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

104

1 trumpeting public health crisis from now in

2 perpetuity may eventually work against us. I am

3 not sure that there is a consensus on that, as to

4 whether it is a current crisis. It is certainly a

5 crisis for the person who has some of these

6 acinetobacters, but whether it is a public health

7 crisis or an impending public health crisis is

8 something I think we really ought to reflect on in

9 terms of our communication about it. That is my

10 personal perspective but I don\'t know that we serve

11 ourselves well by falling into rhetoric.

12 DR. EDWARDS: I just can\'t help but make

13 one comment about that, George. You know, I was

14 discussing this whole issue with my wife not too

15 long ago and she provided me with a concept that I

16 really like, and that was that I think what we are

17 working on here is to try to stop a potential

18 catastrophic situation before it occurs. There is

19 a lot of discussion about all those sorts of

20 strategies going on currently as they relate to

21 some congressional hearings.

22 DR. TALBOT: Yes, and I agree with that

105

1 completely. As I said in my presentation, if

2 vanco. gets out broadly into staph. and vanco.

3 resistance gets out broadly in the community, I

4 mean that is going to be a catastrophe. But,

5 again, just to urge that we be precise and

6 consistent in our terminology so that, as

7 scientists, we clearly state the problem and state

8 its potential repercussions, one of which could be

9 exactly that. And, to George\'s point, it is

10 exactly the reason why we need to keep the

11 companies that are in, in since we know from our

12 visits that once you are out, to get back in is

13 going to take six, seven, eight years, we have been

14 told. So, we have to keep them in if they are in.

15 DR. DRUSANO: Just to make a point, there

16 are two drivers for this whole problem. Number one

17 is resistance but the second driver is economics.

18 Now, we have talked a little bit about the

19 economics from the point of view of getting some

20 congressional changes so that reimbursements for

21 companies can incentivize them to develop

22 anti-infectives, and that is wonderful.

106

1 There is a whole other part of the

2 economics mix that has not been talked about, and

3 Dr. Powers touched on it a little bit, which is to

4 say that when you look, development times are the

5 shortest for anti-infectives for any therapeutic

6 area. That is number one. So, there has to be, I

7 think, an economics analysis by somebody

8 independent for the companies.

9 The other issue is what is the Phase 3

10 failure rate? If you look at one of Dr.

11 Goldberger\'s slides\--I don\'t care whether you use

12 1.3 or 1.7 billion dollars, that is a lot of money.

13 What is the overall Phase 3 failure rate by

14 therapeutic area? I don\'t know the numbers but I

15 would be willing to bet you, because of the say

16 that we collect preclinical data on

17 anti-infectives, that the Phase 3 failure rate is

18 much smaller. So, you have to amortize the cost of

19 a Phase 3 program failure across all of the income

20 that is coming in. So, I think when you look at

21 that, when you look at development times, when you

22 look at margin in terms of profit, that these are

107

1 all things that are economically based that need to

2 be analyzed so that the industry itself sees that

3 this is an economically viable area.

4 DR. EDWARDS: I am going to take the

5 prerogative to break at the moment unless it is a

6 very short comment.

7 DR. HENKEL: It is fairly short. There is

8 one more link between economics and resistance. A

9 couple of times this morning, including in Mark\'s

10 talk, there has been an assumption that use of a

11 new product is necessarily linked to resistance to

12 that product, and I am not sure that is necessarily

13 true. I would like to challenge that in that we

14 should look at it in a little more sophisticated

15 fashion in terms of the activity of a new drug, the

16 concentrations at the site of infection, how well

17 it eradicates the pathogen, and we may actually

18 discover that some new drugs more effectively

19 prevent development of resistance if they are used

20 in an appropriate way as opposed to an older agent

21 which may be marginal in some of those respects.

22 DR. EDWARDS: It is an excellent point.

108

1 Clearly, enough has been spoken already this

2 morning to stimulate a tremendous amount of

3 discussion, which is the purpose and we hope that

4 it will go on, and on, and on. We are going to

5 take a 15-minute break. We are already behind

6 schedule but if we could come back just a little

7 bit after 11:15.

8 I want to thank the speakers from the

9 beginning of this session for these absolutely

10 beautiful presentations. Thank you very much

11 again.

12 \[Brief recess\]

13 DR. EDWARDS: I am going to take the

14 prerogative to reopen the discussion before we move

15 on to the next part and see how it goes here. If

16 the quality of the discussion becomes meritorious

17 enough, we may just take the meeting a little bit

18 further; we will play it by ear. I really felt

19 that we had to terminate that discussion quite

20 prematurely, and by the intensity of the discussion

21 that has gone on in the break, it is really

22 amazingly gratifying to see everyone talking so

109

1 much. I think we are going to go ahead and reopen

2 the discussion for this first part now for a few

3 moments. Would anyone like to introduce a new

4 concept and continue on at this point? John?

5 DR. BRADLEY: The discussion took several

6 turns and I wanted to address some of John Powers\'

7 questions on trying to focus where we are going

8 with our proposals with respect to what the FDA can

9 do and what industry can do, and perhaps an example

10 will help this.

11 In 1998, at the Anti-Infective Advisory

12 Committee, information on community-acquired,

13 multiresistant pneumococcus was presented, and for

14 pediatric meningitis we were very concerned with

15 alarmingly increasing rates of resistance to

16 penicillin and cephalosporins, reports of

17 vancomycin resistance, and we pleaded for the need

18 for testing for quinolones in pediatrics. There

19 were also presentations on otitis media that wasn\'t

20 responding to any currently available oral agents.

21 And, the green light was given. Industry stepped

22 up to the plate and many of these studies actually

110

1 have gone on, taken place, and results, some of

2 which will be presented to the committee next

3 month, are fruitful indicators that this discussion

4 produced a product.

5 But we didn\'t know that resistant

6 pneumococcus, at least that causing meningitis,

7 would turn out not to be a problem because of the

8 introduction of the pneumococcal conjugate vaccine.

9 Ceftriaxone resistance rates are dropping and the

10 vancomycin resistance that was seen in Memphis

11 turns out to not have been applicable to many other

12 centers. We certainly never saw it in San Diego.

13 So, the imperative to study drugs in meningitis,

14 which would seem clear in 1998, here, six years

15 later isn\'t, and for all of the investment that

16 industry puts into these protocols, and it is

17 substantial, they are left with a drug which has no

18 economic benefit to them. That goes back to Dr.

19 Rex\' comments that if you don\'t get successful drug

20 1 you won\'t go to drug 2.

21 So, in part the uncertainty that we are

22 all facing is how bad will the resistance be and

111

1 when will it happen? I think everyone agrees it is

2 going to happen but how can we help legislate some

3 sort of incentive that will keep industry looking

4 for new, novel agents that will address the issue

5 of resistance and allow industry to have an

6 economic incentive so at the end of the day they

7 can go to their shareholders and say, you know,

8 this was a reasonable business decision we made and

9 there is benefit to patient populations.

10 I think to try to focus our discussions on

11 how we can make it worthwhile to all the

12 stakeholders and take it out of just, you know, you

13 make a drug, you sell it, you make a profit

14 scenario is a unique aspect of this particular

15 workshop. The equation for community-acquired

16 infections for things like otitis media, at least

17 in pediatrics, and the equation for

18 hospital-acquired infections like multi-resistant

19 Pseudomonas and Acinetobacter are two different

20 things because, certainly, for hospital-acquired

21 infections they will never be the huge population

22 so they will never be the economic incentive. By

112

1 working together, hopefully, we can come up with a

2 solution that works for everybody.

3 DR. POWERS: Jack, can I respond to that?

4 DR. EDWARDS: Yes.

5 DR. POWERS: John, I think you are raising

6 an important point there about the level of

7 uncertainty and where that comes in. One is

8 regulatory uncertainty related to how to do the

9 trials, etc. But what you just pointed out was

10 scientific uncertainty, something none of us can do

11 anything about. So, if you were developing a new

12 drug for cancer and somebody came up with a cure

13 for all cancers tomorrow, you are kind of out of

14 luck as the company who was developing that drug

15 for cancer. And, that is not a regulatory issue.

16 What I think we hear a lot of is, well,

17 the agency promised us this four years ago. You

18 know, the science changes as we go on, therefore,

19 the risk/benefit for those things actually changes

20 as well. If you kind of try to project into the

21 future though, this is the idea of focus and where

22 we are seeing the least amount of drug development

113

1 for multi-drug resistant gram-negative rods and

2 hospitalized infections but, as you say, that is

3 where the market is the smallest. So, how do we

4 come up with an incentive there that does not seem

5 to fit the supply and demand model?

6 DR. EDWARDS: Would anyone from industry

7 like to comment on that? What would be the

8 incentive?

9 DR. REX: I will make one comment but I

10 really think that some of the other people around

11 the table should weigh in as well. I want to go

12 back to the theme that I raised a minute ago. You

13 know, George asked before the break does industry

14 understand about the fact that anti-infectives are

15 lower risk to develop, and I promise you we do. We

16 understand that once you prove that the drug is

17 safe in Phase 1, doesn\'t cause some funny bad side

18 effect, the likelihood of an anti-infective going

19 on to become a marketable compound is much better

20 than it is for almost any other class. I project

21 that message every time I talk about why we should

22 be doing anti-infectives, along with the fact that

114

1 the cost of anti-infective\--the spend profile is

2 actually very nice. So, all those things are

3 clearly understood.

4 However, we all live in a resource

5 constrained environment, every one of us, in your

6 personal budget, in the budget of any group that

7 you work with, the laboratory that you run, and you

8 can only spend so many dollars on things that don\'t

9 generate return. You also have to spend dollars on

10 things that do generate return. John, you talked

11 about the fact that, you know, a cure for cancer is

12 found and now all the cancer drugs are no longer of

13 value. Companies also recognize that, and that is

14 part of your mixture of risks so you know that you

15 are spreading out in terms of variety of things so

16 if any one thing goes down, you are not about that

17 one thing; you are about the whole pattern of

18 stuff.

19 It is ultimately that overall support for

20 reimbursement for drugs as a whole is actually the

21 critical driver. Without some degree of comfort

22 with that everybody is going to retreat to their

115

1 next position of comfort, which is the big things

2 that make the big money because you know that that

3 is at least stable for the next couple of years.

4 So, it is all of that that really makes a

5 difference.

6 What could IDSA do? You guys are working

7 on anti-infectives and that is great but can you

8 broaden that? Are there other academic groups?

9 Does AAP have a broader initiative that has to do

10 with new drugs for X, Y, Z, whatever these other

11 things are? Is there a way to broaden the scope of

12 what is going on here?

13 DR. EDWARDS: Do you want to comment,

14 Mike?

15 DR. SCHELD: Well, John, we certainly can

16 and we have actually discussed this with a number

17 of other societies, but we have also discussed it

18 with, say, organizations like AARP which represents

19 35 million Americans. I wouldn\'t say that that has

20 gone very far but it is on our radar screen.

21 DR. EDWARDS: Excellent point. Yes?

22 DR. EISENSTEIN: I would just like to

116

1 weigh in a little bit on the problem that everybody

2 recognizes, which is drug resistance and,

3 therefore, physician behavior which is appropriate

4 in terms of trying to maintain the best newest

5 products activity, which is essentially perverse

6 from the standpoint of the marketplace. So, if the

7 marketplace drives or should drive use and this

8 works for most situations. In places where the

9 compound should be limited for public health

10 reasons new ways of thinking I think need to occur.

11 The best example that comes to my mind offhand is

12 that the U.S. Congress has mandated,

13 controversially I would say, for subsidies to be

14 given to certain industrial groups, and the farm

15 population comes to mind, where the farmers are

16 actually paid not to plant crops. If there were

17 such an incentive for drug development where a

18 product could be actually subsidized could be

19 developed and, in a sense, to be put on the shelf,

20 there might be very interesting means by which

21 companies could be willing to take the path towards

22 innovation if they saw that as an opportunity.

117

1 Now, that is fraught with major political

2 issues, certainly not to be solved here but, in a

3 way, it is almost the best use of government, which

4 is to protect extraordinarily difficult to preserve

5 desires of society that aren\'t otherwise solved by

6 the marketplace.

7 DR. EDWARDS: George, let me ask you to

8 comment.

9 DR. TALBOT: That is a very interesting

10 idea. It follows on the theme that Tim mentioned

11 which is the marketplace might. Certainly, the

12 receptivity of the marketplace to new products is a

13 major issue. I think though that my conclusion

14 there was correct. What is going to be required to

15 change that will be scientific data, solid, very

16 robust scientific data, for example, showing that

17 cycling works or something along those lines. I

18 guess the question is what sort of scientific data

19 would be necessary to change that perception and

20 who would generate it.

21 DR. EDWARDS: Yes?

22 DR. TULKENS: Maybe I can make a comment.

118

1 We have a number of examples in countries where

2 consumption is low. One example is Holland where

3 resistance is also extremely low. Now, companies

4 don\'t make much money on that. So, the question is

5 really to discuss can we identify places where

6 compounds are needed but will be restricted?

7 Therefore, what needs to be changing maybe is the

8 pricing. We need to subsidize or to give the

9 companies a high price for compounds we need and

10 which we know will not be used. I don\'t know

11 exactly what the economics are in Holland, but I am

12 not sure that companies get a lot of money out of

13 that country but the point is interesting that

14 sales are about one-third of what they are in other

15 countries, and the resistance rates are almost to

16 zero, very, very low. So, that is maybe one way to

17 answer the question. In all situations where

18 restriction has taken place has always led to a

19 slowdown of the resistance and sometimes no

20 resistance at all for many, many years. So, we

21 really have to design the sort of economic model

22 where compounds are developed, left on the shelf

119

1 and all used very sparingly.

2 DR. EDWARDS: George?

3 DR. DRUSANO: Over the break a number of

4 colleagues came up to me and beat me about the head

5 and shoulders and indicated that, yes, indeed,

6 pharmaceutical companies really did understand in

7 extreme detail the economic utility of antibiotics

8 or lack thereof.

9 I think perhaps I was a bit misunderstood

10 in terms of what I said. It is all the economics.

11 We are proposing here oftentimes that we go to a

12 legislative solution so that we ultimately would be

13 approaching Congress to change the law. Now, there

14 are going to be political issues about supporting

15 such a change in law from legislators. If

16 something like that is going to happen, and this is

17 where my comments were meant to go, there has to be

18 a real clear and transparent economic analysis of

19 what the companies currently do get back from

20 anti-infectives, accounting for all of these

21 issues, so that if you are going to put in place an

22 incentive program nobody can say that the companies

120

1 are being over-incentivized. That has to be

2 transparent as to what you are doing in order to

3 get the companies to get back in. That is where I

4 was coming from.

5 DR. EDWARDS: Other comments? That is an

6 excellent point, complicated. Yes, please?

7 DR. BAX: Richard Bax. We have heard a

8 lot for the last 15, 20 years about antimicrobial

9 resistance. We have heard a lot of people talking

10 with great concern about a lot of things which have

11 been discussed many, many times. Could I just ask

12 the panel and the group what really needs to happen

13 now in order to address this issue of where are we

14 going to get new antimicrobials from. We have had

15 lots of proposals but what simple things\--and I

16 know the answers are complex, but what simple

17 things really need to happen in order to at least

18 start addressing this problem?

19 DR. EDWARDS: George is cringing over

20 there! Perhaps the question is where would the

21 major focus be. I think George has very

22 beautifully shown that solution of this problem at

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1 this point and the perspective looks like it is a

2 multifactorial issue. There isn\'t a single clear

3 course of action that looks like it would solve the

4 situation on the immediate front. George, I am

5 going to ask you\--if you don\'t want to, I will

6 express my opinion but, you know, what should we

7 all as a body put in the highest level of priority,

8 realizing that a multifactorial approach is

9 obviously ultimately going to be the situation.

10 This is really a difficult question because I think

11 it depends on exactly what perspective you are

12 coming from, and I could comment on that. Mike, go

13 ahead.

14 DR. SCHELD: I will take a crack at it,

15 Richard. I think, first of all, when we bring out

16 this \"white paper\" next month it will crystalize

17 some of our thoughts as an organization. We have

18 kind of listed in there many of the solutions that

19 Dr. Talbot so beautifully presented in somewhat of

20 a priority order.

21 But what needs to happen is some of the

22 things that are already on the table. The NIAID

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1 needs to implement their \"Roadmap.\" The FDA needs

2 to get their guidances out there. We need to get

3 this issue up on Capitol Hill for hearings to be

4 held on antimicrobial resistance and the drying up

5 of the pipeline for antibacterials this year. So,

6 that would be what I would suggest as the next

7 step. We are not going to have a wild card

8 exclusivity legislation written and passed in 2004.

9 It may never happen. But what we need to do is get

10 the topic out there and have people talking about

11 it, not just in the media but really at the level

12 of congressional staffers. So, that would be my

13 response.

14 DR. EDWARDS: George?

15 DR. TALBOT: Mike, thanks for taking the

16 heat off me. I was going to be more simplistic

17 about it and say I don\'t think there is one

18 solution. You didn\'t actually say that in so many

19 words but your answer actually was the same. That

20 is why partnering in this is needed.

21 DR. EDWARDS: I think that is a very

22 excellent response, George. I might make one

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1 comment that would be indicative of a direction we

2 are heading in, that is, we just had quite a

3 discussion a few days ago about actually starting

4 to put words on paper regarding proposed

5 legislation. I know that makes Bob Guidos pretty

6 nervous but getting to the words on paper appears

7 to the IDSA as an extremely high priority among all

8 the other things which need to be done.

9 DR. BAX: Maybe it is just the rapid

10 effect of development of niche antibiotics with new

11 modes of action which are actually coming to the

12 marketplace, and nothing actually succeeds like

13 success.

14 DR. EDWARDS: Yes?

15 DR. CRAIG: I wanted to ask Ed Cox, is the

16 guideline for development of drugs for resistant

17 organisms one of the ones that is going to be

18 coming out relatively soon? If not, is there some

19 way that there can be some collaboration between

20 IDSA and the FDA to try and speed that up? I am

21 not sure that taking guidelines to the advisory

22 committee is necessarily the best group. I think

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1 the number of experts on that committee is somewhat

2 diluted by the legal requirements for membership on

3 that committee. Sure, you can add a few experts to

4 it but I think there are probably other venues that

5 can help speed up guidelines and get more input

6 from many other people that are critically involved

7 in clinical trials.

8 DR. COX: With regards to the guidance

9 document on drug development for resistant

10 pathogens, scientifically among the ones listed up

11 there, it is one of the more complex. Certainly,

12 there are some unresolved scientific issues that we

13 are going to need through. So, that one is

14 certainly one that we are very interested in

15 getting out but it may be one of the ones that does

16 take a little bit more time because of the

17 scientific issues that we have to work through

18 there.

19 As part of the process, we do oftentimes

20 take to the advisory committee the guidance

21 documents in draft form and we do get a lot of

22 helpful advice from our advisory committee. Then

125

1 we also post the guidance document publicly for

2 comment. So, you know, I hear your comment and we

3 are working diligently to try and get the guidance

4 documents out there and updated, and that will be

5 one that we are working on but, you know, given the

6 scientific issues there it may take a little bit

7 longer.

8 DR. CRAIG: I think industry wants to know

9 what their costs are going to be, and the guidances

10 are going to determine some of those costs so I

11 think it is an important part of the equation that

12 we need to get answers for.

13 DR. COX: Yes, and I do think with regards

14 to companies that are venturing into development

15 programs, certainly we do welcome the opportunity

16 to have companies come in and we can certainly give

17 advice and guidance with regards to drug

18 development, and specifically drug development for

19 resistant pathogens, in the interim.

20 DR. EDWARDS: Janice and then John.

21 DR. SORETH: Dr. Craig, you remember when

22 you were a chair of advisory committee and we put

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1 forth drafts of a dozen and a half different

2 guidances. I am reminded, as Dr. Talbot and others

3 have said, there are no easy solutions but there

4 wasn\'t exactly a swift upturn in the development of

5 antibacterial compounds when those reissued

6 guidances came out, and as important as it is for

7 us to get new drafts out and brand-new entities

8 that we haven\'t put pen to paper on, such as the

9 resistance guidance, it won\'t serve as any magic

10 bullet. That said, we will have a number of these

11 out by the end of the year, as Dr. Cox has said,

12 but I think it has to come in conjunction with a

13 number of other things going forward to have a

14 meaningful impact and a mature hope that we will

15 have new antibiotics and new classes on the market.

16 DR. CRAIG: My comments came from the fact

17 that I was the chair and I was not convinced, when

18 we did go over them, that that was the best venue

19 for discussing guidelines.

20 DR. POWERS: I think that is part of the

21 point but that is the way we have to operate. We

22 first discussed the criteria for pathogens of

127

1 public health importance in this venue in November

2 of 2002, then took that to the advisory committee

3 in March of 2003. But what I think people need to

4 understand is that as a regulatory agency we cannot

5 partner with just one group when it comes to trying

6 to develop this kind of things. We can have open

7 public meetings like this one to try to gather the

8 information. We put that out in the Federal

9 Register where everybody can comment.

10 The other thing I sort of wanted to say is

11 that when we looked at the development of those

12 previous guidances\--and I have to thank the two

13 people to my right who did a huge amount of work on

14 this, Dr. Albright and Dr. Soreth\--they got called

15 \"draft\" and when I think of these, they are almost

16 always going to be draft. As George pointed out,

17 we will have to update these at some point but we

18 will never make the political mistake, ever again,

19 of calling them \"draft\" because I think there was a

20 lot of uncertainty that went along with that as if

21 they were going to change tomorrow.

22 But when we look back at when the FDA did

128

1 have a contract with IDSA to do this, it took IDSA

2 over four years to put those guidances together.

3 That is not a knock on IDSA; it is to sort of show

4 the amount of work that has to go into actually

5 developing these. Mike called me up and asked me

6 about some slides we showed about sinusitis, back

7 in October of 2003, and said, hey, who did all

8 review of those placebo-controlled trials for you,

9 and we said we did. We reviewed 17

10 placebo-controlled trials that went back from 1962,

11 and let me tell you how interesting it is to try

12 and find what the primary endpoint is in a trial

13 from 1962\--

14 \[Laughter\]

15 \--so there is a lot of work that goes into

16 it to try to actually do this and I think of it

17 like a research project. But if somebody came to

18 me and said, you know, go find a cure for cancer in

19 a year and a half, I would say I need a little bit

20 more time to be able to do that. So, we have done

21 a lot of research on trying to pull these together

22 so that we have the best information that can go

129

1 into them.

2 DR. EDWARDS: Frank, did you have a

3 comment?

4 DR. TALLY: Yes, I have a comment. When

5 you asked about industry and what the problem is, I

6 think we need to come back to industry. If you

7 have a compound, as John said, that survives Phase

8 1 there are multiple development pathways and, yes,

9 you want guidelines and interactions with FDA so

10 you can get there as quick as you can in the least

11 expensive way. But I think one of the crises that

12 you have identified today is really the discovery

13 of novel new compounds against novel new targets,

14 which is a process that is going on right now. I

15 think the crisis that we are seeing is the amount

16 of dollars in \"big\" pharma. The research has been

17 going up dramatically but the amount of dollars to

18 discover those new molecules and antibacterials is

19 going down and therein lies the crux of the

20 problem, and it is because of all the economic

21 stuff we have talked about.

22 It is different for \"big\" pharma and

130

1 \"small\" pharma because \"small\" pharma can see a 100

2 or 200 million dollar product is good for them.

3 For \"big\" pharma that doesn\'t even hit the screen.

4 So, I think the identification of what is going to

5 get us novel new compounds is the crux of the

6 problem that we have here.

7 I must say, at the advisory committee

8 meeting last March there was a bit of nihilism,

9 that we have discovered all the antibiotics we are

10 going to discover and we are in this hopeless abyss

11 at this point. I really don\'t think that is true

12 but I think there are new ways, but it is going to

13 take longer to get them because of the definite

14 decrease in the amount of dollars addressed into

15 this area.

16 DR. EDWARDS: Yes, George?

17 DR. TALBOT: I wanted to comment on the

18 timing of the guidances and I have honestly nothing

19 but respect for how long it takes and how few of

20 you there are, even though John seems to have

21 cloned himself, as far as I can tell, in terms of

22 everything he is doing. That is one of the reasons

131

1 why IDSA certainly supports increased funding for

2 all these efforts.

3 But I would like to make a comment or an

4 observation from my experience and ask industry

5 representatives to tell me whether I am off base or

6 not. The thing about a 6- or 12-month delay in

7 guidances is that industry operates on an annual

8 budget process, and every time the budget goes up

9 before top management there is a full discussion of

10 the risks, regulatory risks, scientific risks, and

11 so forth, to pursuing a particular project as

12 opposed to the risks that exist for other projects

13 in other therapeutic areas. So, I guess I would

14 just be concerned that, in the absence of a

15 guidance and knowing, in fact, that maybe it is

16 going to come out in 3 months or 6 months or 12

17 months, without that certainty that that could

18 delay commitments at the level of industry and even

19 potentially result in cutbacks or

20 what-have-you\--again, I understand your position

21 but I am not sure that it is correct to say that,

22 you know, a difference of 3 months, 6 months, or

132

1 whatever, really may not make too much difference.

2 I think it could in some situations and I would

3 like to hear what industry would have to say about

4 that.

5 DR. WILLIAMS: Tim?

6 DR. HENKEL: Well, I think you and I have

7 had a couple of conversations about guidances

8 before, and while I find them very useful I have

9 operated under the impression that I have heard

10 John mention before. They are starting points for

11 discussion with the agency. They are not anything

12 written in stone. So, where there are voids, where

13 there is nothing out there is where there is the

14 greatest uncertainty. We are going to talk about

15 resistant pathogens; we are going to talk about

16 bacteremia later today. I think those are some of

17 the more problematic areas where some kind of

18 guidance would be helpful so we know if it is

19 feasible to go forward. But that is a later stage

20 of things. As Frank said a moment ago, you don\'t

21 worry too much about what the guidance says if you

22 don\'t have a discovery program and you don\'t have

133

1 compounds coming into development. So, it has to

2 happen at multiple levels.

3 DR. EDWARDS: From the contact we have had

4 with industry, the word \"guidance\" and the issuance

5 of the guidances consistently has been expressed to

6 us for whatever exactly is the reason, and the

7 reason might be multifactorial, at least it keeps

8 emerging as a very prominent part of their

9 response. Renata?

10 DR. ALBRECHT: Just to agree with the

11 comments that have just been made. Again, clearly,

12 we think guidances are important and we are working

13 hard, as many of my colleagues have said, on

14 finalizing those. But just to echo a comment that

15 Ed and others have made, even when there isn\'t a

16 written guidance there is a lot of communication,

17 interaction and meetings with industry. Without

18 mentioning specific drugs or companies, certainly

19 our division\--and Janice can comment on this\--has

20 met and had discussions with multiple companies

21 about developing certain procedures for resistant

22 organisms and what it would involve. I think that

134

1 progress has been able to continue even as we

2 continue to work on the resistant pathogens

3 guidance document. So, the guidance is a starting

4 point, as has been said, but it is not the end-all

5 and be-all, and we are still working with companies

6 to make sure that we don\'t delay any developmental

7 plans that they come and bring to us.

8 DR. EDWARDS: Good. Thank you for your

9 comments. David, let me go ahead and call on you

10 and then I am going to have to shift into the rest

11 of our agenda, I am afraid.

12 DR. SHLAES: I didn\'t want to prolong

13 things but on the issue of the importance of

14 guidance, I think the audience in this room is the

15 wrong audience. I mean, we all know that we can

16 come to the FDA and discuss issues around specific

17 compounds. We have all had that experience. We

18 appreciate it; we know how important it is. It is

19 the management of the companies that need the

20 guidance. Because when we tell them it is okay, we

21 can go to the FDA; don\'t worry about it, they don\'t

22 believe us\--

135

1 \[Laughter\]

2 I am serious. Actually, I was just

3 talking to Dr. Goldberger about this earlier, but

4 the importance of the guidance is not for us; it is

5 for the management of companies and that is why

6 when the IDSA went around to all the companies and

7 talked to CEOs, every other word out of their mouth

8 was \"guidance.\" So, that is the issue.

9 DR. EDWARDS: Well, that is a very good

10 point. Frank?

11 DR. TALLY: It is not only the management

12 of the \"big\" pharma but without a guidance document

13 when you go to the venture capital world or the

14 public market to raise money for small companies to

15 develop drugs, they point to the lack of guidance

16 too, that it is in the area that gives uncertainty.

17 Once you bring in uncertainty to Wall Street they

18 won\'t invest. So, there is a point for a guidance

19 so maybe it should be made much more general so

20 there is something there because in the development

21 of a couple of drugs for resistant organisms it was

22 only the interaction, as we have just talked about,

136

1 with the agency that led us to put the plans

2 together to be able to accomplish approval of those

3 drugs. So, there is a general background and I

4 think in the advisory committee meetings over the

5 last two years that guidance has come out and I

6 have partaken in those, and we have addressed a lot

7 of the issues and I think a lot of them have been

8 resolved, and it would be nice to get them out

9 there, in the general principle, to take that

10 uncertainty away from the investment pocket and

11 from \"big\" pharma, big management. But all of the

12 people doing the research know kind of what to do

13 and interact with the agency.

14 DR. EDWARDS: Those are great points that

15 have just been made that we really haven\'t

16 discussed much in the past, and it is something

17 that we might really want to develop in the future

18 discussions. So, thank you very much. DR. POWERS:

19 I think one of the things we want to say about that

20 though is that for you guys, when you come in\--for

21 us, you know, at the level when the drug is

22 actually getting developed\--for a CEO it seems like

137

1 all we need to put on paper is bring us the drug;

2 we will develop it. But for the nitty-gritty brass

3 tacks of doing those trials, those guidances need

4 to be fleshed out a little more in terms of the

5 level of detail, and I think that is what we have

6 been tried to work on, getting them to that point

7 so that we don\'t have to rewrite them in a year.

8 DR. EDWARDS: At this point we are going

9 to move on to the third part of the program, which

10 is the beginning of the discussion of surrogate

11 endpoints. I will call on Sheldon Kaplan, from the

12 IDSA, to begin the discussion.

13 III. Microbiologic Surrogate Endpoints

14 in Clinical Trials - IDSA

15 DR. SHELDON: Thank you.

16 \[Slide\]

17 Let me say I have a little upper

18 respiratory infection myself and I m actually not

19 taking any antibiotics for that. But I was asked

20 to address, on behalf of the IDSA, microbiologic

21 surrogate endpoints in clinical trials.

22 \[Slide\]

138

1 That has been the subject of a number of

2 workshops and FDA discussions, and I actually took

3 this slide right from the FDA web site, discussing

4 distinctions between biomarkers, a clinical

5 endpoint and a surrogate endpoint. A surrogate

6 endpoint is a biomarker intended to substitute for

7 a clinical endpoint and it has to predict clinical

8 benefit, harm or lack of benefit or harm.

9 \[Slide\]

10 As a result of using a surrogate endpoint,

11 the FDA might reasonably likely have a new drug

12 approach if these endpoints predict clinical

13 benefit on the basis of an effect on a clinical

14 endpoint other than survival or irreversible

15 morbidity.

16 \[Slide\]

17 So, in thinking about this, of course

18 there are already a number of infections for which

19 microbiologic surrogate endpoints are already

20 useful and are used for clinical trials, for

21 example, group A strep. pharyngitis; uncomplicated

22 lower urinary tract infection; Shigella

139

1 gastroenteritis, and there are a number of others

2 and we will hear about some other clinical entities

3 for which microbiologic surrogate endpoints are

4 useful.

5 \[Slide\]

6 For group A streptococcus, symptoms are

7 going to resolve regardless of therapy. The time

8 to resolution could be compared but you will never

9 be able to really compare two agents with respect

10 to suppurative or noon-suppurative complications

11 that occur way too infrequently to use as clinical

12 endpoints.

13 \[Slide\]

14 There are other infections for which

15 surrogate endpoints probably are not useful or are

16 unproven. For skin and skin structure infections,

17 if you are not dealing with an abscess, if the

18 treatment is clinically successful there is nothing

19 to reculture.

20 For pneumonia there is no organism

21 isolated so it would be difficult to determine

22 that, at least in pediatric studies. Perhaps

140

1 sputum cultures in adult pneumonia trials might be

2 a surrogate endpoint.

3 In acute hematogenous osteomyelitis or

4 septic arthritis you are not going to resample the

5 bone at different points into treatment to prove

6 that the bone is sterile. The same would be true

7 for intra-abdominal infections and for viral

8 meningitis and encephalitis it might be difficult

9 to use a surrogate endpoint.

10 \[Slide\]

11 Why is this true? Again, the site might

12 be difficult to resample. In other cases the lack

13 of eradication of an organism may not actually

14 equal clinical failure. If someone has a

15 ventilator-associated pneumonia and the tracheal

16 aspirate still contains the organism, that does not

17 equal clinical failure at all. In other cases you

18 may eradicate the organism but that may not equal

19 substantial clinical benefit, such as in upper

20 respiratory infection due to enterovirus.

21 \[Slide\]

22 There may be other infections for which

141

1 surrogate endpoints are useful. This requires

2 further study, in my opinion, for bacterial

3 meningitis, and I know there has been a lot of

4 discussion on acute otitis media and sinusitis.

5 Actually, I was asked to talk about acute otitis

6 media initially and I decided I would really rather

7 not discuss that issue. It has been one of

8 tremendous controversy and one that has been

9 discussed at this type of venue many, many times.

10 VP shunt infections I think might be an infection

11 for which a microbiologic endpoint makes a lot of

12 sense, to me, for a study. Coagulase-negative

13 staphylococcus line-associated bacteremias seems

14 like a surrogate endpoint that is microbiologic

15 makes sense there, and perhaps pertussis.

16 \[Slide\]

17 But I want to focus on bacterial

18 meningitis again. This has been the subject of

19 major discussions. This was discussed at a

20 workshop in November, 2002. Here are some of the

21 questions that were brought up at that particular

22 workshop: Are there data to show that a

142

1 microbiologic outcome is as good a marker as

2 clinical outcome, or would it be a good surrogate

3 for clinical outcome? Or, would you perhaps miss

4 potential differences of effects on inflammatory

5 responses? How do you best get preclinical and

6 early phase clinical trial data to use in

7 meningitis trials to address some of these issues?

8 That is a very interesting question.

9 \[Slide\]

10 What is the best timing of repeat lumbar

11 punctures to determine the eradication of an

12 organism in meningitis? How many organisms might

13 even be required to say you have delayed

14 sterilization, and what about quantitative

15 cultures? These are really all difficult questions

16 to address. There are very few studies that we can

17 turn to, to look at these issues.

18 \[Slide\]

19 The IDSA guidelines, developed in 1992,

20 have clinical endpoints of cure; survival with mild

21 neurologic sequelae; survival with severe

22 neurologic sequelae which I think are somewhat

143

1 dependent on the observer\--are these clinicians,

2 pediatricians? Are they neurologists doing these

3 examinations? And, of course, death.

4 One of the other problems with some of

5 these endpoints are that clearly some of the

6 neurologic sequelae improve with time so are you

7 going to be looking at the patient at the end of

8 therapy, two or three months later or a year after

9 they have been involved in the study?

10 We can\'t really look at mortality between

11 two agents in the U.S. because our mortality rates,

12 thank goodness, are very, very low.

13 So, I have selected to look at audiology

14 results as one potential surrogate marker. This is

15 an objective measure. It is quantitative.

16 Although, as with other neurologic sequelae, many

17 of these hearing losses may improve with time.

18 \[Slide\]

19 We took a couple of studies, comparing

20 head-to-head antibiotics. We have this study that

21 was published in The New England Journal of

22 Medicine, ceftriaxone versus cefuroxime, a

144

1 randomized trial, very small number really of

2 patients, but we have a repeat CSF culture at 18-36

3 hours. There were no significant differences in

4 the clinical characteristics of the patients at the

5 time of enrollment.

6 \[Slide\]

7 If we focus on the repeat LP culture

8 results and hearing loss, we see that a positive

9 CSF culture in the ceftriaxone group occurred in

10 1/52 versus 6/52 in the cefuroxime group. This

11 actually was not a significant difference although

12 it is clearly a trend. All of the positive

13 cultures were Hemophilus influenzae type b. There

14 was a 4 percent incidence of hearing loss in the

15 ceftriaxone group versus 17 percent in the

16 cefuroxime group, which was almost clinically

17 significant. So, we actually have perhaps a

18 dichotomy where we don\'t see a significant

19 difference in the positive CSF cultures at the

20 second tap but almost a significant difference in

21 hearing loss.

22 \[Slide\]

145

1 If you look further at this, 2/27 patients

2 with H. follow-up type b meningitis had hearing

3 loss, 7 percent in the ceftriaxone group versus 17

4 percent in the cefuroxime group. However, I would

5 mention that all the patients with positive

6 cultures had Hemophilus influenzae type b. Two of

7 six patients who had hearing loss after cefuroxime

8 therapy had delayed sterilization of CSF. But four

9 of the patients who had hearing loss did not have

10 delayed sterilization.

11 \[Slide\]

12 For pneumococcus we also see a slight

13 difference perhaps, 0/8 in the ceftriaxone group

14 and 2/6 in the cefuroxime group. None of the

15 patients with pneumococcal meningitis with hearing

16 loss had a delay in their CSF sterilization.

17 \[Slide\]

18 So, if we do the little calculation that

19 has been performed for acute otitis media comparing

20 bacteriologic success and clinical success, we see

21 that the sensitivity of a sterile repeat CSF is 91

22 percent but its specificity for a repeat CSF being

146

1 positive and showing clinical failure is low,

2 around 30 percent.

3 \[Slide\]

4 If we also look at studies that were done

5 in Dallas over several years, these are four

6 prospective trials conducted consecutively, with

7 three of them also looking at dexamethasone so it

8 is really a hodge-podge of clinical trials, none of

9 these trials compared agents directly. But overall

10 there were 174 children who received ceftriaxone

11 and 159 who received cefuroxime and there were no

12 significant differences between the groups at the

13 initiation of therapy.

14 \[Slide\]

15 If we look at the CSF culture at

16 follow-up, for ceftriaxone it was stated in the

17 paper that they were uniformly sterile; 9 percent

18 of the cefuroxime follow-up cultures were positive,

19 highly significantly different. Whereas, for

20 hearing loss there was no significant difference.

21 So, actually we see something quite different than

22 what was shown in the earlier paper by Schaad.

147

1 \[Slide\]

2 If we look at some more recent studies,

3 meropenem versus cefotaxime for bacterial

4 meningitis, and look at the sequelae\--these are the

5 IDSA sequelae groups, cure, mild sequelae and

6 severe sequelae, and you can see that the two

7 agents were really quite comparable. There were

8 virtually no patients who had positive CSF cultures

9 at the follow-up tap; two in the meropenem group,

10 one in the cefotaxime group. They all happened to

11 be Hemophilus influenzae. So, obviously, many of

12 these patients with severe sequelae had negative

13 repeat CSF cultures.

14 \[Slide\]

15 The same thing is true for a more recent

16 study comparing trovafloxacin to ceftriaxone.

17 There were 8 children who had positive repeat

18 cultures. I believe 5 of these were pneumococcus

19 but, again, the vast majority of patients who would

20 have had severe sequelae must have had a negative

21 CSF culture.

22 \[Slide\]

148

1 So, I think, at least as far as bacterial

2 meningitis is concerned, it is really not clear to

3 me how well a repeat CSF culture at 24-36 hours or

4 18-36 hours after initiation of therapy predicts

5 hearing impairment or the overall outcome with the

6 fact that the majority of patients with severe

7 sequelae have a sterile CSF culture at follow-up.

8 It is not clear at all if the findings for

9 Hemophilus influenzae type b meningitis are then

10 applicable to pneumococcal or meningococcal

11 meningitis, and these are the infections, of

12 course, that we are seeing more commonly now in the

13 United States, although pneumococcal meningitis is

14 really on the decline.

15 So, those are my comments about

16 microbiologic endpoints as surrogate markers,

17 focusing really on bacterial meningitis. Thank

18 you.

19 DR. EDWARDS: Thank you very much. Yes,

20 Barry Eisenstein, from Cubist.

21 Industry

22 DR. EISENSTEIN: Thank you.

149

1 \[Slide\]

2 I am going to be representing the thinking

3 of a number of people within Cubist, particularly

4 those of us involved in clinical development and

5 drug evaluation. What I think the morning

6 discussion was reasonably focused on a fairly high

7 strategic level. What I am going to be talking

8 about is much more tactical, and I like the comment

9 that was made earlier today about thinking globally

10 but acting locally. Perhaps it is the combination

11 of small steps that help us move along the path

12 towards easier registration and then uptake that

13 can help to incentivize industry.

14 What I would like to do is to briefly

15 review some aspects of the Subpart H accelerated

16 approval process and talk about the pros and cons

17 and where that may be helpful to industry; where it

18 may not be as helpful, as least in some of the

19 indications that we are thinking about; and then

20 lead to discussion of a particular example where

21 microbiologic surrogates could be of some value in

22 helping us at least think about ease of

150

1 registration.

2 \[Slide\]

3 The bottom line with surrogate endpoints,

4 of course, is that we want to consider them as a

5 substitute for a clinical endpoint and presumably

6 they should be easier to obtain; they ought to be

7 quicker to obtain. Combination should either make

8 trials quicker or less expensive or smaller. To do

9 that though, we have to be able to demonstrate I

10 believe two things, one of them, you can measure

11 the surrogate precisely and I think this goes to

12 the comments made earlier by the agency that

13 well-designed trials is really what matters here in

14 terms of being able to shorten them and make them

15 smaller. Obviously, there has to be prediction of

16 clinical outcome.

17 \[Slide\]

18 So, if you look at Subpart H, some of the

19 key features for accelerated approval are that,

20 number one, there has to be reasonable likelihood

21 to predict clinical benefit. You have to be able

22 to verify and describe clinical benefit, a key

151

1 component. In this case, there has to be a

2 clinical follow-up after the approval based on the

3 surrogate, a very important point that I will get

4 back to in a moment. I think appropriately, the

5 conditions for which this should be used are

6 limited to those that are considered to be either

7 serious or life-threatening.

8 \[Slide\]

9 So, if we look at some aspects of Subpart

10 H, the incentive to industry, I think their

11 particular value is in situations where there are

12 large patient populations and truly delayed

13 clinical endpoints. A good example is

14 hypertension, cholesterol and HIV, which has been

15 mentioned before. The surrogates in any of these

16 cases allow earlier patient evaluation, submission,

17 approval, but no reduction in overall development

18 cost because of the subsequent requirement for

19 clinical confirmation, on the other hand and in

20 particular, if the population to be treated is

21 large enough the cost can be offset by the earlier

22 approval.

152

1 On the other hand, if one is dealing with

2 smaller populations, and this is particularly the

3 case for some of the \"niche\" antimicrobials that

4 many of us considering given the drug resistance

5 aspect that we are all trying to focus on\--with

6 smaller populations you are obviously dealing with

7 more difficult accruals, higher development cost

8 because of that. The cost of demonstrating

9 clinical benefit still remains.

10 So, the cost of the earlier approval may

11 not be offset and, in fact, you may have to

12 over-enroll in the beginning in a trial that has to

13 be followed for years to ensure that one has the

14 appropriate follow-up. I will give an example of

15 that. Well, I will show my hand. The example I am

16 going to be talking about is osteomyelitis. If one

17 considers the long-term need for follow-up in

18 osteomyelitis, it is quite obvious that one has to

19 start off in this mind set at least with a very

20 large number of individuals to get the right

21 follow-up.

22 \[Slide\]

153

1 So, what about the other approaches? If I

2 say the traditional approach to registration, can

3 one find a way that surrogates can be used? Well,

4 there are some examples. They have been mentioned

5 already. In infectious diseases, urinary tract

6 infection, gonorrhea, pharyngitis where organisms

7 can be shown to be eliminated. But full validation

8 is also often impossible or not feasible for

9 certain situations where one might think a

10 surrogate could be of great use. So, one might be

11 in the VRE case superimposed on an ultimately fatal

12 disease like cancer, where you would like to be

13 able to demonstrate the value of eliminating the

14 VRE because one knows there is high attributable

15 mortality, but in the background of the enormous

16 amount of noise with an ultimately fatal disease it

17 might be difficult and, therefore, one might need

18 to have extraordinarily large populations.

19 Another example, and the one I am going to

20 talk about at more length, is osteomyelitis where

21 there is need for a very long follow-up. Obviously

22 more limited validation could provide enabling

154

1 incentive by reduction error in endpoint

2 measurements. That increases the power of the

3 study, leading to smaller study populations. These

4 study populations, being smaller, are more

5 feasible. IN some cases there can be a shorter

6 time to evaluation, in the case I mentioned about

7 osteomyelitis, and there could be major impact in

8 serious indications affecting smaller number of

9 patients.

10 \[Slide\]

11 Examples of Subpart H and examples of the

12 other approach, I could say\--accelerated approval

13 has been demonstrated with chronic viral

14 infections, particularly HIV. Whether this can be

15 applied to hepatitis C I think is yet to be

16 demonstrated. Tuberculosis has been mentioned.

17 Other antibacterial examples include Synercid for

18 VRE; Biaxin for MAC, but the big caveat there is

19 that mortality was actually higher at the higher

20 dose even though elimination of the microorganisms

21 was shown to be better. So, there are major

22 caveats. Then, ciprofloxaciin for the elimination

155

1 of anthrax where, in this case, an animal model is

2 used to substitute for the obvious inability to do

3 the clinical study.

4 Surrogate endpoints with limited

5 validation for traditional approvals could include

6 bacteremia. I believe we are going to hear much

7 more about that later. I am looking forward to

8 that discussion. Osteo. and prosthetic joint

9 infection, I will have more to say on that in a

10 moment. Then, let me just make a plug again, we

11 have heard this before, for having sensitive

12 isolates being used as surrogates for resistant

13 isolates, VSE, VRE, MSSA, MRSA. An example here is

14 that it might be difficult to be able to get enough

15 samples of, say, VRE such that a label ends up

16 saying enterococcus faecalis and then, in

17 parentheses one sees, vancomycin sensitive or

18 susceptibility organisms only, giving, as I have

19 heard from the field, some misinterpretation that

20 your drug may, in fact, not be adequate at all,

21 useful at all for VRE when, in fact, from all of

22 the scientific evidence, shortly of a fully-fledged

156

1 out clinical study, you have very strong evidence

2 that it can be very effective and very useful. So,

3 just a little plug on that with some very recent

4 experience in that field.

5 \[Slide\]

6 What does it take to make a good surrogate

7 marker? I think Tom Fleming had a very nice paper

8 about eight years ago. Interestingly though, it

9 did not talk about antimicrobials so that one could

10 apply the same teaching. I think here one is

11 dealing with a discussion of causation versus

12 correlation. The best surrogates obviously are

13 both necessary and sufficient in the causation of

14 disease. For microbiologic surrogates, at the very

15 least, one must satisfy Koch\'s postulates and then

16 go beyond that, in a sense, to demonstrate that not

17 only is the organism necessary and sufficient for

18 disease, but elimination of the organism is

19 necessary and sufficient for elimination of the

20 disease.

21 One of the problems, I would say, with

22 meningitis is that because of the significant

157

1 inflammatory cascades that get evoked with the

2 destruction of microorganisms one could, in fact,

3 get some peculiarity and de-linking of some of the

4 very strict causation-correlation coupling there.

5 Obviously, culture sample acquisition is

6 critical. You need to ensure sterile access to

7 otherwise sterile samples. That avoids false

8 positives. You need to avoid sampling error, on

9 the other hand, and you need to avoid false

10 negatives.

11 \[Slide\]

12 Let\'s go on to the example I would like to

13 give, which is osteomyelitis. One could think of

14 several different conditions for osteo.,

15 hematogenous, contiguous and prosthetic joint,

16 which one initially might not think would be a way

17 to develop a drug but there might be a way in here

18 that could be interesting to discuss.

19 Let\'s talk about hematogenous. The

20 initial culture is clean. False positives are

21 unlikely if one gets biopsy and culture results.

22 False negatives though are possible, particularly

158

1 on repeat evaluation, and one also has the

2 difficult problem, as has been mentioned before, of

3 being able to actually go in and get individuals to

4 get their culture results after therapy. Then

5 years later there is the potential for late

6 recurrence. This is obviously a difficult topic to

7 study.

8 For contiguous osteomyelitis, as was

9 discussed in part at the AC meeting on diabetic

10 foot, culture diagnosis is fraught with error, with

11 false-positive and false-negative sampling errors

12 and obviously, again, the potential for late

13 recurrence.

14 Prosthetic joint infection with adjacent

15 osteomyelitis has an initial culture that is clean.

16 It is an open surgery; you can get a biopsy. The

17 post-treatment culture is clean and standard of

18 care, particularly in the two-state procedure that

19 I will describe. There is infrequent late

20 recurrence if, and only if\--and here is the key

21 linkage\--if, and only if, the culture results are

22 negative. To me, this is the definition of a good

159

1 surrogate. Moreover, antibiotics are needed in

2 addition to surgery\--evidence I will show

3 briefly\--indicating that there is no or very weak

4 placebo effect so that there truly is a value of

5 the antimicrobial therapy.

6 \[Slide\]

7 Let\'s talk about the example of Staph.

8 aureus prosthetic joint infection. This is a

9 serious disease I think by any definition.

10 Clinical evaluation of cure requires prolonged

11 follow-up. It is difficult and costly to do the

12 study for a large number of patients if one is

13 going to power this adequately for long-term

14 follow-up.

15 \[Slide\]

16 The two-stage procedure that I mentioned

17 just briefly to describe it is that the infected

18 joint is removed, debrided. There is typically

19 adjacent osteomyelitis. In fact, individuals in

20 the study must have, by the description that I am

21 giving, adjacent osteomyelitis to get in the study.

22 There are optional local antibiotics that I would

160

1 call standard of care, similar to the debridement.

2 Importantly, systemic antibiotics are given for 4-6

3 weeks, after which time individuals go off

4 antibiotics for a period of anywhere from 203

5 months, at which time the surgeon goes back into

6 what should now be a clean field as is able, under

7 visual inspection, to look very carefully at the

8 disease state and do the appropriate biopsies. I

9 would argue one would see high specificity and

10 sensitivity. The results of culture reimplantation

11 currently is used as the indicator of therapeutic

12 success so that the surrogate, in fact, does become

13 the means by which the surgeon makes his or her

14 definition of cure.

15 \[Slide\]

16 Why is it that we can say that systemic

17 antibiotics have an effect? Why wouldn\'t surgery

18 alone be of value? I think the argument could be

19 made in two ways. One of them is that if you just

20 do the one-stage reimplantation where you do all

21 the surgical things but you don\'t allow the

22 antibiotics for a period of time and then a test of

161

1 cure there is a significant failure, double-digit

2 failure rate as opposed to a much lower failure

3 rate with the two-stage procedure, arguing that

4 systemic antibiotics do make difference.

5 I think an even more compelling case can

6 be seen with the other publication in Clinical

7 Orthopedics, where in the two-stage procedure

8 individuals had organisms that were either defined

9 as sensitive or resistant and the failure rate was

10 significantly higher in the resistant organisms

11 than in the sensitive organisms, I think strongly

12 arguing again for the importance of the systemic

13 antibiotics.

14 \[Slide\]

15 On the other side, the negative culture I

16 think is highly predictive by the evidence that I

17 show here, and I won\'t go through it in detail but

18 only to say that the negative predictive value,

19 including the possibility of reimplantation of a

20 new organism at the time of surgery, at worst, is a

21 negative predictive value of 97 percent at 5 years,

22 92-97 at 9 years, so extraordinarily long

162

1 follow-up.

2 \[Slide\]

3 In conclusion, I would say that

4 microbiologic surrogates for accelerated approval,

5 particularly with the Subpart H category, is

6 extremely helpful for large patient populations but

7 microbiologic surrogates with limited validation

8 could be used for traditional approval for the

9 smaller populations. That will enable companies to

10 try to develop drugs for these smaller \"niche\"

11 indications.

12 I would argue that a promising example

13 could be prosthetic joint infection. It is a

14 serious disease. It is difficult to enroll many

15 patients. Clinical test of cure is not a feasible

16 endpoint because it takes 5-9 years or more. There

17 is a clean, predictive microbiologic surrogate

18 endpoint that closely tracks with the ultimate

19 clinical endpoint, and there is a negligible

20 placebo effect. Thanks.

21 DR. EDWARDS: Thank you very much. I

22 think we will go right to Dr. Powers for the third

163

1 presentation.

2 FDA

3 DR. POWERS: Thanks, Jack. This is the

4 fun part, to get off the policy stuff, no offense

5 but we will do some science now.

6 \[Slide\]

7 So, what I wanted to talk about now is

8 sort of our perspective on what we have looked at

9 in terms of surrogate endpoints in clinical trials

10 in infectious diseases. As Dr. Goldberger said, we

11 are in a unique position in that we get to see this

12 information over a broad range of drug applications

13 and studies. I wanted to go through some of the

14 information we have actually seen.

15 You have already heard the definition but

16 I just want to reiterate what Dr. Kaplan gave you.

17 I am going to go over some of the strengths and

18 limitations and the utility of surrogate endpoints

19 in the overall drug development process; talk about

20 some of our regulatory considerations with the use

21 of surrogate endpoints; and then talk about some

22 issues and what we need to do to validate a

164

1 surrogate endpoint.

2 \[Slide\]

3 This doesn\'t show up very well but I just

4 wanted to bring up the issue again of what is

5 really important to patients. Patients don\'t come

6 in and say, \"I\'ve got this E. coli I want to get

7 rid of.\" Patients come in because they have

8 symptoms they want to get rid of, therefore, it is

9 important for us to actually look at how the

10 patients are doing.

11 This is a cartoon from the New Yorker that

12 has a gastroenterologist scope and this person is

13 saying, \"look, this is great; your endoscopy is

14 normal.\" You can\'t read this, but the patient says

15 has all these persisting complaints that are still

16 continuing. This is the situation we want to

17 avoid, getting a surrogate that is telling us you

18 ought to feel great when, in fact, the patient

19 feels crummy.

20 \[Slide\]

21 Just to go over these definitions again, a

22 clinical endpoint is a direct measure of how a

165

1 patient feels, functions or survives. That means

2 we are looking at things like mortality or

3 resolution of the symptoms of disease. The real

4 easy answer to what is a surrogate is that it is

5 anything other that measures how a patient feels,

6 functions or survives. So, that would be things

7 like laboratory measurements or a physical sign

8 used as a substituted for a clinical endpoint. We

9 use these all the time in clinical medicine.

10 Getting an X-ray on a person is really a surrogate

11 of how their pneumonia is doing. We are very

12 comfortable in their use in clinical practice, but

13 the surrogate endpoint by itself does not confer

14 direct clinical benefit to the patient. We all

15 know that we see patients, especially elderly

16 patients, in whom their pneumonia is clinically

17 resolved yet it takes their X-ray 6-8 weeks to get

18 better.

19 \[Slide\]

20 Some examples of surrogates that we use

21 all the time are measurements of the organism

22 itself, like culture or viral load; antigen

166

1 testing; X-rays; CAT scans; endoscopies; and even

2 histologic changes.

3 One of the other things we do is we get

4 into this issue of a surrogate of a surrogate.

5 When you start feeling comfortable with the initial

6 surrogate, you then start to drift even further

7 away from the patient, you look at changes in

8 cultures associated with histology. That is a

9 surrogate of a surrogate. Or, presence of an

10 organism on a catheter tip. I always tell medical

11 students and residents that I teach that catheters

12 don\'t get infected, people do, yet we refer to

13 catheter infections all the time. Finally, there

14 is the issue of elimination of organisms in a

15 population without the disease. Well, gee, if I

16 make the bug go away in uncomplicated UTI, can\'t I

17 just show that making the bug away in a person with

18 asymptomatic bacteria is the same thing? But that

19 ignores the host organism response and there also

20 may be some differences in the organisms that

21 affect those various populations.

22 \[Slide\]

167

1 As Dr. Kaplan brought up, surrogate

2 endpoints are a subset of biomarkers, and there is

3 an entire NIH conference on this with results that

4 were published in Clinical Pharmacology and

5 Therapeutics, in 2001. But biomarkers are very

6 useful for purposes other than measuring endpoints

7 in clinical trials and I think this is a real point

8 of confusion when we start talking especially about

9 culture data.

10 One of the things we have talked about in

11 the advisory committees is that we do want

12 microbiologic information to diagnose the disease

13 in question. So, using a biomarker as a diagnostic

14 tool increases the specificity of the diagnosis.

15 In October of 2003 we talked at great length about

16 this in acute bacterial sinusitis. When we look

17 through our new drug applications if you just took

18 all-comers your rate of actually getting bacterial

19 disease was somewhere around 35 percent. So, that

20 meant that in your trial you were enrolling 70

21 percent of the people that didn\'t have bacterial

22 disease.

168

1 Also, a biomarker can be a risk factor for

2 a disease. For instance, looking at the patient\'s

3 white blood cell count in a patient with a

4 hematologic malignancy gives you a clue that that

5 person is now at risk for a bacterial or a fungal

6 infection when they are neutropenic. Neutropenia

7 is not the disease however. Also, resolution of

8 neutropenia decreases the risk. That doesn\'t mean

9 the disease has gone away.

10 But I think the trickiest part here is

11 looking at biomarkers as an indicator of disease

12 prognosis and contrasting that to a biomarker as a

13 surrogate endpoint for the outcome of the disease

14 in question. I think we get these mixed up all the

15 time. For instance, HIV viral load and CD4 counts

16 in HIV, and the reference I put here is an NIH

17 consensus conference that was published in JAMA in

18 1993. So, 11 years ago these folks got together

19 and showed that HIV viral load is both a good

20 indicator of disease prognosis in HIV and a good

21 measure of treatment outcome. CD4 count is a good

22 measure of prognosis and is not a good measure of

169

1 treatment outcome because a number of people will

2 die even though their CD4 count rises on treatment,

3 and I think that is a really important distinction

4 to make.

5 \[Slide\]

6 Here is one way to look at this. When you

7 are looking at a biomarker as a prognostic

8 indicator what you are doing is you are taking all

9 the people that have a microbiologic failure and

10 all the people that have a microbiologic success,

11 and what you show is that the people who have

12 microbiologic failure are more likely to be a

13 clinical failure than the people who have

14 microbiologic success. What you just came up with

15 was a relative risk. That may or may not tell you

16 anything about the results of treatment. The

17 reason I point out this example is that, if you

18 look here, there are more clinical successes in

19 both of these arms than there are clinical

20 failures.

21 \[Slide\]

22 So, that gets us to the idea of what we

170

1 really want to do when we are evaluating a

2 biomarker as a surrogate endpoint. What we now

3 want to do is look at microbiologic outcomes and

4 outcomes means successes and failures, not just

5 failures. I think that is part of the issue, as

6 Dr. Kaplan referred to in this issue about otitis

7 media which is that that data has concentrated on

8 looking at failures and not at the kids who were

9 also successes. So, what we want to do here on the

10 other side is look at the clinical outcomes, both

11 successes and failures, and match up the concordant

12 patients who are micro. successes and clinical

13 successes or micro. failures and clinical failures

14 to the people who are also discordant in terms of

15 micro. successes, who still fail therapy, or kids

16 in whom the bug is still present but who get better

17 anyway.

18 \[Slide\]

19 Another way to visually represent this is

20 to look at this overlap. So, as Dr. Eisenstein

21 pointed out, you will never expect this to be 100

22 percent; 30 percent of people with severe

171

1 community-acquired pneumonia die no matter what

2 drug you give them. So, we are not expecting this

3 overlap to be 100 percent. But what do you do when

4 the micro. and clinical outcomes don\'t overlap by a

5 great amount, as Dr. Kaplan pointed out in

6 meningitis, where the microorganism is eradicated

7 and the person still does badly, and the otitis

8 media is the flip side where the organism is not

9 eradicated and the kids get better anyway.

10 \[Slide\]

11 So, what are the strengths of surrogate

12 endpoints? Well, they are reproducible. They are

13 standardized, at least in some cases where we have

14 standardized ways of culturing and detecting

15 susceptibilities. They are objective. They can be

16 dichotomous, they can give us a yes/no answer which

17 is easier to analyze; and they can lower the sample

18 size when the success rate is higher with the

19 microbiologic endpoint and, importantly, in chronic

20 diseases, as Dr. Eisenstein pointed out, we can

21 measure it earlier.

22 \[Slide\]

172

1 Let me just show you some information with

2 sample size. If we have a 90 percent success rate

3 here with a microbiologic endpoint, and let\'s just

4 take a 10 percent non-inferiority margin, you need

5 142 patients per arm. If the clinical endpoint

6 there were 70 percent instead of the micro. outcome

7 of 90 percent, you now need 330 patients per arm

8 with the same power and the same non-inferiority

9 margin. So, you can shrink the sample size

10 substantially if you can use a validated surrogate

11 endpoint in a trial. So, that is how a

12 microbiologic surrogate can help us in an

13 individual trial and, obviously, if you can use

14 those in a number of diseases you can shrink the

15 overall size of your drug development program.

16 \[Slide\]

17 Surrogate endpoints, even if they are not

18 validated, can still be helpful early in the

19 clinical development program. They can give us a

20 mechanism of understanding of how the drug actually

21 causes disease. They can give us some knowledge

22 about the clinical pharmacology of the drug or

173

1 guide us in dose selection, which we will talk

2 about at great length tomorrow. They can also give

3 us some proof of principle of efficacy in Phase 2

4 trials, and they can be a basis for selecting

5 compounds to go forward into Phase 3 testing, which

6 is a big part of the FDA\'s Critical Path about

7 trying to eliminate drugs that are not likely to

8 work.

9 Also, they can be helpful in later stages

10 of drug development by bringing treatment benefits

11 to patients earlier than with trials with clinical

12 outcomes when the surrogate endpoint precedes the

13 clinical endpoint by a significant amount of time,

14 such as in HIV infection, to contrast that from

15 acute otitis media where the clinical and the

16 surrogate endpoint will be measured at exactly the

17 same time.

18 \[Slide\]

19 But there is a payoff to this too, and

20 that is, that smaller trial may not provide you

21 enough data to analyze the safety of the drug. So,

22 the absence of an adverse event in a safety

174

1 database of 300 patients only rules out risk of

2 1/100 or one percent. How does that stack up if

3 you see one case of liver failure in those 330

4 patients? We know that the background rate of

5 liver failure in that population is one in a

6 million. So, when you see an issue like this that

7 pops up in a clinical trial\'s database, it really

8 is incumbent on you to study it in more detail

9 before you let the drug out onto the market. But

10 that is also dependent upon the risk-benefit of the

11 drug in question. If it is another drug for

12 sinusitis, you are probably a lot less tolerant of

13 a severe adverse event like liver failure.

14 Also, the benefits in terms of the

15 surrogate endpoint may overestimate the benefit on

16 the true endpoint. For instance, in prophylaxis

17 trials you may show a 90 percent rate of

18 decolonization which translates only into one

19 percent reduction in prevention of infection. That

20 still may be very useful because if that remains

21 constant we can still use that as a measure of drug

22 efficacy. In a treatment trial the rate of culture

175

1 negativity may overestimate the clinical cure rate.

2 I think that is something you can certainly handle,

3 but it wouldn\'t be something that you want

4 clinicians to say, \"well, because it\'s got a 90

5 percent microbiologic cure rate, that means 90

6 percent of my patients are going to get better.\"

7 \[Slide\]

8 But the real issue here for us is that the

9 surrogate endpoint may not predict clinical benefit

10 at all, and that is the really trick issue. Why

11 may it not predict clinical benefit? First of all,

12 the surrogate endpoint must be on the causal path

13 of disease and there is not a lot of question

14 related to this in infectious diseases. Clearly,

15 the microorganism is on the causal path that

16 actually gets you sick. But the real question here

17 is does the intervention which results in a

18 microbiologic effect, is it the only thing that

19 affects the clinical outcomes? Dr. Kaplan already

20 alluded that in meningitis it may not be in that

21 the majority of people who don\'t do well have

22 negative cultures, and there may be some other

176

1 reasons for that. So, the surrogate must capture

2 the full benefit of treatment effect and assumes no

3 other pathway of the mechanism of drug effect.

4 The important point here is that the

5 mechanism of action of the drug may be different

6 from the actual clinical effect of the drug. We

7 have had several meetings where we have been told

8 by consultants who come in to talk to us that the

9 only thing antimicrobials do is eradicate the bug.

10 \[Slide\]

11 We don\'t think that is true, and the data

12 that actually speaks to that talks about this,

13 there may be unmeasured benefits or unmeasured

14 harms that actually occur with the administration

15 of an antimicrobial, and the surrogate needs to

16 take that into account as well. This presumes that

17 our knowledge about how the drug works is actually

18 complete and in many cases it is not.

19 \[Slide\]

20 So, what are some of the unmeasured

21 benefits that may occur? Well, there may be

22 effects of the drug other than eradication. We

177

1 know that there are some inhibitory effects of

2 antimicrobials on organisms. We know that

3 bacteriocidal therapy is not necessary in many

4 infections. It certainly is in endocarditis and

5 meningitis, but no one has ever proven you need

6 bacteriocidal therapy in acute otitis media. And,

7 there may be direct effects of the antimicrobials

8 on the host immune system, and it is fascinating to

9 look this up when you see some of these articles

10 that actually talk about the effects of

11 antimicrobials on phagocytosis and the effects on

12 the immune system in general. So, there are direct

13 antimicrobial host interactions that may impact on

14 the outcome as well.

15 There may be unmeasured harms. As Dr.

16 Kaplan pointed out, lysis of organisms in

17 meningitis may actually have an inflammatory effect

18 that causes worse clinical outcomes. In

19 prophylaxis trials you may be able to get rid of

20 one organism, which then may be replaced by another

21 organism, which then goes on to cause disease as

22 well. Or, you may have other sources of infection,

178

1 other than that affected by a prophylactic drug.

2 For instance, we might sterilize somebody\'s urine

3 and then they go on to get an infection from their

4 skin, or somewhere else.

5 \[Slide\]

6 The other issues are how do we actually

7 measure the surrogate endpoint? Do we know

8 everything we think we know about these surrogates?

9 Dr. Eisenstein already brought up the issues about

10 false-positive and false-negative cultures that may

11 impact on that.

12 \[Slide\]

13 Finally, there is the issue about are

14 there problems with measuring the clinical

15 endpoint? I think especially in relationship to

16 otitis media, investigators have points out this

17 idea of the \"Pollyanna\" phenomenon for years.

18 However, the result of that has been, well, that

19 means we ought to just chuck the clinical endpoint.

20 Well, the thing we need to realize is that this is

21 the gold standard, the clinical endpoint. So, what

22 that means is that we need to find a better way of

179

1 measuring the clinical endpoint. When your gold

2 standard has a problem it doesn\'t mean you can

3 chuck it and just use the surrogate. You need to

4 find a better way of looking.

5 \[Slide\]

6 Here is one of the things we presented at

7 the October, 2003 advisory committee about

8 sinusitis. Although this relates to the

9 oseltamivir trial in influenza, you can see that

10 most people are going to be better in a short

11 period of time from their influenza. If you

12 measured the primary endpoint out here you would

13 never be able to show a difference between drugs or

14 between drug and placebo because you have gone out

15 beyond the time of the natural history of the

16 disease.

17 The other way I looked at this, I jokingly

18 said to one of our medical officers if we evaluated

19 mortality and we had 85-year follow-up, most of the

20 people in both arms of the trial are going to be

21 dead. That doesn\'t have anything to do with the

22 drug\'s effect. So, what we want to do is to look

180

1 at a clinical time point that is relevant to the

2 natural history of the disease. So, looking at

3 some of these self-resolving illnesses, we want to

4 go back either to a fixed time point that we know

5 is relevant to the disease or use a time to

6 resolution of symptoms, and that is what influenza

7 and traveler diarrhea trials did, they used time to

8 resolution of symptomatic disease.

9 \[Slide\]

10 Well, how do you go about looking at some

11 of this? Well, Dr. Kaplan showed you this idea of

12 sensitivity and specificity. If you do a 2 X 2

13 table that compares success with that surrogate

14 marker to clinical success, what you get here is 4

15 cells. These cells were the success of the

16 surrogate and success of the clinical outcome or

17 failure with the surrogate and failure with the

18 clinical outcome are where we have concordant

19 cells. On the other hand, we have these discordant

20 cells, here in red, where surrogate failure still

21 results in clinical success or there is clinical

22 failure even though there is success with the

181

1 surrogate.

2 What we really want to do then, if we look

3 up and down here, on the left, that is sensitivity.

4 If we look up and down here, on the right, that is

5 specificity. But what we really want to do is show

6 the relationship between sensitivity and

7 specificity, which we refer to as concordance or

8 correlation.

9 One way of doing this is actually do a

10 kappa coefficient of correlation, which is another

11 way for a dichotomous variable to actually look at

12 this concordance rate. What makes a good kappa?

13 Well, that is a judgment call obviously, but at

14 least one article in the literature that reviews

15 all this suggests that a kappa of less than 0.4 is

16 marginal or no agreement; a kappa of between 0.4

17 and 0.75 is good agreement; and a kappa of greater

18 than 0.75 is excellent agreement.

19 \[Slide\]

20 What I did, I took these kappas and I

21 turned them into lines so the slope of the line

22 would be equal to what that kappa is. A perfect

182

1 correlation slope would be a slope of 1. So, if

2 you had 80 percent success with the surrogate, you

3 would get 80 percent success in the clinical

4 outcome as well. We know that is not going to

5 happen, especially in severe diseases. There are

6 going to be people who die, no matter what drug

7 they get. So, we are going to see something less

8 than 1 in terms of the correlations of these

9 surrogate outcomes and the clinical outcomes.

10 \[Slide\]

11 What we actually did is to go back and we

12 reviewed some of this information for some of the

13 diseases where we could pool the information on how

14 well did those surrogate outcomes correlate with

15 clinical outcomes. We reviewed 12 clinical trials

16 on acute otitis media that were done with

17 tympanocentesis and came up with a combination

18 kappa of 0.37 for those 12 trials.

19 We also took that Lebel trial that Dr.

20 Kaplan showed and did the same kind of correlation

21 and showed that for acute bacterial meningitis the

22 kappa was 0.14, almost down to the level of a coin

183

1 flip.

2 Again, these are for different reasons in

3 these different diseases. In acute otitis media

4 the discordant part is people in whom the culture

5 is still positive but they are getting better

6 anyway. In acute bacterial meningitis it is the

7 exact opposite where the culture is negative but

8 the people are still having sequelae anyway.

9 \[Slide\]

10 Let me just show you another example.

11 Here are the 12 trials where we looked at the acute

12 otitis media outcomes. It is very interesting that

13 they all kind of group down here, depending upon

14 which drugs you look at, but there is a good bit of

15 variability from 0.14 to 0.42. But look what

16 happens in the one trial in which the surrogate

17 outcome and the clinical outcome were measured at

18 the same time. In the rest of these trials what

19 you saw is that the surrogate was measured on day

20 4-6 on therapy and, yet, the clinical outcome was

21 measured way out here, somewhere beyond 10 days,

22 which we know is beyond the natural history of the

184

1 resolution of otitis media. But this is only one

2 trial where this was done. Is this because this

3 drug worked better? Is it because the surrogate

4 was better for that drug? Or, is it because the

5 timing of the surrogate was done in a more relevant

6 way? We can\'t tell because it is the only trial

7 that was done that way so we still have unanswered

8 questions here.

9 \[Slide\]

10 What happens though if that correlation is

11 different for drug A versus drug B? As I showed

12 you here, it is very different for all these

13 different drugs in acute otitis media. So, if you

14 have a difference between drug A and drug B, what

15 happens is that when you look at the clinical

16 outcomes or the surrogate outcomes here, it appears

17 that drug B is actually superior to drug A. But if

18 those lines don\'t line up, what should happen over

19 here is that on the true clinical outcome drug A is

20 actually superior to drug B. So, what happened is

21 you got told the exactly wrong thing by using that

22 surrogate outcome.

185

1 So, you can see that these are some of the

2 issues that we have to deal with when we are

3 talking about validating surrogate endpoints and

4 the potential for them to tell us the wrong thing,

5 and why it is important to validate the surrogate

6 ahead of time.

7 \[Slide\]

8 In traditional approvals that are based on

9 surrogate endpoints we can only do this,

10 regulatory-wise, where the endpoint is already

11 validated to predict a clinical endpoint. We can

12 do this under Subpart H in accelerated approval but

13 that only applies to serious and life-threatening

14 diseases. Therefore, acute exacerbations of

15 chronic bronchitis, acute bacterial sinusitis and

16 acute otitis media would not really qualify under

17 Subpart H. It also requires confirmatory

18 post-approval trials based on a clinical endpoint.

19 \[Slide\]

20 But here is part of the issue, when you do

21 a trial like HIV, what usually happens is you check

22 the viral load at 24 weeks and then you follow

186

1 those same patients, and they continue on in the

2 trial and you get longer-term follow-up. What do

3 you do in a trial of acute bacterial disease where

4 the clinical and the surrogate endpoint are

5 measured and these people are cured? There is

6 nobody to follow. So, this is the situation like

7 in clearance of VRE bacteremia with Synercid. How

8 does one go on and validate that surrogate endpoint

9 which is a requirement under Subpart H? It then

10 requires you to initiate a second trial.

11 So, what we are getting told is it was

12 really tough for us to do this first trial. Then

13 we have to ask the question how are you going to

14 get the second trial to confirm that surrogate

15 endpoint when it was so difficult to do it the

16 first time, and will we run into logistical

17 problems because once the drug is on the market

18 people won\'t be willing to randomize patients

19 anymore? Accelerated approval requires a

20 confirmatory trial, and we would like to have some

21 discussion today about the logistics of doing that.

22 Finally, validation of the surrogate

187

1 requires a meta-analysis correlating all of these

2 studies that we can possibly look at, which we have

3 tried to do at least for some of these diseases,

4 and even if it correlates it still needs to capture

5 the full treatment effect.

6 \[Slide\]

7 This is one of my favorite quotes. I know

8 John Rex has seen this because I showed this a

9 couple of months ago, but I think it really puts

10 this in place: It is far better to have an

11 approximate answer to the right question which is

12 often vague, than an exact answer to the wrong

13 question which can always be made precise. So, I

14 will stop there and turn it back to you, Jack.

15 Discussion

16 DR. EDWARDS: Thank you very much, John.

17 Those were three very nice presentations. Thank

18 you very much. We are behind schedule. What I

19 think I would like to do is begin the discussion at

20 this point, and then we are going to break for

21 lunch in a few minutes and we will finish the

22 discussion after lunch. So, let us get started, if

188

1 we could. George?

2 DR. DRUSANO: I know that Dr. Powers was

3 at the University of Maryland for a while in the

4 infectious disease section, and he probably

5 remembers Alice Kaplan in the trauma unit. One of

6 my earliest memories was taking care of a trauma

7 patient and in the bad old days they did instant

8 autopsy programs. So, what we found was this

9 patient, with gram-negative pneumonia who got

10 treated with very aggressive antimicrobial therapy.

11 The patient died\--it was pseudomonas\--because

12 exotoxin A had rotted out his lungs. He went to

13 autopsy; had absolutely sterile lungs. The drug

14 did what it was supposed to do.

15 I recognize some of the issues that I

16 think have been very clearly and nicely presented

17 by Dr. Powers. I guess my view is there is only so

18 much that you can ask out of an anti-infective,

19 which is to kill the bug. Now, it is true

20 macrolides may have some immunomodulatory

21 activities but if you are explaining variants, how

22 much of the variants\' outcome is explained by the

189

1 antimicrobial effect versus the immunomodulatory

2 effect? When we talk about the issues of using a

3 clinical endpoint, oftentimes we are missing

4 information. For instance, I think it was of great

5 interest that the neuraminidase inhibitor trial was

6 shown. That was Fred Hayden\'s study and in that

7 they showed very nicely that the clinical

8 endpoints, how you felt, was driven by basically by

9 how much IL6 you had in your plasma.

10 All of this just goes to one point, which

11 is that there are certain issues with clinical

12 endpoints, one of which is where in the clinical

13 course of your disease do you enter the treatment

14 trial and initiate therapy? Consequently, you may

15 have already had too much exotoxin A and there is

16 nothing other than killing the bug that the drug is

17 going to do. So, that is one thing.

18 Another thing is that you may have a

19 particular virulent strain of bug of an influenza

20 virus that you react to quite well and get a lot of

21 IL6. The best neuraminidase inhibitor in the world

22 is not going to make you feel better.

190

1 So, while there are clear-cut problems

2 with just uncritically accepting a microbiologic

3 endpoint, it is also I think important to look at

4 the issues and the sources of variants in clinical

5 endpoints. We make things gold standard by

6 acclamation. We do not make things gold standard

7 because we know from on high. I think one of the

8 first things that needs to be done in this area is

9 to look at the sources of variability and to make a

10 reasoned judgment about when we measure and what is

11 important to us.

12 DR. EDWARDS: Do you want to take that on

13 or do you want to have lunch first?

14 DR. POWERS: Let me give a parting phrase

15 before we head off to eat. That person that died

16 of pseudomonas pneumonia can\'t answer the question

17 of did the drug do what he thought it was going to

18 do for him. I think this gets back to a really

19 important point. Let me use an example from

20 October of 2001. You can give all the drugs you

21 want to somebody with inhalational anthrax and you

22 can make the Bacillus anthracis go away and those

191

1 people die. We cannot say those drugs are

2 effective in the treatment of pulmonary

3 inhalational anthrax.

4 So, I think we have to disabuse ourselves

5 of the notion that it is okay to have a drug just

6 to eradicate the bug when everybody dies anyway. I

7 remember when Mike Ryan was teaching me, back at

8 the University of Virginia, he had this one quote I

9 just love, and he said that is like rearranging the

10 deck chairs on the Titanic. You make all this

11 stuff look good\--we only do this in the ICU, right?

12 Nobody dies without a sodium that is 140 on the

13 button, but the question is what does that do for

14 patients? I would offer that by acclamation the

15 clinical endpoint is the gold standard, and it is

16 by acclamation of the patients and that is really

17 whom we are trying to help.

18 DR. DRUSANO: I can\'t let that one pass.

19 Yes, everything that we do is for the patient but

20 that is the wrong issue. What we are trying to

21 answer, I think and, you guys are the regulatory

22 folks so I don\'t want to get too strong on this\--

192

1 \[Laughter\]

2 \--but the idea is why are we approving an

3 agent? An agent has to be safe and effective, and

4 there is no issue that there will be times\--and I

5 think your mention of inhalational anthrax in much

6 the same way that I mentioned the pseudomonas

7 patient on purpose\--there is no drug that is ever

8 going to salvage those patients. Okay? If I were

9 sick, I would want the drug to salvage me but that

10 is not the right question I would put forth to you

11 for approval of the drug. The only thing you can

12 ask of the drug is not to salvage the patient but

13 to allow the patient to be salvaged if they have

14 entered treatment at a point in their clinical

15 course when they can be salvaged. That is the

16 issue, at least in my view. As a clinician you

17 always know that there is going to be the guy for

18 whom you do everything right, you sterilize him,

19 but for toxin production, for elaboration of TNF,

20 for whatever reason, it is too late. That is not

21 an indictment of the drug; it is an indictment of

22 the pathogenic process.

193

1 DR. POWERS: Before we break for lunch,

2 and I am glad there is so much discussion, in a

3 randomized trial the hope is that those things

4 would even themselves out between the arms of the

5 trial. What we are doing is we are comparing the

6 two drugs and how they function, and if those

7 people die from all those other reasons in both

8 arms equally, that is what we are looking for.

9 Does randomization work perfectly? No. But does

10 that mean you chuck out the baby with the bath

11 water and stop randomizing? That is probably not a

12 good idea either. So, I think the idea is that we

13 know those things occur but it is in a randomized

14 trial that we are trying to even out all those

15 things except for differences between the drugs.

16 DR. DRUSANO: But the issue is not

17 randomization. The issue is endpoints and what can

18 you expect of the drug. It has nothing to do with

19 randomization. You are absolutely right about

20 that. The question becomes what can you ask of the

21 drug, and except in the rare instances, like

22 macrolides where you have some immunomodulatory

194

1 effect, the majority of the variants of outcome is

2 explained by the impact of the drug administration

3 on the number of bacteria that are there.

4 Sometimes, you are absolutely right, it can even go

5 the wrong way. If you get a burst of endotoxin

6 because you have lysed too many organisms, you may

7 get yourself into trouble. But those are the

8 exceptions rather than the rule, and I think it is

9 worth really examining what question it is that we

10 want to answer for the drug.

11 DR. EDWARDS: At this point we are going

12 to break. We should be back at two o\'clock.

13 \[Whereupon, at proceedings were recessed

14 for lunch, to resume at 2:00 p.m.\]

195

1 A F T E R O O N P R O C E E D I N G S

2 DR. EDWARDS: Dr. Drusano had mentioned

3 some points that Dr. Powers was responding to and

4 we had to end in the middle of that discussion. I

5 had to cut Tom Fleming off at the time we stopped

6 and I apologize Tom for that, and I promised him

7 that I would let him begin this part of the

8 discussion with some comments he wanted to make

9 that were directly related to the interchange

10 between John and Dr. Drusano. So, please, Tom.

11 DR. FLEMING: Thanks, John. I think the

12 presentations this morning were really excellent in

13 laying out a lot of the complexities that we face

14 when we are looking at use of potential surrogate

15 endpoints for assessing clinical endpoints and the

16 effects on clinical endpoints. There is a lot that

17 needs to be said and I would like to say but I

18 would like to just begin by following up on

19 something George was saying before the break.

20 In my words, I think it was something to

21 the effect that a drugs should be evaluated on the

22 basis of whether they achieve the anticipated

196

1 biological effect on the anticipated mechanism.

2 Just to look at a few examples in chronic

3 granulomatous disease, gamma interferon was

4 anticipated to affect bacterial killing superoxide

5 production. It didn\'t, yet it did provide the

6 clinical benefit of reducing the risk of recurrent

7 serious infections.

8 We heard reference to the setting of post

9 MI arrhythmias which are a known risk factor for

10 sudden deaths, and anti-arrhythmics provide the

11 intended beneficial effect on suppressing

12 arrhythmias and were used by half a million

13 Americans a year until a trial showed that they

14 tripled the death rate. As we had reference this

15 morning to AIDS patients with MIA bacteremia,

16 increasing clarithromycin doses led to the intended

17 five-fold reduction in bacterial load and, yet,

18 also led to a five-fold increase in mortality.

19 So, if I look at these measures and say

20 what were the intended effects, I think we should

21 use the anti-arrhythmic drugs and we should use

22 high doses of clarithromycin and we shouldn\'t use

197

1 gamma interferon. You would get the opposite

2 conclusions if I were the patient saying what is it

3 that I really care about, and do these agents

4 provide me with what I really care about, in which

5 case I would be used gamma interferon for CGD. I

6 would be using lower doses of clarithromycin and I

7 wouldn\'t be using ecanide and flecanide to suppress

8 my arrhythmias.

9 So, my sense about this is I think you are

10 absolutely right in Phase 1 and 2 trials. I think

11 the intention of those studies should be to

12 establish plausibility of efficacy in a manner that

13 can be done in a timely, doable trial. And, one of

14 the best ways of doing that is to establish whether

15 or not we achieve the intended biological effect on

16 these markers. Absolutely.

17 But once you get to Phase 3, isn\'t it

18 important from the patient perspective to

19 ultimately know whether these agents provide the

20 actual tangible clinical benefit? So, in part of

21 the answer is does the drug achieve the targeted

22 biological effect? That is part of it. But the

198

1 other part of it is, is that effect integral to

2 achieving clinical benefit? In a severe sepsis

3 patient with multiple organ failure I might achieve

4 one element of what would be beneficial, but in the

5 myriad of complexities of what this patient is

6 facing that might not translate to any improvement

7 in 28-day survival.

8 The other critical thing is does the drug

9 affect other and often unanticipated or at least

10 unexpected mechanisms that influence clinical

11 outcomes that could be either positive or negative?

12 If positive, I could be underestimating effects.

13 If negative, by releasing too much endotoxin, as

14 you were saying, I could be achieving unintended

15 negative effects. So ultimately I think there is a

16 great deal of appropriateness to stating if we are

17 developing agents we need to try, as best possible,

18 to understand mechanisms of action of the disease

19 process and how it influences the outcome, and what

20 are the types of interventions that could impact

21 those markers and, mediated through that, plausibly

22 achieve clinical benefit. Phase 2 studies are an

199

1 ideal setting to see whether that is the case.

2 But ultimately, if I am going to market

3 this product for clinical care in a non-research

4 setting, I want to know whether it benefits the

5 patients. So, I want to do a trial that

6 establishes direct evidence about clinical benefit,

7 and in that trial obtain additional evidence about

8 whether or not I achieved the intended biological

9 effects.

10 DR. DRUSANO: We agree about 99 percent of

11 the way, Tom. Let\'s explore the other one percent.

12 The examples that you gave are excellent and clear.

13 The difference is two words, Koch\'s postulates.

14 The difference between what we have shown before

15 and what we are looking at now is we don\'t have a

16 perfect understanding of what goes on with

17 anti-infectives and organisms and pathogenesis and

18 the disease process, but we have a deeper

19 understanding of what was going on and the linkages

20 to outcome in this particular circumstance relative

21 to arrhythmias, relative to CGD disease and many of

22 the other examples that you gave. So, I think

200

1 there is a difference in kind, not a difference in

2 degree here. I think anti-infectives really are

3 different in kind. So, that is number one.

4 Number two, nobody, and certainly not me,

5 is saying throw away the clinical endpoint. The

6 issue is not whether or not you throw it away, it

7 is what is the place where you get the cleanest

8 inferences and, for a variety of reasons, many of

9 the times when we do clinical studies people fail

10 with sterile lungs and there is no way in God\'s

11 green earth is going to salvage that patient.

12 Would you want to be making the mistake of saying

13 that a drug doesn\'t work for what it was intended

14 to do, which is kill microorganisms, when what it

15 is failing at is its inability to salvage a patient

16 who has gone beyond its ability to do that?

17 So, I think that I would agree

18 whole-heartedly, you do need to look at clinical

19 endpoints because we don\'t know perfectly well

20 everything. There certainly are unanticipated

21 effects. There certainly are unanticipated

22 toxicities. I think the clarithromycin story is

201

1 certainly one of those. So, nobody is saying throw

2 it away. The issue is how to make the best

3 inferences on whether a drug is doing what you want

4 it to do. There will always be times when we are

5 wrong because that is the human condition. But I

6 can only speak for myself and if I was going to be

7 making the choices for my disease or my family\'s

8 disease, I would want to know what it does for the

9 bacteria.

10 DR. FLEMING: And I would add that I would

11 ultimately like to know what it does in terms of

12 the clinical conditions that are the ultimate

13 driving factor to my taking the intervention.

14 If I hear what I hear you saying

15 correctly, George, I would agree with it. That is,

16 not all settings are the same and in some settings

17 the level of our understanding about the biological

18 processes through which the disease process

19 influences clinical endpoints and the nature of our

20 interventions and the plausibility that it would

21 have unintended effects, these are critical and the

22 better we understand those issues, the more likely

202

1 it is that the effects on the markers will reliably

2 predict effects on the clinical endpoints.

3 I would only caution that in every

4 clinical setting in which I work with

5 investigators, because of their particular

6 knowledge about that clinical setting, I get a

7 sense from them that they think their setting is

8 different. In their setting, unlike all the other

9 experiences that we have had, we will do better in

10 this particular setting. I would just caution that

11 even if we have a pretty good idea that we have to

12 achieve decolonization in order to prevent serious

13 bacteremia and clinical infection, and we think it

14 is decolonization of the gut, maybe it is, in fact,

15 a broader effect that is necessary. Maybe I am

16 mismeasuring it. Maybe it is a more durable

17 effect. There are many things that make this

18 complicated. Even in a setting where I feel it is

19 perfectly clear, such as mother to child

20 transmission of HIV, what am I trying to do? I am

21 trying to prevent the child from becoming infected

22 with HIV. It is that simple. That is only a

203

1 surrogate for subsequent AIDS-defining events and

2 death but it is that simple. It has to be right,

3 unless what I am doing in a developing country

4 setting is offering formula feeding instead of

5 breast feeding to reduce breast feeding

6 transmission and, thereby introducing impurities

7 from the water supply and introducing infection

8 through that manner. So, even in a simple case

9 like that I can be creating a net effect that isn\'t

10 what I expect.

11 DR. DRUSANO: Tom, I would agree with

12 that, and I think the issue is you never get it all

13 the way right. You never explain 100 percent of

14 the variance and nobody is saying throw away

15 clinical endpoints. It is how you draw your major

16 inferences on whether the drug is working or not.

17 DR. EDWARDS: David?

18 DR. SHLAES: Thanks. If I could just try

19 and go back to the specific example that was raised

20 by Barry because I think there are a lot of

21 problems there because basically it is current

22 medical practice; there is good data to suggest

204

1 that there is a correlation between sterilization

2 and success of reimplantation of a new prosthetic

3 joint. What I would like to do is go beyond that

4 and take what you said and what Dr. Goldberger said

5 and put them together and ask if one successfully

6 carried out a small trial using bacteriological

7 endpoints with an ultimate follow-up for clinical

8 success in prosthetic joints, would one also then

9 get approval for treatment of osteomyelitis and

10 septic arthritis? Because that would be a way to

11 do a reasonably short trial in a serious disease

12 with the complication of a prosthesis present, but

13 then you might be able to extrapolate to some of

14 these other conditions. I wonder how the FDA would

15 feel about something like that.

16 DR. EDWARDS: Dr. Powers?

17 DR. POWERS: I think this gets to our

18 first question up there, David. That is, in what

19 situations and in what kind of diseases would

20 surrogate endpoints be most useful? That gets back

21 to the Subpart H discussion of serious and

22 life-threatening diseases and biological

205

1 plausibility. But it gets also to that last issue

2 on there and, Barry, you can comment on this, if

3 you are going to accept that surrogate endpoint

4 under Subpart H, much like HIV trials, you have to

5 continue to follow those people and see what

6 happens to them clinically. You can\'t just wave

7 goodbye to them and say, well, we have accepted

8 this. That may be different for a chronic

9 osteomyelitis model where you could continue to

10 follow those people as opposed to other diseases

11 where a person is cured and that is it. That is

12 why we wanted to get to these discussions.

13 DR. SHLAES: In what Barry presented he

14 pointed out that that is exactly what he would do

15 so you would get the bacteriological result at a

16 certain point, and then there was the follow-up

17 which essentially was the reimplantation X months

18 later, which would be the final result. Or, you

19 could even wait several months beyond the

20 reimplantation for your endpoint. But I think what

21 he proposed was exactly what you are talking about.

22 So, my question is, (a) do you buy it based on the

206

1 data and, (b) if you buy it, would you extrapolate

2 then to some of the other indications which are

3 studies which nobody does anymore which people

4 would like to do. People would like to have

5 indications for treatment of osteomyelitis and

6 septic arthritis and this might be a reasonable way

7 of getting there. That is all I am asking.

8 DR. POWERS: Well, let me put it this way,

9 as Jack had said earlier, we are not setting policy

10 at this meeting; we are just trying to discuss

11 this. So, can\'t say do we buy it or not at this

12 particular meeting. We are just trying to get

13 these points out on the table to discuss them.

14 The other issue is, and I think maybe we

15 will ask Dr. Fleming to comment on this\--you know,

16 I have a bunch of other slides that I didn\'t

17 include because of time, but just because a

18 surrogate works in one disease and one population

19 does not mean you can extrapolate it to another

20 population. I think that again requires a separate

21 validation. I think we sort of touched on that in

22 the asymptomatic bacteria versus the uncomplicated

207

1 UTI situation. So, I think the question of

2 extrapolating to other people gets to be a sticky

3 one.

4 DR. EDWARDS: Yes, Bill?

5 DR. CRAIG: John, in your analysis where

6 you had the very slow slopes in acute otitis media,

7 how did age impact that? Were those mostly studies

8 done where the average age was older, where

9 placebos worked just as well as the drug and that

10 is why we had the very low values? The one that

11 did start to show some correlation was done in

12 younger kids where, I guess, most of the studies

13 would suggest antibiotics may have a role?

14 DR. POWERS: You have a good point, Bill.

15 That is, is that poor correlation something that

16 has to do with the drug, something that has to do

17 with it being a poor marker, or does it have to do

18 with the natural history of the disease? You saw

19 all the data we have. That is it; that is all I

20 can tell you. Those trials run the range of ages

21 of patients, etc., and one of the things that we

22 want to see, obviously, that I talked about at the

208

1 end is a meta-analysis of effects across all those

2 different populations. You are asking the exact

3 question about can we extrapolate from one

4 population to another and the answer is we don\'t

5 know because we don\'t have the data to be able to

6 cut it that fine and to be able to look. Would

7 there be some better correlations in kids under the

8 age of two? Would there be better correlations if

9 we measured the clinical and the microbiologic

10 endpoint at the same time? Well, I showed you one

11 hint that that may be the case but we don\'t know.

12 So, I think this also gets back to the

13 issue of the FDA\'s Critical Path. That is, what

14 that Critical Path says is that we need to develop

15 better tools, and this is all about tomorrow,

16 developing tools, and we can\'t do that. We need

17 your help in order to develop those tools to try to

18 streamline the drug development process. So, we

19 have done about all we can in looking at what is

20 already out there. Is there a better way of doing

21 it? We hope you guys will build a better mouse

22 trap and come in and show it to us.

209

1 DR. EDWARDS: Other questions? George?

2 DR. TALBOT: Obviously, one of the issues

3 with this whole discussion is the fact that there

4 are some extremely substantive and relevant

5 concerns about using surrogate endpoints broadly,

6 as Tom has pointed out and John, related to, for

7 example, host organism response in a certain

8 setting that can\'t be predicted. I guess, as a

9 broad framework for this and related to your

10 questions, I would urge that progress in this area

11 not be aborted because there can\'t be agreement on

12 a universal philosophy for using surrogate markers.

13 What I would suggest is that if we could even agree

14 on one setting, such as the prosthetic joint one

15 where it seems reasonable to expect that

16 eradication of the bug would be beneficial and

17 intended, and where it also seems unlikely that

18 there would be substantive host-organism

19 interaction related to inflammatory cascades, and

20 so forth, and where there are also some data\--let\'s

21 go for that and at least try and get movement on

22 that.

210

1 With that in mind, I would say this seems

2 quite logical. There is a precedent actually for

3 this. I believe early or part way through the

4 Synercid program a very similar study design was

5 proposed in terms of prosthetic joint infection

6 using the culture result at the reimplantation or

7 post-antibiotic phase as a clinical surrogate

8 endpoint that would be confirmed ultimately by a

9 late clinical follow-up. So, the idea has been

10 around and I think it really deserves a lot of

11 attention. So, I would propose that that be a

12 specific indication that we try to move forward.

13 The residual question is where would that

14 fit in the context of an entire drug development

15 program? Because there is not only the issue of

16 host organism response specific to an indication,

17 there also is a question of do you have an adequate

18 safety database anyway for all the other things

19 that can go wrong with a drug? So, in thinking

20 about that part of the framework, I would say that

21 you could use, for example, this surrogate endpoint

22 for this indication provided that the size of your

211

1 safety database in other indications is adequate,

2 greater than X thousand patients, 100 patients, or

3 what-have-you. If you meet that criteria and if

4 you demonstrated efficacy in other indications, and

5 if you know you have tissue concentrations, then

6 you could go for this as a reasonable indication

7 for a surrogate marker. It would have to meet all

8 those criteria.

9 DR. GOLDBERGER: I want to agree with

10 George. You wouldn\'t be thinking in any case of

11 the design that was talked about for the joint

12 prosthesis as a study that would certainly be there

13 just by itself and that would be the entire

14 submission. I think when you think of it, as

15 George just said, in the context of perhaps a

16 couple of other indications where you can see that

17 the drug was successful in treating serious

18 illness, then I think the extrapolation which,

19 truthfully, in the case of the prosthetic joint is

20 that really that big a leap in any case but, even

21 if it were somewhat of a leap, when it is

22 buttressed by this additional data in serious

212

1 illness, I think that is an extrapolation that is

2 reasonable to make. I think it is always important

3 as we start thinking about these issues to think of

4 the package, the several studies that would come in

5 together and how they could naturally reinforce one

6 another and give people confidence that if you use

7 something unusual as an endpoint in one study, you

8 have other data to make you more comfortable with

9 it.

10 DR. EDWARDS: George?

11 DR. DRUSANO: A lot of what I am hearing

12 harkens back to a little bit earlier this morning

13 when people were talking about how much uncertainty

14 can you bear. You know, everything that we have

15 heard today from Dr. Fleming, from the FDA, Dr.

16 Powers\--everybody is really centered around how

17 much certainty can we bear; how much uncertainty

18 can we bear. Really, I think it is possible in

19 certain defined circumstances where the severity is

20 high, where it is relatively rare, that you might

21 want to bear a little bit more uncertainty to be

22 able to study this in a reasonable manner and use a

213

1 surrogate endpoint\--not every time. If you can

2 study it better and you can get lots of them and

3 get microbiologic and clinical, that is great.

4 But I think we have to focus on where this

5 thing fits in. Tom, I think quite appropriately,

6 said, hey, if you are talking about Phase 1/2, I am

7 your man. It is not too much of a leap from that

8 to say, hey, are we talking about this very severe

9 area where things are relatively rare? It might be

10 worthwhile then to consider what we are talking

11 about in that context.

12 DR. POWERS: I think that is getting back

13 to our questions again. Rather than agreeing is

14 this appropriate for prosthetic joint infection,

15 what we wanted to do was come up with some

16 characteristics of where this would most likely

17 fit. George, you have already enumerated one which

18 is already in Subpart H, and that is serious and

19 life-threatening diseases where perhaps there are

20 not as many therapies out there. So, we already

21 know that under the Subpart H regulations. The

22 question is what other characteristics of a disease

214

1 would people want to see?

2 So, the question I certainly have when I

3 think about this is, you know, it seems to fit more

4 with chronic diseases like HIV where you can keep

5 following the people over time. The question we

6 have run up against is what happens when the people

7 are either cured or dead and you need to go do that

8 second confirmatory trial. If you told us how

9 tough it was to do the first one, how are you going

10 to do the second one to be able to do that

11 confirmation? So, there seems to be a difference

12 between the chronic illnesses where this would seem

13 to apply more easily at least versus the acute

14 illnesses, and do people see any differences

15 between those?

16 DR. DRUSANO: Absolutely.

17 DR. POWERS: Let me ask another question.

18 Bill, you brought up a really good question, and

19 that is are we doing this the best way we can? So,

20 let\'s take otitis media as an example. Do we want

21 to see another double tympanocentesis trial with a

22 tap at day 4-6 and a clinical endpoint getting

215

1 measured 28 days out? If not, how are we going to

2 get the information that we need to do this in a

3 better way?

4 DR. CRAIG: Well, as I said before I think

5 most of the data, at least that I have seen,

6 suggests that children under two are the ones where

7 antibiotics have their role. So, clearly, I think

8 if you wanted to try and show the clinical success

9 and possibly differences from so-called approved

10 drugs that are out there, that would be the

11 population to look at. If you keep adding in older

12 kids for which placebos work just as well you

13 dilute out the effect that you are going to see and

14 you end up with equivalence when really it might

15 have been a superior drug.

16 Now, you probably can, possibly by using

17 double taps and then still looking at clinical, be

18 able to reduce your numbers because you are down

19 where it can be complete eradication to where you

20 don\'t get any eradication. On the other hand, you

21 know the placebos will bring it on up to 60 percent

22 response, 70 percent response even when the

216

1 organism is not eliminated. As a result, you are

2 looking at differences that are much smaller and

3 much harder to see differences in.

4 So, I think you need to get to the

5 patients that really need the antibiotics. I think

6 that is why we have a problem with AECB, that is,

7 clearly identifying who those patients are. We

8 think purulence in the sputum is very important but

9 that still doesn\'t necessarily identify those from

10 the data that is out there right now. So, I think

11 that is a much harder disease to look at.

12 Sinusitis\--I don\'t know how right now to

13 be able to identify the people for which

14 antibiotics are really going to work. Hopefully,

15 some of the tap studies that they are doing with

16 catheters, in that situation, will give us more

17 data on the efficacy of antibiotics and let us know

18 how much spontaneous response occurs because that

19 is the other part that you need in the equation to

20 be able to look at these things rationally to know,

21 if someone is given a placebo, how much of the

22 organism is going to be eliminated, and those

217

1 things. We have that kind of data for otitis.

2 There is not a lot of reason for me to think that

3 it is going to be markedly different in sinusitis

4 but I think we need the data to be sure.

5 DR. POWERS: It sounds like what you are

6 saying is that we need two pieces of information.

7 We need to know how these people would do with

8 placebo from both the bacteriologic and the

9 clinical point of view so we can do that

10 correlation in the people who don\'t get drugs, and

11 that would seem to apply to otitis, AECB and to

12 sinusitis as well, in all three situations.

13 DR. CRAIG: Although I think I would have

14 difficulty doing that based on current data of

15 doing placebo in kids under the age of two. I

16 really do feel that that is a group where

17 antibiotics are needed and we would probably have

18 difficulty getting that by our ethical boards.

19 DR. POWERS: Well, at least it is the

20 population that really has the disease.

21 DR. CRAIG: Yes.

22 DR. POWERS: I guess that is part of the

218

1 other issue. When we looked through this

2 information, it seems to be is it that those kids

3 do worse or do they actually just have the illness

4 as opposed to the kids above the age of two who may

5 be the kids who don\'t really have it.

6 DR. EDWARDS: George?

7 DR. DRUSANO: Dr. Powers, I would just

8 like to kind of reflect a question back at you. I

9 mean, part of what we are talking about is the

10 difference between the clinical and microbiological

11 outcome, and a lot of this we just don\'t understand

12 well enough. For instance, the oseltamivir study

13 was a key one to have shown, in a sense, that they

14 did measure IL6 area under the curve. I guess I

15 would ask the agency suppose I was able to do a

16 study in kids less than two years of age in otitis

17 media, and we were looking at a beta-lactam or

18 quinolone and then a macrolide, and we were able to

19 look every day at a clinical score and then we were

20 able to not do the same kids but randomized kids to

21 get tapped at day 4, day 5, day 6 and day 7 so we

22 could look at time to sterilization, and if we

219

1 could explain all of the clinical stuff on the

2 basis of damping down IL6, or something like that,

3 how would the agency interpret that relative to

4 something like, you know, we killed all the bugs

5 and over here they got better earlier because not

6 all the bugs were gone but they got rid of the IL6?

7 How would those things be balanced in an

8 evaluation?

9 DR. POWERS: I think, George, what you are

10 saying is validating IL6 as an endpoint, if I am

11 interpreting what you are saying correctly, and

12 that is what we are asking people to do. The

13 question in short-term, self-resolving acute

14 illness is what would have happened if those people

15 got nothing? I think that is a lot tougher

16 question than saying how would we interpret this in

17 a serious and life-threatening disease where we

18 would not expect people to get better

19 spontaneously? So, in short-term disease there is

20 an added complexity to that that goes in there.

21 But I am glad you brought up oseltamivir.

22 The primary endpoint in those trials was not IL6.

220

1 The primary endpoint was time to the patient

2 getting better. But what the company did in that

3 case was they actually do a patient-reported

4 outcome tool that they validated ahead of time

5 where patients filled out information twice a day.

6 Without that you never would have been able to show

7 that or do that correlation with IL6. I think that

8 is one of the pieces of the puzzle that is missing

9 here. It isn\'t easy sometimes to measure these

10 clinical endpoints in a valid way. If you don\'t

11 have a valid outcome measure tool for measuring

12 clinical outcomes the analogy I use is you took a

13 piece of paper and you put lines on it and you

14 called it a ruler, even though it may not be

15 measuring anything that you can be clear on what

16 you got at the end of the day. People have done

17 this before in terms of measuring patient-reported

18 outcomes. In fact, I was just looking through this

19 in Rosenfeld and Kline\'s book on evidence-based

20 otitis media. I was surprised to find an entire

21 chapter on patient-reported outcomes in acute

22 otitis media.

221

1 So, what is clear to us is this idea,

2 again going back to the Critical Path, that we need

3 to develop better tools here on how to measure

4 clinical endpoints. Because it is tough doesn\'t

5 mean you can just throw away the clinical endpoint.

6 We still need to develop a good way to actually do

7 this.

8 DR. EDWARDS: John?

9 DR. BRADLEY: In your discussion prior to

10 lunch you were making correlations between

11 microbiologic outcomes and clinical outcomes. To

12 go back to otitis because it is such a messy

13 infection to look at, one of the reasons that we

14 started doing double tap studies or single tap

15 studies is that the clinical diagnosis of otitis is

16 extremely difficult and you won\'t get a lot of

17 agreement between clinicians as to what is bona

18 fide otitis or not. Viral mediated disease gets

19 you something that looks very close to bacterial

20 otitis. So, getting the actual microbiologic

21 information has been critical. Likewise, in

22 following up to see if you got a microbiologic

222

1 effect of the antibiotic, the second tap has turned

2 out to be very helpful.

3 Clearly, there are kids who will stay

4 clinically symptomatic despite sterilization,

5 probably because of the viral disease that set them

6 up for their otitis in the first place. We all

7 recognize that. And, there are a few children who

8 will get better, as you commented, despite having

9 persisting organisms in the middle ear.

10 For each illness there is the spontaneous

11 cure rate and I think that if you develop

12 guidelines which include a kappa value that is

13 appropriate for that particular infection entity

14 you can take the information regarding the

15 discontinuity of a micro. and clinical endpoint and

16 build it into that particular illness based on data

17 that has been collected. So, the kappa for

18 meningitis would be different than the kappa for

19 otitis.

20 DR. POWERS: Right, John. You are

21 bringing up exactly what we are saying. To be able

22 to use those\--you are again talking about what

223

1 George was saying, validating the endpoint first.

2 DR. BRADLEY: Right.

3 DR. POWERS: And there could be some

4 issues in validating that endpoint. We already

5 talked about it. Is it a problem with how we

6 measure the surrogate? Is it a problem with how we

7 measure the clinical outcome? One of the things I

8 didn\'t get to talk about is what was the clinical

9 outcome that we compared it to in otitis. There

10 may be some problems with how that clinical outcome

11 is measured.

12 But there are two points you brought up

13 that I wanted to get at. First, the major

14 discordant area in acute otitis media is not kids

15 with prolonged viral illness who still remain ill.

16 There are very few of them. The major discordant

17 area is the huge number of kids that still have the

18 bug that got better anyway. I think it is

19 important to understand that because when we talk

20 about measuring clinical outcomes in otitis, that

21 is what people say to us\--well, but if they are

22 still sick it is because of the viral illness.

224

1 That is not the cell where the problem is. The

2 cell in that 2 X 2 where the problem is everybody

3 is better regardless of whether the bug is gone or

4 not.

5 The second issue\--you brought up two

6 issues about it. One was making a microbiologic

7 diagnosis at entry versus using it as an endpoint,

8 and those are very different. As I was saying, a

9 biomarker for diagnosis is different than using it

10 for an endpoint. The July 2002 advisory committee

11 on otitis voted unanimously that we ought to be

12 using a baseline tympanocentesis to get these kids

13 into the trial. What remains at issue now is how

14 useful is microbiologic information to us as the

15 sole measure of efficacy? We are not saying it is

16 not important as a part of the mix, but as the sole

17 measure of efficacy in these trials.

18 DR. CRAIG: John, all the data that you

19 showed was not double tap.

20 DR. POWERS: Yes, it was. There are 12

21 double tap studies in the literature. All of those

22 that I showed you were double tap trials comparing

225

1 the bacteriologic outcomes at day 4-6 with clinical

2 outcomes, usually those clinical outcomes being out

3 sometime beyond day 10, except for the one trial I

4 showed you where it was day 4-6.

5 DR. DRUSANO: John, in the same vein, in

6 the discordant cell\--and I know nothing about those

7 trials\--was there any quantitation? I mean, there

8 is a big difference between saying the bug is there

9 or the bug is not there as opposed to saying 10

6

10 versus 4/ml or something.

11 DR. POWERS: That is a great point. There

12 is no quantitation. That is why I was asking you

13 guys the question of is there a better way to do

14 these? What we are seeing is these correlations

15 don\'t look so great the way we are doing it. So,

16 there are a couple of pieces of the puzzle that fit

17 here. Can we measure the surrogate in a better way

18 or a better time? Can we measure the clinical

19 outcome in a better way or a better time to be able

20 to put these together?

21 What I am trying to articulate to you guys

22 is we can\'t do that. We can only review what we

226

1 are handed. So, to be able to validate these

2 surrogates we need somebody out there, either on

3 the industry side or the academic side, to think

4 about this; realize that maybe we can improve upon

5 the way we are doing it and actually try to look at

6 those differences.

7 DR. DRUSANO: The other question is who

8 should be validating endpoints? I mean, is there a

9 place here\--maybe not the agency as a regulatory

10 body but maybe NIH as a governmental agency to see

11 here is a standard way. You know, we are going to

12 invest not in drug A but we are going to invest in

13 learning how to have an endpoint for thus-and-such

14 a disease amongst anti-infectives. It seems to me

15 if you are having sponsors do this all the time, it

16 is learning and throwing it away because then the

17 next sponsor maybe doesn\'t do it. But if we have

18 something that is more general where there is an

19 outside body that does not have an interest, or as

20 much of an interest, it may be something that can

21 be done once well to everybody\'s satisfaction, and

22 then picked up so that the actual level of the

227

1 submissions gets better.

2 DR. EDWARDS: George, I need a little

3 clarification on that. You are asking the question

4 who should validate the endpoints. Are you asking

5 that question in reference to clinical endpoints

6 only or both?

7 DR. DRUSANO: Both.

8 DR. EDWARDS: All right. Dennis?

9 DR. DIXON: Certainly the NIH is

10 interested in that. We are approaching that in a

11 number of ways, through both investigator-initiated

12 approaches and through our contract mechanisms.

13 One of the things we try to bring into our clinical

14 trials is incorporation of diagnostic and endpoint

15 assessments. We even have free-standing contracts,

16 such as invasive aspergillosis where the focus is

17 on developing the diagnostic. We did try and put

18 this in context, as a couple of people have said

19 today, and not separate from drugs the importance

20 of a diagnostic to define the illness early enough

21 so you can do treatment trials versus empiric and

22 prophylaxis trials and so you could also do

228

1 prevention studies. So, we tried to put that whole

2 aspect into perspective. Diagnosis, prevention and

3 treatment is the triad that we try and fold into

4 just about all of our approaches.

5 DR. POWERS: Dennis, could I ask you a

6 follow-up question because you and I have talked

7 about this before a couple of times? That is, what

8 would the level of interest be? It seems to me

9 like a whole third of the NIH budget now is for

10 bioterrorism-related issues. But what would the

11 interest be for common diseases like this, like

12 acute exacerbations of chronic bronchitis and acute

13 otitis media, and doing some of this work on what

14 seem to be the more mundane but, yet, the reasons

15 why people actually get antimicrobials for the vast

16 majority of folks?

17 DR. DIXON: Well, we do have investigators

18 submitting applications for just those kinds of

19 issues.

20 DR. POWERS: So, if this group were to put

21 together those kinds of studies and submitted them

22 to you, that would be something you guys would be

229

1 interested in taking a look at?

2 DR. DIXON: Yes, within the constraints of

3 the mechanisms and I am sure that is going to be an

4 issue given the 500,000 dollar direct costs

5 limitation for many of the mechanisms across the

6 NIH. But we have infrastructures in place, such as

7 the clinical trials networks, that have dedicated

8 resources to which these questions can be brought.

9 DR. DRUSANO: Along those lines, can

10 PhARMA contribute to the funding of the trials so

11 they are supporting something that is going to

12 benefit everybody in PhARMA? Is there a mechanism

13 for that?

14 DR. DIXON: Well, they do in a number of

15 ways, George. That is one of the examples that

16 some of the people in this room know through the

17 bacteriology and mycology study group. The issue

18 of resources which came up in John Rex\' discussion

19 is that the resources are going to be limiting to

20 federal agencies as well as to families and to

21 companies and the balancing priorities. We have

22 been able to manage that through the bacteriology

230

1 and mycology study group by funding the

2 infrastructure and PhARMA bringing the product

3 forward and paying the per capita. Those trials,

4 by and large, do not go forward unless there is

5 industrial partnership.

6 DR. FLEMING: The question was asked who

7 should participate in validation. I would hope

8 that everybody would be involved in validation. I

9 think it is not a simple thing of we are going to

10 take on this one project and when this is completed

11 we will have validation. You have given, John,

12 some examples in acute otitis media and the

13 clearance of the bug, and the problem there was

14 some people who didn\'t have clearance, a number of

15 them still had clinical success.

16 In essence, the totality of the mechanisms

17 of what influence outcomes aren\'t being fully

18 captured simply by at least our quantification of

19 clearance of the bug. We could be underestimating

20 the overall ability to achieve success in acute

21 otitis media. We could be overestimating it in

22 inhalation anthrax where clearing the bug isn\'t

231

1 going to be enough.

2 In essence, it takes a much richer

3 understanding and the arguments that you have been

4 giving about looking at the kappas and the

5 correlations, that is a step. We might call it a

6 necessary but not sufficient step. A classic

7 example I like to give, and I have referred to this

8 already, is mother to child transmission of HIV.

9 We know, in fact, that the essence of what matters

10 there is viral load and there is an extremely

11 strong correlation. In fact though, women who have

12 higher viral loads have lower CD4 counts, in

13 addition to also having a much higher risk of

14 transmission. If you look at her CD4 count, there

15 is great correlation with her risk of transmission

16 of HIV, but it is not the causal mechanism. If I

17 intervene before labor and delivery with IL2 I can

18 spike her CD4 240 cells, 250 cells, and it is not

19 going to do anything about transmission. If I

20 intervene with ART and reduce her viral load I may

21 not influence her CD4 count very much but it is

22 going to have a lot to do with transmission. It is

232

1 an example of John\'s drug A versus drug B, or

2 intervention A versus intervention B. IL2 is going

3 to look a whole lot better than ART on CD4 but it

4 is a whole lot worse in achieving the intended

5 benefit.

6 I have to understand the causal mechanisms

7 here. It is a myriad of issues here. I need to

8 understand the correlations. That establishes

9 plausibility. That gets my foot in the door. If I

10 have a strong correlate it is at least a potential

11 surrogate. To go beyond that I need three things.

12 I need to understand as clearly as possible what

13 are the mechanisms by which the disease process

14 influences the outcome. And, is my specific

15 measure, if it is a microbiological measure, is it

16 capturing the essence? Many times you might be

17 right but you are not measuring it the right way.

18 CD4 count is not a very good surrogate in HIV, not

19 because the essence of the status of the immune

20 system isn\'t highly relevant to whether you are at

21 risk for AIDS-defining events, but it is a noisy

22 measure.

233

1 Maybe in the acute otitis media setting

2 what we really need is not just a dichotomization,

3 clearance or not, but in essence a much better

4 sense of the nature of the clearance.

5 Secondly, we have to understand quite

6 clearly the plausibility that an intervention that

7 is sufficiently potent to achieve its intended

8 mechanism\--how can we be so confident that it

9 won\'t, in fact, induce unintended mechanisms?

10 So, those are tall orders and it is in

11 essence, in my view, the reason that, in truth,

12 there are very few validated surrogates. However,

13 there is a continuum. How well we understand that

14 influences the likelihood of reliability.

15 Ultimately, from a data perspective, to validate a

16 surrogate should not in essence be based on whether

17 the pregnant woman with HIV, the higher her CD4

18 count, the lower her risk of transmission\--that

19 correlation is great; my kappa would be terrific,

20 and in no way is that a valid surrogate because it

21 is simply correlated with what is truly causal.

22 What I really need is an array of studies

234

1 that will establish what is the level of effect on

2 the marker and what is the level of effect on the

3 clinical endpoint to show that there is, in fact, a

4 prediction or a correlation in those measures.

5 That is why raised the question of who should be

6 involved in validation of surrogates, we all have

7 to be involved because the ultimate validation of

8 the surrogate is going to depend upon our increased

9 understanding of the biological processes of the

10 disease process and the mechanisms of action,

11 unintended as well as intended, of the

12 interventions, and then having an aggregation of

13 trials that measure effects on both to ultimately

14 see whether or not we have the level of prediction

15 that we are hoping.

16 DR. DRUSANO: First of all, what I meant,

17 Tom, was not to throw all out the information

18 because I guess I had always intended that all of

19 us should do this with all the points of view that

20 we bring to it. But what I don\'t want to see is,

21 you know, drug company A validates this thing,

22 doesn\'t really publish it well enough and then drug

235

1 company B comes in and does the same stupid trial

2 and doesn\'t use the validated measure. My view

3 that I was trying to get across is that there

4 should be a funding mechanism, and I was glad to

5 hear Dennis say what he said\--a have a funding

6 mechanism where the FDA can have input, NIH has

7 input, IDSA has input, that all the people that

8 really need to be there are at the table and the

9 thing starts the validation process. And, it may

10 take a year, two years, three years. Viral load

11 wasn\'t validated in a year; it took a decade. But

12 when we validate it, hopefully, then it is out

13 there for everybody to see and every company picks

14 up that way of doing it. Again, the level of the

15 trials rise and we don\'t have these issues.

16 DR. POWERS: George, you make an excellent

17 point. If you read the oseltamivir trial, it says

18 in there we used a validated patient-reported

19 outcome tool; data on file at the company.

20 Therefore, no one else can use that validated tool.

21 We have thought about that. We are trying to move

22 forward with trying to at least get off the ground

236

1 patient-reported outcomes in sinusitis and AECB

2 because we want to get these into the public domain

3 where everybody can use them, and it would be great

4 to have partners to be able to do that.

5 DR. EDWARDS: Yes?

6 DR. SCHENTAG: Jerry Schentag, Buffalo.

7 Tom, you have given us a very comprehensive

8 description of what is necessary to validate a

9 surrogate like microbiologic outcome for example.

10 By the way, I believe it applies to clinical as

11 well. The problem, of course, is that that is a

12 discouragingly long list that requires a long

13 evolution of the process and it occurs without

14 consideration perhaps of the fact that you could

15 very easily validate a microbiologic surrogate if

16 you just simply did all of those studies in an

17 animal, if you infected it and treated it, and then

18 you have all that information available as prior

19 data that goes into that. In essence, that is what

20 we have done with antibiotics over the years. We

21 have pretty much been through that whole business

22 of validating the microbiologic endpoint versus

237

1 drug, versus concentration, separated out with a

2 resistant organism will kill you if you don\'t treat

3 it with the right thing, etc., etc., etc.

4 What I am trying to figure out is if, in

5 fact, any of that is useful here. I mean, there is

6 a big disconnect right now between that because if

7 we have to start over, assuming a micro. endpoint

8 is potentially not useful and even clinical

9 endpoint is not useful, which has been our course

10 over the last five years or so, maybe we do a

11 disservice to all our hard work that has gone into

12 validating these endpoints in other systems besides

13 human. How do we use it? How do we bring it

14 together?

15 DR. FLEMING: If I understand the essence,

16 you are saying if we do carry out studies in

17 animals, for example, where we can look in a

18 controlled manner at what is the effect on the

19 microbiologic marker and what is the effect on the

20 intended clinical endpoint\--

21 DR. SCHENTAG: Correct.

22 DR. FLEMING: \--I do view those to be

238

1 useful supportive evidence. The question is are

2 they the ultimate answer? Well, the answer to that

3 is, again, the validation of the surrogate depends

4 so heavily on understanding the mechanisms by which

5 the disease process influences the clinical

6 outcomes and understanding the intended and

7 unintended effects of the intervention. The

8 question is are those mechanisms the same in

9 animals and humans? Are the effects of the

10 intervention the same in animals and humans? To

11 the extent that they are, this is going to be very

12 valuable information. How uncertain are we though?

13 In many cases we are uncertain\--certain enough or

14 confident enough to appropriately use this to enter

15 into studies in humans and then to through the

16 Phase 1/2/3 steps. Can it in some way though

17 actually be used in a more reliable manner than

18 that? My answer to that is only if we can provide

19 persuasive arguments that these mechanisms in

20 animals are reliably representing the mechanisms in

21 humans.

22 DR. SCHENTAG: Well, we do have situations

239

1 where we have pretty close concordance between

2 micro. outcome and clinical outcome, like

3 life-threatening infections, resistant pathogens,

4 that sort of thing. I submit that maybe that is

5 the place where we might argue that it is easiest

6 to make the leap between what we have learned in

7 animals and what we can learn in humans. I agree

8 completely with what has been said, that in

9 diseases where it is not clear that the bacteria is

10 the cause of the disease in the first place, like

11 bronchitis for example or sinusitis, it is almost

12 impossible to do a validation. That is because I

13 think the clinical outcome is just as bad or as

14 weak a surrogate as the micro. outcome is in that

15 situation. We don\'t know. We don\'t know if it

16 causes the disease in some ways, so how are we

17 going to be sure clinical outcome is the result of

18 an antibiotic?

19 John made that point earlier. He said the

20 micro. outcome is always a surrogate. I think

21 sometimes the clinical outcome is a surrogate and

22 the micro. is the primary endpoint. You know, it

240

1 is going to depend on the causality that you can

2 link between your antibiotic effect and your

3 disease resolution, and we have that in some

4 diseases and not others, but that is the place

5 where you can use animal data as supportive

6 perhaps. I don\'t know; I am just fishing here.

7 DR. POWERS: I think what you are getting

8 here is awfully tough to ask a chinchilla if it has

9 ear pain, or to ask the mouse whether it is

10 coughing or not. So, I think there are some

11 limitations to asking some of those symptomatic

12 resolution questions in an animal model.

13 But let me go back again for a second

14 because we seem to keep getting confused on this

15 point. If you look at what we showed up there, the

16 clinical endpoint is how a patient feels, functions

17 or survives. That is the gold standard. You can\'t

18 say when it doesn\'t function well, then the micro.

19 becomes the gold standard. If the clinical outcome

20 doesn\'t function well because of some issue it

21 means we need to find a better way to measure the

22 clinical outcome. It does not automatically

241

1 validate the microbiological outcome. I think that

2 is a real important point to get across.

3 DR. EDWARDS: Dennis, I think yours is

4 going to be the last comment before we go on.

5 DR. DIXON: Thank you, Jack. I would just

6 like to come back to the example of aspergillosis

7 because it built on the example that John Powers

8 made earlier about the workshop that was held with

9 FDA and NIAID a year ago on endpoints in clinical

10 trials and the importance of fever as a marker for

11 aspergillosis. After a long discussion of that, I

12 am not sure we answered the value of fever and it

13 was still undetermined. But what came out of that

14 is that we need a better way to identify the

15 presence of fungus, which is what we know will be

16 involved in the outcome or at least the instigation

17 of the disease for aspergillosis.

18 So, one of the ways you can approach that

19 is through animal models, and we dedicate resources

20 specifically to diagnostics for aspergillosis, not

21 just yes and no but the degree of infection. So,

22 that is set up to have a model of a small animal

242

1 and a large animal, something like a mouse and

2 something like a rabbit, for both quantitative and

3 qualitative tracking of the infection so that it

4 can be brought back into the clinical setting, put

5 into one of trial infrastructures to see if the

6 correlation pertains from mouse to person.

7 We would like to be able to do that for

8 every single disease, but I am pretty sure that we

9 can\'t all at one time, but there are approaches in

10 using tools in animal models and refining tools

11 from the basic research forefront that can make

12 their way through to help with answering some of

13 these questions.

14 DR. EDWARDS: I am going to take the

15 prerogative here to tell you how we are going to

16 proceed, that is, I have two people who urgently

17 want to add comments before we conclude and I am

18 going to give them a total of five minutes between

19 the two, Tom and George. Then we are going to go

20 into the next session. We have intentionally

21 decided not to try to end at 3:30 today. We are

22 planning to end sometime around 4:30. So, we are

243

1 not just going to go on and on; we are going to

2 have a fixed ending point that, hopefully, is going

3 to be acceptable.

4 This is such an important area, the whole

5 area of the surrogate markers, and we have so few

6 opportunities to get together to discuss these

7 kinds of issues that we really felt it was

8 critically important that we try to get as far as

9 we possibly can. So, let me ask Tom and then

10 George to just very briefly comment and then we

11 will go on.

12 DR. FLEMING: And I will try to keep it

13 from one to two minutes of those five minutes. We

14 didn\'t answer question three, and I wanted to at

15 least allude to it. What are the issues for

16 obtaining validation of a surrogate necessary for

17 fulfillment of Subpart H?

18 It is important just to remember that

19 Subpart H is intended as a way to get earlier

20 access in serious disease conditions to

21 interventions that are promising. The marker that

22 we use doesn\'t have to be established to be

244

1 reliably predicting clinical endpoints, clinical

2 effects. That is what we have been talking about,

3 how complicated that is. It just has to be

4 reasonably likely, the concept being if it is, get

5 the agent out there while you then validate. You

6 are still held to having to show the same level of

7 evidence to validate.

8 It is a little sobering though to see how

9 that process is working, and if you are interested

10 I would encourage you to go back and look at the

11 transcript from the March 12th and 13th, 2002

12 oncology drugs advisory committee where they

13 reviewed 8 of the 12 accelerated approvals that

14 were the first 12 that occurred in oncology from

15 1995 to 2000. The average time between the

16 accelerated approval and projected completion of a

17 validation study is 10 years. Why? It is just

18 really hard to randomize patients to controlled

19 studies once you have given the agent an

20 accelerated approval with the impression that it is

21 effective.

22 Secondly, one of the reasons it is great

245

1 to work with industry is because of their sense of

2 urgency. Is that the same after they have an

3 accelerated approval? I would suggest that it

4 appears that it isn\'t.

5 Thirdly, in 3 of those 8 cases the first

6 validation study was done and it was quite negative

7 but the agent is still out there. Why? Because it

8 is extraordinarily complicated to pull the agent.

9 So, there is, in fact, I think a great

10 deal of uncertainty about what do you do when you

11 get an accelerated approval, do the validation

12 study and it is not persuasive. In essence, if you

13 are going to leave the agent out there after a

14 fairly non-persuasive validation study, then I am

15 arguing that accelerated approval is tantamount to

16 full approval. If it is, then why should we be

17 using criteria that are less rigorous than full

18 approval criteria?

19 So, the motivation for Subpart H is

20 compelling. The realities of the complexities of

21 being able to complete validation studies in timely

22 ways, and taking proper action when they are done

246

1 is highly complicated.

2 DR. EDWARDS: Thank you. George?

3 DR. TALBOT: I just wanted to raise the

4 general question for the agency and all of us to

5 consider as to whether these discussions are not as

6 fruitful as they might be because we are locked

7 into a terminology which is no longer relevant

8 completely. I am thinking about the indications.

9 We always talk about acute otitis media; we talk

10 about acute bacterial sinusitis; we talk about

11 acute exacerbations of chronic bronchitis as though

12 these were unitary diseases. We know they are not

13 and people have mentioned that, but maybe it would

14 be easier to move forward if there were more

15 precision in exactly what it is we think needs to

16 be treated. The corollary to that could be that it

17 would be easier to define the potential benefit of

18 a surrogate marker. For example, in acute

19 bacterial sinusitis one could say that if one

20 enrolls patients on day one the bugs are all going

21 to go away probably in 99.5 percent of those

22 patients and the patients are going to get better

247

1 if there were bugs to begin with. So what?

2 On the other hand, if you take patients

3 who are culture positive on day one and are still

4 culture positive and symptomatic at day seven, and

5 then treat those, I would submit to you that you

6 could perhaps prove more readily that in that

7 instance the eradication of the bug would prove to

8 be a very good surrogate marker for subsequent

9 clinical improvement.

10 In conclusion, let\'s be sure that we don\'t

11 lump when we need to split. Let\'s think about how

12 that should be reflected in the indications that

13 are open for regulatory approval, and let\'s think

14 in these studies about how to define the specific

15 subpopulations where you could expect benefit for

16 getting rid of the bugs, as George said, and where

17 you might find a valid surrogate marker.

18 DR. POWERS: I think Dennis brought that

19 up. We need better diagnoses of some of these

20 things and then selecting the correct patient

21 population is a big issue. That was sort of

22 three-quarters of what we talked about at the

248

1 October, 2003 advisory committee. But how would

2 you find that right population? You have to do the

3 study.

4 DR. TALBOT: You do, but just in terms of

5 guidance and so forth, you need to think about that

6 catch-all indication of AECB. Maybe there should

7 be some brain-storming about how to better define

8 some of those things. It is not an issue for

9 complicated UTI perhaps or for acute bacterial

10 meningitis, but for these other things I think it

11 is really germane.

12 DR. POWERS: Right. You don\'t have that

13 with HIV because you know the person has HIV before

14 you treat them, and we do have this issue with a

15 lot of acute bacterial diseases.

16 DR. EDWARDS: Excellent points. We are

17 going to take a ten-minute break now and then we

18 will get started and, again, we are shooting for

19 4:30.

20 \[Brief recess\]

21 DR. EDWARDS: We will ask Tim Henkel to

22 begin the discussions with his presentation on

249

1 bloodstream infections. Tim, I think we are ready

2 to go.

3 IV. Discussions about Bacteremia as an

4 Indication/Issues with Clinical Trials

5 with Endocarditis - Industry

6 DR. HENKEL: Thank you, Jack.

7 \[Slide\]

8 I am going to do something a little bit

9 different than we have done before. I am going to

10 talk about one particular study, as you can see

11 from the slide, a Phase 2, randomized, controlled

12 trial of dalbavancin versus vancomycin for

13 catheter-related bloodstream infections. George

14 Talbot has stepped out of the room, but I think we

15 might subtitle this splitting when we should be

16 lumping instead of vice versa.

17 I want to talk just briefly about a little

18 bit of the regulatory background, the guidance

19 documents in operation when we started this study;

20 just a bit of history of the indication. I will do

21 that fairly briefly because I think David will

22 touch on that later. Then I want to spend some

250

1 time talking about the design of the study, the

2 criteria used for getting patients in, and then at

3 least operationally the results, what happened

4 these criteria to try to conduct a clinical trial

5 today. What were some of the limitations; what

6 were some of the challenges? What I won\'t do is

7 talk about safety and efficacy results of the

8 study. Those will be presented at a scientific

9 meeting in the coming weeks.

10 \[Slide\]

11 So, let\'s go back a little over a decade.

12 In 1993 the Anti-Infective Drugs Advisory Committee

13 recommended elimination of the bacteremic sepsis

14 indication. In 1998 AIDAC had a discussion of

15 catheter-related bloodstream infections as an

16 indication. But draft guidance followed in 1999.

17 As of 2004, no drug has been approved for

18 catheter-related bloodstream infections. So, let

19 me review the entirety of the published literature

20 controlled trials for CR-BSI.

21 \[Slide\]

22 It is a single study, Sam Raad. It is a

251

1 study with Synercid versus vancomycin, published in

2 The European Journal of Clinical Microbiology and

3 Infectious Diseases. It was actually initiated I

4 think following the advisory committee but before

5 the issuance of the daft guidance. It is a study

6 of 39 patients, upon analysis, 16 of whom did not

7 have gram-positive bacteremia. So, there is not a

8 great deal of information out there. But this was

9 the context in which we started the study and put

10 this design together. We certainly did have a

11 number of discussions with the agency about the

12 design because of that background, even though it

13 was a Phase 2 study.

14 \[Slide\]

15 Let me go through a few of the pertinent

16 features of the design. It was Phase 2, as I said.

17 It is randomized, controlled, open-label with

18 vancomycin as a comparator at the standard dose.

19 We looked at both clinical and microbiological

20 entry criteria for the study which I will describe

21 a little more later.

22 The patients, in order to be entered\--the

252

1 idea was catheter-related bloodstream infection

2 but, of course, upon entry you don\'t know all the

3 information you need in order to make that

4 determination so I will come back to that in a

5 minute. The primary endpoint of the study was the

6 global response at follow-up, that is, the combined

7 clinical and microbiological response. So, you had

8 to be a success both clinically and

9 microbiologically to be a success in the study.

10 This was actually in the modified intent-to-treat

11 population. The sample size initially planned was

12 about 60 patients per group, and we planned

13 descriptive statistics with 95 pc confidence

14 intervals in this Phase 2 study.

15 \[Slide\]

16 In order to be entered into the study a

17 patient had to have a documented gram-positive

18 bacteremia, that is, at least a single positive

19 culture in order to be entered, or empiric

20 enrollment based on signs and symptoms such as

21 elevated temperature, hypothermia, an elevated

22 white blood cell count or leukopenia, tachycardia,

253

1 tachypnea or transient hypotension. In fact, very

2 few patients were enrolled on empiric grounds and

3 most were enrolled with at least one positive blood

4 culture for a gram-positive organism.

5 \[Slide\]

6 In terms of exclusion, patients could not

7 have received more than 24 hours of prior

8 antibiotic therapy that was effective against a

9 gram-positive organism isolated. So, those were

10 reviewed on a case-by-case basis. They could not

11 have an alternate focus of infection identified at

12 the time of enrollment in the study. They couldn\'t

13 have had recent Staph. aureus bacteremia from a

14 source other than a central venous catheter. They

15 had to be patients who, it was anticipated, could

16 be treated with two weeks or less of antibiotic

17 therapy. The creatinine clearance needed to be

18 greater than 50 ml/min simply because appropriate

19 studies for adjustment doses hadn\'t been completed

20 at the time this Phase 2 study was started. They

21 couldn\'t be severely neutropenic, that is, an ANC

22 less than 100 for more than 72 hours. they

254

1 couldn\'t be on chronic immunosuppressive drugs and,

2 of course, you couldn\'t have documented resistance

3 to either of the study drugs since it was a

4 randomized trial.

5 \[Slide\]

6 There are a number of microbiological

7 methods in the draft guidance which were

8 implemented in this study. We tried to look at

9 catheter cultures where they were available. We

10 tried to look at time to positivity of catheter

11 cultures versus peripheral cultures, again where

12 available. We looked at insertion site exudate

13 cultures if they were present. Then, in addition,

14 for certain organisms, which I will elaborate on,

15 we looked at the antibiograms as well as pulse

16 field gel electrophoresis to confirm identity of

17 pairs.

18 \[Slide\]

19 Let me just go over the outcome

20 definitions. They are binary. Success means you

21 were improved such that you didn\'t need additional

22 antimicrobial therapy. If you were failed you had

255

1 persistence of signs and symptoms and additional

2 therapy was required. In terms of the

3 microbiological it was fairly straightforward, you

4 could culture the pathogen isolated at baseline or

5 not.

6 \[Slide\]

7 There were several categories of infection

8 identified up front. Definite catheter-related

9 bloodstream infection was defined as one of the

10 following: Either a positive peripheral blood

11 culture plus a positive semi-quantitative catheter

12 tip culture; a positive quantitative lumen wash

13 culture or a positive hub or tunnel exudate

14 culture. You could also have more than a 5-fold

15 increase in the concentration of organisms of an

16 identical pathogen from a central venous catheter

17 versus a blood culture drawn peripherally, of in

18 centers where this could be done, you could have a

19 more than 2-hour difference in the time to

20 positivity for the peripheral culture versus a

21 centrally drawn culture.

22 They are fairly rigorous definitions and I

256

1 should say that these are slightly more relaxed

2 than in the guidance for catheter-related

3 bloodstream infections.

4 \[Slide\]

5 We had a second category of probable

6 catheter-related bloodstream infection. For Staph.

7 aureus, if you had a single positive peripheral

8 blood culture in the absence of any other source of

9 infection, you could be considered probable CR-BSI.

10 For all other organisms you had to have at least 2

11 blood cultures positive for the identical species,

12 at least one of which was drawn peripherally.

13 \[Slide\]

14 The study was initiated at 34 centers in

15 North America, with an enrollment period of 17

16 months. Less than half of those centers actually

17 managed to enroll a single patient, and 2,639

18 patients, the vast majority of whom had at least

19 one positive blood culture with a gram-positive

20 organism, were screened and 75 patients were

21 enrolled. So, I will save you the trouble of doing

22 the math. That is about 2.8 percent of the

257

1 screened patients.

2 It makes several points. First of all, no

3 surprises\--gram-positive infections in patients

4 with central catheters are common. It is easy to

5 identify them; it is hard to enroll them in a

6 clinical trial.

7 \[Slide\]

8 The reasons for the screening failures are

9 shown here. In 30 percent of the cases there is

10 inadequate culture data, and this is not the lack

11 of the first positive culture; this is the lack of

12 the second culture, the lack of the availability of

13 a catheter tip, a lumen wash, or the absence of an

14 exudate culture. In many cases those are actively

15 discouraged at clinical sites around the country.

16 Very few centers are able to look at time to

17 positivity of blood cultures, and relatively few

18 sites do semi-quantitative blood cultures as well.

19 So, it is extremely difficult to get

20 patients into a study and meet those definitions of

21 catheter-related bloodstream infections. In 20

22 percent of the cases there was prior antibiotic

258

1 usage that excluded a patient from enrollment.

2 This doesn\'t comment on the number of patients who,

3 because of other infections that developed during

4 the study, received an antibiotic, for example, the

5 patient who developed a urinary tract infection

6 with a gram-negative organism but was treated with

7 a drug that had gram-positive activity. In 20

8 percent of the cases renal insufficiency was the

9 reason given. There were additional foci of

10 infection identified in 13 percent of patients. In

11 9 percent there were mixed gram-positive and

12 gram-negative infections, and neutropenia in 6

13 percent. So, you can see quite readily that under

14 the current guidance this is a challenging

15 indication in which to do a study.

16 \[Slide\]

17 Let me just sum that up by saying this is

18 a common disease. Gram-positive bacteremia in

19 patients who have a catheter in place is

20 exceedingly common. That is no surprise. Patients

21 who meet the definitions of catheter-related

22 bloodstream infections, however, are very rare.

259

1 This is a heterogeneous population. There are

2 patients with coag. negative staph; there are

3 patients with Staph. aureus; a smaller number of

4 patients with enterococci.

5 The inclusion/exclusion criteria used for

6 the study\--when you exclude 97 percent of the

7 patients screened, I think it is not a stretch to

8 say the generalizability of the results is highly

9 questionable. What can you do with that? I think

10 the patients who were studied were well

11 characterized, however what is a clinician to do

12 with that information if you don\'t know how it

13 pertains to the population you are treating every

14 day?

15 Other issues\--I mentioned the

16 microbiological methods required to defined this

17 entity of catheter-related bloodstream infections

18 are not standard of care in most places, and they

19 are not the sorts of things you can impose upon a

20 clinical laboratory in order to do a clinical

21 trial.

22 There is no approved comparator, which

260

1 might become an issue for a Phase 3 study. That

2 would certainly be an issue for discussion with the

3 agency before anyone would go down that road.

4 So, in my view, a Phase 3 study with the

5 current design is really not feasible. I do not

6 see how it could be done. If one wanted to use a

7 brute force approach, open hundreds of centers and

8 screen tens of thousands of patients, at enormous

9 cost, conceivably it could be done but you would

10 have to question what the results would tell you.

11 I don\'t think they would be generalizable.

12 So, what I would like to urge the group is

13 to consider alternate approaches to bloodstream

14 infections. I don\'t want to imply that catheter-

15 and device-related infections are not important.

16 It is a common clinical problem and there are many

17 things we don\'t know\--which patients require

18 treatment? Who could simply have a catheter pulled

19 as opposed to needing treatment? Which patients

20 can be treated through an infection? Are there

21 patients with coag. negative staph. you can

22 effectively treat without removing the catheter?

261

1 What is the appropriate duration of therapy? So,

2 these are very important clinical questions but not

3 answerable with this kind of study design.

4 So, as I said at the opening, I think this

5 may be a case where lumping rather than splitting

6 might be the way forward. I would urge the group

7 to think more about other ways to look at

8 bacteremia in general. I know we will hear from

9 David comment on whether we can look at bacteremia

10 as a stand-alone indication. I think we have to do

11 something completely different than this if we are

12 to evaluate new drugs for bacteremias. Thanks.

13 DR. EDWARDS: Thank you very much, Tim.

14 Ralph Corey, from Duke, will extend the discussion

15 now. Ralph?

16 IDSA

17 \[Slide\]

18 DR. COREY: Let me first acknowledge Vance

19 Fowler whose data I am stealing. Vance and I

20 started a group called SAVAGE, a dramatic name, in

21 1994 when he was an intern. I had good ideas; he

22 loaded the trucks. Now he has the good ideas and I

262

1 make the lectures.

2 \[Laughter\]

3 \[Slide\]

4 Let\'s talk about clinical trials. I stole

5 this slide from David Ross. You know, talking

6 about issues of bacteremia as an indication, he

7 clearly pointed out that bacteremia is obviously a

8 multifaceted disease and if you clear Staph. aureus

9 pneumonia with bacteremia, you clear the pneumonia

10 and you are probably clearing the disease most of

11 the time. So, having an indication for Staph.

12 aureus pneumonia with bacteremia is, I think,

13 breaking this down way too far. However, there is

14 a middle group here that is very, very important

15 that doesn\'t have an obvious source of infection.

16 \[Slide\]

17 In 1998 as you have heard, the

18 Anti-Infective Drug Advisory Committee had a big

19 meeting. I read through 200 pages of transcript of

20 this meeting, and this is the way I summed it up.

21 Truthfully, there were a lot of great ideas, a lot

22 of the people are here, and they said bloodstream

263

1 infections of known tissue origin\--you know, the

2 cure of the origin depends on the cure of the

3 bacteremia, and those are examples.

4 \[Slide\]

5 However, the bloodstream infection of

6 known catheter origin, removal of the catheter, one

7 to two weeks of antibiotic leads to cure. But what

8 was interesting is that Staph. aureus,

9 enterococcus, Candida, coag. negative staph. and

10 gram-negative rods were all catheter-associated

11 bacteremia. Can they all be lumped together? I

12 think one of the things we want to do is talk about

13 why they shouldn\'t be lumped together but perhaps

14 the trials can be.

15 \[Slide\]

16 The conclusions became guidelines for

17 trials of anti-infective agents in patients with

18 documented catheter-associated bloodstream

19 infections, and there are some problems.

20 \[Slide\]

21 First of all, as Tim just said, we have

22 this huge problem with requiring proof of catheter

264

1 infection. The catheters are in the trash bag by

2 the time you are trying to enroll these people.

3 That is one of the problems. All the problems that

4 he mentioned are big ones.

5 One of the key points that we started with

6 in 1994 is\--and I didn\'t believe this, this second

7 thing\--that the origin of bloodstream infections

8 defines the complication potential. Does it?

9 Basically, if you have a catheter-associated

10 bloodstream infection, does that mean it is benign,

11 especially standard staph? If you give them two

12 weeks of therapy they are all cured; you don\'t have

13 to think further? That is wrong, and we have data

14 to show that is wrong. Overall, there are other

15 markers that have to be added to that to help you

16 define the uncomplicated group.

17 This goes to the third point of the

18 guidance combines virulent and less virulent

19 organisms. Is there treatment for Staph. aureus

20 and coag. negative staph? We don\'t even know if we

21 need treatment for coag. negative staph.

22 catheter-associated bloodstream infections. Can

265

1 you just pull the catheter? Probably in 99 percent

2 of the people you can. We haven\'t been able to

3 define that one percent. In Staph. aureus, can you

4 just pull the catheter? No one in the room would

5 do that. With candida, would you do that?

6 The final thing is this allows approval

7 for more benign diseases, catheter-associated

8 disease, if it well defined, without subsequent

9 requirements obviously for trials in

10 life-threatening disease. That is not the agency\'s

11 problem but it is sort of all of our problem. Are

12 we testing the drug in a population in which it is

13 not going to be used?

14 \[Slide\]

15 Let\'s look at these five organisms.

16 Everybody in the room knows this chart. I have

17 sort of never seen it put together like this, so we

18 put it together. Staph. aureus is a rare

19 contaminant. It does cause septic shock. But the

20 interesting thing is column three, \"metastatic

21 infection.\" It loves to cause metastatic infection

22 and, obviously, you can look at the resistance

266

1 column.

2 Coag. negative staph.\--often a

3 contaminant. It doesn\'t cause many metastatic

4 infections. That rate is going up now. Actually

5 in our endocarditis group of almost 2,000 patients

6 we have 100 cases of native valve coag. negative

7 staph. endocarditis. I wouldn\'t have believed it

8 in a thousand years. So, the bug is getting worse.

9 Enterococcus? Enterococcus is sort of a

10 wimp; it is just a wimp. It loves to get resistant

11 but it often doesn\'t cause disease. Occasionally

12 it can though.

13 Gram negative rods, we all know they don\'t

14 cause metastatic infections usually. Then candida,

15 and then you have to break this out in the normal

16 host and the non-normal host. Obviously, you have

17 to break out coag. negative staph. with devices in

18 and with devices out b it loves devices.

19 \[Slide\]

20 So, you really have to split down to what

21 you want to study. We wanted to study Staph.

22 aureus first. The reason I show this slide from

267

1 The New England Journal, by Frank Lowy is that it

2 just shows all the receptors that Staph. aureus has

3 on its outer coating that bind to things. It binds

4 to collagen. It loves to cause metastatic disease

5 and that is the point of this picture.

6 \[Slide\]

7 I want to walk through this because this

8 is data that is really unique. This comes out of

9 the SAVAGE group. Out of about 1,300 patients

10 then, there are about 1,700 now enrolled. These

11 are all the patients with Staph. aureus bacteremia

12 at Duke Hospital in the last ten years,

13 prospectively identified and entered.

14 There are 368 patients with uncomplicated

15 Staph. aureus bacteremia, any source, all-comers;

16 no metastatic infection identified at that time,

17 time of entry; treated for 14 days. The cure rate

18 was 63 percent. Recurrence rate was 6 percent in

19 this group; attributable mortality, and this is our

20 best guess, is about 6 percent; and other mortality

21 was 20 percent. Then, there are still a few that

22 we don\'t have all the data on for that particular

268

1 characteristic.

2 If you keep going and you say, okay, I

3 want this same group but I want it

4 catheter-related, and the way we defined

5 catheter-related is we couldn\'t find another source

6 and the guy has a catheter in. That is it; not it

7 was inflamed; not that you could get pus out of the

8 tunnel; not that you did differential blood

9 cultures\--none of the other, just a simple clinical

10 diagnosis; we can\'t find another source and the

11 patient had a catheter in.

12 Now all of a sudden, the cure rate goes up

13 to 75 percent. The recurrence rate goes down;

14 attributable mortality goes down; overall mortality

15 goes down.

16 \[Slide\]

17 We take this a step further because we had

18 an algorithm saying what is uncomplicated, which we

19 will get to. We said, as Sam Raad had suggested a

20 long time, maybe if they defervesce in 72 hours

21 that really helped define a group that was

22 uncomplicated, and if they had a follow-up blood

269

1 culture we figured that at 24-48 hours after the

2 start of antibiotics and after pulling the line, if

3 they had a positive culture then that, again,

4 defined a group that was the uncomplicated group.

5 They were going to do well. We give them two

6 weeks; they are not going to get endocarditis; they

7 have not gotten staph. infections and, indeed, we

8 are up to 81 percent cure rate, with a recurrence

9 rate that is 3 percent, and all three of these were

10 re-infections, like in a person who has more lines

11 in or is an IV drug user. The attributable

12 mortality is way down and overall mortality is also

13 down.

14 Finally, we are down to the last group

15 where we have all the others, catheter associated,

16 defervesced within 72 hours, negative follow-up

17 culture and a negative echocardiogram, and now our

18 cure rate is 88 percent and our recurrence rate is

19 3 percent, and these are re-infections. Basically,

20 95 percent of these guys were cured if they didn\'t

21 die of another disease.

22 So, we recommended if you are going to do

270

1 short-term therapy, we started out with just one

2 week, and we recommended TEEs on everybody whom you

3 were going to treat. But the trouble is that that

4 breaks the group down to about 35 patients and the

5 cure rate again goes into the 90s and the mortality

6 is lower yet.

7 \[Slide\]

8 So, what do we gain by all this? This is

9 a picture just looking at 370 patients to 65

10 patients. You lose patients as you go down, as you

11 more accurately define, there is no question. But

12 when you are down at the bottom you have a

13 well-defined group, well characterized, with a cure

14 rate of over 85 percent.

15 \[Slide\]

16 So, we proposed new definitions, and this

17 has actually been discussed by several people in

18 the room\--John, David\--and saying uncomplicated

19 bloodstream infection health care associated, and

20 that includes the outpatients and nursing homes

21 with IV catheters, etc.; no signs or symptoms of

22 metastatic infection; follow-up blood cultures, and

271

1 this is the strongest predictor, the follow-up

2 blood culture. If it is positive you are in deep

3 trouble, yes, you have problems. So, if you get a

4 positive blood culture 24-48 hours in\--this has

5 actually been published just a few months ago.

6 Defervesce within 72 hours; and then an echo

7 showing no valvular disease, basically you just

8 have trivial insufficiency or stenosis; your valves

9 are good. Removable focus obviously has to be

10 removed; no hardware in place and non-neutropenic.

11 That is what defines it. We can do trials, you

12 know, adding these bottom ones back in.

13 \[Slide\]

14 The complicated ones are follow-up blood

15 culture positive despite removal if intravascular

16 catheters; no signs and symptoms of metastatic

17 disease upon enrollment except uncomplicated IE.

18 You can say, hey, I am going to take all-comers; I

19 will take the guys who got vertebral last year when

20 they show up. If you have bone data, that is

21 another way of doing it but then you have to have a

22 lot more data up front to make sure that you are

272

1 not going to get into trouble. Again, no hardware.

2 The length of the fever may be either less

3 or greater than 72 hours. Defervescence may get

4 greater or less than 72 hours and echo is not

5 necessary before enrollment in this group.

6 \[Slide\]

7 Inappropriate, we thought, were signs and

8 symptoms of metastatic disease on presentation;

9 removal focus\--that is one thing that we feel very

10 strongly about; you have to remove the focus; and

11 hardware. We have real good data that if you have

12 a hip in or knee, you have about a 25 percent

13 chance of seeding the hip or knee if you have

14 Staph. aureus in the bloodstream. That is 1,000

15 patients from Duke in New Zealand. There is also

16 data on prosthetic valves; it is about 25 percent.

17 So, hardware in place is something you have to

18 really think about, whether you want to include

19 those in a trial. Neutropenia I think defines a

20 whole different group of people that we have to

21 deal with, with data that they don\'t do as well.

22 \[Slide\]

273

1 I am not going to go through this, what is

2 significant and which hardware you have to remove.

3 I think that you don\'t have to remove all hardware

4 and you have to define it fairly well. For

5 instance, plates and screws are not at high risk.

6 Knee joints are probably the highest risk and hips

7 are probably second.

8 \[Slide\]

9 The present guidance for a drug\--and this

10 is my interpretation so you guys can correct me,

11 beat on me, or whatever\--for a drug for MRSA that

12 is coming on the market to really handle MRSA as we

13 all hate it and vancomycin, we are all worried, is

14 not powerful enough, is to start out standard skin

15 studies, a randomized, double-blind study of skin

16 and skin structure, and then go on to Phase 2 and

17 do two randomized, double-blind studies of

18 uncomplicated bloodstream infections, and these are

19 catheter-associated, preferably superiority\--I am

20 just reading it out of the guidance from

21 \'98\--followed by a randomized, double-blind study

22 of complicated bloodstream infection.

274

1 Assumption one is that step one predicts

2 success in step two. Does that happen? And, does

3 step two predict in step three or failure in step

4 three? Do we have to go step-wise? This is

5 something that makes all of us a little nervous.

6 We like to check it out in easier infections and

7 make sure it works. Do we need to do that?

8 Assumption two is that completion of step

9 one leads to step two. Why? I can do a skin study

10 and stop and say it is a good drug; use it.

11 \[Slide\]

12 So, our proposal is that we change the

13 definitions first to uncomplicated bloodstream

14 infections and complicated bloodstream infections.

15 Like Tim was talking about, we think about new

16 trial designs. That doesn\'t mean we change them;

17 we just think about them.

18 \[Slide\]

19 One of my first thoughts is\--and I take

20 full blame for these\--that a Phase 2 randomized

21 trial in skin infections, followed by an

22 open-label\--and actually, I have spent a fair

275

1 amount of time with our Ph.D. statisticians at Duke

2 looking at what is the downside of this\--50

3 patients open-label. Now, open-label causes a

4 problem in this because you may just say, hey, I am

5 going to pick a 26 year-old healthy guy and I am

6 going to get to my cure rate of 85

7 percent\--open-label study with a new

8 anti-infective, and I reach a target value that is

9 comparable to the value that we get with what we

10 consider good care. If you reach 85 percent, you

11 go on to your large Phase 3 trial in both

12 complicated and uncomplicated disease combined. If

13 you don\'t reach 85 percent, you back off and have

14 to do a double-blind study in Phase 2. That is one

15 thing.

16 \[Slide\]

17 Middle of the road, do your skin study and

18 then go straight to a large open-label, randomized

19 study of all the patients with Staph. aureus

20 bacteremia and with frequent adjudication. You

21 want to adjudicate every five patients, or you want

22 to have a DMS look at every two patients, it

276

1 doesn\'t matter, whatever makes people feel

2 comfortable. But go rapidly. Combine the two;

3 don\'t split them out.

4 \[Slide\]

5 Finally, the head of our clinical research

6 institute is a cardiologist, Rob Califf, who is a

7 little bit outrageous but has done a lot of big

8 trials, and one of the things we were talking about

9 is when we have a heart attack drug we don\'t test

10 it in stable angina; we test it in heart attacks.

11 You sort of say, well, gee, I am going to take this

12 drug and I am just going to test it in the people

13 that it is going to be used in. I think that we

14 have to think this way. Whether we look at each

15 patient separately and make sure we are doing the

16 right thing, but I think that otherwise what is

17 happening is we are using drugs and testing them in

18 the clinical arena by people who aren\'t testing

19 them; they are just using them and that is what is

20 happening.

21 So, I think that you start the study of a

22 new anti-MRSA drug, as an example to bloodstream

277

1 infections, taking all-comers and looking at the

2 results. Obviously, you have to have your basic

3 package and obviously this doesn\'t take any

4 consideration of what you have to have on the side

5 for safety. For instance, you have to have a

6 safety database of\--I don\'t know\--2,000 patients,

7 whatever, but you can do easier trials. You can do

8 skin trials looking at safety of the drug and do a

9 large pivotal trial with both complicated and

10 uncomplicated disease. That is all I have and we

11 can talk about this.

12 DR. EDWARDS: Thank you very much, Ralph.

13 David Ross, from FDA.

14 FDA

15 DR. ROSS: Well, I feel like I have the

16 hard part here because after two really fascinating

17 talks I have to try to make the regulatory issues

18 interesting. I just promise I won\'t talk about the

19 Code of Federal Regulations.

20 \[Slide\]

21 What I would like to do is just very

22 briefly review the regulatory history of

278

1 bloodstream infection and bacteremia; talk about

2 defining anti-infective indications; and then talk

3 about primary bloodstream infection as an

4 anti-infective indication. In terms of defining

5 things, my sister is an attorney and she told me

6 once that the only thing she ever learned in law

7 school is why two situations that are exactly alike

8 are actually completely different. So, with that

9 in mind, I think we should just keep in mind that a

10 lot of what we do in terms of defining indications

11 is saying who is a describable group of patients.

12 \[Slide\]

13 If you look in the PDR there are ten drugs

14 indicated for bacteremia or septicemia or both.

15 All of these were labeled prior to 1992. Having

16 looked at some of the reviews, it was actually

17 quite interesting. The labeling was really based

18 on either very non-specific or completely

19 unspecified clinical manifestations that really

20 pooled a few patients from different studies, for

21 example, pneumococcal pneumonia, urinary tract

22 infection and so on. These NDAs included

279

1 bacteremia that was associated with focal infection

2 at a defined anatomic site, as well as bacteremia

3 that had no known origin. As I mentioned, patients

4 were pooled from multiple trials of multiple

5 indications.

6 \[Slide\]

7 This was not a particularly satisfactory

8 situation for anybody. Nobody really knew what we

9 were studying. In a 1993 advisory committee

10 meeting there was presentation of data from a large

11 NDA data set that suggested in that particular data

12 set that bacteremia did not affect outcome. The AC

13 discussion concluded that bacteremia is associated

14 with infection at a primary anatomic site; that

15 patients who have a systemic inflammatory response

16 syndrome in bacteremia form a very heterogeneous

17 population. It really was unclear in terms of

18 making a distinction on the basis of bacteremia in

19 this data set if bacteremic SIRS patients did worse

20 than non-bacteremic SIRS patients.

21 \[Slide\]

22 So, the conclusions at that time were that

280

1 bacteremia per se was less important than the site

2 of infection in terms of classifying infections and

3 defining indications. The study of bacteremia or

4 septicemia or what was then proposed is bacteremic

5 sepsis as a separate indication was not feasible

6 given the heterogeneity of the patient population,

7 and I will talk some more about that in a minute.

8 However, it was felt that because this was

9 information that was important to prescribers that

10 labeling should include bacteremia in the context

11 of site-specific infections, for example, pneumonia

12 with associated bacteremia.

13 \[Slide\]

14 I said this to some extent when I gave a

15 variant of this talk back in \'98, why should we

16 reconsider this? Well, we all know there is an

17 increased incidence of bloodstream infections due

18 to resistant pathogens and without an identifiable

19 primary source. There is data suggesting that when

20 you can identify the primary source for a

21 bacteremic infection the outcome is worse.

22 But I also think it is important to think

281

1 about some issues as far as how we measure the drug

2 effect in bloodstream infection and first and

3 foremost is patient heterogeneity. Getting to this

4 lumping versus splitting question, there are the

5 differences in natural history for different

6 pathogens. Obviously, there is a much different

7 attributable mortality for bacteremia due to Staph.

8 aureus than that due to coag. negative staph.

9 There are differences in the epidemiology

10 associated with various pathogens and their

11 virulence. Finally, for the purpose of clinical

12 studies\--let me distinguish that very clearly from

13 clinical practice\--we need to define a discrete

14 clinical syndrome that we can describe in labeling

15 and use as a basis for studies.

16 \[Slide\]

17 Let me just give two different patients

18 here. This gets back to the question of is

19 bacteremia per se important. We obviously think it

20 is but it is not the only important thing. These

21 are two patients from a recent NDA, a 28 year-old

22 woman with category 1 community-acquired pneumonia,

282

1 and a 52 year-old man who falls in category 5.

2 The 28 year-old woman is bacteremic. I am

3 sorry, my graphics didn\'t come out. There wasn\'t a

4 question mark about whether those cultures were

5 obtained; they were, in fact, obtained. For the

6 first patient they both showed penicillin

7 susceptible Strep. pneumo. In the second case only

8 the sputum culture showed Strep. pneumo. But even

9 though one patient is bacteremic and the other is

10 not, their predicted mortalities on the basis of

11 the Port study are very different.

12 \[Slide\]

13 Furthermore, in terms of heterogeneity, I

14 think it is very important to recognize that not

15 all bacteremias are the same. Again, these are

16 real patients. This was a 76 year-old man whom I

17 helped take care of a few years ago at the VA, down

18 in the District. This poor gentleman came in with

19 Staph. aureus all over the place. He had it in his

20 lungs, he had it in his CSF and he had it in his

21 blood. The health staff did a great job of trying

22 to save him. They got an MRI while he was in the

283

1 unit. I still don\'t know how they did that. But

2 he died.

3 Another patient who had a graft through

4 which he was getting hemodialysis also had Staph.

5 aureus bacteremia, had a follow-up because culture

6 that was positive, but this patient did okay. He

7 had a negative echo; negative Doppler. We weren\'t

8 quite sure what to do with him. We weren\'t quite

9 sure what infection he had so we gave him four

10 weeks of IV vanco. and he did great.

11 But you can see in the context of a

12 clinical trial that these two patients are very,

13 very different. In terms of describing them in

14 labeling, it is hard to combine them.

15 \[Slide\]

16 So, right now we have site-based

17 anti-infective indications, and these are defined

18 in the Points to Consider document which we still

19 do refer to from time to time, although I will

20 leave out the delta discussion.

21 Infection at a specified body site due to

22 a specified susceptible microorganism is how we are

284

1 currently defining indications. The reason we

2 chose this is that this really accounts for

3 differences in drug efficacy for infections at

4 different sites. As a very simplistic example, we

5 think that meningitis is more difficult to treat

6 than skin and skin structure infections for a

7 variety of reasons.

8 It allows us to enroll patients more

9 accurately, or colleagues in industry to enroll

10 patients into adequate and well-controlled studies

11 and demonstrate efficacy. Then, in terms of

12 telling physicians and other providers who can

13 benefit from the drug, it allows us to describe the

14 drug efficacy in labeling.

15 \[Slide\]

16 The essentials of an anti-infective

17 indication are that it has to be a recognized

18 disease or condition, or an important manifestation

19 of a disease. In practice, that means it has to be

20 a definable syndrome with specific clinical

21 manifestations, diagnostic criteria and therapeutic

22 requirements. It has to be possible to demonstrate

285

1 drug treatment effect in trials using clinically

2 relevant endpoints, and this effect has to be

3 describable in labeling in the form of an

4 indication and usage section.

5 \[Slide\]

6 I have shown this slide before but just to

7 take some kind of simplistic ideas, UTIs are an

8 indication; dysuria is not. Osteo. is an

9 indication; an elevated sed rate is not, and so on.

10 Prophylaxis against postoperative infection is

11 indication, whereas decrease in skin colonization

12 is not.

13 \[Slide\]

14 In terms of the relationship of different

15 indications in bacteremia, I think it is important

16 to recognize\--I sort of stole this slide back from

17 Dr. Corey, so forgive me\--at any rate, I think it

18 is important to recognize that we have this group

19 here that is undefined and right now the question

20 is what to do with them. It is also important to

21 recognize that just because you can get a drug in

22 here, into the bloodstream, it does not necessarily

286

1 mean that you are going to be equally successful

2 getting it into a vegetation or getting it into

3 consolidated pulmonary parenchyma, and so on.

4 So, I think it is important that efficacy

5 in treating bacteria in the blood be combined with

6 evidence with efficacy for other tissues. I think

7 extrapolating from simple bacteremia to

8 tissue-based infections may be difficult.

9 \[Slide\]

10 Let me just talk briefly about the

11 distinction between bloodstream infection versus

12 bacteremia. The former term I am using to describe

13 a clinical entity if it, in fact, exists, whereas

14 the latter is a lab entity, a lab finding. We have

15 certainly recognized in labeling candidal

16 bloodstream infection or candidemia as an accepted

17 individual, which is frequently primary without an

18 identified underlying infection, and it can be

19 defined as a clinical syndrome in trials and for

20 purposes of labeling.

21 In contrast, E. coli bacteremia is not

22 accepted as an AI indication. It is virtually

287

1 never primary. There is a variety of potential

2 sources, for example, the GI or GU tracts, and

3 there is a wide variety of clinical manifestations

4 depending on that underlying infection.

5 \[Slide\]

6 I think any discussion of bloodstream

7 infection and associated bacteremia also has to

8 address the issue of whether we can use bacteremia

9 as a surrogate endpoint, and we have been talking

10 about this particular finding all day, that as you

11 increase the dose of clarithromycin you are more

12 effective at reducing bacterial load but less

13 effective at keeping patients alive. That is not

14 the same, for example, as Staph. aureus

15 bacteremia\--different population; different but.

16 But if we want to move to Staph. aureus it has been

17 shown that addition of gentamicin to a regimen for

18 endocarditis sterilizes the blood more quickly but

19 it does not improve mortality. So, again, I think

20 it is important to be cautious in terms of what the

21 meaning of bacteremia is as an outcome measure.

22 \[Slide\]

288

1 Let me finish we some questions. First,

2 is there a distinct patient population with primary

3 bacterial bloodstream infection that can be

4 identified at the time of randomization into a

5 clinical trial?

6 If so, how should patients with BSI who

7 demonstrate evidence of metastatic infection

8 post-randomization be classified with regard to,

9 first, whether the BSI was primary or secondary at

10 the time of randomization and, two, how should they

11 be considered in terms of outcome?

12 Finally, in terms of definitions, what

13 combination of clinical manifestations, diagnostic

14 criteria, including exclusion criteria, therapeutic

15 requirements and clinical endpoints would define

16 primary BSI due to a specified bacterial pathogen

17 as a unique individual in labeling? Thanks very

18 much.

19 Discussion

20 DR. EDWARDS: Thank you very much, David.

21 We are going to open these presentations for

22 discussion now. Could we put those questions back

289

1 up? Any comments? George?

2 DR. TALBOT: My first question is, is

3 there a consensus that catheter-related bacteremia

4 is not a viable indication?

5 DR. EDWARDS: John, I think you are going

6 to have to answer that.

7 DR. POWERS: Well, we certainly agree

8 there are problems in studying that. George, you

9 and I talked about delta at the last meeting and

10 that is the question, what is the treatment effect

11 in those people? Ralph brought this idea up if you

12 are studying a less severe disease.

13 So, there are a couple of issues here I

14 think. One is the specificity of the diagnosis.

15 The most common organism you are going to find in

16 catheter-related bloodstream infections is

17 coagulase negative staph., which also has the

18 highest rate of contaminants. I thought you were

19 going to show that. Dave had a slide on this and

20 it actually showed the high rate of contamination

21 with that organism versus Staph. aureus.

22 The second thing is, which is sort of the

290

1 point you brought up at the last session, how do

2 you pick the right patient population, and it is

3 really hard for Staph. aureus to be able to do

4 that. Then, if we are going to do non-inferiority

5 trials here, which I assume would be what we would

6 be discussing, what is the treatment effect? Ralph

7 brought up that we don\'t know if you just take the

8 catheter and don\'t do anything for Staph.

9 epidermidis.

10 Then the other point is Tim\'s. Why should

11 we care that it comes from a catheter versus

12 something else? Then, the last thing is when you

13 look at these meta-analyses on catheter-related

14 bacteremias and diagnosing them, what is the gold

15 standard for comparison to those things? There

16 isn\'t one. So, is 15 CFU off the tip of a catheter

17 really the god standard or would we actually look

18 at that?

19 So, there are a lot of issues related to

20 that that I think become very problematic that we

21 have thought a lot about since that guidance came

22 out. But this really points out an issue with

291

1 guidances, and that is that now we don\'t think that

2 this is such a great idea what do we tell people

3 that might be in development for this particular

4 indication?

5 DR. TALBOT: I think you have highlighted

6 a lot of important scientific issues. I think,

7 just trying to speak from the IDSA perspective, if

8 we are here to speak about what could encourage

9 drug development for anti-infectives, it seems to

10 me that what we have at the moment isn\'t doing that

11 because there has been, to my understanding, no

12 indication granted for these. I don\'t know how

13 many trials are in progress but, clearly, what we

14 have now, it seems, isn\'t working for anybody. I

15 guess I would venture to say that.

16 So, the choices are either to dramatically

17 revise the guidance for catheter-related

18 bloodstream infection to the extent that it would

19 be clear that it would be feasible and highly

20 pragmatic to perform the study, and that the

21 results would be clinically meaningful. As Tim

22 pointed out, how can you generalize from one

292

1 percent of your screened population? So, that is

2 one choice. The other choice is to say, well, we

3 gave it the best shot; let\'s look at another model

4 of bloodstream infection, say, with staph. and try

5 to do better there. Either way, I think from

6 IDSA\'s perspective would be a great step forward.

7 DR. POWERS: I think one of the other

8 issues is that we are sort of granting indications

9 already that include patients that have Staph.

10 aureus bacteremia. So, daptomycin in complicated

11 skin and soft tissue trials include people that

12 have methasone-resistant Staph. aureus bacteremias.

13 The linezolid trials for hospital-acquired

14 pneumonia included people like that. And, are we

15 actually raising the bar by requiring people to

16 have positive blood cultures in those settings?

17 Right now what we have done is looked at

18 subsets of people who are bacteremic. The way we

19 have used it really is to ensure the specificity of

20 diagnosis, that we know that those people who have

21 a positive blood culture really have the disease in

22 question and that helps give us some certainty.

293

1 So, the question here is what information would be

2 gained by doing separate trials of Staph. aureus

3 bacteremia, and would that add anything either to

4 clinicians\' knowledge about how the drug is

5 effective in these particular settings, and would

6 it be something that would be palatable for folks

7 in industry? Would it help them or would they

8 perceive it as here is yet another thing we have to

9 do?

10 DR. TALBOT: If I could just comment on

11 one of the things about bacteremia with complicated

12 skin, and I would like to hear what Frank, Tim and

13 Barry have to say, but I wonder, having seen a

14 number of trials, just how representative those

15 data are. My impression is that the vast minority

16 of patients have bacteremia and they are only in

17 there because in the setting of an investigational

18 drug trial they slipped in somehow. The

19 investigator didn\'t really think they were that

20 sick, or what-have-you, and then they show up and

21 they are doing okay so they are kept in. But I am

22 not sure that that is answering the question about

294

1 how the drug does in bacteremia. If you want to

2 answer that question I think you need to set out to

3 study it.

4 DR. EDWARDS: Yes, David?

5 DR. ROSS: Let me make two points, one

6 about the issue of catheter-related bloodstream

7 infection and the other about sort of the

8 development strategy if one was going to have BSI.

9 First off, Tim outlined very, very nicely

10 I think the difficulties with this sort of study.

11 There are two things I think that drive this, and

12 everyone is aware of this but let me just restate

13 them. First off, these are non-inferiority trials

14 in general because nobody feels comfortable saying

15 we shouldn\'t treat these patients with coag.

16 negative staph. in their blood if we think it is

17 real, even though we don\'t know the magnitude of

18 the treatment effect. But, as John pointed out,

19 coag. negative staph. is more likely to be a

20 contaminant than if you have a peripheral blood

21 culture. So, in order to try and reduce the noise

22 in these studies and make sure that where two drugs

295

1 look similar it is because they are similar, not

2 because there are a lot of patients who don\'t

3 really need treatment. The CR-BSI guidance was

4 written to try to be very strict, but it is a

5 problem.

6 I am grateful to Tim for sharing the

7 experience with this trial because we all have had

8 the experience of rolling our eyes when we are told

9 there is a consult or there is a patient with one

10 positive blood culture for coag. negative staph.,

11 how long do we need to treat him for? You know, we

12 all say, well, you don\'t. But in the context of a

13 clinical trial it becomes much more difficult, more

14 expensive to say we have to prove that it is not

15 real. That is number one.

16 Number two, just to get to the issue of

17 package, sequence and that sort of thing, I think

18 our intent with the guidance, the original guidance

19 was that catheter-related bloodstream infection and

20 complicated skin and skin structure infections

21 share some pathophysiologic features. One of our

22 thoughts was that those two could support each

296

1 other, not necessarily having to do them I think in

2 a sequential way. In terms of rational drug

3 development you might not need to show efficacy for

4 cSSI before going on to catheter infections. You

5 could actually proceed simultaneously. Potentially

6 you could see the same sort of strategy with

7 primary BSI of unknown origin, that it could be

8 supported by other indications being developed at

9 the same time.

10 DR. COREY: David, you gave the examples

11 that, you know, these people are vastly different,

12 the young woman with pneumonia, etc. But the same

13 thing happens with other diseases that are lumped

14 together. You have a young man with single vessels

15 coronary disease who has an MI and you treat him

16 with a 2B3A and you have an 80 year-old who has had

17 three MIs who has no left ventricle and has an MI.

18 the mortalities of those two groups are

19 phenomenally different and yet they are treated

20 under MI studies. I don\'t see why we are doing

21 that.

22 We have to test these drugs in the

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1 population in which they are going to be used. We

2 are trying to think here how we can get there

3 quicker and not lose safety. I don\'t want to hurt

4 or harm a patient; nobody here wants to harm a

5 patient and, yet, we do want to get new drugs on

6 the market and available to us before vancomycin

7 becomes totally useless.

8 DR. ROSS: I absolutely agree with you. I

9 think that is a very good point. Let me point out

10 that those two patients were actually enrolled in

11 the same trial under the same criteria, and I think

12 that is absolutely appropriate. I think, you know,

13 we have a validated prediction rule for saying how

14 different these patients are, and is that because

15 the patients are different or because the drugs

16 that they are being treated with are different? I

17 think that in the case of other conditions

18 associated with bloodstream infection, with

19 bacteremia let me say, it is certainly valid I

20 think to be able to enroll people with the same bug

21 who have very different prognoses as long as we can

22 define at baseline how they are liable to do so we

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1 can separate the underlying protoplasm from drug

2 effect.

3 DR. COREY: One of the problems with at

4 baseline is that that is one of our big problems

5 with a trial like this. You enroll them before you

6 know what their prognosis is. If one of your big

7 criteria is the follow-up blood culture, then you,

8 at that point, can start defining them as

9 complicated or uncomplicated bacteremia. But if

10 take all-comers I think the cut point really is at

11 14 days. If you take all-comers with Staph. aureus

12 bacteremia and you treat them, at 14 days you are

13 going to know whether you are going to stop at that

14 point because there is no evidence of metastatic

15 disease and the patients respond, or whether you

16 are going to go on and after that point new

17 metastatic infections become complications. So, if

18 you do take an all-comers trial, it is fairly

19 complicated to set up but it can be done.

20 DR. ROSS: If Dr. Fleming has any thoughts

21 on this I would be grateful for your thoughts on

22 this. If we are defining patients on the basis of

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1 a post-randomization event, since randomization is

2 frequently the major defense against entry of

3 statistical biases, how do we deal with that?

4 Obviously, we can prespecify the analysis and try

5 to deal with things that way but if you have a

6 relatively small trial where there are imbalances

7 between treatment arms, how do we deal with that?

8 DR. FLEMING: If you want to characterize

9 a subgroup for example, a subset of your patients,

10 ideally you would like to have that information at

11 time zero. Obviously, you have to have that

12 information at time zero at time of randomization

13 if you are going to use that for your eligibility

14 criteria.

15 What is critical is to be able to

16 establish that whatever measures you are actually

17 collecting post-randomization were in no way

18 influenced by the randomization. So, if you are

19 collecting information post-randomization that is

20 helping you to better characterize your patients,

21 if you want to use that for subgroup analyses you

22 have to be persuasive that those factors weren\'t

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1 influenced by the effect of the knowledge of the

2 intervention to which the patient was assigned.

3 DR. ROSS: For example, just to take a

4 ridiculous example, let\'s suppose you have an

5 unblinded study and you are more likely to sample

6 the patient\'s blood post-randomization based on

7 treatment assignment, that could be an example. I

8 mean, that is obviously a ridiculous example but

9 that is one theoretical way\--

10 DR. FLEMING: Then you couldn\'t be

11 confident that the integrity of randomization would

12 be preserved.

13 DR. ROSS: But if, on the other hand, you

14 had, let\'s say, a standardized protocol for

15 collecting blood cultures post-randomization at 72

16 hours and no excuses accepted, otherwise the

17 medical student who is supposed to get it gets an F

18 for the rotation, then that would be okay in terms

19 of having post-randomization classification of

20 populations.

21 DR. FLEMING: Yes, you could have a blood

22 sample taken at baseline to identify gram-negative

301

1 sepsis, or something, and actually not determine

2 the results of that until after randomization. The

3 problem I have with that though is that the

4 practicality is that you are getting a result in a

5 population that isn\'t defined or isn\'t known at

6 time zero. Ideally, what I want to do is a trial

7 that will represent real world; that will allow me

8 to assess what is the effect in a population based

9 on time zero information that I would know in the

10 real world.

11 DR. POWERS: I think one of the other

12 issues gets back to our previous discussion about

13 surrogate endpoints, and that is the differential

14 effect between drugs. We know from data in terms

15 of data like vancomycin versus nafcillin in terms

16 of time to clearance of because cultures that there

17 appear to be differences across those drugs which

18 do not appear to translate into clinical outcomes.

19 So, it would be hard to imagine\--even if you

20 specified in the protocol, clinicians aren\'t going

21 to change what they are going to do if they see

22 that blood culture remaining persistently positive

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1 in one group of patients versus the other.

2 DR. COREY: I think we have to be careful.

3 That data all comes from Erol Sandy\'s group and

4 that was a combined trial between the University of

5 Virginia and UCSF, and it was mostly IV drug

6 abusers and the mortality in that study was

7 incredibly low. The chances of finding a

8 difference with a week of gentamicin was almost

9 impossible. They just didn\'t have the negative

10 outcomes to do that. That is the only study I know

11 of where we don\'t show a benefit even though we

12 show only a one day improvement in clearance. It

13 was a 6 day to 5 day improvement in clearance. So,

14 with a small improvement in clearance and no

15 outcomes or very few outcomes\--you know, these are

16 young men with right side endocarditis\' they didn\'t

17 die.

18 DR. POWERS: But how many times have you

19 heard vancomycin isn\'t as good a drug for Staph.

20 aureus bacteremia as nafcillin, based on that

21 information? So, there is a belief out there\--

22 DR. COREY: Yes, but that comes from a lot

303

1 of different data. That comes from the data on

2 right side endocarditis with nafcillin with gent.

3 where you can treat for two weeks but if you use

4 vanc. and gent. you tend to fail at a high rate.

5 That comes from looking retrospectively and in our

6 database prospectively at patients with MSSA and

7 the considerable number who got vanc. because, you

8 know, they are on dialysis, and looking at

9 outcomes. There is a lot of data to support the

10 feeling that vanc. isn\'t as good a drug. There is

11 not a prospective head-to-head trial because nobody

12 will fund it.

13 DR. EDWARDS: David Shlaes?

14 DR. SHLAES: Actually I agree with Dr.

15 Corey that you could, in fact, define a trial based

16 on Staph. aureus primary bacteremia very

17 reasonably. But the other thing to understand is

18 that when you talk about real world there is

19 nothing more real world in hospitals than primary

20 bacteremia. This is probably the most common

21 reason why people are treated with antibiotics for

22 nosocomial infection in hospitals. You get a call

304

1 in the middle of the night; a patient has a fever;

2 you worry about catheter-related bacteremia and you

3 treat the patient empirically. If you look at

4 antibiotic use in hospitals in the United States

5 and basically globally, 70, 80 percent is empiric

6 use and this has to be one of the most common

7 reasons for empiric use of antibiotics. So, there

8 is nothing more real world than this issue.

9 So, what I would submit is that you could,

10 in fact, construct a trial along the lines proposed

11 by Dr. Corey with reasonable inclusion and

12 exclusion criteria, but then the question is would

13 you be willing to take\--going back to one of Dr.

14 Goldberger\'s suggestions\--the data on the more

15 virulent pathogen, which is almost never a

16 contaminant, Staph. aureus, and apply that or

17 extrapolate that to a disease due to coag. negative

18 staph. which, of course, is a much less virulent

19 pathogen? So, that would be something I think to

20 consider.

21 DR. POWERS: That is one of the things

22 when we brought that up in March of 2003 that the

305

1 advisory committee did not feel comfortable with,

2 and that is extrapolating from different

3 microbiologic causes and, clearly, there are

4 differences, as Ralph showed, between Staph.

5 epidermidis and Staph. aureus. But the real

6 question there would be could we use that data from

7 Staph. aureus to support some other indication

8 where Staph. aureus is very common, like

9 complicated skin infections? So, when we were

10 talking about this internally we were thinking

11 maybe bacteremia with Staph. aureus would not stand

12 alone as an indication by itself if that was the

13 only study you wanted to do for drug approval, but

14 perhaps it could give us some important information

15 as supportive information for other diseases where

16 Staph. aureus may be more common, like

17 hospital-acquired pneumonia, complicated skin

18 infections, etc. to try to use it in a supportive

19 role.

20 There are some other issues here though.

21 The post-randomization thing is not minor, and we

22 have come up against this in empirical therapy

306

1 trials in both the fungal and antibacterial realm.

2 How do you define baseline infection versus

3 breakthrough infection? So, you get into the trial

4 and on day three you pop up with your big phrenic

5 abscess. How do I know that wasn\'t there at the

6 start versus this is progression of the disease on

7 therapy which one would consider a failure?

8 But let\'s get back to the issue of

9 supportive information. Would that be something

10 that would be helpful for people, at least

11 extrapolating from Staph. aureus to other diseases?

12 DR. EDWARDS: Anyone want to answer that?

13 Bill?

14 DR. CRAIG: To me, the important thing for

15 Staph. aureus bacteremia is that we are also

16 treating potential endocarditis. So, that is an

17 area that I think almost needs to be studied along

18 with bacteremia so that somehow you can put the

19 endocarditis patients in there to make sure that if

20 you are going to treat severe bacteremia you are

21 also going to be effective against endocarditis,

22 whether you can add them in as an open part or

307

1 somehow get them into the mix, because at many of

2 your smaller community hospitals, if they get a

3 staph. bacteremia, they are not going to

4 necessarily have the techniques to go ahead and

5 rule out endocarditis. So, I think you need to

6 have that included somehow into the clinical trial.

7 DR. POWERS: Bill, you read my mind. I

8 have written at the bottom of my page is this a

9 tacit approval for endocarditis? So, I think that

10 becomes something we are very concerned about, that

11 when people have bacteremic patients and they can\'t

12 find something, they assume\--why do we treat those

13 people for four weeks? They assume it is

14 endocarditis and treat them. So, we have done

15 something like this with candidemia where we took

16 people with primary bloodstream infections with

17 candidemia but looked at the patients that had

18 organ disease within that trial, and that gave us

19 some comfort that, gee, this drug looks like it

20 works for hepatosplenic candidiasis. We did not

21 require people to go out and study 50 cases of

22 hepatosplenic candidiasis but we looked at that

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1 subset within there.

2 The two subsets here we want to see are

3 both right-sided and left-sided endocarditis

4 because those do not appear to be the same disease

5 in terms of outcome and prognosis.

6 DR. EDWARDS: John Rex?

7 DR. REX: I wanted to make a comment about

8 the thing that I did in my previous life, which is

9 study candida bloodstream infections, and how that

10 actually has some parallels to this debate because

11 99 percent of what we have just been hearing has to

12 do with Staph. aureus. With candidemia you

13 actually are in a situation where you almost never

14 know why it is in the blood. Right? So, we don\'t

15 have these debates in the fungal world about is

16 this candidal pneumonia with candidemia or is this

17 candidal osteomyelitis with candidemia. So, you

18 might call it primary though truly it is never

19 primary. The candida did not materialize via a

20 transporter beam into the bloodstream. It got

21 there via a catheter or via some hole in the gut or

22 some other thing. The same thing is true of Staph.

309

1 aureus. It did not materialize in the blood; it

2 got there via some mechanism. Your problem though

3 is that you don\'t know what mechanism drove it

4 there. You can eliminate some of the obvious

5 suspects. The patient doesn\'t have pneumonia; the

6 patient doesn\'t have a UTI; the patient doesn\'t

7 obviously have osteomyelitis right now, isn\'t the

8 right age for bacteremic osteomyelitis.

9 So, what you are left with then is this

10 group of unknown primary or catheter. Then you ar

11 sitting there, staring at this patient, in bed with

12 a catheter in the vein and you say to yourself, all

13 right, is it the catheter or not? I have looked at

14 hundreds of cases of candidemia and I have looked

15 at catheter cultures until it drove me nuts. What

16 I conclude from all that is that I don\'t know for

17 any given patient\--patient in bed 12 has a catheter

18 in place and the catheter has to come out; there is

19 no question, it has to come out for all the

20 patients, but for this particular patient I can\'t

21 tell you but I know that on aggregate the patient\'s

22 catheter has to come out. As a consequence, I

310

1 think there is a disease here, as David Shlaes

2 said, this is it. This is the disease you have to

3 treat. You are staring at a patient in bed 12 and

4 you have to treat him.

5 From my standpoint, there are really three

6 groups of candidemic patients. They are people

7 without a catheter; they are people who have a

8 catheter and somebody pulls it; and they are people

9 who have a catheter and somebody doesn\'t pull it.

10 And, I can show that there are differences in the

11 way that those three groups behave, more or less,

12 on an aggregate basis but for individual patients I

13 don\'t know which is which. So, I think you

14 actually have to treat them. Maybe you stratify

15 across the three if you are enrolling them into

16 your trials but even then it is very hard to do

17 that because somebody says they are going to pull

18 the catheter but then it turns out they don\'t, and

19 it is all very complicated and very painful and

20 irritating.

21 So, there is definitely an entity that

22 must be studied because it is a disease that a

311

1 clinician has to treat, and that is really what I

2 want to say. Can Staph. aureus bacteremia without

3 a probably source other than a catheter\--I have

4 just made up a label indication for you\--is that

5 something that by itself should get a drug

6 approved? I don\'t think so. I think you ought to

7 have something else to go with it. But by itself

8 is it a thing that I want to know about? Yes, it

9 is definitely something that I want to know. I

10 want to know what happens and I want to know

11 something about what happens when I do and do not

12 remove the catheter.

13 So, that is the end of my sermon on this.

14 It is a very hard area and Tim\'s story about having

15 to screen 2,600 patients to find 70 in whom they

16 proved that it was the catheter\--you know, I think

17 that is a bold maneuver. I thank you for that data

18 because that tells the rest of us that we

19 never-ever, ever want to attempt to do that.

20 \[Laughter\]

21 And, I thought candidemia was bad enough.

22 But at least of you screen 2,600 patients with

312

1 candidemia you will enroll 200 and be able to do a

2 study. I have done that. So, it is possible to do

3 that study. But here you are telling us that you

4 can\'t really do it and you have just shown us that

5 if you take the group of patients who have this in

6 their blood with Staph. aureus, you have a high

7 relapse rate. You have an opportunity top measure

8 a serious disease and, thus, in the three studies

9 that I helped do for candidemia the first study was

10 about candidemia. For the second the disease was

11 candidemia and its complications. That is what it

12 really I think all boiled down to, it was \"and its

13 complications.\" When you get down to a low relapse

14 rate, a low secondary event rate then you are

15 actually feeling pretty good about what you have

16 done.

17 DR. EDWARDS: David, let me ask a

18 question. It is now 4:30. We are basically at

19 about the beginning third of this discussion in my

20 estimation and we need to make a decision as to

21 what we are going to do about that. Keep going? I

22 am sorry, I promised 4:30. Why don\'t we shoot for

313

1 another 15 minutes? Okay? Then we will use that

2 as a cutoff.

3 DR. POWERS: Can I sum up what we have

4 heard so far and then we can get to the parts we

5 haven\'t covered?

6 DR. EDWARDS: John, you know, I have been

7 planning to do a summary and I am so completely

8 incapable of doing that at this point that I would

9 love to have you do that.

10 DR. POWERS: About this part of the

11 session, anyway, I think what we heard was that

12 primary Staph. aureus bacteremia without another

13 source could be an indication that supports other

14 disease entities in which Staph. aureus would also

15 be common, things like complicated skin and

16 hospital-acquired pneumonia. That database of

17 Staph. aureus bacteremia would include patients

18 with both right- and left-sided endocarditis

19 because we are essentially treating a lot of people

20 like that and some amount of information within

21 there in well-characterized cases, with a positive

22 echo, that we are sure have endocarditis\--because

314

1 this is what Dr. Goldberger has been talking about.

2 We don\'t think the placebo cure rate in those

3 people is very high. So, that would give us some

4 really good, helpful information that the drug is

5 actually effective in those diseases. And, I think

6 it is problematic to extrapolate that to Staph.

7 epidermidis because they are not the same kind of

8 organism but it could be useful in extrapolating to

9 complicated skin and hospital-acquired pneumonia,

10 etc. as part of a package.

11 Now, what I think we have left to

12 discuss\--

13 DR. EDWARDS: John, excuse me, I just need

14 to ask one question about that. When you say

15 support\--

16 DR. POWERS: This means one study in this

17 bacteremia plus endocarditis group would support

18 one study\--that is a really good question. What

19 does the word support mean?

20 \[Laughter\]

21 You know, what I said last week when

22 somebody came in with this, I said you have a tent

315

1 pole and no tent because you have to have something

2 to support. It doesn\'t mean you can get

3 hospital-acquired pneumonia with no

4 hospital-acquired pneumonia trial. It means doing

5 one study of hospital-acquired pneumonia and that

6 would go together in terms of each of those linking

7 to each other. Dr. Goldberger I think has used

8 this idea of, you know, in the Civil War they used

9 to stack the rifles up against each other to hold

10 them up together. That is what we are looking at,

11 each of these things supporting the other but there

12 has to be something there to support. That word

13 gets used very loosely\--\"I have no cases and no

14 isolates but here is my other stuff; I should get

15 approval for this completely different indication.\"

16 DR. TALBOT: I wanted to comment on the

17 support issue also from a slightly different

18 perspective because, just speaking about what I

19 heard, I heard support from the clinicians, over

20 there, for Staph. aureus bacteremia in one of its

21 variants and with adjustment for what you know at

22 the time of enrollment. I heard that that in and

316

1 of itself would be a valid indication. When you

2 commented about that supporting something else,

3 that actually causes me concern because I am not

4 sure I would want to go into what would be, of

5 necessity, a Staph. aureus bacteremia/possible

6 endocarditis before knowing a lot about the drug,

7 such as did it really work in a well-performed

8 development plan for complicated skin with a lot of

9 staph? Do you know anything about staph. if it is

10 in the urine, etc.? So, I actually would be

11 thinking about that as happening only if you have a

12 very convincing demonstration of success in other

13 indications and if you have a very convincing

14 rationale for dose selection for endocarditis based

15 on PK/PD, animal and clinical data.

16 DR. POWERS: This is a great dovetail for

17 tomorrow\'s discussion and it is what Dr. Schentag

18 brought up. There are well developed rabbit models

19 for endocarditis. It this a place where an animal

20 model would be helpful in terms of giving some

21 proof of principle to do you have any shot of being

22 effective in endocarditis so that you could use

317

1 that before you go forward in a Phase 3 trial, and

2 the dose selection issue as well.

3 DR. TALBOT: Well, the experts in that can

4 debate that but, frankly, when I was a practicing

5 clinician I wouldn\'t want to enroll my patient who

6 might have endocarditis in a study with a drug that

7 was going to its Phase 3 studies.

8 DR. COREY: I disagree with that, George.

9 I think the animal model is a good model. The

10 rabbit model is a good model. There is also Claude

11 Carbone\'s group in Paris, looking at penetration of

12 carbon-14 labeled drug into vegitations. So, we

13 can get some really good idea of penetration, and

14 we have every other group, from heart attacks to

15 oncology, where we are testing our drug in patients

16 with metastatic cancer or with cancer, and we test

17 them in heart attaches and, yet, we are sort of

18 afraid to say, okay, we are not going to test them

19 complicated bacteremia and endocarditis until we

20 have all these other things behind it, and I don\'t

21 think that is right. I think that leaves us right

22 now with no drugs approved for endocarditis, yet we

318

1 are treating endocarditis. So, the only people

2 testing them are the private practitioners, like

3 me, sort of saying, well, I will give this drug but

4 I have no trials to back me.

5 DR. TALBOT: I just want to comment.

6 First of all, as I said, I am not a current

7 clinician and I am not an expert on endocarditis so

8 I appreciate and respect your comments. I guess I

9 was coming more from the sorts of issues I have

10 seen. Certainly, a drug with potential should be

11 studied in this indication. The only question I am

12 posing\--maybe that is a better way to put it\--is

13 when in the development process it is appropriate

14 to do that. For some drugs, with George\'s Monte

15 Carlo and so forth, maybe it is fine but I guess\--

16 DR. DRUSANO: No, it is not.

17 DR. TALBOT: But I guess thinking about

18 some of the development programs I have seen, for

19 sure, I would want there to be as an iron-clad dose

20 rationale as possible; a totally consistent

21 preclinical PK/PD basis. There is an issue of

22 safety. This is a very ill patient population. If

319

1 you are talking about going directly into Phase 3

2 with a compound with a limited safety database from

3 Phase 2, I would be concerned about unexpected

4 safety issues which could then have a very

5 unfavorable impact, regardless of bacteriologic

6 efficacy, on the outcome of patients in that study.

7 So, those are the questions. The challenge is to

8 move into it as quickly as possible and I agree

9 with your premise that that should be the goal, but

10 just have a couple of caveats about how quickly you

11 do that on the basis of the information.

12 DR. ROSS: First off, I want to endorse

13 Dr. Rex\' statement. There are no normal blood

14 flora; the Staph. aureus doesn\'t just get there.

15 One question I would like to ask, and I am not

16 asking anybody for any commitments to come in for a

17 pre-IND meeting, is what would people say is the

18 level\--if there were a Staph. aureus BSI indication

19 and guidance of some sort on how to go about

20 developing drugs for that, what do people think

21 would be the level of interest on the part of \"big\"

22 pharma, \"small\" pharma, whoever, in terms of

320

1 developing drugs for that indication?

2 DR. EDWARDS: Who would like to respond to

3 that? Frank?

4 DR. TALLY: I thought when we first

5 discussed this in \'98 and, actually, at an internal

6 FDA-industry meeting we also discussed it, and I

7 thought at that time there was of a lot of interest

8 in the pharmaceutical companies and in our company

9 for that. We were looking forward to doing that.

10 When we saw the criteria for the

11 catheter-associated infection we took a different

12 tack at that point in time, for many of the reasons

13 that Tim just outlined. Having experienced that in

14 a couple of other studies, it is a problem. So,

15 took the route of going a little bit in the

16 opposite way because there is an indication for

17 endocarditis. So, we took the route to go

18 endocarditis bacteremia, and then you can get it.

19 That is a tortuous route to go, and we are

20 in right in the middle of a study, as you well

21 know, and we have screened 3,000 patients to get

22 100, about double the amount that you have. They

321

1 are tough studies to do. But it is the type of

2 thing when you do complete it, if it is successful,

3 that is very important to the treating physicians,

4 and that is what they are asking us for.

5 DR. EDWARDS: Dave Shlaes, would you mind

6 commenting on that question?

7 DR. SHLAES: I think you are going to find

8 more interest from the smaller pharmaceutical

9 companies who are more concentrated in the hospital

10 market right now than from large pharmaceutical

11 companies who have traditionally been more

12 concentrated in the community market. That doesn\'t

13 mean that this will change but I would guess that

14 that would be kind of a generalization industry

15 sort of view.

16 DR. EDWARDS: Thank you. Yes, George?

17 DR. DRUSANO: I would like to kind of go

18 back to Dr. Corey\'s statement. I can only speak

19 for myself. I think, first of all, an animal model

20 is a necessary but insufficient condition to

21 support going into something as serious as

22 endocarditis. That is number one.

322

1 Number two, I think you have to be very

2 careful about the animal model that you use. You

3 know, people shouldn\'t use a mouse eye infection

4 model when the target is derived from mouse eye

5 infection models to do a PD assessment and say, oh,

6 we can hit that; we should probably go right into

7 endocarditis. So, I think you have to be very

8 careful about the database that you generate for

9 preclinical-clinical bridging. So, that is number

10 one.

11 Number two, I can only talk about our IRB

12 and our IRB, if you tried to go right from a Phase

13 1 environment into an endocarditis trial, you would

14 just get laughed out. I think, again, a necessary

15 condition is to have some reasonable expectation

16 that the drug actually works in lesser infections.

17 We learn all the time, but I do remember back in

18 the \'80s we had cefonicid when euthanasia was

19 indicated. That thing got approved but we didn\'t

20 know enough about protein binding at the time and

21 we had a lot of endocarditis failures with that

22 drug. I would, sure as heck, before I went into

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1 something like endocarditis want to know for the

2 patient\'s sake that it really worked.

3 DR. COREY: But did the previous skin

4 trials predict that there were going to be

5 endocarditis failures? I think the problem is you

6 are assuming that studies in skin and skin

7 structure infections are going to help us predict

8 what is going to happen in the serious infections,

9 and I don\'t think they are. I go back again, the

10 fourth time I am mentioning it, to we test drugs

11 for MI prevention in a highly lethal disease in

12 patients who have MI. We do not take those

13 sequentially through a series of other diseases

14 that don\'t exist. We do our preclinical as best we

15 can. We get a drug, we test it. We find out that

16 our bugs are highly susceptible. We find out it

17 penetrates into the right area. We look in our

18 data for drug levels in humans as Phase 1. Then we

19 go test it in diseases that we really care about.

20 I remember being overseas and we talked to the

21 French about skin studies, and they just laughed at

22 us because we don\'t need another drug for skin

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1 studies. We need a drug for bacteremia.

2 DR. POWERS: Ralph, you are getting to a

3 great point. So, it is okay that we give the drug

4 to people that don\'t need it, and then what do we

5 know about how the drug works. I think this

6 dovetails greatly into what we are going to talk

7 about tomorrow, that is the utility of what happens

8 in Phase 2. We see a lot of people going from

9 Phase 1 to Phase 3. Nobody wants to take it from

10 the test tube and give it to somebody for

11 endocarditis. What is the role of small Phase 2

12 pilot trials where we could actually get some proof

13 of principle that would make people feel

14 comfortable and go forward?

15 DR. DRUSANO: That is a different story.

16 I mean, at the end of the day you have to have some

17 idea that the drug works. In point of fact, in

18 cefonicid trials there were some hints that the

19 complicated skin and skin structure trials didn\'t

20 quite get to exactly where you wanted to go, and

21 before you go into something like meningitis, like

22 endocarditis, you know, the lesser infections are a

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1 necessary, again, but insufficient condition. If

2 they don\'t work in complicated skin and skin

3 structure it is unlikely to work in endocarditis.

4 Whether you say it as a function of I have to see

5 some well-controlled trials or I have to see some

6 good, well-designed translational Phase 2 trials,

7 that is fine; you know, six of one and half a dozen

8 of another and we are talking basically about the

9 same thing. I would be happy with that. But I

10 think before you go into things like endocarditis,

11 like meningitis you have to be very clear that your

12 drug actually does work.

13 DR. EDWARDS: Thank you. George, while we

14 are talking about dovetailing to tomorrow, we are

15 going to do that at this moment. If I could just

16 have one second though, tomorrow we really have our

17 work cut out for us. The intensity of the areas of

18 discussion are, if anything, more so than they are

19 today. I wanted to just thank everyone for the

20 extremely high quality presentations and extremely

21 thoughtful discussions, and I think we have all

22 learned a tremendous amount from what has gone on

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1 today and have a lot to build on from here on.

2 I am not going to try to summarize today

3 at this moment because of the hour and, besides

4 that, tomorrow you are likely to get a higher

5 quality summary than you are right now. So, I am

6 going to conclude. We resume at nine o\'clock

7 tomorrow morning. Again, thank you all very, very

8 much. Thank you.

9 \[Whereupon, at 4:45 p.m., the proceedings

10 were recessed, to resume on Friday, April 16, 2004

11 at 9:00 a.m.\]

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