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 

                                                               121

  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 

                                                               122

  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 

                                                               123

  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 

                                                               124

  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 

                                                               126

  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 

                                                               297

  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 

                                                               298

  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 

                                                               299

  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 

                                                               300

  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 

                                                               302

  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 

                                                               308

  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 

                                                               323

  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 

                                                               324

  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 

                                                               325

  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 

                                                               326

  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.]

 12                              - - -