1 DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION INFECTIOUS DISEASES SOCIETY OF AMERICA INTERNATIONAL SOCIETY OF ANTI-INFECTIVE PHARMACOLOGY FOOD AND DRUG ADMINISTRATION ANTIMICROBIAL DRUG DEVELOPMENT WORKSHOP Thursday, April 15, 2004 9:05 a.m. Advisors and Consultants Staff Conference Room 5630 Fishers Lane Rockville, Maryland 2 PARTICIPANTS John E. Edwards, Jr., M.D., Moderator INDUSTRY: Lisa Benincosa, Ph.D. Mike N. Dudley, Pharm.D. Barry Eisenstein, M.D. Dennis M. Grasela, Pharm.D., M.D. Timothy J. Henkel, M.D., Ph.D. John H. Rex, M.D. Frank Tally, M.D. Gregory A. Winchell, Ph.D. ACADEMIA: Ralph Corey, M.D. William A. Craig, M.D. Harmut Derendorf, Ph.D. George L. Drusano, M.D. Thomas Fleming, Ph.D. Robert J. Guidos, J.D. Sheldon L. Kaplan, M.D. W. Mike Scheld, ,M.D. Jerome J. Schentag, Pharm.D. George Talbot, M.D. Paul M. Tulkens, M.D. FDA: Renata Albrecht, M.D. Edward Cox, M.D., MPH Mark J. Goldberger, M.D., MPH John Powers, M.D. David Ross, M.D., MPH Janice Soreth, M.D. MISCELLANEOUS: John S. Bradley, M.D. Dennis M. Dixon, M.D. J. Todd Weber, M.D. 3 C O N T E N T S Opening Remarks, John E. Edwards, M.D. 4 I. Progress Report Since Last Workshop IDSA, W. Mike Scheld, M.D. 9 FDA, Edward Cox., M.D., MPH 21 Discussion 36 II. Continuing Discussion on Incentives for Drug Development IDSA, George Talbot, M.D. 41 FDA, Mark Goldberger, M.D., MPH 62 Discussion 85 III. Microbiologic Surrogate Endpoints in Clinical Trials IDSA, Sheldon Kaplan, M.D., Baylor College of Medicine 137 INDUSTRY, Barry Eisenstein, M.D., Cubist Pharmaceuticals 148 FDA, John Powers, M.D. 163 Discussion 187 IV. DISCUSSIONS ABOUT BACTEREMIA AS AN INDICATION/ ISSUES WITH CLINICAL TRIALS IN ENDOCARDITIS INDUSTRY, Timothy J. Henkel, M.D., Ph.D. 249 IDSA, Ralph Corey, M.D. 261 FDA, David Ross, M.D., MPH 277 Discussion 288 4 1 P R O C E E D I N G S 2 Opening Remarks 3 DR. EDWARDS: Welcome, everyone. My name 4 is Jack Edwards and I am from the Harbor UCLA 5 Medical Center School of Medicine at UCLA, and also 6 am a member of the Antimicrobial Availability Task 7 Force of the IDSA, and I will be coordinating the 8 meeting today. 9 I would first like to say that we are very 10 grateful to the staff at the FDA and the IDSA for 11 several months of a great deal of work that has 12 gone into the preparation of this meeting, which is 13 really the second in what we hope is a continuum of 14 meetings to address this issue that we, from the 15 IDSA, have become quite acutely aware of, and that 16 is the long-term, if you will, paradoxical 17 diminishment in the availability of anti-infectives 18 over the last several years, particularly in the 19 area of antibacterials, which is somewhat 20 paradoxical as it is occurring at a time when our 21 needs are just increasing dramatically due to 22 resistance problems and we have the specter of 5 1 bioterrorism in the background as well. 2 The IDSA has been studying the issue 3 acutely over the last two years and this meetings 4 is a result of efforts to try to bring the issue 5 into a sharper focus and for all of us to think of 6 solutions that will correct this trend. The 7 meeting, we are hoping, is going to be informal. 8 This is not an FDA advisory board meeting, and I am 9 going to be encouraging informality and interchange 10 as much as possible during the whole meeting. Some 11 of you may remember at the last meeting we had a 12 little trouble breaking the ice at the beginning 13 and I started to tell my favorite biostatistician 14 joke, but then I realized that there were several 15 biostatisticians in the room who might not think it 16 was funny so we passed on that. But I do want to 17 try to keep this informal, collegial, interactive 18 and we will be trying to stimulate conversation as 19 we go along the whole way. 20 Just a couple of brief announcements, we 21 have changed the order a bit from what you saw 22 posted on the web site. There are revised 6 1 schedules on the table there and I hope you all 2 have them. So, the order will follow that 3 dispersed schedule. I will make some other 4 announcements later regarding lunch, and so forth, 5 as we go along. 6 Without delaying, I want to formulate 7 thanks to some individuals and I am going to do 8 that throughout the meeting here. I would like for 9 us to begin by going around the table and each 10 person at the table introducing themselves with 11 their affiliation. Then we will get right into our 12 first discussion area. Mike, would you begin? 13 DR. SCHELD: Sure. I am Michael Scheld. 14 I am from the University of Virginia and I am here 15 representing the IDSA. I am the immediate past 16 president of the Society. DR. TALBOT: Good 17 morning. My name is George Talbot. I am with 18 Talbot Advisors and I am here with IDSA today. 19 DR. DERENDORF: I am Harmut Derendorf, 20 from the University of Florida, and I am president 21 elect of ISAP. 22 DR. ROSS: David Ross, and I am with the 7 1 Division of Anti-infective Drug Products, FDA. 2 DR. COX: Ed Cox, Deputy Director for ODE 3 IV, CDER, FDA. 4 DR. GOLDBERGER: I am Mark Goldberger, the 5 Director of ODE IV, CDER, FDA. 6 DR. POWERS: John Powers, Lead Medical 7 Officer for Antimicrobial Drug Development and 8 Resistance Initiatives in ODE IV. 9 DR. ALBRECHT: Renata Albrecht, Director, 10 Division of Special Pathogen and Immunologic Drug 11 Products, FDA. 12 DR. WEBER: Todd Weber, I am the Director 13 of the Office of Antimicrobial Resistance, National 14 Center for Infectious Diseases at CDC. 15 DR. DIXON: I am Dennis Dixon. I am from 16 the National Institutes of Health, National 17 Institute of Allergy and Infectious Diseases, and I 18 am Chief of the Bacteriology and Mycology Branch. 19 DR. FLEMING: Thomas Fleming, Chair of the 20 Department of Biostatistics, University of 21 Washington, and I am disappointed I didn't hear 22 your opening joke last time! 8 1 [Laughter] 2 DR. TULKENS: I am Paul Tulkens, from 3 Brussels, Belgium. I am the past president of ISAP 4 and I am running a pharmacology group at the 5 Catholic University of Louvain, Brussels. 6 DR. WINCHELL: I am Greg Winchell, from 7 the Clinical Drug Metabolism Department at Merck. 8 DR. HENKEL: I am Tim Henkel. I am the 9 Chief Medical Office of Vicuron Pharmaceuticals. 10 DR. BENINCOSA: I am Lisa Benincosa, from 11 Pfizer Global Research and Development. 12 DR. REX: I am John Rex. I am the Medical 13 Director for Infections, AstraZeneca 14 Pharmaceuticals. 15 DR. COREY: I am Ralph Corey. I am from 16 Duke University, here on behalf of IDSA. 17 DR. TALLY: I am Frank Tally. I am Chief 18 Scientific Officer at Cubist. 19 DR. DRUSANO: George Drusano, Co-director 20 of Ordway Research Institution and a third past 21 president of ISF. 22 DR. EISENSTEIN: Barry Eisenstein, Head of 9 1 R&D at Cubist. 2 DR. CRAIG: Bill Craig, from the 3 University of Wisconsin, also a past president of 4 ISF. 5 DR. BRADLEY: John Bradley, from 6 Children's Hospital, San Diego. I am representing 7 the IDSA. 8 DR. EDWARDS: Thank you very much. At the 9 end of the last meeting we really developed a 10 rather intricate set of plans for progress to be 11 discussed at this meeting. I am going to now ask 12 Mike Scheld to begin with his comments regarding 13 the progress report from the IDSA since the last 14 meeting. Mike, thanks. 15 I. Progress Report Since Last Workshop 16 IDSA 17 DR. SCHELD: Thanks very much, Leo and 18 thank you Jack. 19 [Slide] 20 I thought I would start out with a slide 21 that I took of the rotunda at the University of 22 Virginia. As you have heard, I am Michael Scheld. 10 1 I am from the University of Virginia. If you can 2 dim the lights in here, it looks a lot better. If 3 you don't know, Mr. Thomas Jefferson founded the 4 University of Virginia and he considered it one of 5 his greatest achievements. In fact, if you visit 6 Monticello, his home and his grave site you won't 7 even find the fact that he was the third president 8 of the United States on his head stone. It 9 mentions the University of Virginia and a few other 10 things, like the Declaration of Independence. 11 To put his life in perspective, I will 12 just tell you one little anecdote. When John 13 Kennedy was president he had a dinner here in 14 Washington, at the White House, for all the Nobel 15 prize winners that were then alive. This was back 16 in 1963. At the end of the dinner he made the 17 comment--there were about 150 Nobel laureates in 18 attendance and he made the comment that this room 19 has not seen such an assemblage of intellect since 20 Thomas Jefferson dined here alone. That sums it up 21 pretty well. 22 [Laughter] 11 1 [Slide] 2 As you have heard, we formed an 3 Antimicrobial Availability Task Force within the 4 Infectious Disease Society of American, and what I 5 am planning on doing today is to just remind 6 everybody where we were in November, 2002 in our 7 workshop. 8 A perception that we had at the time which 9 was basically that as resistance was rising 10 research and development of antibacterials was 11 declining; some evidence for that perception in the 12 interim, and then I will tell you a little bit 13 about the work of the task force. 14 This is really a two-part presentation. I 15 am going to go over the membership of the task 16 force and what I think their charge should be and 17 how they should go about their business, because I 18 put this task force together during my presidency 19 at IDSA. Then George Talbot will take up the 20 second half where we will tell you a little bit 21 more about what we have learned along the way, as 22 well as some potential solutions. 12 1 [Slide] 2 So, back in November of 2002 I think the 3 themes or the workshop were basically a delta 4 issue, and we are not going to go there today, 5 fortunately; that antibacterial resistance was 6 increasing at a time when antibacterial research 7 and development was declining. We talked a good 8 deal about PK/PD and surrogate endpoints, and you 9 will hear more about that during the course of this 10 workshop. Then we discussed three disease states, 11 acute exacerbation of chronic bronchitis, 12 meningitis and hospital-acquired pneumonia. At the 13 end I will make a comment about the AECB efforts of 14 the IDSA as well. 15 [Slide] 16 So, this was our perception, and the years 17 at the bottom are completely arbitrary. Obviously, 18 antibacterial research and development was 19 declining before 1998, as well antibacterial 20 resistance was increasing. 21 [Slide] 22 Some evidence for this, and this is just 13 1 one example from the CDC where you can see the 2 increase in MRSA as well as vancomycin resistant 3 enterococci, resistant pneumococci and 4 fluoroquinolone resistant Pseudomonas. In my own 5 hospital about 40 percent of our bloodstream 6 isolates of Staph. aureus are now MRSA. About 15 7 percent of enterococcal bloodstream isolates are 8 VRE. We have about 35 percent overall penicillin 9 resistance to pneumococcus in central Virginia. 10 Our fluoroquinolone resistant Pseudomonas is now in 11 excess of 30 percent. 12 [Slide] 13 There are many threats to antibacterials. 14 I think one is bacterial resistance. Obviously, 15 drug shortages in recent years--we have had 16 problems with a supply of penicillin, gentamicin, 17 meropenem and others. The pipeline is rather dry 18 and there is a void in public policy which is 19 something that the IDSA has tried to address. 20 [Slide] 21 This shows antimicrobial research and 22 development from a paper by Spellberg et al. which 14 1 includes Dr. Edwards as one of the co-authors, 2 which I am happy to say is in press and maybe it is 3 published today. 4 DR. EDWARDS: I think it is today. 5 DR. SCHELD: Today--tax day; happy tax 6 day, everybody. You can see your taxes at work 7 here! It is published today in Clinical Infectious 8 Diseases, if you want to access it. This shows you 9 the total number of new antibacterial agents during 10 five-year intervals. Back in 1983-'87, you can see 11 that that number was 16 and it steadily went down 12 until 1998-2002 when it was only 7. Last year 13 there were only 2 new antibacterials approved. 14 [Slide] 15 This is just since 1996 where you see the 16 number that have been actually approved and 2002 17 was a pretty bad year for antibacterial approvals. 18 We had zero in that year. In 2003 there were two 19 again. 20 [Slide] 21 So, in 2002, out of 89 new drugs there 22 were no new antibacterial drugs that were approved. 15 1 If you look through the annual reports of the 15 2 major pharmaceutical companies, you find nearly 400 3 agents in development but only 5 of them are new 4 antibacterials. 5 [Slide] 6 Since 1998 there have been a new drugs 7 approved, but I would just point out here that only 8 a few of them are truly novel in that they have a 9 new target, like linezolid as well as daptomycin, 10 in 2003, and we have clarithromycin which was 11 approved. I guess it was about April 1 of this 12 year. So, there are not very many, and many of 13 them also hit another target. 14 [Slide] 15 So, back in December of 2003 the NDA 16 pipeline, or so-called "pink sheet," lists a few 17 drugs in Phase 3 antibacterial development. Only 18 tigecycline is really a broad spectrum agent that 19 has activity against many gram-positive and 20 resistant gram-negative pathogens. I just point 21 this out because in the same publication there are 22 18 novel oncology agents listed. There are 16 1 obviously a lot more you could add to this list, 2 like dalbavancin and others but this is just one 3 example in the published literature of what is in 4 Phase 3. 5 [Slide] 6 I am going to skip this in the interest of 7 time because George is going to show it in a few 8 minutes. 9 [Slide] 10 So, we put together an Antimicrobial 11 Availability Task Force and this is their charge, 12 which is to develop novel public policy to ensure a 13 sustainable supply of safe and effective 14 antimicrobial drugs to protect public health. The 15 initial focus was on the antibacterial development 16 because that was the area where we felt the crisis 17 was most acute. 18 [Slide] 19 The task force members are listed here. 20 It is probably pretty hard to see them, but I would 21 like to acknowledge and thank each of them 22 individually. John Bartlett was kind enough to 17 1 chair the task force. He couldn't be with us 2 today. He is from Hopkins. John Bradley is here. 3 Jack Edwards is here. David Gilbert deserves our 4 thanks because he has really done a lot of work on 5 the task force and, in addition, he worked very 6 hard at putting this workshop together. I serve. 7 Dave Shlaes is here, as is George Talbot, Frank 8 Tally and Dave Ross and John Powers have been 9 really a tremendous help in framing our thoughts 10 for how to move forward. I also should acknowledge 11 Bob Guidos who is sitting here as head of public 12 policy as IDSA. Our staff have been 13 extraordinarily helpful in putting together our 14 work plan. 15 [Slide] 16 This is the work plan as I envisioned it 17 when we formed our task force. It was basically to 18 understand the problem; publish our research and 19 the findings of our surveys. The first of these 20 publications is published today. Discuss with the 21 stakeholders--we made many field trips and I will 22 give you a couple of examples. The "white paper" 18 1 is in production, which will be used to discuss 2 this issue with other stakeholders, including 3 policy makers, congressional leaders, etc. We hope 4 to have that out within another few weeks. Then, 5 develop some solutions and you will hear about some 6 of our suggestions from Dr. Talbot in a few 7 minutes. 8 [Slide] 9 Back in October of 2001, CDC, NIH, FDA and 10 others put together a public health service action 11 plan to combat antimicrobial resistance, and there 12 were three major elements: to stimulate the 13 development of priority products to combat 14 antimicrobial resistance; streamline the regulatory 15 process and to identify incentives for development. 16 I think it is fair to say that all three of these 17 elements are included in our "white paper" and have 18 formed our thinking on many of these issues over 19 the last 18 months. 20 [Slide] 21 We call our "white paper" "Bad Bugs, No 22 Drugs." We have sought input from the major 19 1 stakeholders in this issue, including our 2 membership which now is over 7,500 physicians, 3 researchers and health care providers. To put that 4 in some perspective, that membership in the early 5 1990s was about one-third of that, about 2,500. We 6 have had many discussions with the FDA, CDC, NIAID, 7 Health and Human Services and senior pharmaceutical 8 executives, as well as venture capital companies 9 and members of Congress and legislators. 10 [Slide] 11 So, we have met with a number of the 12 groups listed on the right. We met with Tony Falci 13 and many others at NIAID. We have had discussions 14 with HHS and CDC, Judy Gerben and Jim Hughes. We 15 met with Commissioner McClellan as a group from 16 IDSA. We have had many meetings with Congress. We 17 have met with representatives of a number of 18 pharmaceutical companies that are listed there: 19 Abbot, Bristol-Myers Squibb, GaxoSmithKline, 20 Novartis, Pfizer and Vicuron, and others including 21 venture capital. We will outline what we learned 22 from some of those field trips in a few minutes 20 1 with Dr. Talbot's presentation. 2 [Slide] 3 Lastly, when we met before I think most of 4 us would agree that the literature on the treatment 5 of acute exacerbation of chronic bronchitis and the 6 role of antimicrobial therapy, at best, is 7 unsettled. So, we have basically put together 8 another joint task force between the IDSA and the 9 American Thoracic Society. There are 12 10 individuals involved in this. The chair from the 11 IDSA side of it is Tim Murphy, from State 12 University of New York in Buffalo. And, they have 13 started their work which is basically to develop a 14 protocol and budget. I had envisioned this to be 15 placebo, an old antibiotic and a new antibiotic 16 type of clinical trial. Implement a network 17 because such a network for bacteriology and 18 bacterial infections really needs to be done 19 nationwide; and then submit this to the NIAID for 20 funding. 21 Where it stands is they have started their 22 work and I am hoping that by our June board of 21 1 directors meeting for the IDSA we will have a draft 2 protocol to start to discuss at that level and 3 submit it later this summer. 4 So, Jack, that is kind of what we have 5 been up to in the IDSA and I will leave it up to 6 Dr. Talbot to give the second half of this 7 presentation, but thank you very much. 8 DR. EDWARDS: Thank you very much, Mike. 9 I am now going to ask Ed Cox, from FDA, to comment 10 from the FDA perspective. 11 FDA 12 DR. COX: Good morning and welcome, 13 everyone. 14 [Slide] 15 What I will be doing today is providing an 16 update since our last meeting in November of 2002 17 of some of the activities that folks at the FDA 18 have been involved with related to antimicrobial 19 resistance and antimicrobial drug development. 20 I will cover a variety of topics, 21 including some of the activities we have been 22 involved with at scientific meetings, both advisory 22 1 committee meetings and workshops; the work that is 2 ongoing with regards to guidance development; the 3 work that John Powers has been working tremendously 4 hard at with the folks at Focus Technologies and 5 our database through our contract with them. Then 6 I will also discuss some of the input that we got 7 from an advisory committee with regards to the 8 criteria for resistant pathogens of public health 9 importance, and then just briefly mention the newly 10 announced Critical Path initiative. Then I will 11 also just touch on some of the work that we have 12 been involved in at FDA with regards to preserving 13 the utility of our existing antimicrobial agents. 14 [Slide] 15 First, just to mention the March 4 FDA 16 anti-infective advisory committee. As part of that 17 meeting, there were presentations on the patterns 18 of antimicrobial resistance in Streptococcus 19 pneumonia and how this patterns, based on the data 20 analysis from the Focus database, related to 21 scientifically-based resistant pathogen claims for 22 Streptococcus pneumoniae. 23 1 Again, John Powers work showed the high 2 rate of cross-resistance between penicillin 3 resistant strains of Streptococcus pneumoniae and 4 many of the other commonly used antimicrobial 5 agents for respiratory tract infections. The 6 result of this was the concept of the multi-drug 7 resistant Streptococcus pneumoniae labeling claim. 8 [Slide] 9 Just to show some of the data from Focus 10 Technologies that were used in supporting the 11 concept of the multi-drug resistant Streptococcus 12 pneumoniae claim, this sort of schematic of the 13 scatter plot, that I will be showing you in just a 14 minute, shows drug Y on the Y axis with the 15 increasing MICs from the origin outward. Then on 16 the X axis, drug X, again increasing MICs from the 17 origin outward. So, those strains that are highly 18 susceptible to both drug X and drug Y will 19 congregate in the lower left hand corner. Those 20 strains that are resistant to both strains will 21 congregate in the upper right-hand corner. 22 [Slide] 24 1 If we look at a drug like cefuroxime, 2 which is shown here on the Y axis again with 3 increasing MICs and penicillin on the X axis with 4 increasing MICs from the origin outward, we see the 5 correlation of resistance between these two drugs 6 with the isolates congregating on the diagonal. 7 [Slide] 8 Just to contrast, this is a quinolone 9 antimicrobial agent on the Y axis and penicillin on 10 the X axis, and here we don't see the correlation 11 that we had seen with cefuroxime and penicillin 12 during the time period at which these isolates were 13 collected. 14 So, these data were very helpful to us as 15 one of the advisory committee discussions about 16 multi-drug resistant Streptococcus pneumoniae, and 17 were important in the subsequent MDRSP claims that 18 have since been awarded in labeling. 19 [Slide] 20 Also, on March 5 at the FDA Anti-Infective 21 Advisory Committee we had the opportunity to get 22 advice from the committee with regards to 25 1 developing criteria for resistant pathogens of 2 public health importance. The idea behind these 3 criteria is to identify those resistant pathogens 4 of public health importance that would warrant 5 claims in product labeling. The discussions at the 6 advisory committee helped refine the criteria for 7 resistant pathogens of public health importance. 8 In addition, there was discussion about the pros 9 and cons of a list that was brought up at the 10 advisory committee meeting. 11 [Slide] 12 The criteria that were discussed and 13 somewhat refined based upon the advice of the 14 advisory committee are that for a resistant 15 pathogen of public health importance in a 16 particular indication, that there be limited 17 available therapies due to multi-drug resistance of 18 the organism if the organism caused serious or 19 severe disease; that the drug to which the organism 20 is resistant, that is the drug within the resistant 21 pathogen claim, is commonly used in the disease 22 under study; that the organism is of sufficient 26 1 prevalence in the population with the disease under 2 study, or that the drug is used to control the 3 spread of disease within a population, for example 4 an anti-tuberculosis agent in the treatment of TB 5 would prevent the spread of TB in a population. 6 Then, also that there be clinical correlation of in 7 vitro resistance with core clinical outcomes. 8 [Slide] 9 Just to provide a little more comment on 10 the criteria, the idea is not that the pathogen 11 would need to fulfill al the criteria on the list, 12 but that these would be the criteria that would be 13 evaluated in looking at the resistant pathogen to 14 determine if it rose to the level of being a 15 resistant pathogen of public health importance 16 within a particular indication. 17 When we look at resistant pathogen claims, 18 typically what we are looking for is evidence of 19 activity in the treatment of the particular 20 indication, including successful treatment of 21 susceptible strains of the pathogen. Then also, in 22 addition, clinical activity in the treatment of the 27 1 resistant pathogen of interest in the particular 2 individual of interest. Part of the rationale here 3 is that there may be differences in the patient 4 characteristics of those patients who have 5 resistant organisms compared to those who have 6 susceptible organisms. 7 With regards to the ultimate application 8 that would result, priority review be based upon 9 the results of the clinical trials. It is also 10 important to note that there may be different 11 approaches here to bringing the drug application in 12 and that a drug application that comes in that 13 doesn't have all the data in hand for the resistant 14 pathogen claim can still be judged on the merits of 15 its safety and efficacy for the treatment of the 16 indication, and may then subsequently come in at a 17 later point in time for a resistant pathogen claim 18 if sufficient data were accrued. 19 [Slide] 20 There are a number of previously granted 21 resistance claims. I will just mention a couple of 22 them here, methasone resistant Staph. aureus with 28 1 claims for VRE, claims for beta-lactamase producing 2 H. flu, penicillin resistant Strep. pneumo. and 3 then more recently multi-drug resistant Strep. 4 pneumo. in resistance claims that have been 5 previously awarded in product labeling. 6 [Slide] 7 Also during the March 5 meeting, there was 8 an interesting discussion about relating clinical 9 data from one disease to another. The idea really 10 and the concept behind this is that for a drug 11 application that comes in and that covers a number 12 of different indications within the respiratory 13 tract, if that package of data were well anchored 14 in two adequate and well-controlled studies in 15 community-acquired pneumonia and there were also 16 studies in AECB and acute bacterial sinusitis, it 17 may not be necessary, you know, for a program that 18 is well anchored in two adequate and 19 well-controlled CAP studies to have two additional 20 studies in each of the additional respiratory tract 21 infection indications that are coming in as part of 22 the package. Part of this would depend upon the 29 1 single studies that would be conducted in the other 2 indications would be done in a well characterized 3 population and have good microbiologic 4 characterization of the patients under study. 5 Some of the concepts that were brought up 6 at the committee with regards to such an approach 7 would be that it would be important to have similar 8 microbial etiologies across the indications; 9 similar tissue distribution of the antimicrobial 10 agents in the target organs; and also that other 11 factors that should be considered would be the 12 severity of the disease. For instance, typically 13 any sort of supporting data we extrapolate from the 14 more severe disease to the less severe disease, not 15 the opposite way. Also, that there be 16 consideration of the host factors. It would be 17 more difficult or the directionality here would be 18 one from taking the data from--it wouldn't be 19 appropriate to take data from an immune competent 20 population and use that to support an indication in 21 an immune suppressed population because there may 22 be host factors there that would need to be 30 1 considered. 2 [Slide] 3 In September of 2003 there was a BAMSG/FDA 4 workshop that involved folks from academia, the 5 industry and also the FDA in discussions of 6 clinical trial design for empiric antifungal 7 therapy in febrile neutropenic patients. There 8 were a lot of interesting discussions about the use 9 of fever both as an inclusion criterion and then 10 also with regards to endpoints in studies of 11 patients for antifungal therapy for febrile 12 neutropenia. There were also discussions on 13 clinical trial design for investigating combination 14 antifungal therapies. For looking at a regimen of 15 A plus B, how do we know or how do we demonstrate 16 that there is an advantage of A plus B beyond the A 17 and B agents from which the regimen is composed? 18 [Slide] 19 Then, in October, 2003, additional 20 discussions of the anti-infective drug products 21 advisory committee on clinical trial design for 22 diabetic foot infections, defining the condition 31 1 itself; getting the inclusion and exclusion 2 criteria that would be used in a clinical trial. 3 Also issues about getting microbiologic diagnosis 4 in patients in patients with diabetic foot 5 infections were discussed, and also how to measure 6 the outcomes in these trials. 7 Clinical trial design in acute bacterial 8 sinusitis--there was also a lot of discussion that 9 was helpful to us in our ongoing efforts to update 10 the acute bacterial sinusitis guidance document. 11 The discussion centered around ways that we may 12 enrich the population in the acute bacterial 13 sinusitis studies such that a larger proportion of 14 the patients have bacterial disease. Really, you 15 know, the ultimate role here is if we can enhance 16 the population for those patients that have acute 17 bacterial sinusitis we may be able to demonstrate a 18 larger effect size in such a population and, 19 thereby, the trials my be able to be done more 20 efficiently. 21 There was also discussion about the role 22 of microbiologic diagnosis. Currently, sinus tap 32 1 is the procedure that is used in the microbiologic 2 diagnosis of acute bacterial sinusitis. There was 3 also some discussion about some newer technology 4 that might be used to diagnose acute bacterial 5 sinusitis and make a microbiologic diagnosis of 6 acute bacterial sinusitis. 7 Another issue that was discussed by the 8 committee was in those patients with acute 9 bacterial sinusitis, who don't have urgent acute 10 bacterial sinusitis, the possibility of dong 11 superiority trial designs which would be something 12 like an active plus symptomatic therapy versus 13 other symptomatic therapy. Again, such an approach 14 may allow for more efficient study of acute 15 bacterial sinusitis to be conducted. Another 16 possible option would be a dose-response approach. 17 [Slide] 18 We are updating and developing new 19 guidance documents in a variety of areas, including 20 acute bacterial sinusitis, acute bacterial 21 exacerbation of chronic bronchitis, acute otitis 22 media, acute bacterial meningitis and drug 33 1 development for resistant pathogens. A lot of the 2 advice that we have gotten at the advisory 3 committees over the last year and a half has really 4 been very helpful to us in updating our guidance 5 documents, and we hope to have several of these out 6 really quite soon. 7 [Slide] 8 One other thing I just wanted to mention 9 is the Critical Path initiative. The Critical Path 10 "white paper" was issued in March of 2004, and it 11 recognizes the advances in basic biomedical 12 sciences and the high cost of bringing a medical 13 product to market. The idea behind the Critical 14 Path initiative is to make the process of bringing 15 a product to market a more efficient process. It 16 calls for advances in the applied sciences in 17 medical product development, in essence, to develop 18 a better product development tool kit. The idea is 19 if we can get better tools to assess safety and to 20 demonstrate efficacy earlier on, we may be able to 21 more efficiently guide drug development. This will 22 be an effort that will require the joint efforts of 34 1 academia, industry and FDA in order to successfully 2 bring it forth. 3 [Slide] 4 Then just changing gears a little bit and 5 talking about some of our efforts to preserve the 6 utility of our existing antimicrobial agents, the 7 final rule labeling requirements for systemic 8 antimicrobial drug products intended for human 9 issue was issued in of 2003 and became effective in 10 February of 2004. This rule amends our labeling 11 regulations for systemic antimicrobial drug 12 products to require that they include a statement 13 in labeling about appropriate and prudent use of 14 antimicrobial agents. It also encourages 15 physicians to counsel their patients about 16 appropriate antimicrobial use. It is estimated to 17 impact approximately 669 systemic antimicrobial 18 drug products. 19 [Slide] 20 Another component of our efforts to 21 preserve the utility of existent antimicrobial 22 agents is the "Get Smart" program that is 35 1 co-sponsored with the CDC. It is an education and 2 outreach program that is directed towards both 3 consumers and then also health professionals. The 4 goal here, again, is to inform both the public and 5 health professionals about the importance of using 6 antimicrobial agents appropriate and prudently in 7 order to preserve their useful life span. 8 [Slide] 9 In summary, since the November 2002 10 meeting we have had a number of scientific meetings 11 on labeling issues and clinical trial design for a 12 number of indications. There has subsequently 13 been, since the meeting in 2003, awarding of 14 multi-drug resistance Streptococcus pneumoniae 15 claims. We have gotten important input on the 16 criteria for resistant pathogens of public health 17 importance. We have had discussions about 18 streamlining drug development through relating 19 clinical data from one disease indication to 20 another and how we might approach that in a 21 conceptual fashion. We have gotten a lot of 22 important input about clinical trial designs for a 36 1 variety of different therapeutic indications. 2 These meetings and the science that has come out of 3 them have been very important to us in updating the 4 guidances, and our work is ongoing there and we 5 hope to have a number of the guidances documents 6 out soon. Then, just briefly, the Critical Path 7 initiative, which will have an impact on drug 8 development in the near future; then our ongoing 9 efforts to preserve the utility of our existing 10 antimicrobial agents. So, there has been a lot 11 done since the last meeting and there is still more 12 to do. With that, I will close. Thank you. 13 Discussion 14 DR. EDWARDS: Thank you very much, Ed. 15 That was very nice. Now we have a few moments for 16 discussion and I would like to invite any comments 17 anyone would like to make. I might just start by 18 reflecting on the fact that I think it is obvious 19 that a wholehearted effort has been made by 20 everyone involved as a result of the meeting last 21 time. Virtually every point both of you have 22 addressed was brought up at that meeting and plans 37 1 were made to go forward to address them, and it is 2 very gratifying to see the responsiveness. 3 Are there any questions from the audience? 4 I am going to ask one and I realize is going to be 5 somewhat difficult to answer, but regarding the 6 guidances, you mentioned soon. Is it possible to 7 give us a little more thought about what that means 8 exactly? 9 DR. COX: We have made good progress and I 10 think there are three or four that we hope to have 11 out prior to quarter four of 2004. We are working 12 hard and we hope to have them out soon. You know, 13 one other comment too, from these meetings we do 14 get a lot of important scientific information and 15 we can informally or actually in the setting of 16 meetings guide companies and use this information. 17 So, the updating of the guidance documents is 18 something that we are working hard on and hope to 19 have out there soon. 20 DR. EDWARDS: Any other questions? Let me 21 ask one other, Ed. In your description of the 22 finding of resistance, it wasn't quite clear, is 38 1 that a combined effort with CDC or is that within 2 the FDA advisory committee exclusively? 3 DR. COX: Yes, there has been input that 4 was discussed at the FDA advisory committee and 5 folks from the CDC were present, along with our 6 guest representatives and also the advisory 7 committee. So, in essence, I would say that is an 8 effort in developing those criteria where we have 9 had input from both our advisory committee and also 10 from folks at the CDC to help guide the further 11 development of those criteria. 12 DR. EDWARDS: Yes, in the back? 13 PARTICIPANT: [Not at microphone; 14 inaudible]. 15 DR. EDWARDS: To get it on the record we 16 will have to have it repeated into the microphone. 17 DR. COX: So, the question was about the 18 use of a development program which would be 19 anchored in, say for instance, two studies in 20 community-acquired pneumonia and then for 21 additional studies in the respiratory tract, such 22 as acute bacterial sinusitis, acute exacerbation of 39 1 chronic bronchitis were it may not be necessary to 2 do two adequate and well-controlled studies; it may 3 be possible to do one well characterized adequate 4 an well-controlled study in combination with the 5 two studies anchored in community-acquired 6 pneumonia, and the question asked would it be 7 advisable to meet with the FDA, if one were 8 considering such an approach. I think the answer 9 there is definitely yes, to get folks in and talk 10 to us about their proposed program because this is 11 an issue where I think it is important to get an 12 understanding of the protocols that will be used 13 for those other studies, and certainly having a 14 well characterized study will be very important in 15 the setting of trying to use support across the 16 indications. Also, I think it will be important to 17 have a discussion with anyone who is proposing to 18 take such an approach in order to understand which 19 indications they were planning to rely upon for 20 some degree of cross support. So, I do think it 21 would be advisable to come in and talk with us and 22 we would certainly welcome the opportunity to do 40 1 so. 2 DR. EDWARDS: Thank you. George? 3 DR. DRUSANO: This is just a quick 4 question for Dr. Scheld. Michael, one of the 5 things that you had presented was the IDSA 6 initiatives to provide incentives for sponsors to 7 stay in or reenter antimicrobial drug development. 8 Many of those proposed kinds of incentives I think 9 are probably beyond the scope of regulatory 10 agencies and actually fall within the purview of 11 Congress in terms of actually having to change 12 laws. Is there any way that the outcomes of these 13 kinds of meetings are being sent to appropriate 14 congressional leaders for this kind of 15 consideration? 16 DR. EDWARDS: George, if I may, that was a 17 perfect introduction to George Talbot's address and 18 he is going to be addressing the specific answer to 19 that question. So, George, I will ask you to go 20 ahead now, if you will, please. 21 II. Continuing Discussion on Incentives for 22 Drug Development - IDSA 41 1 DR. TALBOT: Well, good morning, everybody 2 and thank you for the opportunity to continue the 3 discussion on incentives. 4 [Slide] 5 I am doing so on behalf of the 6 Antimicrobial Availability Task Force of IDSA. It 7 has been my privilege to participate in that group. 8 I have to say, in looking at this first slide, that 9 it makes me realize that it is always different to 10 follow Mike Scheld as a speaker, not only because 11 of his articulate expression of difficult concepts 12 but also because of his first slide, which is that 13 beautiful slide of the rotunda and I have no 14 similar slide. As I was sitting here I was 15 thinking, you know, I work out of the home and it 16 probably wouldn't be appropriate to show a picture 17 of the rotunda in my home, but I will have to come 18 up with something, Mike, to match you next year. 19 [Slide] 20 My presentation objectives for today are, 21 first of all, to update workshop attendees on 22 AATF's efforts to clarify factors responsible for 42 1 the decrease in antimicrobial R&D, which we have 2 been discussing over the years. 3 And, I would like to discuss the full 4 range of possible solutions and not just the 5 financial incentives. The title is incentives but 6 we have been looking at a range of possible 7 solutions and it is not fair really to call all of 8 them incentives. 9 [Slide] 10 As an overview, I can summarize what AATF 11 has learned during the past year. Some of these 12 statements may seem to be truisms but I think it is 13 important to state them up front anyway. 14 We do believe that there is a problem, 15 that there is a decrease in antimicrobial R&D. We 16 had some discussions about whether that was in fact 17 correct or not at the beginning of our meetings, 18 but it seems clear to us that there is a problem. 19 It is clearly a problem that is complex and has a 20 multifactorial etiology. It is also susceptible to 21 oversimplification, the "if only," if only pharma 22 would put more resources into this; if only the 43 1 regulatory process would be quicker; if only 2 Congress would do this or do that. It is just not 3 that simple. There is no easy, single solution 4 that we can see at this point. 5 The good news is that there are potential 6 approaches apparent. One thing that is absolutely 7 clear is that the progress will require a long-term 8 commitment by all of us and its success will be 9 dependent upon the active collaboration of 10 essential partners. 11 [Slide] 12 The problem, as Mike stated, is clear. It 13 is summarized in this Institute of Medicine report 14 for the year 2003. I have highlighted in italics, 15 my italics at the bottom, the statement that as of 16 the time of this report only four large 17 pharmaceutical companies with antimicrobial 18 research programs remained in existence in 2002. 19 One of the questions we had was, well, is that 20 really true or not and we attempted to answer it. 21 [Slide] 22 Regardless of the result or the output of 44 1 what is going on is this slide that Mike also 2 showed you from the Spellberg paper, showing the 3 decrease in total approved antimicrobials in the 4 U.S. We do have two in 2003 and one now in 2004 5 but the trend is certainly down. Interestingly 6 enough, in looking at the FDA's Critical Path 7 paper, there seems to have been a general trend in 8 approvals of new entities over this time frame so 9 it is not just restricted outcome the 10 antibacterials, although all of us, of course, 11 feels this most acutely. 12 [Slide] 13 So, have learned a lot, and primarily from 14 interactions with our stakeholders which include 15 pharmaceutical companies, venture capital 16 interests, FDA, CDC, NIAID and HHS. We have also 17 reached out to the scientific and lay press to 18 discuss the issues with them and, as Mike 19 mentioned, we have had interactions with Congress. 20 [Slide] 21 What are some of the issues for pharma? 22 Well, one thing I want to start with here is 45 1 something that came across to us loud and clear, 2 that many individuals and groups within the 3 pharmaceutical industry are deeply concerned about, 4 and also committed to, the future of antibacterial 5 R&D. There is no question that there are many 6 totally devoted individuals and even some groups 7 for this area and that has to be acknowledged. 8 But it is true also to say that "big" 9 pharma is becoming disengaged. There are some 10 notable exceptions but what we are finding is that 11 the greatest concern is the dearth of resources 12 being applied at the discovery level. So, although 13 there are things later in the pipeline, what we are 14 seeing is a diminution in the resources applied at 15 the discovery level. The reasons for this are 16 clear to those in the room. They have been 17 elucidated elsewhere, but it simply is reduced to 18 the fact that "big" pharma sees a better return 19 from the treatment of chronic diseases, whereas, in 20 contrast, antibacterial therapies are costly to 21 develop, on a part maybe with many other 22 therapeutic agents. But since they are short 46 1 course and used for acute illnesses the potential 2 economic return is less. 3 There is another specific issue here, 4 which is this third one, that many of these 5 antibacterial therapies are not embraced by the 6 marketplace. We are all familiar with the issues 7 of cost which apply across therapeutic areas, but 8 there is the issue of resistance, legitimate 9 scientific concern about promoting the emergence of 10 resistance and that does play a role in how rapidly 11 the uptake of these agents occurs. 12 The other interesting thing we have hard 13 from senior pharma people, which surprised us as ID 14 physicians, is that this is often viewed as a 15 satisfied market. There are antibacterials. We 16 have heard this in three different areas that may 17 reflect the fact that they see it as one market as 18 opposed to segments, but when they look at the 19 market overall they see a satisfied market in 20 comparison to some other potential areas. Finally, 21 these are rarely blockbusters. 22 [Slide] 47 1 What else did we did we hear? Well, for 2 "big" pharma any further uncertainty, regulatory 3 uncertainty for example is a disincentive. Within 4 "big" pharma there is competition for resources 5 among different projects so whenever an 6 antibacterial project is discussed at a resource 7 allocation meeting and it is competing against 8 other therapeutic area products, if there is 9 regulatory uncertainty or marketplace uncertainty 10 it is a disincentive, at least at the margin. 11 Further intellectual property protections 12 are of interest to some but question upside. Tax 13 credits were actually very interesting to one 14 person in senior level pharma, and that is 15 something I will come back to. 16 One key message that came across though 17 from those who are both in and those who are out is 18 that because of the enormous hurdles for 19 establishing and maintaining a discovery 20 infrastructure, it is essential to try to keep 21 those companies that are in this field in because 22 once they go, reestablishing that infrastructure is 48 1 extremely different and time consuming. 2 [Slide] 3 What about "small" pharma? "Small" pharma 4 is more engaged I think in our interactions with 5 them for several reasons. First of all, the 6 financial return is better matched to their size. 7 The market opportunity for them is more clear and 8 for them regulatory uncertainty is probably a 9 lesser concern. We heard this from a few people. 10 If you are focused on antibacterial therapies, 11 well, there is no competitions with other 12 therapeutic areas and if you have a question about 13 how to approach a certain product you can go and 14 talk to Mark, Ed, John and David for example. 15 The focus for these companies is 16 dichotomous. Some are really developing 17 in-licensed compounds only, late stage. Others do 18 have robust discovery efforts, as far as we can 19 tell from looking at the publicly available 20 information on web sites. But the question in the 21 end is will this be enough? Even if there are six 22 or eight of these companies involved in discovery 49 1 research, will they be able to advance these 2 products through to the market? Especially the 3 community market with large trials may be required. 4 So, one of the things that we are seeing is that a 5 lot of these products are focused on the hospital 6 market where the hurdles are less. 7 [Slide] 8 One of the things smaller companies need, 9 of course, is access to venture capital. It is 10 essential. In a totally unscientific sampling 11 which involved speaking to a few VCs, we saw again 12 a dichotomous opinion on this. Some VCs see the 13 dearth of discovery efforts as an opportunity for 14 long-term investment, but others consider this 15 whole area very high risk, specifically because of 16 the restrictions on use of marketed products. What 17 we are seeing happening at the moment is that when 18 companies are being evaluated often it is the 19 late-stage products in the portfolio that are 20 driving the decision whether to finance the company 21 or not. There is a lot of expertise in the room. 22 People may have had different experiences. These 50 1 are generalizations but I think at least in some 2 cases that is true. 3 [Slide] 4 Turning to FDA, we had several 5 conclusions. First of all, it is clear to us, 6 absolutely clear that FDA understands the problem. 7 FDA wishes to partner in finding solutions and 8 regulatory uncertainty they understand, when 9 present, further clouds the development process. 10 This is highlighted in the Critical Path report. 11 With this as a foundation for moving forward 12 though, the FDA has certain unavoidable 13 constraints, and appropriately so. They must 14 maintain scientific rigor in their evaluation. 15 They have to give due consideration to adequate 16 data on safety and efficacy. Also, they have 17 limited flexibility per statutory constraints. For 18 example, they cannot waive user fees for specific 19 high priority products. That requires, as George 20 was asking, legislative intervention. 21 [Slide] 22 We have colleagues here from CDC and 51 1 NIAID. We realize that there are substantial 2 relevant efforts that have been proposed by these 3 groups. I have listed two of them. There have 4 been progress reports for the first. The outline 5 of the NIH "Roadmap" is impressive in terms of the 6 potential help it might give to this process. So, 7 we are enthusiastic about that and hope that these 8 programs can be implemented. 9 We certainly think that more funding could 10 be used for critical efforts, and more could be 11 done to foster inter-agency collaboration, training 12 and outreach specifically regarding antibacterial 13 drug development. Now, I say that last point with 14 the recognition that if you look at the "Roadmap" 15 there really is due acknowledgement of these issues 16 and we are simply adding our voice to try to 17 encourage work in this area. 18 [Slide] 19 What about the scientific and lay press? 20 Well, pipeline concerns are of interest to both the 21 scientific community and the public. That has been 22 clear to us and we are seeing articles directed to 52 1 a wide readership across both areas. 2 One point we have concluded is that our 3 communications to the media should highlight not 4 only measures to decrease resistance or decrease 5 the emergence of resistance, but also to ensure the 6 pipeline. 7 [Slide] 8 I have a sampling on three slides of just 9 some articles that have come out that show that 10 this issue has captured the attention of the lay 11 press, as shown on this slide-- 12 [Slide] 13 --general scientific readership with 14 articles in Nature and Science and The Lancet. 15 [Slide] 16 Then ID specialty journals, with this last 17 one being the one that Jack just mentioned has come 18 out today. 19 [Slide] 20 Congress is a key part of the solution 21 process and there are some vocal and effectiveness 22 supporters for addressing the issues. We have 53 1 found that; it is clear. But it is also clear that 2 the focus of policy-makers is elsewhere at the 3 moment, quite understandably, for bioterrorism and 4 for everything else that faces the country at this 5 point. 6 Bioshield I, which has passed the House 7 and has been given some money by Congress, offers 8 some hope of solutions but it is pretty narrowly 9 focused and, for that and other reasons, has 10 substantial constraints. It seems to us that more 11 attention and action are needed at this level. 12 [Slide] 13 So, what could IDSA do to define 14 solutions? Well, first of all we want to raise 15 awareness of the problem in multiple venues, always 16 speaking outcome the needs of patients. We would 17 like to brainstorm with you, with all our partners 18 in this, on possible solutions, partly because many 19 of these potential solutions are not in our area of 20 expertise. We do hope, however, that we can act as 21 a catalyst when appropriate to help things move 22 forward. 54 1 [Slide] 2 Part of rasing awareness is making a lot 3 of visits. You have heard about the field trips. 4 I have listed here some of the other things that we 5 have done that Mike alluded to also. I would 6 highlight also the "white paper" which will 7 summarize our interpretation and some detailed 8 recommendations, and that is due to be released in 9 May. 10 [Slide] 11 Turning now to potential solutions, I will 12 discuss these in a very broad way and, hopefully, 13 this will foster some discussion if you have all 14 had enough caffeine this morning--I see mostly open 15 eyes out there. One key thing is partnering of 16 stakeholders. This cannot be, in our view, a 17 finger-pointing exercise. We all have different 18 responsibilities, different goals, different 19 agendas but I think there is agreement and the AATF 20 things there is agreement that this is an issue 21 which requires everyone's attention in the interest 22 of the public health, and we hope that we can 55 1 continue to play and important and constructive 2 role in partnering efforts. 3 [Slide] 4 Another potential solution that must be 5 mentioned is whether there could be changes in the 6 marketplace that would alter the economic equation 7 by enhancing greater receptivity to new 8 antibacterials. We heard this theme a number of 9 times. We have to say, however, that we feel that 10 potential change in this area are constrained due 11 to cost, concern regarding promotion of resistance, 12 and a desire to hold antibacterials of last resort 13 in reserve. 14 Actually, I was speaking to a VC the other 15 day and he was very politic. He said, you know, 16 one of the things we see is that because infectious 17 disease physicians are among the most educated and 18 most sophisticated of all physicians, there is a 19 tendency for them to hold these drugs in reserve. 20 It was a phone conversation so I couldn't see if 21 his tongue was in his cheek but I think there is 22 truth to that but, you know, from their perspective 56 1 it is a real disadvantage. 2 Our conclusion at the moment is that in 3 this area change is unlikely unless scientific data 4 are developed to justify different usage patterns. 5 We are not suggesting that; we are just saying that 6 that is what would be required to drive any change, 7 in our opinion. 8 [Slide] 9 Regulatory adjustments are also important. 10 You have heard a lot this morning already from Ed 11 about what is going on. The coming updated 12 guidelines are I think going to be a major step 13 forward. We all believe that. One thing we would 14 encourage is that there be periodic and timely 15 review and revision so that companies would know 16 what the cycle might be for that and perhaps have 17 greater assurance that changes in clinical medicine 18 would be reflected in the guidelines. That is 19 something for FDA to consider. 20 We also believe that it would be useful to 21 encourage novel clinical trial designs to gather 22 information on drug efficacy against resistant 57 1 pathogens. The final bullet is something we will 2 be discussing later today but we do believe that is 3 important. 4 [Slide] 5 NIAID is responsible for implementing the 6 "Roadmap" for translational research. That is an 7 incredibly excellent document in my opinion, having 8 not waded through all of it but through the 9 executive summary, to be honest. 10 There are some specific things we would 11 suggest for consideration that could foster 12 antimicrobial R&D--more collaborative planning with 13 industry and academia, a point made in the 14 "Roadmap." More training, fellowship curriculum, a 15 point made in the "Roadmap." Perhaps using the 16 NCI/FDA model to create an NIAID/FDA program to 17 help streamline development. Funding research into 18 rapid diagnostics in the document is something we 19 have talked about for a long time that would really 20 help in appropriate antimicrobial use and in 21 clinical trial design. Then, Mike mentioned 22 funding placebo-controlled trials. 58 1 [Slide] 2 To turn briefly to legislative, there are 3 ongoing activities that have an impact. The GAO 4 study of this problem that we are talking about 5 today has yet to be launched. Bioshield is in a 6 bit of abeyance at the moment. But the Best 7 Pharmaceuticals for Children Act is a good example 8 of how Congress can come together to create some 9 incentives for industry to pursue particular 10 studies. 11 In the future we have what has been called 12 Bioshield II, appropriately or not, S.666, 13 Lieberman and Hatch, and Dr. Guidos has been 14 working very closely with Chuck Ludlam in that 15 office to understand the implications of that Bill. 16 But we believe overall that unique problems will 17 require unique solutions. 18 [Slide] 19 Here are a few of the things that we are 20 suggesting for legislative consideration. These 21 will be discussed in more detail in the "white 22 paper." But we believe that for priority 59 1 antibacterials, those that meet unmet medical 2 needs, there are several things that might help 3 spur R&D. Use of incentives that have been shown 4 elsewhere to successfully spur R&D, such as R&D tax 5 credits which give up-front now dollars as opposed 6 to dollars at the end of a products life when, in 7 fact, you don't know if the product is even going 8 to be there and making more money. As one 9 pharmaceutical person put it to us, you know, 10 getting us another year at the end of the life of a 11 drug when a drug doesn't make any money to begin 12 with doesn't help us. Up-front dollars might. 13 Supplemental IP protections ought to be 14 considered. There is the wild card patent 15 exclusivity or extension that we can discuss more 16 if there are questions. Also, mechanisms to 17 facilitate the interest and success of smaller 18 companies. I have listed one here. 19 [Slide] 20 We have also suggested that it might be 21 useful to consider a commission on antibacterial 22 resistance with a broad representation from 60 1 stakeholders, those in this room. The charges 2 would be to identify priority pathogens and decide 3 which antibiotics should receive the benefits of 4 legislative initiatives and incentives. 5 [Slide] 6 Another important legislative interaction 7 is to increase funding for essential programs. 8 Those of you who conduct these programs know what 9 you need. We would like to be there to support you 10 in terms of requests that you can verify for 11 appropriate increases in funding. 12 [Slide] 13 Finally, again for fair balance I have to 14 identify the number of groups that have 15 accountabilities and responsibilities. We would 16 note that the corporate world can point with pride 17 to many pro bono initiatives for human health. I 18 have listed a few; there are many others. We don't 19 view this as an actual crisis at the moment but if, 20 for example, this impending crisis explodes with 21 vanco. resistance in community staph., in addition 22 to all these other things that need to be done, the 61 1 public will need the help of the pharmaceutical 2 industry to address this problem. 3 [Slide] 4 These considerations will all be discussed 5 in detail in the "white paper," to be released in 6 May. 7 [Slide] 8 By conclusion, I would say there is a 9 problem. It is multifactorial with no single, easy 10 solution. We strongly believe that essential 11 partners are engaged. That is very, very 12 encouraging to us. We also believe that potential 13 solutions are apparent. 14 As for IDSA's role, we stand ready to make 15 a long-term, constructive commitment to help 16 address this brewing public health crisis. 17 [Slide] 18 So, the question is "Bad Bugs, no Drugs." 19 However, can we help? And we want your input. 20 [Slide] 21 Finally, some final notes--I have listed 22 potential conflicts and I would like to add 62 1 acknowledgments to the AATF members, to the factual 2 input we have received from John and David who are 3 ad hoc members of our task force; IDSA staff and 4 all the people with whom we have spoken. Thank you 5 very much. 6 DR. EDWARDS: Thank you very much, George. 7 That was a very nice summary of a very complex set 8 of issues, all of which we could discuss in 9 extensive detail and, hopefully, will off an on 10 during the course of the meeting. 11 I would like now to ask Mark Goldberger, 12 from the FDA, to comment on the incentives issue. 13 Mark? 14 FDA 15 DR. GOLDBERGER: It is a pleasure to be 16 here. I think George has covered a lot of the 17 issues already. Hopefully, I can made a few 18 additional remarks without being overly redundant 19 to allow adequate time for discussion. 20 [Slide] 21 As everybody has said, the issue is that 22 antibiotic resistance is increasing. Whether it is 63 1 truly the crisis now, we need to keep in mind, as 2 has already been emphasized, that development of 3 new drugs, of course, does not occur overnight. I 4 was interviewed--I forget by what 5 publication--recently and we were talking about 6 this issue and that is the message I tried to 7 emphasize. The great majority of patients can 8 still be treated with the available antibiotic 9 therapy, although there are already pockets in 10 ICUs, etc., where real problems are occurring. But 11 we can't look just to the present. We have to look 12 at the trends in resistance and take into account 13 what we think might happen three, five, seven years 14 from now and recognize that the trends suggest that 15 the problem will get worse and that we need a lead 16 time to get new products out there. That is one of 17 the things always to keep in mind. You can't be 18 thinking just about where you are today; you have 19 to be thinking about where you are likely to be 20 tomorrow. 21 Also, as has been noted and really gets to 22 some of the core tensions in trying to move 64 1 forward, we have to keep in mind that, on one hand, 2 we are looking for new products but, on the other 3 hand, realistically we would like to preserve the 4 usefulness of both those new products and existing 5 products as long as possible. If you think about 6 it, you realize there is a certain tension between 7 doing those two things. 8 [Slide] 9 A lot of the issues have already been 10 covered in terms of thinking about development. 11 One way, maybe very simplistically, to think about 12 them are regulatory/clinical trial issues; 13 scientific/medical issues and then economic issues. 14 George has already talked a lot about all these 15 three categories and I will just make a few 16 additional comments. 17 [Slide] 18 I think there has been a lot of discussion 19 about the need for formal guidances and I think we 20 recognize we have, in some respects, been somewhat 21 slow in getting some updated guidances out there. 22 Sometimes one of the problems with having a lot of 65 1 meetings and interactions is that you are 2 constantly getting new information which, of 3 course, make you think maybe we should modify the 4 guidance but I think it is time to move forward 5 with those that are really of the highest priority. 6 There is some thought a little higher up 7 within our Center, for instance, that maybe one of 8 the issues why there are so many guidances that 9 haven't been completed--and I should say that 10 although we certainly have more than our share on 11 antimicrobial drugs, there are plenty of other 12 guidances that haven't been completed either. Is 13 that they are, in fact, a little too long, 14 sometimes a little too detailed and perhaps there 15 is a way of simplifying them which would allow the 16 time for preparation and getting them out to be 17 shortened. So, that is something that we obviously 18 need to work on. 19 We certainly have been using advisory 20 committee input and we find that to be quite useful 21 as, of course, are meetings like this which have 22 the advantage of being a little more flexible in 66 1 terms of the type of participants and I think that 2 that is extremely helpful. 3 There are also a lot of regulatory tools 4 that already exist. The reason I emphasize this 5 is, as has already been mentioned, you have to look 6 at the things that you can do potentially now and 7 the things that you might like to do but would, for 8 instance, require new legislation. I think 9 everyone understands that the legislative process, 10 for the most part, does not occur overnight, and 11 getting things passed with the many levels of 12 competing priorities is not an easy thing. 13 Therefore, if there are some things you can do now 14 that would be beneficial, you want to really try to 15 take advantage of those. 16 We have regulatory tools that I won't get 17 into now but I talked about a couple of years ago. 18 Our Subparts E and H, fast track designation, all 19 of which talk about how one can expedite the 20 development of drugs for serious illness. They 21 involve increased communication. They involve 22 looking at clinical trial programs. They involve 67 1 uses of surrogate markers, etc., and I will talk a 2 little bit more about some of these issues in a 3 couple of minutes. Some of them will be the 4 subject of additional discussion over the course of 5 this meeting. It is important to keep in mind 6 though that one of the advantages is that these are 7 tools that exist now. Finally, there are certain 8 types of exclusivity that already exist which may 9 be useful, and I will talk a little bit about that 10 in a couple of minutes. 11 I will say for complex issues and for 12 innovative products, at the end of the day I think 13 that still the most important tool that exists, 14 which we certainly use and which someone asked a 15 question about a couple of minutes ago, is actual 16 communication with the company in question over the 17 specifics of their product. Even when guidances 18 exist, remember, guidances are tailored broadly to 19 a specific disease entity or maybe large numbers of 20 types of drugs. They rarely would provide the 21 level of detail that an individual firm, especially 22 with an innovative product, needs to decide how to 68 1 move forward. At the end of the day, that is still 2 the most useful tool that exists. Certainly, in 3 recent times I have had, with a variety of 4 products, that kind of intense interaction and that 5 probably increases, more than anything else, the 6 chance of bringing things to a successful 7 conclusion. I want to emphasize, as I said a few 8 moments ago, that that is still something that we 9 are very interested in doing for products that have 10 the potential to add value. 11 [Slide] 12 We are going to talk throughout the course 13 of this meeting about some clinical trial issues, 14 and one of the goals is to try, as much as is 15 possible, to reduce the size of the clinical trial 16 program. That involves ultimately addressing a 17 tradeoff between our ability to assess, for 18 instance, effectiveness and the resources required 19 to perform a trial. That is, the more data you 20 have about the drug, in general the more you might 21 understand about it for efficacy and certainly from 22 safety, at least insofar as one talks about, for 69 1 instance, rare events. 2 That is not necessarily an insurmountable 3 problem and something you have heard us talk about 4 in the past is the idea of substituting quality for 5 quantity in at least some clinical studies. That 6 is, smaller studies performed on well characterized 7 patients might yield more useful information than 8 very large, open-label studies which may enroll 9 hundreds or thousands of patients but may not 10 provide much in the way of really useful data. I 11 think that is an issue we, hopefully, can move 12 forward on with some of these concepts, as well as 13 what I like to call strengthening the link to 14 clinical inference. It is sort of following up on 15 what Ed talked about a few minutes ago. That is, 16 how studies and data fit together as a package as 17 to how much mileage we can get from getting 18 indications to support one another. 19 Now, what Ed proposed and discussed may 20 not have sounded that radical but, in fact, what we 21 are thinking about doing is going beyond the old 22 model where hospital-acquired pneumonia, for 70 1 instance, might support community-acquired 2 pneumonia. But moving outside the respiratory 3 tract, you aren't going to get much support for a 4 respiratory indication. So, the idea that for 5 serious illnesses looking at several serious 6 individuals across the body, so long as you have 7 adequate data, for instance, on tissue penetration, 8 etc., and some decent microbiology, might form a 9 package that would allow you to have a smaller 10 number of overall studies than would otherwise be 11 the case. It is something we have talked about 12 once with our advisory committee. We think it is a 13 fruitful area for moving forward. We have had 14 discussions with at least one firm about using this 15 type of approach, which we also think may serve as 16 a tool to also look at studies of resistance 17 indications as well. 18 [Slide] 19 What are some of the consequences of the 20 preceding? I mean, serious illness should be able 21 to lead to expedited evaluation. Expedited 22 development should be able to lead to reduced 71 1 costs. One of the issues that you have to always 2 worry about is does expedited development equal 3 less certainty re benefit and risk. George sort of 4 commented on this as well. 5 You know, those are always issues that, as 6 a regulatory body, we have to deal with but in 7 general everyone has to deal in this area with 8 uncertainty. The FDA deals with uncertainty. The 9 clinicians who will be using the drugs will have to 10 deal with uncertainty. Industry has to deal with 11 uncertainty. People don't always do well with 12 uncertainty, and without wanting to reopen the 13 delta issue at all, that is a good example with 14 uncertainty. That is, some staff within FDA were 15 concerned about widening the delta, increasing the 16 level of certainty as to whether the drug really 17 works. Companies then perceived that this idea of 18 narrowing the delta would produce greater 19 uncertainty as to whether they could get their 20 products approved. 21 So, no one really ultimately came out 22 ahead with that effort of looking about 72 1 uncertainty, but we have to keep in mind when we 2 talk about drugs for infectious diseases that we 3 know, first of all, some of these diseases are 4 serious so you would like to have some idea of how 5 well the drug works. If you have a new drug for 6 serious illness, you are willing to tolerate a 7 certain amount of uncertainty about how well it 8 really works, particularly if the alternatives are 9 few and far in between and you will tolerate some 10 degree of uncertainty about safety if, in fact, the 11 drug seems to be producing some decent activity. 12 Certainly, HIV and oncology are areas where that 13 has been the case. 14 As you think about drugs more broadly for 15 less serious illnesses, naturally the willingness 16 to tolerate uncertainty becomes a little less. But 17 this is an issue that we always have to keep at 18 least in the back of our minds as we move forward, 19 that as we seek to expedite a program we do have to 20 deal with some of the ramifications of expedited 21 development. 22 [Slide] 73 1 Well, what are some of the scientific 2 issues that exist? Certainly there has been a lot 3 of interest in the use of surrogate markers, and 4 certainly infectious diseases is one of the big 5 areas where surrogates have been used successfully. 6 Certainly everyone is familiar with how useful they 7 have turned out to be for HIV drugs. We have 8 certainly got enough data to know that surrogate 9 markers can be quite useful in getting a handle on 10 a drug for tuberculosis. We have some good data 11 now from studies that were done a few years ago 12 that allow us to look at two-month sputum 13 conversion rates, and more particularly, at early 14 relapses to predict how well a drug will look down 15 the road and allow approval actions to be taken 16 probably years earlier. 17 You can get into somewhat messy situations 18 with surrogates. An example that I was very 19 involved in a number of years ago was the use of 20 clarithromycin for the treatment of M. avium 21 bacteremia. I think we were all comfortable that 22 reduction in bacteremia was a good thing and 74 1 subsequent long-term trials that were conducted, 2 using a second drug to prolong bacteremia, I think 3 did show some real benefit to patients. On the 4 other hand, we also noted that even though higher 5 doses of clarithromycin led to somewhat greater 6 suppression of bacteremia, survival was actually 7 worse. 8 Outside the infectious disease area, we 9 know from some of the studies in cardiac disease 10 that some of the surrogates, such as suppressing 11 ventricular premature depolarizations, don't always 12 lead to the kind of result that you are looking 13 for. So, surrogate markers are extremely 14 promising. They do require though some attention 15 to detail. You need to have the right trials, the 16 right data to feel comfortable. 17 One other thing that may not be a big 18 issue with short-term studies of antibacterial 19 drugs but can be a bigger issue with longer-term 20 study of disease, and certainly in infectious 21 disease it is, let's say you measure a surrogate 22 early on in the course of the disease and it looks 75 1 like it is responding very well. There is an 2 assumption there that what you do in terms of 3 managing the patient subsequent to measuring that 4 surrogate is the appropriate thing. Remember, the 5 surrogate measures what happened before it. If, 6 for instance to use tuberculosis, you measure what 7 happens to the sputum at two months and it looks 8 very good, but then part of your new experimental 9 regimen is a radical change for the last several 10 months of treatment in your regimen and that is not 11 such a good follow-up regimen, your overall result 12 may not be what you expect. You always need to 13 keep that in mind. Nonetheless, we think that this 14 is a very fruitful area for moving forward with. 15 What are other things? We are going to 16 talk a lot about the use of preclinical and early 17 clinical trial data, PK/PD data in combination with 18 clinical trials to dose select, to more efficiently 19 move forward in development and, hopefully, to end 20 up with smaller clinical trials. I think that is 21 again a very fruitful area. 22 We always have to keep in mind that a lot 76 1 of the PK/PD we often get in terms of data is, of 2 course, from the blood since the blood is most 3 accessible but, in fact, sometimes the infections 4 are in the tissue and we have to be comfortable 5 about how we make those extrapolations. 6 An area that I think may turn out to be, 7 for new, innovative drugs, fruitful is the role of 8 infections due to susceptible organisms in the 9 study of drugs for resistance claims. What I mean 10 by that is if you have a brand-new molecular entity 11 that, say, for enterococci has the same activity 12 against vancomycin-susceptible, 13 vancomycin-resistant enterococci, what role can the 14 susceptible organisms in diseases cause by the 15 susceptible organisms play in the overall 16 evaluations since, frankly, things like that would 17 simplify the overall approach and have a greater 18 number of patients. I think that is an area we 19 need to do some thinking about as well. 20 An area I am not sure what to say about 21 and I kind of put this up so that, hopefully, we 22 will hear from industry is issues about discovery, 77 1 which have already been covered some by George. 2 You know, I hate to phrase it like this but suppose 3 we were able to wave a magic wand and a lot of the 4 problems with economic return and other things that 5 are of concern to industry disappeared magically, 6 and they felt that this was a fruitful area to put 7 resources in, where are we with the level of 8 science that would allow us, in fact, to think that 9 the discovery programs would start to yield 10 fruitful entities that could be scaled up and be 11 effective in treating people? The question is how 12 comfortable are we with our science at this point, 13 and I leave that to folks from industry who are in 14 a much better position to address it. 15 [Slide] 16 This is a graphic following up on what Ed 17 brought up about the Critical Path. It is just to 18 point out one of the goals that FDA would like to 19 do, basically assisting in looking at problems in 20 safety, efficacy and even manufacture that may be 21 of concern to industry and, hopefully, over time a 22 partnering with industry in areas that we can be of 78 1 assistance in for looking at some of the road 2 blocks, some of the problems. As is known, we do 3 have access to more data than any one company has. 4 There are always questions about how much of that 5 data can be made public but certainly certain 6 analyses can be done that may be of help to 7 industry. 8 An area, for instance, that is relevant to 9 what we are talking about here today is how much 10 data we could get or have additional companies 11 supply from older applications to allow us to do 12 even more work than what we have already started to 13 do in the validation of surrogates in certain 14 infections. That is just one example. 15 The Critical Path initiative is something 16 that is just under way. The hope is that over time 17 it will yield useful information that will assist, 18 for instance, in the safety area. One of the big 19 problems is that you get through your development 20 program and you are in your Phase 3 studies or 21 sometimes, actually, even after approval when 22 unexpected safety problems come up and that can 79 1 have a very negative impact either on drug approval 2 or what happens to the drug in the postmarketing 3 period. 4 One of the questions always is are there 5 better tools that might exist that would allow one 6 to reduce the likelihood of things like that 7 happening, short of having much, much larger 8 trials. So, that is one example of the kind that 9 might out of the Critical Path initiative and, 10 hopefully, in moving forward that would be of help 11 in this particular discipline as well. 12 [Slide] 13 As far as some of the economic incentives, 14 there is orphan exclusivity that exists, seven 15 years of marketing exclusivity. I believe 16 Waxman-Hatch exclusivity, which provides 17 substantial add-on to drugs to make up for the 18 development time that was lost or the patent life 19 that was lost during development, is now available 20 for new entities that were not the subject I think 21 of applications before late 1997. So, that is 22 something for brand-new entities that I think may 80 1 be of help. I think many of you are familiar with 2 the pediatric exclusivity as well. 3 One of the reasons that, of course, and 4 this is not any great shock to industry, as to why 5 economic incentives are considered desirable is 6 that it has become very expensive to develop new 7 drugs. Now, there are a lot of numbers floating 8 around and they seem to have gone up rather 9 dramatically over the last few years but, suffice 10 it to say, whether it is 1.1 billion or 1.7 billion 11 or even a little less than a billion, it costs a 12 lot of money to get a product through and you, 13 therefore, needs to have a substantial return and 14 that is one of the concerns that you are hearing 15 from industry as to perhaps why anti-infective 16 drugs are not that desirable--it costs this much 17 money; what are your chances of getting it back? 18 Remember, without getting into the 19 concepts of net present value, you are paying the 20 dollars up front. The money you are getting back 21 is down the road so those dollars are worthless. 22 That is also an issue as well in terms of thinking 81 1 about the streams of income, income and outgoing. 2 [Slide] 3 What are the other economic incentives? 4 George touched on this, you know, expanding 5 eligibility for orphan designation; the Bioshield 6 like purchase arrangements; issues of wild card 7 exclusivity, that is, you develop a new 8 antibacterial and you would like to add some months 9 on to any product you like, or other exclusivities 10 or enhanced patent protection. 11 The issue is that all of these require 12 legislation. I don't think I have to remind people 13 that the budget situation is tight and things that 14 are going to add costs and, for instance, wild card 15 exclusivity adds can add a lot of healthcare costs. 16 I am not sure how attractive these things are at 17 the level of Congress, but one of the nice things 18 about having the IDSA involved is that the IDSA, as 19 a scientific medical organization, is the kind of 20 organization that can bring ideas forth, whereas, 21 you know, within the government you are not 22 supposed to be lobbying Congress. But the IDSA is 82 1 free to talk about these issues and see what kind 2 of feedback they get back from them. 3 [Slide] 4 What are the downsides? Again, George 5 covered this pretty well. Fundamentally, most of 6 the that is short course and, in spite of the 7 issues about resistance, the fact is that most of 8 the therapy works pretty well. The need is 9 greatest for resistant and related infections but, 10 of course, the market is most attractive for 11 infections in the primary care setting. So, we 12 have that sort of tension as well. What companies 13 would like are drugs that large numbers of people 14 would take. On the other hand, that has its own 15 set of problems in terms of perhaps some excess use 16 and what that would do to the usefulness of the 17 drug. The need is greatest for resistant and 18 related infections. In some respects, certain IV 19 drugs that might be more hospital based would be 20 highly desirable but not very attractive, at least 21 to larger companies. 22 To think about this, it is useful to 83 1 remember that it is not all of anti-infective drug 2 development that has been adversely affected. We 3 only need to think about what is going on with HIV 4 drug development where the therapy is not short 5 course. It is not as highly effective and there is 6 enormous activity going on. So, I think it is not 7 so much that it is anti-infective therapy per se; 8 it is the particular characteristics of the type of 9 anti-infective therapy that we are talking about. 10 [Slide] 11 An unresolved issue that we bring up every 12 time that we have no good solution, but it goes 13 back to the uncertainty issue of which we spoke a 14 few minutes ago, there is a basic tension between 15 encouraging antimicrobial development and 16 preserving the usefulness of current and new drugs. 17 In essence, what you are saying is we want you to 18 spend X amount of money to develop a new drug, 19 knowing that people will be going out there and 20 telling the practitioners not to use it too much. 21 You know, if you strip it of everything else, it 22 gets down to that. It is hard to know how to work 84 1 through that problem to get a level of comfort 2 sufficient to make the necessary investments. 3 Absent sufficient balance between these activities, 4 on one hand, adequate investment may not occur or 5 the benefits of such investment may be short-lived. 6 [Slide] 7 We obviously can't develop a drug, and 8 that is not just FDA but IDSA as well so, 9 obviously, industry needs to play a great role. I 10 think it is worth mentioning again that new types 11 of exclusivity and patent protection would require 12 new legislation. We do know that if we can 13 expedite development we can lower costs and I think 14 that is one of the goals that we are all talking 15 about. It may not look like a direct cost but it 16 has the same value, shortening overall development 17 will cost less. We always worry internally that 18 promotional claims derive from statements in 19 labeling. Statements in laboratory come from how 20 much data you have about the product and we would 21 probably have less here. Truthfully, if we could 22 work through all the other problems I don't really 85 1 view that as something that is insurmountable. All 2 right, thanks a lot. 3 DR. EDWARDS: Thank you very much. It was 4 a very beautiful discussion. Comments? We have 5 now a period of time for discussion. Dr. Rex? 6 Discussion 7 DR. REX: Those were great talks. I want 8 to pick up a theme that has been left sort of to 9 the side of both of them but one that is very 10 important in that it is part of my daily life. 11 What has gone on so far with the antimicrobial task 12 force is absolutely laudable in that it has started 13 the conversation; it is asking very hard questions 14 about real issues, things like delta and regulatory 15 uncertainty. 16 But I was particularly pleased to see the 17 discussion of the question of infrastructure, the 18 need to build the infrastructure and the need to 19 maintain the infrastructure. I can make some 20 contrasts between "small" and "large" pharma here. 21 I want to make them mainly to say that they are not 22 really the key driver. "Small" pharma excels in 86 1 certain areas; perhaps does a little better with an 2 established molecule or an early possible molecule. 3 "Big" pharma has the bigger tools; may have the 4 bigger library; can do the high throughput 5 screening. In my own particular case at AZ we have 6 about 200 discovery scientists that are working on 7 antibacterials and antimicrobials. 8 But what you really have to do, you have 9 to roll the dice enough times. You have to be 10 smart and pick your targets but you also have to be 11 lucky and that takes a lot of dice rolls, which 12 takes a bunch of money over a bunch of time. 13 Ultimately, we are all working in a cost 14 constrained environment, even small and large. 15 Somebody has to go to the bank. My banks is the 16 rest of the company. The bank for a small firm is 17 the venture capital. 18 So, what does it take to protect this 19 infrastructure? You have this very valuable group 20 of people who are working away and you want them to 21 keep going. Well, the point that I want to make, 22 and this is sort of an unpopular theme these days 87 1 but I can state it simply by saying without profit 2 on drug number 1 there will be no drug number 2 3 because there will be no company to carry forward 4 with drug number 2. 5 This then speaks to the larger issue of 6 what is going on with the way that pharmaceutical 7 industry is being pressed with issues about 8 reimbursement--payor strategies, cross-port 9 importation. These issues are bigger than what is 10 going on in this room today. They are bigger than 11 the NIAID. Some of them are at the NIH level; some 12 of them are the multinational level and you are not 13 going to fix them today. 14 So, I do not want to dissuade this group, 15 the IDSA. What you are doing is incredibly 16 valuable. Only you can make this contribution to 17 influencing the conversation, but the bit that I 18 would like to add as one more comment on your 19 slides is that there is this other thing that has 20 to go on at the same time. It is sort of like the 21 comment about acting locally but thinking globally. 22 You have to act at your sphere of influence. By 88 1 improving the quality of the guidelines you and the 2 FDA can help us reduce our uncertainty internally. 3 And, that is very valuable when you are working 4 internally to get one program funded versus another 5 program. 6 But there is this other bit that really 7 does need to be considered in the same breath. I 8 do not have an answer for it but if you don't start 9 asking questions about it, it is kind of like the 10 ten-year lag on drug development, you won't have an 11 answer when you need one. So, that is my comment 12 about the additional piece that is here that needs 13 to be addressed from our perspective. 14 DR. DRUSANO: Thanks. I would like to 15 actually address this comment to both Dr. Scheld 16 and Talbot. In both presentations there is a 17 dramatic slide looking at the number of approvals 18 of anti-infectives over time. As we saw, there was 19 an inexorable down slope to that number. So, the 20 real issue becomes two things. Number one, how 21 much of a crisis are we in, in terms of new drugs 22 coming along? Number two, and a little bit more of 89 1 a subtle point, is how long is that trough going to 2 last? Because, as John pointed out, you do need a 3 certain infrastructure. When companies get out you 4 don't jump back in and then go straight to full 5 production overnight. 6 One of the things that I think would be 7 helpful to make the case, particularly to Congress, 8 is to examine two things. Like we do with 9 controlled clinical trials, it is nice to see not 10 just anti-infectives in the number of approvals per 11 year, but to have some control therapeutic 12 areas--what is happening in pulmonary? What is 13 happening in oncologics? How many approvals are 14 there per year in those to make a point to see if, 15 indeed, this is as bad as we think it is. 16 As to the duration of the trial, how many 17 anti-infective INDs are being filed because that is 18 the other side of the coin? You don't know how low 19 that trough is going to be and how long it is going 20 to be down there unless you know what the activity 21 currently is in companies that are filing new 22 anti-infective INDs. I think we know the answer to 90 1 that but it would be nice to have that data to make 2 the point to regulators, to Congress. It will make 3 I think the situation much clearer. 4 DR. EDWARDS: Thanks, George. 5 DR. POWERS: George, ask and you shall 6 receive. We will now show you the slides that 7 actually answer your question. This is twice in a 8 row and I am not a shill, I promise. We didn't pay 9 George off for this one! 10 This keeps getting asked and, George, I 11 was thinking when you showed your slide of how many 12 people from the press have called, Jason Brosky, 13 from our press office, calls every day and asks 14 this question. So, we tried to put some slides 15 together and one of the reasons I want to show this 16 is to get this information out into the public 17 domain. 18 [Slide] 19 Mike showed 1996 onward, but I thought it 20 would be very instructive to show back to 1980 what 21 has actually happened with these drugs, and you can 22 see that it is an up and down process, as you would 91 1 expect. We go from some highs and we got some lows 2 that actually even preceded. 3 The other thing that is important to 4 notice though is that in the years in which there 5 are no drug approvals, look what happens 6 afterwards. So, we see this blip. So, some of 7 this is related just to the vagaries of the 8 calendar where there was a drug that was in 9 development that just happened to spill over into 10 the next year. 11 [Slide] 12 If you do a trend analysis of this, it is 13 true that the overall trend is decreasing. It goes 14 from an average of 2.7 drugs out here, in the 15 1980s--I did it in a ten-year span. In the 1990s 16 it is 2.5 and there is really not enough data yet 17 in the 2000s to actually say what is going on, but 18 the average there was 1.25 from 2000 to 2004. 19 Ed Cox and I were discussing yesterday 20 when you talk about safety analysis and you say, 21 well, this drug had a 1.5 percent adverse event 22 rate and the other one was 0.2, but what you really 92 1 need to look at is the details of what is in there. 2 So, let's look at the details of what are these 3 drugs because I think the idea is too what are we 4 asking for. 5 [Slide] 6 George, here is the question you were also 7 asking about all drug approvals, what is happening 8 overall. As you can see, there is this up and 9 down. We had a blip in 1996 and then it is coming 10 back down overall. The dark line here is for small 11 molecule drugs, which is what we deal with in the 12 anti-infective divisions. The bottom line here is 13 for biological products. So, that is actually a 14 little bit on the up-slope whereas what we are 15 seeing is the small molecules come down. So, that 16 is the answer to your question of what is going on 17 overall in terms of drug development. This slope 18 has been going down since 1996 for everything so 19 that mirrors the trend of what is going on. Then 20 let's look at the mean clinical and approval phase 21 links. The yellow one here is how long it takes 22 your drug in the clinical time and the blue part is 93 1 how long it takes to get approved. This was done 2 by the Tufts Center for the Study of Drug 3 Development so this was independent of the FDA that 4 somebody looked at this. 5 When you look at this over time you can 6 see that the clinical phase has lengthened, yet the 7 time to approval phase where the FDA looks at the 8 drugs has actually shrunk over time. So, on the 9 whole it is a little bit longer than it was, but 10 part of this is due to the increase in the clinical 11 phase program. 12 [Slide] 13 Then this asks the other question of how 14 long does it take to get your antimicrobial 15 approved. This looks at all of the drug 16 classes--anesthesia drugs, cardiovascular, 17 anti-infectives, CNS and anti-neoplastics. Here 18 are the anti-infective drugs. They are at the 19 bottom of this rung almost the entire time from 20 1982 to 2001. So, when you look at this the mean 21 clinical and approval phase lengths are shorter, 22 which would argue that it is actually less 94 1 expensive in terms of time for anti-infective 2 drugs. 3 [Slide] 4 If you go to the next slide, it is the 5 median. So, this way, looking at the median we are 6 saying, well, are outliers driving this system? Is 7 this shorter just because HIV approvals take a 8 shorter time? The answer to that doesn't look like 9 that is true either. If you look, anti-infectives 10 are again at the bottom of this. The median 11 clinical and approval phase lengths for 12 anti-infectives are also shorter than the other 13 drug classes as well. 14 [Slide] 15 So, if you look at this, back in the 1980s 16 to 2001 the mean was 18.6 months and the median was 17 14. Over here, in 1998 to 2001 it is now 8.8 in 18 six months mean and median for anti-infectives. 19 Some of that is really short for HIV, as you can 20 see, 4.6 and 4.1. So, some of this is driven by 21 the HIV model. 22 [Slide] 95 1 But here is the real important part to 2 look at, what was getting approved back in the 3 1980s and the 1990s. This gets to what I think 4 Mark was talking about, about quality versus 5 quantity. What do we want to see? If you look at 6 the left side of this graph, it is pretty much 7 yellow so what was in there was predominantly 8 beta-lactam drugs and we looked at every one of 9 these. You have some real big sellers here like 10 bacantacillin, Ceftin, cefuroxime and cefpirome. 11 No insult intended to people who made those drugs. 12 But when you look at these numbers, they are driven 13 by a lot of drugs that really didn't get a lot of 14 clinical usage. 15 If you look to the right here, what we see 16 in the 1990s is the blue that starts to pop here 17 with all the qinolones in the 1990s. But then when 18 you look over here there is much more variety of 19 colors because the kinds of drugs we are trying to 20 see is a greater variety than what we were seeing 21 in the past. 22 [Slide] 96 1 This gets to the issue of new drug 2 classes. Mike mentioned that there have been two 3 new drug classes approved since 2000. It occurred 4 to us, well, when were the last new drugs approved? 5 So, without just looking at the overall picture you 6 may get a skewed view. 7 If you look at this, the first antibiotic 8 approved are the sulfonamides in the 1930s, and I 9 shouldn't say approved, just clinical usage because 10 the efficacy standards for the FDA were not 11 introduced until 1962 with the Kefauver-Harris 12 amendments, and you can see the majority of drug 13 classes were introduced prior to that point in 14 time. 15 Now, what we used to define drug class 16 here is what the IDSA used in their "white paper," 17 and that means novel binding site for the 18 antimicrobial. That is why we lumped macrolides, 19 lincosamides and streptogamins together and 20 telithromycin got lumped in with the macrolides as 21 well. 22 So, what you see here is that most of the 97 1 drug discovery occurred in the 1930s, '40s and '50s 2 and the last truly novel class was trimethoprim in 3 1968. So, there hasn't been any new drug discovery 4 for 40 years and those two new drug classes from 5 2000, if you look at it from that point of view, is 6 actually a pretty good thing. 7 That is enough; I will stop there but I 8 just wanted to show sort of the idea and get back 9 to the question of what are we asking for. I think 10 when IDSA folks met with Commissioner McClellan one 11 of the points he made was that we need to be very 12 focused about what we are asking for. So, the idea 13 is do we want a lot more, you know, oral 14 cephalosporin drugs to add to the mix to make the 15 numbers go up, or are we looking for more quality 16 drugs that are going to relate to antimicrobial 17 resistance? 18 DR. EDWARDS: Would either of you two like 19 to comment on those comments? If you don't, I 20 will. 21 DR. SCHELD: Well, I will say what I think 22 we are asking for--I am not particularly interested 98 1 either professionally, personally or as a 2 representative of IDSA in a number of new oral 3 cephalosporins that have overlapping spectra with 4 what is already on the market. What I think we, as 5 physicians, are most concerned about, as George 6 rightly put it, to put the patient first, is the 7 escalation in gram-negative resistance in 8 Acinetobacter of untreatable infections in our 9 soldiers coming back from Iraq with Acinetobacter 10 pneumonia and things like that. How to go about 11 putting that case out there with the legislative 12 solutions is not going to be easy. We also 13 recognize, just as everybody said here this 14 morning, if we had a new drug which would be active 15 against Acinetobacter that is only susceptible to 16 Clistin tomorrow, the ID people in every hospital 17 around this country are going to try and reserve it 18 in some capacity. So, you have this Catch-22 that 19 we have talked about before. 20 As George said, the solutions are not 21 simple. It is going to be multifactorial but I 22 think we, as an organization, should put that type 99 1 of a global out there for a legislative solution. 2 That is where I am coming from. 3 DR. EDWARDS: We have had about 50 years 4 of experience with anti-infectives now as a 5 species. I think we are still in the beginning 6 stages of learning about them. If we imagine that 7 in the last few years--well, in some ways, John, 8 you have shown some data that shows a little bit of 9 a consistency in terms of the types of agents, new 10 agents that have been coming out. We are saying 11 there is a critical diminishment in the larger 12 pharmaceutical company research and development 13 programs at the present time. I think we have as 14 good data as we can possibly get for that. Then, 15 we also have the curve that we keep referring to of 16 the approval of new entities. 17 How that compares to other classes of 18 drugs I am not sure is all that relevant, to tell 19 you the truth, because we are faced with an 20 existent problem now. We have learned that 21 antibiotics, to quote without naming specifically 22 some of the people we have talked to, define their 100 1 own life span, and they are unique drugs in 2 comparison to other drugs for two reasons. One is 3 that they do define their own life span. I mean, 4 that is not totally unique but it is a very 5 prominent characteristic of the antibiotics. 6 Secondly, most of us can't think of very many other 7 classes of drugs where the thought leaders 8 immediately start discouraging their use once they 9 are developed. That is certainly not the case with 10 oncology drugs. A new oncology drug is just 11 immediately embraced by the community. So, we have 12 a unique problem with this class of drugs from 13 those two perspectives. 14 Yes, George, we feel we are in a crisis. 15 I just wanted to make two small points about that 16 because data is being collected, and all, and I 17 don't want to emphasize that, but those of us who 18 are seeing patients on a regular basis are spending 19 the majority of our time trying to figure out 20 strategies for how to deal with them within the 21 confines of the resistance issues. Mark has made a 22 very important point, which is that for most of the 101 1 organisms we are dealing with we do have available 2 drugs that work. When we start talking about VRE 3 and MRSA, then we have a real strong exception but, 4 even though that fact exists, one has to look at 5 what physician behavior is. 6 I would like to use this example, in a 7 large metropolitan hospital where many patients are 8 seen per day with a localized cellulitis, prior to 9 the last few years those patients were started on a 10 cephalosporin and were dismissed from the hospital 11 emergency room, and the cost of providing care for 12 that individual was relatively small. Now the 13 concern is that they may have something like an 14 MRSA, and it is so high that the specimen is 15 cultured; arrangements are made for a follow-up 16 visit; the patient is started on a regimen of 17 antibiotics that is more expensive and more toxic 18 than a cephalosporin would be, such as rifampin and 19 trimethoprim sulfa. 20 So, if you were really to do the statistic 21 and say how many of those people did have MRSA 22 simple cellulitis requiring a specific antibiotic, 102 1 the answer would probably be very small but, 2 nevertheless, a tremendous expenditure is made 3 towards taking care of that patient because of the 4 spectra of the problem. So, that is a whole 5 separate issue that is related to the fact that 6 while there is a certain armamentarium, there is a 7 shift away to a different strategy in order to 8 protect the individual patient. I hope I have made 9 that point clear. 10 One question that George asked that I also 11 was wondering about is do we have access to IND 12 data? I know that is confidential data, but do we 13 have access to numbers? DR. POWERS: I can tell 14 you that as a part of the Critical Path initiative 15 there was a review done of INDs. I think this is 16 in that document and this is not just for 17 anti-infectives, which I don't think we would be 18 able to release for proprietary reasons, but the 19 overall number of INDs in all the drug classes 20 being submitted to the agency has gone down. I 21 don't remember the exact numbers. But that was one 22 of the reasons why that Critical Path was 103 1 undertaken. 2 DR. EDWARDS: George? 3 DR. TALBOT: Just a couple of comments, 4 that graph in the Critical Path paper was really 5 quite dramatic I think. I don't know the numbers 6 behind it, but for all classes the number of 7 submissions has gone down which has two points. 8 One is it is a great thing that the FDA is looking 9 at this problem across all classes but, as Jack 10 said, we still have a unique problem with 11 antibacterials. 12 I think the other question that you had, 13 George, is whether it is a crisis or not. 14 DR. DRUSANO: I believe it is a crisis, 15 George, no question. I just wanted to clarify a 16 little bit. 17 DR. TALBOT: Well, Jack expressed that 18 concern also. I think I would point out that one 19 person's crisis is another person's problem. The 20 word crisis is very easy to use. Public health 21 crisis is a very easy phrase to use. I would just 22 urge that we be precise in our use of that because