


      side, the information has gone out to physicians


      primarily, as well as the website.


                DR. PAZDUR:  Correct.


                DR. MARTINO:  And from AstraZeneca,


      information has been provided to physicians, as


      well as to the lay public.


                DR. OCHS:  Yes.


                DR. MARTINO:  At this point, I will take


      some questions, but please keep them brief and




                Dr. Hussain, you are first.


                DR. HUSSAIN:  It is a question to either


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


      you are possibly thinking about targeted


      population, I saw that there were no women




      mentioned and no adenocarcinoma.


                Does that mean if you were a smoker and a


      woman, that the smoker component takes over as far


      as your potential benefit, or that if you are an


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


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


      discuss that particular issue since there is a lot


      of interconnection and interplay.


                MR. CARROLL:  Thank you for your question.


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


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


      interplay between the factors of interest, be they


      Asians, be adenocarcinoma, gender.


                The data, as I said, were finalized


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


      kind of analysis requires multivariate analysis to


      actually see which factors are contributing, which


      are the ones that are predicting the treatment




                That is something that we do plan to do in


      the next coming weeks and months to provide that


      data to the FDA, so we can answer the very




      important question that you have raised, because I


      am not sure we have the answer to that today.


                DR. MARTINO:  Dr. Perry.


                DR. PERRY:  I am not sure who gets this


      question, but I have been under the impression that


      in Europe particularly, the incidence of squamous


      cell carcinoma was considerably higher than in the


      United States, so I am somewhat surprised of a 48


      percent incidence of adenocarcinoma histology


      worldwide, particularly when two-thirds of the


      patients seem to be from Europe.


                How do you know that these are


      adenocarcinomas, is this the local pathologist's


      interpretation, and are they inclined to overread


      them as adenocarcinomas rather than as non-small


      cell carcinomas not otherwise specified?


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


      come and speak to that point.


                DR. BARGE:  Thank you.  Alan Barge,




                We have not done central pathology review.


      All of the diagnoses were the ones that were




      confirmed by the hospital pathologists, so we


      couldn't answer your question directly, I am




                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




                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




                DR. BOTWOOD:  Thank you.  Nick Botwood,


      AstraZeneca.  We did look at compliance on this


      trial and found that over 90 percent of the


      patients were compliant and had taken at least 95


      percent of their medication.


                This was based primarily on data that we


      collected in the CRF in terms of any documented


      dose interruptions for whatever reason, and then we




      went on to further validate that, to actually look


      at the number of tablets that were returned and


      looked at the number of tablets that had actually


      been prescribed to validate that what was in the


      CRF was actually the correct information.


                DR. RODRIGUEZ:  Along those lines, was


      there a required or concurrent diarrhea prophylaxis


      program, and was compliance to that also monitored?


                DR. BOTWOOD:  That wasn't, no.


                DR. RODRIGUEZ:  It is interesting because


      your failure to treatment has a significantly


      different profile with regards to symptoms and


      adverse events.  It seems that the patients on the


      Iressa arm, a higher proportion were taken off


      study because of those problems, is that correct?


      That is what your bar graph seemed to show.


                DR. BOTWOOD:  Kevin Carroll can answer


      that question, please.


                MR. CARROLL:  If I am correct, you are




      asking whether there was a difference in withdrawal


      due to--


                DR. RODRIGUEZ:  Yes, side effects.


                MR. CARROLL:  Side effects.  As I showed


      when we went through the adverse event data, there


      was very little difference between the two


      treatments in terms of withdrawal due to adverse


      events, and in terms of the data that we obtained


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


      fewer--Iressa failed fewer patients due to


      progression than placebo, so I don't think the


      difference was there in the way that perhaps you




                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




                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






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


      patients that went on to receive any subsequent


      chemotherapy was 10 percent, and this was balanced


      between the Iressa and placebo arm.


                DR. LEVINE:  Just to further that a little


      bit, even complementary therapies in Asia, and so


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


                DR. BOTWOOD:  It was extremely small.


                DR. LEVINE:  My other question related to


      the concept of secondary smoke.  In Eastern Europe


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


      even individuals who say that they weren't smokers


      may have been exposed, and therefore, did you look


      at cotinine levels or anything?  That might be


      something to explore, or did you look at that?


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


      at that. When we looked at the smoking demography


      of the patients from Eastern Europe, approximately


      85 percent of the patients from Eastern Europe were




      heavy smokers, and they had a higher median year


      exposure than the patients from other regions, but


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


                DR. MARTINO:  Dr. D'Agostino?


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


      time keeping my questions solely to the material


      that has been circulated as opposed to asking a


      million questions about the study, but the question


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


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


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


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


                I understand that the study did run its


      course, and then you did an analysis with unclean


      data or not completely clean data, and then later


      on had clean data, or was the analysis you are


      reporting an interim analysis?


                DR. SCOTT:  The analysis that we reported


      on in December was not an interim analysis.  It was


      based on final survival data, but it had been yet


      to be validated.


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




      validation. Thank you.


                DR. MARTINO:  Dr. Proschan.


                DR. PROSCHAN:  You mentioned that the


      Phase II trials identified subgroups, and ethnicity


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


      you specifically decided to break it into Asian


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




                DR. SCOTT:  We can have Mr. Carroll talk


      about the rationale behind the subgroups that we


      planned for Trial 709, and then perhaps have Alan


      Barge talk about why we think so.


                MR. CARROLL:  The subsets that we have


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


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


      subsets, of course, and they were determined


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


      also information that came out in June of this year


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


                There, there was an evaluation of Asians


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


      findings in the IDEAL trials where our Japanese




      patients had a much higher response rate was a


      motivation to look at that subset amongst others


      that were deemed to be clinically relevant.


                Perhaps I can now turn to my colleague,


      Dr. Barge, to answer the second part of your




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


      good deal of speculation as to why patients of


      Asian ethnic origin appear to do better on this


      class of drug.  There have been some quite


      interesting publications very recently.  In fact,


      this week there was a publication from Dr. Gazda


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


      frequency of activating mutations of the kind that


      Dr. Ochs described is much higher in Asian


      populations, particularly female Asians, and


      particularly female Asians with adenocarcinoma.


                The Phase II studies that we conducted in


      various Asian countries all show that the frequency


      of responses are much higher in those populations,


      and we have seen response rates as high as 60 or


      even 80 percent in selected populations of Asian




      nonsmoking females.


                Whether or not that is all driven by


      activating mutations we don't know, but that is


      certainly a very strong hypothesis at the moment.


                DR. MARTINO:  Mrs. Ross.


                MRS. ROSS:  Thank you, Madam Chair.


                If I understand correctly, the primary


      purpose of this hearing is to evaluate or just to


      discuss the transparency of the post-approval


      process and the adequacy of the notifications.


                In that regard, I would like to advise the


      rest of the panel of other steps that were indeed


      taken by both AstraZeneca and the FDA, and I would


      like to thank Dr. Pazdur in particular for his help


      on this.


                As the only lung cancer advocacy


      organization nationwide, we started receiving many


      phone calls from patients who were somewhat


      panicked when they heard the news in the press that


      Iressa might be pulled.  The press always leaps to


      the worst possible conclusion, as you all know.


                These people were discussing stockpiling




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


      panic out there. Dr. Pazdur responded, and


      AstraZeneca did, by helping us draft more


      information, more plain English information to put


      up on our website and to tell people over the phone


      when they called in a state of panic about Iressa.


                I think that should be noted.  I think


      that overall, the process was extraordinarily


      transparent and more than adequate in dealing with


      the situation.  Again, I would just like to thank


      FDA and AstraZeneca for all they did.


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


      make a comment?


                DR. TEMPLE:  Just one question.  We


      certainly never at any time thought that someone


      who had apparently responded to the drug should


      lose access to it.  That was never in doubt.


                But I wanted to ask you about where


      AstraZeneca is at the moment.  This was, shall we


      say, an optimistic presentation.  The study, after


      all, failed.  You had opportunities to identify


      subsets before the study that would be your primary




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


      enough to do that.


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


      distinction, Ralph may want to comment more--these


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


      did not win.  That is different from subset


      analyses in a study that did win.


                But what I really want to know is where do


      you come out on the question of new patients with


      non-small cell lung cancer being started on Iressa


      now.  The material you put out says you should


      consider other drugs.  Fine.


                But would it be your view that at the


      present time, optimism about the future and data


      that might come forward notwithstanding, a person


      with this disease should really not be started on


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


      your view anymore?


                DR. SCOTT:  Our view is that what was


      stated in the Dear Doctor letter then is what is


      today, that physicians should consider other


      options armed with the information from this




      particular trial.


                If I could ask Dr. Kris to come up and


      talk about how this has played out in his practice,


      maybe Dr. Burris, as well.


                DR. KRIS:  To answer your question, Dr.


      Temple, I think the most important thing is to put


      this into a context of what is available for a


      patient with advanced non-small cell lung cancer


      particularly after the failure of initial therapy.


                I think that the information that we have


      today is that there are some patients, those with


      an EGFR mutation, that have, and the literature


      today says that they have an 89 percent chance of


      having a response, and in those patients, when you


      look at their duration of response and survival, it


      is clearly prolonged.  In the trials that looked at


      survival in mutation positive and negative people


      being treated, it is much better with treatment.


                So, as a clinician, my first point is to


      find those people that have that extraordinary


      chance of benefit, that is, mutation-positive


      people, and the two surrogates for positive




      mutation we have today, that is, never smoking


      status for U.S. population and worldwide, is


      probably Asian, and it is not simply Japanese.


      There are reports now from Taiwan, from China,




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


      are looking at the mutation status of the people


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


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


      overwhelming and knock everybody's eyes out.


                But at the moment you have no prospective


      data on that subgroup for survival.


                DR. KRIS:  The only prospective data that


      exists on the treatment of mutation-positive


      patients is, frankly, an extrapolation to the never


      smoking patients.


                DR. TEMPLE:  I understand.


                DR. KRIS:  But those are


      placebo-controlled trials.


                DR. TEMPLE:  But what I am really asking


      is what you really mean, and we will probably have


      to have subsequent discussions, one might say that




      you should use the drug with very similar


      properties, similar mechanism, et cetera, that has


      actually been shown to improve survival.


                Are you saying something to the contrary


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


      thought it was clear, but from your presentation, I




                DR. KRIS:  Well, I frankly think that the


      most critical slide there was looking at the hazard


      ratios for the two substances, for gefitinib and


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


      not an AstraZeneca hat right now, and that


      clinician's hat is that there is effect there.


                You can argue the p value of 0.04 versus


      0.07, and there are people here that can do that


      much better than I, but from the clinician


      standpoint, you have to make that choice.  But you


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


      patient, you have a man with a squamous cancer


      sitting in your office that is smoking today, and


      his likelihood of benefit by the literature is


      extraordinarily small, well under 5 percent.


                So, for that patient, you are going to


      make another choice, so that the choice for the


      patient is not going to be decided by this trial as




      a clinician.


                DR. TEMPLE:  I am really asking about what


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


      for an EGFR order of treatment now based on


      available data.  I actually thought you thought


      that for the moment, one should use the drug that


      actually won, but I no longer perceive that in your




                DR. KRIS:  I am talking about from a


      clinician's standpoint, and I interpret the whole


      of the data as unbelievably consistent.  I mean I


      think it is extraordinary that when you look at the


      mutations, when you look at the response rates


      across country, across drug, it is how consistent


      it is, particularly the smoking observation.


                DR. TEMPLE:  The pattern may be the same.


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


      as the other one even though the pattern is the


      same.  It is possible.


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


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


      data in my estimation, and this is one piece of


      data today.


                DR. PAZDUR:  But Mark, you pointed out


      that you may look at the mutational status in




      making a decision, but really, in the United


      States, only a small number of people really have


      that available to them.


                DR. KRIS:  Rick, from a practical


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


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


      limited availability right now.  The decision is


      made on clinical grounds, and the surrogates for


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


      never smoking status and Asian birth, and that is


      how we make our decision.


                DR. PAZDUR:  I have another question for


      AstraZeneca.  In your presentation, you noted a


      decrease in new prescriptions.  Could you tell us


      what you mean by new prescriptions for Iressa, does


      that mean new patients or simply renewal of




      prescriptions of existing patients that are already


      on it, or can you distinguish between that?


                DR. SCOTT:  The new prescriptions are not


      new patients, they are a mixture of patients that


      are getting a refill of prescriptions, because


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


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


      be for new patients, but I will ask Carolyn


      Fitzsimons to talk about that data, how we are


      interpreting it with the availability of other


      information that is indicative of most--


                DR. PAZDUR:  Because we are very much


      interested, following up on Bob's question, how


      many new patients--


                DR. SCOTT:  Right, and I will ask Carolyn


      Fitzsimons to come and speak to that.


                MS. FITZSIMONS:  Thank you.  Carolyn


      Fitzsimons, AstraZeneca.


                If I can just show the slide as to what is


      happening with the prescription data and try and


      answer your question, Dr. Pazdur, in terms of


      specifically new patients.


                We have not been able to secure a source


      to actually define new patients, so we have to take


      the new prescription data as indicative of what is




      happening in the marketplace.


                The new prescription data, as Mark has


      just explained, is not wholly attributed for by new


      patients.  It encompasses every time a new


      prescription is written, so a repeat prescription.


                From the data that we have and is shown


      here, on the significant decrease that we have seen


      in new prescriptions, a 58 percent decrease since


      the announcements of Trial 709.


                It is our belief, based upon the duration


      of therapy of an Iressa patient who is currently


      receiving the product, that the majority of these


      prescriptions are now being written for patients


      who were prescribed Iressa prior to the


      announcements of Trial 709, and are receiving


      ongoing therapy from consultations with their


      physician, therefore, we assume they are deemed to


      be benefiting.


                We have conducted some market research




      earlier in February to try and further establish


      what is happening with new patients, and from that


      data, we have established that physicians are aware


      of the Trial 709 results, and are not longer


      choosing Iressa as their EGFR inhibitor of choice,


      they are choosing erlotinib, and 86 percent of them


      indicated that from the market research.


                DR. SCOTT:  If I could ask Skip Burris to


      come up and talk about what has happened at


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


      is reflective.


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


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


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


      and he and Mark were certainly talking about one


      issue, but we felt the need to issue some




                Certainly those guidelines were that those


      patients that were being treated with Iressa,


      should be continued on Iressa, that those patients


      who fit into a class where it is felt it


      appropriate that an EGFR inhibitor should be




      utilized, that erlotinib or Tarceva would, in fact,


      be the preferred agent in the short term, that


      there should be consideration given based on the


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


      patients were intolerant of one or the other, to


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


      has occurred in at least several patients.


                Lastly, and maybe most importantly, is the


      fact that as a conscious decision, analyzing the


      data within our group, we have continued to accrue


      and randomize patients on a count done quickly


      yesterday, 9 patients, in fact, randomized to


      Iressa in a controlled Phase III trial in patients


      with refractory lung cancer.


                So, the believe of the group, as Mark


      alluded to, certainly subsets that will benefit,


      but we have continued to accrue to trials comparing


      a new agent with Iressa in this setting, so that


      accounts for some of the new prescriptions written


      in our group, as well.


                While the comment, and I certainly agree


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




      have a winner here in the sense that there is not


      randomized data between erlotinib and gefitinib to


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


      this class is heading into what subsets will


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


      head the differences in the two.


                Certainly there are small differences in


      terms of mechanism of action, pharmacology and




                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




                I just had a quick question actually for


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


      are you, that doctors should not be allowed to


      write new prescriptions for Iressa?


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


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


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


      prescription--a new prescription for Iressa in




      someone who is already on the drug and responding


      to it is not an issue.


                MRS. ROSS:  New patient new to the drug.


                DR. TEMPLE:  I am more worried about what


      AstraZeneca is telling people.  I thought it was


      fairly clear they thought, given a choice, for


      someone who wants that mechanism, they would use


      the drug that actually showed a benefit, not the


      drug that didn't.


                I no longer am clear that that is their


      goal after this presentation today.  It sounds much


      more ambiguous than that, and I am just trying to


      find out what it is.  I thought the comment about


      what is being done in Tennessee makes a lot of


      sense, if you think that therapy is appropriate,


      use the drug that won.


                Look, we have been pushing, if anything,


      the idea that there are subsets of the population


      that are more likely to respond than others, and


      that has been I think apparent from the earliest


      data with Iressa.  There undoubtedly are


      differences among subsets of the population.


                But Ralph can comment on this.  All of


      those differences in a trial are much more credible


      when the trial wins overall or when you have




      specified that as the primary endpoint.  It remains


      somewhat after the fact, not implausible given the


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


      are much more likely to respond.


                All those things are probably true, but


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


      which has a quite successful overall clinical


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


      time people would suggest that you use the one that


      actually had the favorable result.


                I thought that was the direction


      AstraZeneca was urging people to go.  I am not as


      sure of that after hearing the presentation today.


                DR. SCOTT:  Could I--


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


      question here.


                Has the FDA had the opportunity to review


      the materials that have been prepared by




                DR. TEMPLE:  Yes.


                DR. MARTINO:  You have.  So, you have


      seen, in fact, the written materials?


                DR. PAZDUR:  The written materials, yes.


                DR. MARTINO:  Okay.  And can I trust that


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




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


      decided that they are okay with you?  I




                DR. TEMPLE:  We did.  I am now slightly


      nervous about them.


                DR. MARTINO:  I understand the concept of


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


      a committee, can judge is the steps that they have


      taken, the material that they have supplied, and


      the content, the written content in that material,


      is it fair, appropriate, and informative.


                What their intent might be in their gut


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


      understand your question, but it is not really what


      this committee can deal with.


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




      question?  I mean I thought that what we were


      looking at was basically this letter, and that I


      think is fine, and I think it reflects what the


      data shows.


                I am bothered by the presentation that


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


      and then showing this presentation, because the


      presentation has a completely different bent to it,


      and my question was going to be, what is their


      presentation to the field, is it just this letter,


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


      than the people who are running the studies.


                The ones who are running the studies


      obviously have to see this, but what is the


      collection of M.D.'s being told?


                DR. MARTINO:  That is an important


      question, that, I would like the company to answer




                DR. SCOTT:  If I could respond first and


      have Judy Ochs talk about the intent of the letter.


      Again, the intent of the letter in December is the


      intent today, and I will have Judy Ochs talk about




      the intent, please.


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


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


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


      letter is true.  It is no less true today.


                The presentation today, however, reflects


      some time, now that we have the full totality of


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


      be submitted to you.  The FDA will review it.


      Again, many times when one goes through protocols


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


      be some aspects to the interpretation.


                The bottom line, that the trial did not


      meet statistical significance has not changed.


                DR. MARTINO:  One more question and then I


      will turn to the open forum, please.


                DR. REAMAN:  You did show data today about


      a particular subgroup or subgroups that do appear


      to potentially have more of a benefit than others,


      the corollary being that there is a large group


      that don't appear to have any benefit.


                Is that data that has only been made




      available to you since the letter went out in


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


      of that in the communication?


                DR. OCHS:  When the letter went out, that


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


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


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


      people, on Tuesday, and the data went out Friday


      morning, it was that quick a happening.


                Again, I think as we are looking at the


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


      say is that as Kevin presented in his presentation,


      all of the patients, if you look at the hazard


      ratios, it is to the left in terms of potential


      benefit for Iressa.


                There obviously are, as Kevin pointed out,


      variability, but nonetheless, we are looking at a


      trial that barely missed reaching statistical


      significance, so it is not like there wasn't


      benefit, it did not meet a statistically defined


      endpoint to which we all agree, and to which we


      would not change our recommendation to physicians




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


      Kris and Dr. Burris have brought up other things,


      other data that is out there, other information.


                And I think one of the things that has


      happened is that Iressa has been around for a


      while, people have had some experience, so people


      will be looking at the literature.  Certainly, the


      first opportunity for the data as a whole to be


      seen is today.


                We submitted it to a scientific forum


      where it will be presented.  There will be


      questions asked.  It will be questioned, and it


      will be submitted to peer-reviewed journals.


                          Open Public Hearing


                DR. MARTINO:  Thank you.  We will continue


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


      to turn to the open public hearing.  There are


      several of you that have asked to speak, so the


      microphone that you will be using is in the center


      of the room.


                Allow me to read the following in


      anticipation of your presentations.


                Both the Food and Drug Administration and


      the public believe in a transparent process for


      information gathering and decisionmaking.  To




      ensure such transparency at the open public hearing


      session of the Advisory Committee meeting, the FDA


      believes that it is important to understand the


      context of an individual's presentation.


                For this reason, FDA encourages you, the


      open public hearing speaker, at the beginning of


      your written or oral statement to advise the


      committee of any financial relationship that you


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


      known, its direct competitors.


                For example, this financial information


      may include the sponsor's payment of your travel,


      lodging, or other expenses in connection with your


      attendance at the meeting.


                Likewise, the FDA encourages you at the


      beginning of your statement to advise the committee


      if you do not have any such financial relationship.


      If you choose not to address this issue of


      financial relationship at the beginning of your




      statement, it will not preclude you from speaking.


                Ms. Clifford, if you will announce our


      speakers, please.


                MS. CLIFFORD:  Peter Lurie is our first




                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




                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




                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




                You will notice, too, that in Europe, the


      marketing application for Iressa has been withdrawn




      and that in Japan, the Ministry is giving serious


      consideration to removing the drug from the market.


                As you all know, Subpart H is the


      mechanism through which this drug was approved, and


      to emphasize, that accelerated approval law makes


      clear that the FDA may withdraw approval of a fast


      track product "if a post-marketing clinical study


      fails to verify clinical benefit." That is


      certainly the case over here.


                In fact, even prior to approval, there


      were a couple of studies that showed lack of


      clinical benefit, and the two instant studies were,


      in the words of the FDA medical officer,


      "unambiguously negative," and the medical officer


      made the observation that "the FDA has never


      received a cancer drug application for accelerated


      approval when definitive data in another related


      setting showed a lack of efficacy."


                Those were first line therapy trials,


      which were both negative with respect to mortality,


      and the drug on the market for third line therapy,


      of course, we will acknowledge the principle in




      oncology is that a drug is most likely to work as


      first line therapy rather than third line therapy,


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


      the ISEL has confirmed.


                So, we have these two negative mortality


      studies even going into the approval of this drug.


      Now we have the ISEL study, which shows a very


      small survival difference, 27 versus 22 percent,


      but not statistically significant under the primary


      data analysis.


                As you will notice from the slides


      presented by AstraZeneca this morning, the overall


      quality of life was also not benefited by Iressa.


                Instead, what we have seen, you have all


      heard of rescue chemotherapy, I think what we have


      seen here is rescue biostatistics.  A number of


      subanalyses that have been done, some of them


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


      You will notice from your briefing materials that


      some subanalyses are described as prespecified, but


      the second table is one that implicitly are not


      prespecified. The Asian group is among them.


                How many of these subanalyses have been


      done?  Why is it that the rather simple to conduct


      multivariate analysis has not been done, and why is




      it that conveniently none of them are ready for


      this meeting?


                In response, we have seen the FDA put out


      a letter.  We have seen another letter from


      AstraZeneca, which in effect are telling patients


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


      kind of public health approach is this to have a


      letter from a drug company that, in effect,


      suggests that patients not take their drug?


                That doesn't seem like an adequate public


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


      still taking the drug, 331 new prescriptions in the


      week of February 18th. The company may claim that


      these are not new patients, but there is no


      evidence for that either.


                The fact is that there is a drug on the


      market which has clear, proven mortality benefit,


      and patients can easily be diverted from the


      effective therapy to this one for which there is no






                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




                How ironic this is.  A company gets a drug


      on the market through an accelerated approval


      process and then when the data turn out to be


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


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




      multivariate analysis that we haven't done, and the


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


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


      in time for this meeting.


                These EGFR analyses should be thought


      about in the following context.  In the Phase II


      trial, there was no relationship between the


      expression of EGFR and outcomes. There is no


      calculation of a positive predictive value for


      these mutations.


                Clearly, people without them are


      responding and vice versa.  We really don't know


      the positive predictive value, and as was also


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


      something--and even AstraZeneca admits this--that


      can be used to distinguish patients at present, and


      therefore, decide whether or not to provide them


      with therapy.


                If this is important enough a question, it


      should be researched, and the IND is the


      appropriate mechanism to do that.


                Finally, to close, with Subpart H, if ever




      there was a drug that was slated for and eligible


      for removal from the market under Subpart H, this


      is it, a drug, which even for the


      indirect--sorry--for the surrogate marker had


      minimal benefit in the Phase II uncontrolled,


      non-placebo-controlled, even unblinded trial,


      minimal benefit on the surrogate markers, clear


      dangers, proven effective therapy in terms of


      reducing mortality, and now patients continue to be


      placed on the drug, and three negative mortality




                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






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


                MS. FENTON:  Okay.  How is that?


                Again, Laurie Fenton, the President of The


      Lung Cancer Alliance.  We are the only national


      organization that is dedicated exclusively to


      advocating on behalf of lung cancer patients, their


      caregivers and survivors.


                I believe you have my statement, so I will


      condense what I would like to present today.


                AstraZeneca has provided grants in the


      past for educational programs, but they have not


      compensated me in any way today to present what we


      are here to share.


                The Lung Cancer Alliance understands that


      the FDA is required by statute to evaluate drugs by


      looking at safety and efficacy data in large


      populations of patients to determine whether


      benefits outweigh the risks.


                Interestingly, we have discovered that


      Iressa does not fit neatly into this protocol, and


      while Iressa's current clinical trial data has not




      revealed dramatic survival benefits overall, it has


      shown striking benefits for a small subset of the


      larger population, with less side effects and


      quicker response rates.


                As was shared earlier, we received many


      phone calls from patients who were extremely


      concerned that Iressa could be pulled from the


      market, particularly a drug that had helped them so




                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




      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




      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




      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




      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




                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




      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






                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




                Shortly after that, I learned from the




      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.




                DR. MARTINO:  Thank you, ladies and




                          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




      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




                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




      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




                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




      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




                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. 




      I have myself not used it in the setting of lung




                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




                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,




      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




                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




      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




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


      myself, so we have to be very clear about those




                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




      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




      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




      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




      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




                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




                Who is next on my list here?  Dr.




                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




      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




                So, maybe we need an accelerated review of




      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




                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




      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.




                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




      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




      medical community, at least the lung cancer




                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




      that they are on is going to be pulled away from




                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




      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




                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




      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




                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"




                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




      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




      significantly worse than no treatment, but that


      hardly ever happens, but it doesn't support the




                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




      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




      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




      behalf of someone?


                DR. TEMPLE:  He stated that he had no




                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




                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




      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




                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




      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




      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




                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




      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




      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,




      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




      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




      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




      part of this meeting.






                    Call to Order and Introductions


                DR. MARTINO:  Good morning, ladies and




                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




                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




      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




                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




                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,




                DR. COLMAN:  Eric Colman, Medical Officer,




                DR. AVIGAN:  Mark Avigan, Office of Drug






                DR. TEMPLE:  Bob Temple, Office Director,




                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




                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


      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




                A copy of the waiver statements may be


      obtained by submitting a written request to the


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




      of the Parklawn Building.


                With respect to the FDA's invited industry


      representative, we would like to disclose that Dr.


      Antonio Grillo-Lopez is participating in this


      meeting as an acting industry representative acting


      on behalf of regulated industry.  Dr. Grillo-Lopez


      is employed by Neoplastic and Autoimmune Disease




                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




                Thank you.


                DR. MARTINO:  Thank you.


                Dr. Pazdur will now address the group and




      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




      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




      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




                            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




                It is also approved for hypercalcemia of


      malignancy and Paget's Disease of bone.


                You have heard the Aredia approval dates.




      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




      licensing trials for Aredia.  They were


      double-blind, randomized, placebo-controlled,


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




                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




                Zometa was approved for hypercalcemia of


      malignancy in August of 2001.  At that time,


      Novartis submitted a supplemental NDA for the bone




      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




                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




      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




      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