ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE**
>
> Thursday, July 11, 2002
>
> 8:30 a.m.
>
> Marriott Washingtonian Center
>
> 9751 Washingtonian Boulevard
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> L. Barth Reller, M.D., Chair
>
> Tara P. Turner, Pharm. D., Executive Secretary
>
> MEMBERS
>
> David M. Bell, M.D.
>
> Alan S. Cross, M.D.
>
> Steven Ebert, Pharm.D. (Consumer Representative)
>
> Mary P. Glode, M.D.
>
> James E. Leggett, Jr., M.D.
>
> Judith R. O\'Fallon, Ph.D.
>
> Jan E. Patterson, M.D.
>
> Julio A. Ramirez, M.D.
>
> Ciro V. Sumaya, M.D.
>
> Ellen R. Wald, M.D.
>
> CONSULTANTS (VOTING)
>
> P. Joan Chesney, M.D.
>
> G. Scott Giebink, M.D.
>
> Robert M. Nelson, M.D., Ph.D.
>
> CONSULTANT (NON-VOTING)
>
> Vernon M. Chinchilli, Ph.D.
>
> GUESTS (NON-VOTING)
>
> Ron Dagan, M.D.
>
> Alejandro Hoberman, M.D.
>
> Colin D. Marchant, M.D.
>
> George H. McCracken, Jr., M.D.
>
> Jack L. Paradise, M.D.
>
> Michael E. Pichichero, M.D.
>
> Coleman Rotstein, M.D.
>
> FDA
>
> Renata Albrecht, M.D.
>
> Rosemary Johann-Liang, M.D.
>
> Mark Goldberger, M.D. M.P.H.
>
> John Powers, M.D.
>
> George Rochester, Ph.D.
>
> Thomas Smith, M.D.
>
> Janice Soreth, M.D.
>
> [C O N T E N T S]{.underline}
>
> Call to Order: L. Barth Reller, M.D. 4
>
> Introduction of Committee 5
>
> Conflict of Interest Statement: Tara P. Turner, Pharm.D. 8
>
> Guidance Development: John H. Powers, M.D. 11
>
> Development of Antibiotics for Otitis Media:
>
> Past, Present and Future:
>
> Janice M. Soreth, M.D. 22
>
> Design Issues in Antimicrobial Treatment
>
> Trials of AOM:
>
> G. Scott Giebink, M.D. 41
>
> Experience with Tympanocentesis:
>
> Clinical Diagnosis of AOM:
>
> Michael Pichichero, M.D. 59
>
> Double Tympanocentesis Studies:
>
> Ron Dagan, M.D. 76
>
> Limitations of Clinical-only Studies:
>
> Colin Marchant, M.D. 100
>
> Study Designs for Acute Otitis Media Trials:
>
> What Can Each Design Tell Us?
>
> C. George Rochester, Ph.D. 118
>
> Lesson Learned from Past Approvals:
>
> Thomas Smith, M.D. 134
>
> Study Considerations: Recurrent/Treatment
>
> Failure AOM:
>
> Rosemary Johann-Liang, M.D. 148
>
> Open Public Hearing
>
> Michael R. Jacobs, M.D., Ph.D. 168
>
> Jack L. Paradise, M.D. 187
>
> Summary and Charge to the Committee:
>
> Renata Albrecht, M.D. 192
>
> Committee Discussion and Vote 203
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order**
>
> DR. RELLER: Good morning. I am Barth Reller and I should like to call
> the Advisory Committee meeting to order.
>
> We have an exciting agenda with multiple presentations, multimedia. It
> is very important that we adhere strictly to the schedule to enable
> full discussion of this important topic - Clinical Trial Design for
> Studies of Otitis Media.
>
> This is coming to fruition of a great deal of work that has been done
> by many individuals over the years. To help us adhere to the schedule,
> Dr. Tara Turner, our executive secretary, will be having a light
> system that will quietly but firmly give the speakers notice when
> there are two to three minutes left depending on the length of the
> talk, two minutes for the short talks and three minutes for the 15- to
> 20-minute talks.
>
> We will see the light, you will see the light that will go yellow,
> when it is time to send up red when your time is up, and a short
> period thereafter, the floor will open, and like the Mozart opera,
> there will be a display and disappearance.
>
> We will begin with an introduction of the committee members and
> starting on my far, far right, actually, the consultants and the
> committee members, and to the far right, Dr. Pichichero, the name and
> affiliation.
>
> **Introduction of Committee**
>
> DR. PICHICHERO: Michael Pichichero, professor at the University of
> Rochester Medical Center and practicing pediatrician, Elmwood
> Pediatric Group, Rochester, New York.
>
> DR. MARCHANT: Colin Marchant, Pediatric Infectious Disease at Boston
> University and Tufts University.
>
> DR. HOBERMAN: Alejandro Hoberman, Department of Pediatrics, University
> of Pittsburgh School of Medicine, Children\'s Hospital.
>
> DR. DAGAN: Ron Dagan, Professor of Pediatrics and Infectious Diseases,
> Ben-Gurion University, head of the Pediatric Infectious Disease at
> Soroka Medical Center in Beer Sheva, Israel.
>
> DR. GOLDBERGER: I am Mark Goldberger from the Office of Drug
> Evaluation IV, FDA.
>
> DR. POWERS: John Powers, Office of Drug Evaluation IV, FDA.
>
> DR. ALBRECHT: Renata Albrecht, Division of Special Pathogens and
> Immunologic Drugs, FDA.
>
> DR. SORETH: Good morning. I am Janice Soreth. I am the Division
> Director for Anti-Infectives at FDA.
>
> DR. SMITH: Tom Smith, medical officer in the Division of
> Anti-Infectives at the FDA.
>
> DR. JOHANN-LIANG: I am Rosemary Johann-Liang. I am the medical officer
> at the Division of Special Passages.
>
> DR. NELSON: Robert Nelson, Children\'s Hospital, Philadelphia.
>
> DR. GLODE: Mimi Glode, Pediatric Infectious Disease, University of
> Colorado, Denver.
>
> DR. BELL: David Bell. I am Assistant to the Director for Antimicrobial
> Resistance in the National Center for Infectious Diseases, Centers for
> Disease Control and Prevention in Atlanta.
>
> DR. TURNER: Tara Turner, Executive Secretary for the committee.
>
> DR. RELLER: Barth Reller, Division of Infectious Disease at Duke
> University Medical Center and Director of Clinical Microbiology there.
>
> DR. PATTERSON: Jan Patterson, Medicine Infectious Diseases, University
> of Texas Health Science Center, San Antonio.
>
> DR. WALD: Ellen Wald, Division of Pediatric Infectious Diseases,
> University of Pittsburgh School of Medicine.
>
> DR. SUMAYA: Ciro Sumaya, School of Rural Public Health, Texas A&M
> University System Health Science Center.
>
> DR. GIEBINK: Scott Giebink, Professor of Pediatrics and Director of
> Infectious Diseases, Director of the Otitis Media Research Center,
> University of Minnesota Medical School.
>
> DR. O\'FALLON: Judith O\'Fallon, statistician at the Mayo Clinic
> Cancer Center, Rochester, Minnesota.
>
> DR. CHINCHILLI: Vern Chinchilli, biostatistician, Penn State Hershey
> Medical Center.
>
> DR. CHESNEY: Joan Chesney, Pediatric Infectious Disease, University of
> Tennessee, Memphis, College of Medicine.
>
> DR. RAMIREZ: Julio Ramirez, Chief, Infectious Diseases, University of
> Louisville, Kentucky.
>
> DR. EBERT: Steve Ebert, Pharmacy and Infectious Diseases, University
> of Wisconsin, Madison.
>
> DR. LEGGETT: Jim Leggett, Infectious Diseases, Oregon Health Sciences
> University.
>
> DR. CROSS: Alan Cross, Infectious Diseases, University of Maryland,
> Baltimore.
>
> DR. ROTSTEIN: Coleman Rotstein, Infectious Diseases, McMaster
> University, Hamilton, Ontario.
>
> DR. McCRACKEN: George McCracken, Infectious Disease, University of
> Texas Southwestern Medical School.
>
> DR. PARADISE: Jack Paradise, Department of Pediatrics, University of
> Pittsburgh School of Medicine and Children\'s Hospital in Pittsburgh.
>
> DR. RELLER: Thank you. It\'s an exciting day. Dr. Soreth and
> colleagues have assembled what is recognized, it\'s like a Who\'s Who
> in Otitis Media in the world, if not the universe.
>
> Dr. Turner will read our Conflict of Interest statement.
>
> **Conflict of Interest Statement**
>
> DR. TURNER: The following announcement addresses the issue of conflict
> of interest with respect to this meeting and is made a part of the
> record to preclude even the appearance of such at this meeting.
>
> The Food and Drug Administration has prepared general matters waivers
> for Drs. Joan Chesney, Jan Patterson, Julio Ramirez, James Leggett,
> Steven Ebert, Ciro Sumaya, and Vernon Chinchilli.
>
> A copy of the waiver statements may be obtained by submitting a
> written request to the Agency\'s Freedom of Information Office, Room
> 12A-30, of the Parklawn Building.
>
> All other participants did not report any financial interests relevant
> to today\'s meeting; therefore, waivers were not necessary to permit
> their participation.
>
> The topic of today\'s meeting is an issue of broad applicability.
> Unlike issues before a committee in which a particular product is
> discussed, issues of broader applicability involve many industrial
> sponsors and academic institutions.
>
> The committee members and invited guests have been screened for their
> financial interests as they may apply to the general topic at hand.
> Because general topics impact so many institutions, it is not prudent
> to recite all potential conflicts of interest as they apply to each
> participant.
>
> FDA acknowledges that there may be potential conflicts of interest,
> but because of the general nature of the discussion before the
> committee, these potential conflicts are mitigated.
>
> We would like to note for the record that Kenneth Brown, M.D., is
> participating in this meeting as an industry representative, acting on
> behalf of regulated industry. As such, he has not been screened for
> any conflicts of interest.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which FDA participants have a financial
> interest, the participants\' involvement and their exclusion will be
> noted for the record.
>
> With respect to all other participants, we ask, in the interest of
> fairness, that they address any current or previous financial
> involvement with any firm whose products they may wish to comment
> upon.
>
> I have a brief announcement. Dr. Kenneth Brown will not be able to
> join us today. He is ill.
>
> Thank you.
>
> DR. RELLER: Thank you, Tara.
>
> We will begin the presentations with Dr. John Powers speaking about
> guidance development.
>
> **Guidance Development**
>
> **John H. Powers, M.D.**
>
> DR. POWERS: Thanks, Dr. Reller. I am really privileged to be the first
> one to get to test drive this trap door that is underneath my feet, so
> in case I fall through the floor, you will know why.
>
> Today, I would like to welcome the members of the committee, our
> guests and consultants, the members of the audience, and our
> colleagues at the FDA.
>
> \[Slide.\]
>
> Most of you were here for the advisory committee meeting that we held
> for two days back in February of this year, in which we dealt with
> some issues related to non-inferiority trials or deltas in
> antimicrobial drug development, and on the second day we talked about
> development of antimicrobial drugs for resistant organisms.
>
> At that time, we stated that that meeting was the first in a series of
> meetings that we were going to talk about related to antimicrobial
> drug development. So, here we are today fulfilling that promise,
> talking about acute otitis media.
>
> We really see this again as part of a continuing discussion and we
> plan future advisory committees to talk about other guidances, as
> well, as well as to continue the discussion about otitis media.
>
> We are also planning a workshop, cosponsoring that with the Infectious
> Disease Society of America and the Pharmaceutical Research and
> Manufacturers Association in the fall of this year.
>
> \[Slide.\]
>
> The divisions that deal with antimicrobial drug products in the FDA
> are the Division of Antiviral Drug Products, Anti-Infective Drug
> Products, and the Division of Special Pathogen and Immunological Drug
> Products.
>
> All three of these are subsumed under the Office of Drug Evaluation IV
> and as part of the Public Health Action Plan dealing with
> antimicrobial resistance, the office has been given additional
> resources to deal with antimicrobial drug development and resistance
> issues. I am honored to be the lead medical officer to move those
> initiatives forward.
>
> In an attempt to move this process of guidance development forward,
> which was started by Dr. Lillian Gavrilovich \[ph\] when she was the
> acting head of Anti-Infectives, and then since moved forward by Dr.
> Renata Albrecht, and also in order to provide some internal
> consistency with the kind of guidance that we offer to drug sponsors,
> and also we like to promote some interactions both within and outside
> the FDA.
>
> \[Slide.\]
>
> Why do we have these guidances in the first place? Well, these
> guidances are really not regulations, they are not absolute
> requirements, but actually they are very helpful both for us within
> the FDA and also for drug sponsors.
>
> In terms of the drug sponsors, they provide an outline for the scope
> of data that they need to show the efficacy and safety of their drug
> products, and we often heard from industry that they want to know the
> kinds of things that we are looking for.
>
> These guidances are also helpful within the FDA to provide some
> internal consistency in the kinds of guidance that we offer to drug
> sponsors. Over the years, there have ben several iterations of these
> guidances, and Dr. Janice Soreth will talk to you this morning about
> how each of these guidances has impacted on the development of trial
> design in acute otitis media.
>
> All of these guidances are based on the best available science and
> regulatory knowledge at the time they were written, but one of the
> things that makes medicine both fun and challenging is that the state
> of our knowledge is constantly changing.
>
> \[Slide.\]
>
> So, why revise these guidances and why talk about them now at this
> point in time? Well, obviously, there are those changes in the
> knowledge of infectious diseases, and since the 1992 guidance, there
> have been several meta-analyses published on the effect of
> antimicrobial therapy and the natural history of acute otitis media.
>
> Also, even since the 1998 guidance, the Agency for Healthcare,
> Research, and Quality has published an evidence report again relating
> to the natural history and the impact of antimicrobial therapy on
> acute otitis media.
>
> Also, over the years we have seen a change in the resistance patterns
> of the common organisms associated, not only with acute otitis media,
> but also with many other infectious diseases.
>
> Finally, there have been advances in the science of clinical trials.
> Both the FDA, PhRMA, and European and Japanese regulatory agencies
> have participated in the International Conference on Harmonisation in
> an attempt to bring some global consistency to how we develop
> antimicrobial drugs.
>
> Also, over the years, this committee has discussed several of the
> clinical trials related to acute otitis media, and we have learned
> some lessons from those which we now need to incorporate into our
> future guidances.
>
> \[Slide.\]
>
> Each of the guidances is arranged in a similar way and covers these
> important points in design, conduct, and analysis of trials. They talk
> about the definition of the disease and how to actually diagnose it,
> the study characteristics, the inclusion and exclusion criteria for
> that particular disease which again includes diagnostic criteria, but
> also defines the populations of interest for that particular disease,
> the drug and dosing regimens used in that particular infection, the
> evaluation of patients, and the timing and definitions of the
> outcomes, and finally, statistical considerations.
>
> That is an awful lot to talk about in one single advisory committee,
> so what we are going to try to cover today, related to acute otitis
> media, is not all of these points, not to say that the ones we won\'t
> cover aren\'t important, but just given the time constraints that we
> have today, we are not really going to touch on specific drugs and
> dosing regimens, and although the statistical considerations are very
> important, we hope to touch on those at a future meeting, and not
> specifically to discuss statistics per se today.
>
> \[Slide.\]
>
> The first thing we are going to talk about is definitions of disease.
> Obviously, it is important that the terms that we use are specified,
> so that the results that we look at are comparable across trials.
>
> In the AHRQ evidence report, they examined almost 3,500 clinical
> trials in acute otitis media, and their conclusion was that the basic
> definition of acute otitis media used in many of those trials varied
> considerably.
>
> Also, the definition of disease is important when we talk about
> particular subsets of patients, for instance, children with recurrent
> disease and treatment failure versus children who are experiencing
> their first episode of acute otitis media.
>
> It would be appropriate to analyze these populations separately if the
> cure rates were radically different in children across those groups,
> or, as we have heard from this committee before related to the
> development of fluoroquinolone drugs for pediatrics, if it would be
> appropriate to limit the use of those drugs to appropriate patient
> populations.
>
> \[Slide.\]
>
> The second thing we would like to talk about are study
> characteristics, what do we learn from different types of trials, and
> Drs. Dagan, Giebink, and Marchant are going to talk about this today,
> as well as George Rochester from the FDA.
>
> When we talk about superiority versus non-inferiority trials, one of
> the main things we deal with again is that issue of the
> non-inferiority margin. In the non-inferiority trial, we need to know
> the benefit of antimicrobial therapy over placebo in order to be able
> to set that margin.
>
> That actually brings up the issue of the role of placebo-controlled
> trials in allowing us to determine that given that there is still a
> significant controversy about the actual magnitude of the benefit of
> antimicrobial therapy in acute otitis media.
>
> Placebo-controlled trials have been done in Europe, and I put this
> trial up here by Damosieaux in the British Medical Journal that was
> published in the year 2000. This trial enrolled children with a
> clinical diagnosis of acute otitis media and also looked at clinical
> outcomes, and it did enroll children who were between the ages of 3
> and 24 months of age. So, these have been done in places other than
> the United States.
>
> \[Slide.\]
>
> When we look at inclusion and exclusion criteria, again, we are
> defining patients who actually have the disease, and one of the issues
> that we will talk about today\--again, some of our consultants will
> bring this up\--is the issue of clinical trials which use only
> clinical diagnostic criteria versus the value of baseline
> tympanocentesis in defining children who actually have bacterial
> otitis media.
>
> Also, we can use the inclusion and exclusion criteria to define
> specific populations of children. The population of children most
> likely to have acute otitis media is those kids between the ages of 6
> and 18 months, therefore, what is the role of data in children who are
> over 2 years of age and how can we use that in applying it to all
> children with acute otitis media.
>
> Also, Dr. Rosemary Johann-Liang will talk today about evaluating
> patients who failed prior antimicrobial therapy or prophylaxis, and
> mostly those kids have been excluded from prior trials, and should we
> be looking at them today as a separate indication.
>
> \[Slide.\]
>
> Here is the big issue when we talk about enrolling children who may
> not have a disease which is amenable to antimicrobial therapy. If we
> look at the top bar and the bottom bar, let\'s just say that is Drug A
> versus Drug B.
>
> If we just say for the sake of argument that 80 percent of kids in a
> particular trial get better either because they have viral disease or
> self-resolving disease, we then look at only the population of
> interest only comprises about 20 percent of the trial.
>
> There is a difference between the two drugs, and say in the 20 percent
> of interest, 15 percent of kids get better in one arm of the trial,
> but 10 percent get better in the other.
>
> If we then look at the overall cure rates in that trial, for the top
> drug, the overall cure rate would be 95 percent. For the bottom drug,
> the overall cure rate would be 90 percent. Therefore, the difference
> between the two drugs that we would examine in this particular trial
> would only be 5 percent, driven primarily by the large number of
> children with viral or self-resolving disease.
>
> On the other hand, if we just do the percentages in the population of
> interest, the cure rate in the children for Drug A would be 75
> percent, and the cure rate in the children for Drug B would be 50
> percent. So, the first point would be the cure rate would be much
> lower, but the other point is that the difference between the two
> drugs would be orders of magnitude larger, namely, 25 percent in this
> particular example.
>
> So, enrolling children in the trial who may get better spontaneously
> or who do not have bacterial disease has a huge impact on the outcome
> of the trial.
>
> \[Slide.\]
>
> Lastly, we look at microbiologic and clinical outcomes, how good is
> the correlation between bacteriologic and microbiologic outcomes, and
> some of our consultants will talk about that today, as well as the
> role of the second tympanocentesis in determining differences in
> microbiologic outcomes and evaluating efficacy for resistant
> pathogens.
>
> One of the other things we would like to talk about today is the
> timing of assessments, should we still be looking at some fixed
> endpoint or should we look at something like time to resolution of
> symptoms.
>
> The last thing is what actually defines a clinical cure and how do we
> measure it.
>
> \[Slide.\]
>
> Finally, even if we wanted to do the perfect trial, the issues are:
> What are the barriers to doing that, that are practical issues, what
> are the barriers to performing tympanocentesis, are placebo-controlled
> trials practical in the United States, how acceptable are these
> procedures to patients and parents, and can we perform trials more
> efficiently while still getting useful data from those.
>
> \[Slide.\]
>
> This has been a multi-person effort from folks at the FDA. I would
> like to thank all the people that have contributed to this, some of
> whom you will see speaking today, as well as our support staff without
> whom this would not be possible at all.
>
> Thanks very much.
>
> DR. RELLER: Dr. Soreth will now talk about development antibiotics for
> otitis media, past, present and future.
>
> **Development of Antibiotics for Otitis Media:**
>
> **Past, Present and Future**
>
> **Janice M. Soreth, M.D.**
>
> DR. SORETH: Good morning. I would like to add my thanks and my welcome
> to committee members, invited guests who are experts in the field,
> members of academia and industry, and consumers who may possibly be in
> the audience, as well, and to my FDA colleagues.
>
> Let me state at the outset that although we probably could have done a
> better job in having a multinational group here representing the
> mavens in otitis, I think we have done a fairly decent job in inviting
> the mavens in the field.
>
> There are a few others who I wish, on retrospect, I had been able to
> invite, but I guess at the end of the day, there is only so much time
> and so much money.
>
> As Dr. Powers said, this won\'t be the last meeting we have on
> guidance development in general or in the furthering of the guidance
> document for developing an antimicrobial for otitis media as we fully
> expect that we will get additional written comments to a docket, whose
> number I will give you later, so that if your thoughts at this point
> are not at a point where you wish to speak them at a microphone, you
> still will have ample opportunity to make written comments to us here
> at FDA and submit them, so that we can review them and, as is fitting,
> incorporate them into whatever the next iteration of the guidance is.
>
> I feel especially privileged to come before you today because I was an
> otitis-prone child, and I think it had a tremendous effect on my
> development as a child and as an adult, because for much of my
> childhood, I don\'t think I could hear very well, so muffled is my
> perception, my memory of what it was like to learn language in between
> many, many bouts of otitis media.
>
> I am convinced that at some point I had that bioactive membrane that
> Dr. Giebink spoke of some years ago where the middle ear cavity is not
> just filled with pus, but probably has a pseudocolumnar epithelium
> that is secreting gunk all the time, which intermittently gets
> infected. That is quite a challenge for any anti-infective to go after
> and probably different from the garden variety not often happening
> acute otitis media.
>
> I have also given birth over a decade ago to an otitis-prone child, so
> I have a special vested personal interest in this field, as well as
> professional interest, despite the fact that I turned out to be an
> internist, and many of the pediatricians in this from Pitt were my
> mentors, for I am also a Pitt alumna.
>
> With that as background, then, let me go to the next slide.
>
> \[Slide.\]
>
> We had, starting in 1977, written guidance, which I will briefly go
> through, followed by a period of formal silence, that is, nothing
> written between \'77 and \'92, although there was not silence in the
> office, there was not silence in speaking with academicians in the
> field or with industry. A lot went on, and I will try again briefly to
> summarize what is now oral history, anecdote, et cetera, and I will
> count on my other senior colleagues in both special pathogens and
> anti-infectives to keep me on track and speak up if I misspeak and
> misremember.
>
> In \'92, the Anti-Infectives Division came out with a
> Points-to-Consider document, talking about many different indications
> and infections, and how to go about trying to get a claim for them in
> one\'s antimicrobial product development, and that dovetailed in \'92
> with a contract that we had with probably some of the folks in this
> room and others, with IDSA, in writing, and what you call this depends
> on where you are. If you are in the FDA, you call these the IDSA
> guidelines, and if you are in the IDSA, you call them the FDA
> guidelines.
>
> Finally, in 1997 and \'98, we took another hit at coming up with an
> iteration of a draft guidance on many different infections including
> acute otitis media, and in \'97 and \'98, brought the guidance
> document formally then before this committee, whose composition in
> \'97 and \'98 was different because members do rotate off and go back
> to doing what they always do, or doing it in addition to this, I
> should say, because we appreciate that you have very, very full
> schedules and full professional lives, so again our thank you for your
> full participation in today\'s proceedings.
>
> \[Slide.\]
>
> I say \"back to the future\" because I think, as you will hear today,
> we started in the seventies with a paradigm under which all children
> underwent tympanocentesis if they entered a trial with the clinical
> diagnosis of acute otitis media. We are going to read this at that.
> Some may think that is overkill, others may think it is the only way
> to go if you want to understand the microbiologic etiology of this
> infection.
>
> So, questions that will come up throughout talks and certainly in the
> discussion this afternoon will focus on whether or not we need to
> return to a paradigm in which we have tympanocentesis for all, and
> then if we develop that further, should it be tympanocentesis at
> baseline only or tympanocentesis at baseline combined with a look, a
> further tympanocentesis, a repeat tympanocentesis on therapy, does
> that make scientific sense, is it ethical, and so forth. I am sure
> these will come up in our discussion, I hope they will, should all
> failures be tapped, is that practical, can you often do it, what do
> you do with a child at 3:00 a.m. on the eve of Christmas, Hanuka, New
> Year\'s, whatever, and it\'s virtually impossible to get it done.
>
> One of the pivotal trials that we have held or recommended to
> companies to do is something we refer to as a \"clinical-only\" trial,
> a trial in which you make a clinical diagnosis of acute otitis media,
> and we will argue about whether or not that is an easy call, a
> difficult call, or something in between, are those studies serving us
> at this point.
>
> I fully believe that any guidance document written, is written with
> the best of intentions in mind, and while some issues that we discuss
> today may appear to be Monday morning quarterbacking, I think that it
> is true that guidance documents and such provisions are written with,
> at that time, the best thinking in mind, the best of intentions, the
> most efficient way to get at testing a hypothesis and coming up with
> answers that are good for the public health, but as Dr. Powers said,
> our knowledge changes over time, at least we hope that it does, and we
> hope that it improves over time and maybe that is why we call it the
> practice of medicine, hoping that at some point, we really will get it
> completely straight and right and perfect.
>
> Is there a role for placebo-controlled trials? I was happy to hear a
> report on NPR, because that is where I get a lot of my information,
> that when put to scrutiny, arthroscopic surgery in adults compared to
> placebo is no better, at least if you believe the data that have just
> come to light, and may be deleterious.
>
> Is it time, is it neat and right at this point to consider the \"P\"
> word, placebo-controlled trials, in the context of studying patients,
> primarily children, many of them under 2, who have acute otitis media
> or who have an otitis media even if it\'s somewhere between acute and
> chronic
>
> Regardless of the paradigms that we talk about in a given clinical
> trial development program, are we talking one trial, multiple trials?
> I don\'t expect that all of these ideas will be developed in today\'s
> proceedings. We do have a full agenda, many, many speakers with many
> things to say, and just note parenthetically that this will be one of
> a number of discussions in a public forum that we will have on this
> document, on guidance development for acute otitis media and going
> forward.
>
> So, what is the bottom line, what do we know, what do we need to know
> to conclude that a drug works and it is safe for children with otitis
> media?
>
> \[Slide.\]
>
> What are some of the stats? Well, over 25 million visits for otitis
> media yearly, and that is just in the United States, and we know that
> we are part of a global community, so there are millions more out
> there in other countries, accounts for 1 out of 3 pediatric visits,
> and I have done my share to contribute to that number.
>
> By 1 year of age, upwards of 60 percent of children have at least one
> episode of acute otitis, and 17 percent more than 3. By 3 years of
> age, 80 percent have had more than one episode of otitis, one or more,
> and 46 percent, greater than 3 episodes.
>
> It is a spectrum of disease. I am a lumper, not a splitter, and I see
> things along a continuum starting out with garden variety acute otitis
> media where there is pretty much a normal middle ear cavity and pus in
> it versus changes in histopath\--I always wanted to be a pathologist,
> but I didn\'t get there for a number of reasons\--changes in the
> histopath that bring you over to a fundamentally different protoplasm
> in that patient, bioactive membrane, and do we lump all of these
> children together in a single study, if we do, should we be cognizant
> of that and come up with schemes in which we stratify to understand
> the effect of a drug in different subpopulations, and then do we power
> it to be able to look at.
>
> So, anything that we say today, as much as may not have the time to
> get into all the nitty-gritty for the statistical plan and
> considerations, that is not to say that we are not cognizant that that
> is an incredibly important part of clinical trial design.
>
> I am looking at some of our dear statisticians smiling at me, because
> I think that we have to recognize that anything that you might
> recommend to us today has definitive implications for clinical trial
> design sample size.
>
> If you are talking about non-inferiority margins, necessarily, delta
> determinations, the \"D\" word, and we ma not get to the specifics of
> numbers today and what do you recommend and what do we think, et
> cetera, but at some point in the discussion, it will rear its head. It
> is going to grow arms and legs, and it will be in front of us to deal
> with.
>
> Likewise, the implications of clinical trial design, non-inferiority,
> placebo-controlled, whatever, have implications for the whole economic
> side of the house, one that we don\'t often talk about, but is
> obviously a very important part of the business of drug development,
> for if we take a tack or accept a recommendation that at the end of
> the day, completely skyrockets by orders of magnitude what is costs to
> do a clinical trial, I am afraid we won\'t get it, because there is
> only so much money that a corporation or NIH, or anybody, has to put
> to the study of anything.
>
> So, we have to have a balance between what is I think right in terms
> of science and regulation, and the good of the public health, because
> ultimately, we are taking care of pediatric patients, patients in
> general, at the same time that we are cognizant of the fact that there
> is, by and large, corporate development of new anti-infective
> compound, not individuals working in their basements or in their
> garages, and that if it is much more profitable to develop, and
> practical and doable, to have a cardiac drug used forever and ever by
> a population or a drug for Alzheimer\'s that there is only so much
> money in the pocket that can be devoted to the study of any given
> entity and that common sense and practical issues also necessarily
> come to play.
>
> \[Slide.\]
>
> So, let\'s go back to 1997, to the guidance on acute otitis media. The
> number of trials in this guidance were not addressed, but there was a
> case definition that spoke to having clinical evidence of acute otitis
> media or evidence of inflammation of the tympanic membrane and middle
> ear.
>
> The guidance document recommended or required that in both studies,
> you have a tap at baseline, and it went to say that a second tap was
> desirable to obtain data on middle ear fluid concentrations and the
> promptness of bacteriologic eradication or cure.
>
> Endpoints were both then clinical and microbiologic, and while the
> document did not specifically address a test of cure, it did recommend
> a four-week follow-up period.
>
> I think at times, people and groups, and so forth, went back and forth
> on this. If you have a tap on therapy, you know it is sterilized, end
> of story, you don\'t have to worry about it anymore, you just need to
> see the patient at the end of the treatment course and no longer.
>
> Others have argued, no, you really need to look at the patient for
> several weeks beyond that period of time, so that you can see whether
> or not the effusion resolves to make sure the child doesn\'t relapse,
> and certainly in the setting of an active control trial, that you can
> compare even longer term what happens even if at the end of day, you
> want to argue, but that is not really drug effect, you can\'t hold the
> drug\'s feet to the fire, so to speak, four weeks out, five weeks out,
> six weeks out.
>
> Again, I expect this to come up in our discussions and be further
> developed.
>
> \[Slide.\]
>
> The 1977 guidance concluded that in the absence of culture of the
> middle ear fluid, no specific claim could be made regarding the
> effectiveness of any anti-infective drug.
>
> \[Slide.\]
>
> In the eighties, as I mentioned, there was no new formal guidance on
> otitis, and what I am going to give you now is what we talked about in
> the corridor, anecdote, the lowest level of evidence of what was going
> on, but in our internal discussions of acute otitis media, we really
> talked quite a lot about the requirement to perform or the heavy
> recommendation to perform tympanocentesis on every child enrolled in a
> trial.
>
> From what I remember from those discussions a decade ago, and
> admittedly, my memory is not what it used to be, but what I remember
> from those discussions is that we often heard from colleagues in
> industry and others that the procedure was not that easy to do and was
> not well known by many, many pediatricians, many family practitioners,
> the very folks who were taking care of these children, and that it was
> much more involved than a venipuncture.
>
> That may be incorrect. I am just telling you what we heard that I
> think caused a fundamental shift in paradigm that led to what we came
> out with in \'92 from IDSA or from the FDA. Too few were really
> trained to do it or do it well. It seems to be slowing down enrollment
> in trials, hampering enrollment in trials, and that the cost was going
> up in requiring that every child have a tympanocentesis.
>
> So, was there a better way to design these trials, better, without
> costing the patient anything, better for the efficiency of doing a
> trial, and at the same time, in that better way, not give up the
> opportunity to know whether a drug works or not.
>
> \[Slide.\]
>
> The 1992 points-to-consider then said that two trials should be
> conducted in investigating a drug and its treatment effect on acute
> otitis media. One could be a clinical-only study in which no
> tympanocentesis was necessarily performed at baseline to establish
> equivalence to an approved product, and that a second trial that had
> both clinical and micro endpoints would be done with, at a minimum, a
> tympanocentesis at baseline.
>
> The case definitions should be rigid. This is an important point,
> because I think, at least my understanding of what was going on back
> in the early nineties, was that we thought we really could come up
> with a rigid case definition, a look to the TM, a set of signs and
> symptoms that would be virtually pathognomonic for acute otitis media
> mediated by bacteria.
>
> I see Dr. Pichichero is smiling because I think he is going to give us
> information that is other than what I said, that it is at times maybe
> more often than not, not such a straightforward call. It is probably
> why I went into internal medicine. Those little structures were so
> little, you know, sometimes it is really hard to tell is this acute
> otitis media with effusion, is it otitis media with effusion with a
> child who is sick otherwise and has something else going on, but not a
> bacterially-mediated otitis media, could we have been in error that we
> thought this was so straightforward that we could say rigid case
> definition, this child has a bacterial-mediated acute otitis media, no
> need to do a tympanocentesis?
>
> The 1992 points-to-consider strongly encouraged\--oh, my gosh, is that
> red light going on, the yellow, I have another minute and a half,
> okay, I will move faster\--tympanocentesis was strongly encouraged in
> patients who were therapeutic failures at any point in the trial, and
> the endpoints, as I mentioned, both clinical and micro. Test of cure
> wasn\'t specifically mentioned in terms of the timing.
>
> \[Slide.\]
>
> The open micro study should establish acceptable outcomes in, you know
> 25 patients with H. flu, 25 patients with Strep pneumo, and 15 with M.
> cat.
>
> \[Slide.\]
>
> By and large, this dovetailed with what was published in the IDSA FDA
> guidelines.
>
> One other think I want to mention about the \'92 document and then to
> move on, the 1992 points-to-consider document stated that the micro
> trial could be uncontrolled, could be non-comparative, and the
> interpretation of that almost exclusively was is non-comparative, so
> once we say something can be some way, it probably will be, so we have
> to be very careful what we ask for because we know we will probably
> get it.
>
> \[Slide.\]
>
> In \'97 and \'98, then, when we revamped the guidance document and
> took it before the Advisory Committee, we again spoke of two trials, a
> micro study, which could be non-comparative, but should have more
> numbers in it, and a comparative clinical trial. Again, case
> definition, please let\'s tighten it because I think we were certainly
> beginning to appreciate at that point that it wasn\'t maybe so very
> easy to have a rigid case definition, that there was a lot of wiggle
> room and a repeat tap to be considered day 3 to 5 as a critical
> measure of treatment efficacy, perform tympanocentesis in all
> failures, primary efficacy endpoints being clinical at the test of
> cure and pathogen eradication.
>
> This test of cure, we have talked about a lot in the past five years
> in product-specific meetings, and the consensus at the last couple of
> meetings, when we have talked about Augmentin ES, or talked about
> azithromycin, short course treatment, I think the consensus that we
> have is that when we are looking at test of cure from the clinical
> perspective, we should define that closer to the end of therapy, and
> that still do a look several weeks out as another measure outcome, but
> the test of cure be closer to that last pill that is taken for
> clinical.
>
> \[Slide.\]
>
> Further recommendations that came from the committee were to enroll
> more patients under 2 years of age, because as we look back at
> different products in development over the past 15 years, some had few
> or no children under the age of 2, very striking, so I am sure we will
> talk about that at length, and gain much more experience in this era
> of resistance.
>
> \[Slide.\]
>
> Increase the number of patients under 2, I have said that, and we just
> skip forward.
>
> \[Slide.\]
>
> Timing of assessment of clinical outcome. Primary endpoint, I have
> mentioned, again, the recommendation to encourage that those who fail,
> have another tap, whether it is the second tap or the third or
> whatever, and that the most informative tap would be baseline to
> understand what was the etiology, and then a consensus that on-therapy
> taps could tell us a lot.
>
> Whether or not that has to happen all the time, some of the time,
> again, I am sure we will get into.
>
> \[Slide.\]
>
> Experience has told us that this can be a difficult clinical call in
> some hands, and that even when the inclusion criteria are tight, we
> have experienced in looking across many different drug development
> programs that some investigators bat .800, 80 percent of the time they
> have a positive culture, and others are batting .200, 20 percent of
> the time they are getting a positive culture, so something is going
> on.
>
> \[Slide.\]
>
> So, back to the future. We want to revisit the case definition, is it
> strict, is it strict enough? Trial design considerations, I have
> really already talked about, as well as endpoint and timing of
> assessments.
>
> I think at some point in our discussions today, we will revisit the
> issue of placebo-controlled trials because what we want to understand
> is not only does a drug work in this disease, but the general question
> of what is the role of antibiotics development in acute otitis media.
>
> I want to hold up for a moment as I walk off before the floor swallows
> up in Don Giovanian fashion\--thank you for that opera reference\--the
> management of acute otitis media and evidence report by colleagues at
> the Agency for Healthcare Research and Quality, it was actually done
> on contract to a group in I believe Southern California led by Dr.
> Michael Marcy \[ph\] if you have not read this, and I think many of us
> have not.
>
> On the FDA side, I want to thank Dr. John Powers and Dr. Erika
> Brittain for bringing this to my attention. It is quite a
> comprehensive report that is certainly I think teaching us a lot about
> what we thought we knew and what we do know.
>
> \[Slide.\]
>
> The key question is again what do we need to know, what constitutes
> substantial evidence that a novel antimicrobial drug works and is safe
> for children with acute otitis media or some other variety of otitis
> media.
>
> With that, I will stop and I will turn the podium back over to Dr.
> Reller.
>
> DR. RELLER: Thank you.
>
> Dr. Scott Giebink will now speak to Design Issues in Antimicrobial
> Treatment Trials of Acute Otitis Media.
>
> **Design Issues in Antimicrobial Treatment**
>
> **Trials of Acute Otitis Media**
>
> **G. Scott Giebink, M.D.**
>
> DR. GIEBINK: As we are getting started, since Dr. Soreth went back in
> time, it is unfortunate that Medline searches only go back to 1968,
> because what this group needs to know, and I want to put in the public
> record, is that we are all indebted to a physician/scientist at the
> Mayo Clinic, between 1958 and 1962, who conducted four separate
> clinical trials of acute otitis media, comparing antibiotics we
> wouldn\'t consider today, but put the whole issue of AOM design on the
> table, and that now retired Professor of Pediatrics is Gunnar Stickler
> \[ph\], who had maintained a life-long interest in otitis media, and
> really brought us out of the dark ages into the era of clinical trial
> design for otitis, and as we have heard already, there have been lots
> of innovations and we refinements to that over the years, but it
> really started with those publications in 1958 to 1962.
>
> It is worthwhile going back and looking at some of those for some of
> the early thoughts on design.
>
> \[Slide.\]
>
> Well, I wanted to pick up a few design issues now, to just basically
> put them on the table for your consideration, and I thought I would
> start by saying the obvious, that we really have three ways we look at
> outcome in these otitis media trials.
>
> The one that has been mentioned is a bacteriologic cure, which is
> basically defined as sterilization of middle ear fluid, eradication of
> the original pathogen, and that obviously requires an on-therapy tap,
> just as a second urine culture would require in urinary tract
> infection.
>
> We have issues that Dr. Dagan is going to talk about later that relate
> to eradication of organisms versus growth suppression of organisms,
> that I think to be considered by the committee.
>
> The second, of course, is clinical cure. Dr. Soreth just mentioned
> that. This is the resolution of clinical signs and symptoms. For
> reasons that should become apparent over the next couple of hours, the
> test of cure is really too obscured by issues of relapse and
> reinfection to be useful in measuring otitis media outcome, so as Dr.
> Soreth mentioned, moving that test down to end of treatment makes a
> lot more sense, and I will say a bit more about that in a moment.
>
> Finally, Dr. Craig has put into the literature, as have others, issues
> of pharmacokinetics and pharmacodynamics, and our use of the kinetic
> parameters to describe an expected clinical and bacteriologic outcome,
> and the parameter that seems to be holding up over time or at least
> the last half-dozen years is this parameter Time over MIC.
>
> There, the issue I think that needs to be more considered is whether
> we can really rely on Plasma Time over MIC or should we be talking
> about Middle Ear Fluid Time over MIC, and this will get into some of
> the characteristics of chronic otitis media I will mention in just a
> moment.
>
> \[Slide.\]
>
> Now, the design issues, the four specific design issues I would like
> to comment on here in the next 15 minutes are some of the issues
> around the double tap design and using that in a non-comparative
> setting. I know that Dr. Dagan is going to amplify on this
> considerably.
>
> I have already mentioned that the sub-issue there is the timing of the
> second tap and the related issue, the question of eradication versus
> growth suppression.
>
> The second issue that I would like to show you some data on is the
> issue of enriching subject populations in clinical trials for the
> infection with penicillin resistant and multidrug resistant
> Streptococcus pneumoniae, PRSP.
>
> The bottom line is I will show you that the risk factors for PRSP
> infection are those very same risk factors for recurrent and chronic
> otitis media, so that by enriching, by definition, you change the
> subject population, and then you have questions about generalizing
> data results from such a trial back to the whole population at large.
>
> It has become clear, certainly in studies we have done, in studies Dr.
> McCracken has done, and several others, that these PK parameters that
> we talk about are valid in a particular patient, but they are
> incredibly variable. There is a tremendous variation in PK parameters.
>
> The otitis media pharmacokinetics probably don\'t relate very well to
> the murine models where these PK parameters have been used
> extensively, and one of the big issues is most of the PK studies in
> humans are single-dose studies, and single-dose studies don\'t measure
> drug accumulation over time. We know that that is a factor in the
> middle ear.
>
> So, using PK and PD parameters as surrogates of clinical effectiveness
> or bacteriologic effectiveness, I think is problematic.
>
> Finally, I would like to show you evidence that otitis media severity
> at entry correlates, not only with clinical cure, but also with
> bacteriologic cure, and these issues have rather large implications
> for sample size determinations in clinical trials.
>
> It is a fact that we have actually known for a decade, but has not
> been strongly considered in most trial design.
>
> \[Slide.\]
>
> I am going to show you the exact same numbers Dr. Soreth just showed
> you, that there are 24 million visits at least as of about 1995, in
> the United States for AOM, a tremendous burden in very young children.
>
> The reason I put in, in half of the 7 to 12 million cases of
> pneumococcal otitis, 25 to 40 percent are now resistant to penicillin,
> the reason I put this number up there is to emphasize that very small
> differences in treatment response have an impact on millions of
> children, so when we talk about 3, 5, 7, 10 percent differences in
> outcome, we are talking about 2, 3, 4 million children, and we
> shouldn\'t lose sight of that fact as we make these decisions, which
> seem very small in terms of percentage response, but very large in
> terms of number of children affected.
>
> \[Slide.\]
>
> I would like to use the data from Pittsburgh, and Dr. Paradise and
> Drs. Wald and Hoberman can amplify on this later. This was a study led
> by Phil Kaleida at Pittsburgh in the late 1980s, early \'90s, looking
> at a placebo-controlled trial of AOM.
>
> I remember sitting on the opposite side of the table with Ellen and
> Jack in the early 1980s as this was being designed, going through all
> the ethical questions about placebo-controlled trials, and I am
> delighted to hear that it will come back on the table here for
> discussion, because I think it is time to do that.
>
> Let me just make a point about enrollment severity, the severity of
> otitis media at entry. These are the bacteriologic data from that
> study that show that there is a tendency of a difference in the
> bacteriology of mild versus severe AOM. You will notice that the
> incidence of pneumococcal otitis in the severe group is almost twice
> that of the mild group, and the Hemophilus-infected ear is lower in
> the severe group than in the mild group. I believe Dr. Dagan is also
> going to talk about his recent fairly large experience with Hemophilus
> otitis when he talks.
>
> So, there is a difference in the bacteriology, I believe, of mild and
> severe otitis media.
>
> \[Slide.\]
>
> In that study, the older children, I believe the age cutoff was 2,
> were given placebo treatment compared to
>
> amoxicillin, the younger children had myringotomy if they had severe
> otitis.
>
> If we lump together the placebo and the myringotomy groups, we see
> that there is a 92 percent spontaneous resolution rate that we have
> already seen in the mild group and the 76 percent spontaneous
> resolution rate in the severe group. Those differences were
> significantly different, but small compared with amoxicillin.
>
> Now, what happens when you put together the bacteriology and the
> clinical response?
>
> \[Slide.\]
>
> That is what I have done in this rather jumbled slide, but I think you
> can follow me through here. In the first line of the mild and the
> severe group are the percentages we just saw two slides ago of those
> different bacteria isolated from the ears.
>
> On the second line of both groups are the spontaneous cure rates that
> were described 30 years ago by Virgil Howie in his studies in
> Huntsville, Alabama, and have been large correlated by other placebo
> studies since then with bacteriology, that there is a spontaneous cure
> rate of about 20 percent with pneumococcal otitis, about 50 percent
> with Hemophilus, about 70 percent with Moraxella catarrhalis, roughly
> 30 percent in the mixed groups, and, of course, 100 percent when there
> is no growth in the middle ear fluid.
>
> So, multiplying the first and second line together, you see the
> bacteriologic cure rates that would be anticipated, and on the far
> right are the total cure rate adding up that row, 63 percent
> bacteriologic spontaneous resolution or cure with mild AOM and 50
> percent with severe AOM. That delta of 13 percent is one of the deltas
> that we speak of.
>
> If you remember on the previous slide, the clinical cure rates from
> the Kaleida study. Here is a 92 percent and a 76 percent, a delta of
> 16 percent. So, these deltas are very similar, but the magnitudes, as
> the statisticians can comment later on, are quite different, and these
> differences have big implications for sample size and are an issue
> that I think need to be discussed further in the day.
>
> \[Slide.\]
>
> The group that Dr. Marchant was a member of in Cleveland a number of
> years ago, led by Susan Carlin, most recently summarized all of their
> experience with clinical and bacteriologic outcomes, and demonstrated
> that if you compare clinical with bacteriologic outcome, the clinical
> status failure or success predicts about 93 percent of the
> bacteriologic responses, and it misses about 63 percent with a
> specificity of only 37 percent, 15/40.
>
> \[Slide.\]
>
> The cells I think of interest really are these cells, this one and
> this one, and that is the discordance between the bacteriologic and
> clinical response, and you might ask then why is there bacteriologic
> success in the absence of clinical success.
>
> A couple of the reasons for this are the presence of persisting
> bacterial and host inflammatory mediators in the middle ear, which we
> know continue the inflammatory process after organisms have died, and
> concurrent viral infections that may be related to or have nothing to
> do with the middle ear bacterial infection, but cause what is
> interpreted as a clinical failure.
>
> That constitutes about 6 percent of the total pie, and then we have
> about 9 percent bacterial failures with clinical successes. Why does
> this happen? Perhaps it\'s because we have low-grade pathogens in the
> middle ear or these pathogens are growing more slowly because of
> inhibitors in middle ear fluid. This gets to the issue of bacterial
> suppression in double tap studies.
>
> \[Slide.\]
>
> Other reasons for persistent symptoms during treatment, in addition to
> concurrent viral infection, is obviously that the organism continues
> to grow either because of noncompliance with treatment or resistant
> organism, or because the drug does not distribute into the ear, and I
> am going to comment on that in just a minute. Dr. Soreth mentioned the
> continuum of otitis media, and I will show you why I think that is
> critically important.
>
> The persistence of inflammation after organisms have cleared and then
> the very rare case of immune deficiency that impairs the response to
> clearing those organisms, those are all reasons that symptoms may go
> on during treatment related or unrelated to continued bacterial
> presence and emphasize why a clinical outcome is so problematic in
> this disease.
>
> \[Slide.\]
>
> The group in Finland has probably, along with Tasni Chalmatri\'s group
> in Galveston, have done a lot in the last decade to tell us about
> respiratory viral infection in otitis media.
>
> It has been clear for a long time that respiratory virus play a major
> role in acute otitis media, and in addition, the studies, particularly
> in Finland, show us that in the absence of bacterial isolation from
> the middle ear, respiratory virus play a large role, as do absence of
> any pathogen in the middle ear causing the clinical diagnosis of acute
> otitis media, and since all of these ears were tapped, this 16 percent
> had middle ear fluid.
>
> I think that represents the host clearing the organism by the time the
> needle is put into the ear, but you will notice in each one of these
> bars, Pneumococcus, Hemophilus, Moraxella catarrhalis, that there are
> ears with both pneumo and respiratory virus and without. So,
> respiratory virus play a very important role in this disease.
>
> \[Slide.\]
>
> This diagram may be one of the most important summaries of otitis
> media pathogenesis that I could show you because it demonstrates how
> heterogeneous this population of otitis media really is.
>
> The acute uncomplicated acute otitis media, which perhaps every child
> gets before they go to school, at least 80 percent get this disease
> documented in medical record studies, these days has very few
> suppurative complications although we do occasionally see mastoiditis
> still today. We just had a child with facial nerve palsy due to
> mastoiditis last week. So, these issues do continue to occur, but they
> are much less common now than they were 50 years ago.
>
> The difficulty in designing a clinical trial is that we have this
> conundrum of a clinical mixture of AOM and chronic otitis media with
> effusion, shown in the green here, most of which in young children is
> mucoid otitis media or \"gunk,\" I think Dr. Soreth called this, is
> these glue ears, and many of these ears are becoming acutely infected
> and appear to be AOM, but, in fact, pathologically, are chronic OME
> with a superinfection, and studies are starting to demonstrate that
> drugs distribute more poorly into the chronic OME ear than they do the
> AOM ear.
>
> Then, we have children that go on to those nonsuppurative sequelae
> that include hearing loss, as well as pathology of the middle ear.
>
> So, when we enrich a subject population for recurrent otitis media or
> for penicillin-resistant pneumococcus, we are creating a study cohort
> that is not representative of uncomplicated AOM, and yet, the
> indications go back to that uncomplicated AOM population and one has
> to ask the question is this a valid extension of those studies.
>
> \[Slide.\]
>
> I have just put side by side here for you, fairly well accepted risk
> factors for PRSP on the left, and for AOM treatment failure and
> recurrence on the right, and you will notice that there is a
> tremendous similarity, antibiotics within the last month, in the case
> of treatment failure, any AOM diagnosis within the last month,
> recurrent or persistent AOM for PRSP, recurrent and persistent
> sinusitis, as well, infection during the winter or spring for PRSP,
> obviously is an AOM risk factor, too, young age, young age at the
> first otitis episode, daycare center attendance, which Dr. Wald\'s
> studies demonstrated clearly.
>
> For treatment failure, not necessarily for PRSP, bilateral versus
> unilateral disease. So, when we select for treatment failure or PRSP,
> we are getting both.
>
> \[Slide.\]
>
> This is a figure that I extracted from Dr. Wald\'s study that
> demonstrate this very clear increased incidence of OM complications of
> common upper respiratory infections based on daycare size from the
> home care, group care, to the center care group in the children that
> are less than 1 year.
>
> \[Slide.\]
>
> In more recent studies, the day care center A, B, and C, all in the
> same community showed extension of a multidrug-resistant Type 14
> pneumococcus that spread across the community through these daycare
> centers.
>
> It was not detected in general pediatric practices. So, daycare
> centers serve as a reservoir for transmission of organisms that cause
> AOM and these penicillin-resistant pneumococci to show you the impact
> of multiple risk factors.
>
> \[Slide.\]
>
> This is a study that Dr. Daly, with our group, did back in the
> mid-1980s, taking just three risk factors - bilaterality, daycare, and
> otitis for more than four weeks at entry in this AOM epidemiologic
> trial, looking at the percentage of children that had OME persisting
> six weeks later, and you will notice if they had none of these risk
> factors, a third of them had persisting OME.
>
> If they had all three risk factors, two-thirds of them had persisting
> OME. So, risk factors are very important in identifying this subset
> that have persisting disease.
>
> \[Slide.\]
>
> Dr. Dagan is going to say a lot more about carriage rates, but it is
> all about these very young children.
>
> \[Slide.\]
>
> The rates of pneumococcal resistance by drug are shown in the figures
> that you have. They are all significantly greater rates of resistance,
> these are susceptibility rates, are lower rates of susceptibility in
> ear infection compared to eye, respiratory, blood, and central nervous
> system.
>
> \[Slide.\]
>
> And younger children have lower rates of susceptibility or higher
> rates of resistance than older children.
>
> \[Slide.\]
>
> Finally, pneumococcal conjugate vaccine selects those very serotypes
> that are carrying the resistance genotype, at least today, and you
> will notice here that the seven types contained in the Wyeth-7 valent
> conjugate vaccine include the most frequent resistant types including
> two types that are closely related to serotypes in the vaccine with
> fairly high resistance rates not found in the non-vaccine types,
> indicating that routine pneumococcal conjugate vaccine, I believe is
> going to have a significant impact on the early childhood rates of
> PRSP, and it is going to make the design of studies for enrichment
> with PRSP very difficult in the next few years if we can get enough
> conjugate vaccine in the pipeline to immunize all of these children.
>
> \[Slide.\]
>
> So, in conclusion, I would again emphasize, as the previous speakers
> did, the importance of controlling enrollment in these trials and call
> your attention to the fact that bacteriologic and clinical cure rates
> are very tightly related to these clinical definitions.
>
> The importance of end of treatment cure, not test of cure, at 25 to 30
> days.
>
> The issues with enriching for PRSP that we have just finished talking
> about, and, finally, the issue of pneumococcal conjugate immunization
> and its anticipated impact on PRSP prevalence in young children, all
> issues for us to consider.
>
> Thank you.
>
> DR. RELLER: Our next speaker is Dr. Pichichero. The presentations have
> been wonderful, although each drifting into the red zone. We will pick
> up the time one way or the other, so think about it either eating into
> lunch or eliminating breaks.
>
> Dr. Pichichero.
>
> **Experience with Tympanocentesis:**
>
> **Clinical Diagnosis of AOM**
>
> **Michael Pichichero, M.D.**
>
> DR. PICHICHERO: Thank you, Dr. Reller.
>
> As I mentioned in my introduction, I am blessed or privileged
> depending on your religious viewpoint, to continue to practice primary
> care medicine half-time, as well as spending the other half of my time
> at an academic medical center. As such, tomorrow morning at 8
> o\'clock, I will be seeing patients once again as one pediatrician in
> a 10-pediatrician private practice group in Rochester, New York.
>
> In sitting at my desk, I calculated that as a pediatrician, I have
> looked at in excess of 100,000 ears over my 20-year career, and that
> number will continue to climb. Many of my patients are the children of
> physicians or nurses, and many of them are on clinical trials.
>
> I have participated in over 150 clinical trials, about 20 of them
> involving tympanocentesis, and this year, for the first time, we
> intend to attempt a double tympanocentesis trial at the encouragement
> of my former student, Dr. Ron Dagan, who was a fellow in our training
> program, so student became teacher. I don\'t know how it will go in
> that patient population, but we are going to give it a try.
>
> My presentation will have three components. As Dr. Reller implied, it
> is a multimedia presentation. The first part will be a 12-minute video
> demonstrating a tympanocentesis procedure by myself on one of my
> patients. Then, I have a mannikin, and I am going to actually perform
> a tympanocentesis for the committee on an infant mannikin, live. That
> will take two or three minutes.
>
> Then, I am going to show a video, which we produced in collaboration
> with the Pittsburgh group, Dr. Hoberman and Kaleida, on otitis media
> diagnosis.
>
> These three pieces of teaching material are used in workshops which
> are taught around the country since 1999. Faculty of those workshops
> include Dr. Giebink and Dr. Marchant, and we have now trained in
> excess of 3,000 primary care providers in the tympanocentesis
> procedure through these workshops. Less than 10 percent of them went
> on to actually do tympanocentesis as a routine in their practice, as
> we do in our practice in Rochester.
>
> If we could roll the first video.
>
> \[Video.\]
>
> DR. PICHICHERO: Hello. I am Michael Pichichero of Rochester, New York,
> and I am going to be performing a tympanocentesis procedure on this
> young man, 4-year old Nicholas.
>
> Tympanocentesis procedure, which we perform in our office every day,
> has a series of indications, so these are met in all of the children
> to one degree or another. Tympanocentesis in our office is performed
> when a child is toxic in their appearance in association with acute
> otitis media. We also will perform a tympanocentesis if the child has
> a very bulging eardrum to the point where we anticipate it is going to
> rupture spontaneously anyway.
>
> We also perform a tympanocentesis in the highly febrile patient, which
> would be acute otitis media with fever over 102 degrees Fahrenheit
> orally in the teenager or young adult, or over 104 degrees Fahrenheit
> in the young child, such as Nicholas.
>
> We also would perform a tympanocentesis on the patient who has been
> unresponsive to previous antibiotic therapy. There is some discussion
> whether we would perform the procedure after a single failure of
> first-line therapy, such as amoxicillin or
> trimethoprim-sulfamethoxazole, whereas, most every physician expert in
> otitis media would agree that following failure with first-line
> therapy, such as amoxicillin, end of failure with a second-line
> therapy, that in this circumstance, a tympanocentesis can be very
> helpful to determine whether there is a pathogen present, and if so,
> what is the pathogen and what would be the preferred antibiotic
> therapy for that isolated bacterial species.
>
> The benefits of tympanocentesis include immediate relief of pain in
> the crying child who is suffering from the pain of a bulging tympanic
> membrane, we can provide instant relief, as acute otitis media really
> is an abscess of the middle ear space.
>
> We can determine whether the infection is a bacterial etiology or if
> it\'s a viral etiology, and if it is of a bacterial etiology, we can
> perform sensitivity testing in order to determine whether the organism
> will be killed with traditional first-line agents or whether a
> second-line agent would be preferred in this circumstance.
>
> Tympanocentesis has the benefit of draining an abscess, which we know
> is therapeutic in and of itself, and last but not least, we feel that
> tympanocentesis can improve a physician\'s diagnostic accuracy.
>
> Nothing is more self-educating than to diagnose acute otitis media,
> perform a tympanocentesis, and find that the ear tap is dry, the
> patient never had acute otitis media.
>
> Also, we think that it is very beneficial if you perform a
> tympanocentesis and no bacteria are isolated, then, no additional
> antibiotics are necessary, and that can be very beneficial, as well,
> in avoiding the unnecessary overuse of antibiotics.
>
> For the tympanocentesis procedure, we typically do not provide any
> anesthesia, we don\'t put the children to sleep. Some offices do give
> a medicine called Versed, which is taken orally, and then the child
> becomes very sleepy, but then they have to remain in the office for an
> hour or so before they are completely recovered.
>
> Other times we will give a child some tylenol with codeine and a
> little valium mixed in to make the child relax, but in the case of
> Nicholas, his eardrum is so bulging with infected fluid, actually, I
> think he is going to feel relief rather than pain when we perform the
> tympanocentesis.
>
> It is like opening a pimple or a boil yourself. When you open it up,
> it actually feels better, and you don\'t even feel the needle go
> through. So, that is what we are anticipating with Nicholas.
>
> So, the first thing we will do is we will lay him down, make sure he
> is completely still with something we call a papoose board. My nurse
> will hold his head firmly, and then we will look into his ear with the
> Welch-Allen otoscope, not this one which you are used to seeing me
> examine him with, but rather we use this otoscope because it allows me
> to put the needle through, and I can still see through this mirror, so
> I am watching the whole time exactly what I am doing, so I put the
> needle exactly in the spot I want in the eardrum, so that there won\'t
> be any damage to his eardrum.
>
> To do the procedure, we take a needle that looks like this. It\'s a
> spinal needle, and I bend it and hook it to a syringe, and then, as
> you see in this picture, the needle will be inserted through the ear
> canal until it touches the eardrum, and then we will suck the fluid
> off of the middle ear space in order to\--the needle will be inserted
> through the ear canal until it touches the eardrum, and then we will
> suck the fluid off of the middle ear space in order to culture it and
> in order to drain that middle ear abscess.
>
> There are some potential rare or hypothetical complications from
> tympanocentesis. Certainly, you would expect the possibility of some
> bleeding because we are going to put a hole, a tiny hole through his
> eardrum, and some pus and fluid may come out of the eardrum puncture
> site which I create with the tympanocentesis needle.
>
> That should stop in a day or two as the hole heals over. Usually,
> three days after a tympanocentesis is performed, you can\'t even tell
> where the hole was.
>
> Now, if the child is not properly restrained and they move their head
> about in the middle of the procedure, then, there are other possible
> complications where the little ear bones behind the eardrum could be
> scratched or injured, and there are blood vessels back behind the
> eardrum, and they could be scratched or injured, so that is why it is
> necessary for us to restrain your child and hold him very still during
> the procedure. The only real risks are when the child moves very
> suddenly and very unexpectedly, and they are not properly restrained.
>
> A critical element to the tympanocentesis procedure is proper
> immobilization. Here, Mrs. Koon will put Nicholas into our papoose
> board, and my nurse Julie will secure him into the papoose board.
>
> We usually do allow the parent to remain in the room throughout the
> procedure to reassure their child, and we will papoose children up to
> the age of about 4 or 5 years of age. After that, it may not be
> necessary to papoose the child, but in all cases, we require an
> assistant to restrain the child at the arms, and a second assistant
> who will restrain the child at the head.
>
> We then will remove the spinal needle from its container. We use a
> 20-gauge. Other physicians who practice tympanocentesis recommend an
> 18-gauge needle. Of course, the stylet is removed and then the sterile
> syringe is attached to the spinal needle, and then the needle must be
> bent at a 45- to 90-degree angle, approximately one-third from the
> hub.
>
> So, I will bend it thusly, and this depends on your own comfort level
> and how you hold your hand during the procedure, but in all cases, the
> needle must be bent, but the precise angle according to your own
> comfort zone.
>
> Now, we maintain sterility by keeping the sheath over the spinal
> needle tip until we are ready to proceed with the actual procedure.
> Visualize the tympanic membrane. I am proceeding now down through the
> canal. I am right at the tympanic membrane, everybody takes a breath,
> and there we are.
>
> We suck back the fluid, pull out, and we are finished. It is as quick
> as that.
>
> So, we are going to perform the tympanocentesis procedure. The
> speculum is inserted. We visualize, we ask the nurse assistant to pull
> back on the pinna. We now insert the needle through the speculum,
> through the ear canal, get in good position, we are ready, and, pop,
> we are through. We draw the fluid. We pull out and we are done.
>
> For needle placement, here is a normal ear for orientation. The
> preferred location for the tap, interior quadrant, where the light
> reflex is. An acceptable alternative is the posterior/inferior. It is
> essential to completely avoid the entire superior half of the tympanic
> membrane.
>
> Now, here is an image of an abnormal ear bulging with infection.
> Again, the preferred location for the tap is the anterior-inferior
> quadrant. An acceptable alternative is the posterior-inferior
> quadrant. it is essential to completely avoid the entire superior half
> of the tympanic membrane.
>
> Following the tympanocentesis procedure a decision is made regarding
> antibiotic selection. This can be guided by gram staining of the
> tympanocentesis material showing gram-positive or gram-negative
> bacteria, and then specifically directed at the pathogen and
> penicillin-susceptible versus resistant pneumococci, if isolated,
> beta-lactamase positive or negative, Moraxella or Hemophilus, as
> isolated. So, you can do directive therapy.
>
> Of course, follow-up is necessary. We usually see the children back in
> three weeks, sooner if the bleeding or fluid persists beyond a day or
> two, or any alarm on the part of the parent.
>
> \[End of video.\]
>
> DR. PICHICHERO: Okay. That is a tympanocentesis. If we could have the
> lights up, please.
>
> \[Demonstration\]
>
> DR. PICHICHERO: This is a baby mannikin. We train pediatricians how to
> do tympanocentesis with this mannikin. The manikin is loaded with a
> disk. The disk looks like this. This is four tympanic membranes. You
> will see that in the top half of the tympanic membrane, when it is in
> the right position, will be a red dye. If the needle goes in through
> the red dye, you fail the test.
>
> In the bottom half, you see a yellow pus. If the needle goes into the
> yellow pus, be it anterior or posterior, you have had a successful
> tympanocentesis. If you put the needle too far, you get a blue dye.
> This is to indicate that you have now hit the posterior\--you have hit
> bone, periosteum bone at the posterior aspect of the middle ear space.
>
> So, when we test our doctors, it is very easy. You have either got red
> dye, yellow dye, or blue dye.
>
> This mannikin is engineered for the disk to go into a position, so
> that when it slides into the head, it is has the proper angulation and
> anatomical position of a real child.
>
> Here is the otoscope that you saw in the video. You turn it on. I have
> already pre-bent my needle, and I won\'t maintain sterility today. So,
> you look into and you locate your anatomy. I can see the red dye and
> the yellow dye, and then go into, I progress down, I puncture,
> withdraw the fluid, and come out, it\'s that fast.
>
> We can do another one. Rotate the disk one-quarter turn. In it goes.
> Again, put my light on. You see it. The red is the top, the yellow is
> at the bottom. I go in, puncture, draw the fluid, and come out. It\'s
> as quick as that.
>
> I personally performed a little over 1,000 tympanocentesis. I have not
> had any major complications. I have had a few patients with minor
> complications like the hole stays open for more than two or three
> days. I had one where I did hit the posterior wall, and the bleeding
> was sufficient that there was blood that stayed in the middle ear
> space for a little over a week, which made me quite nervous, but
> resolved on its own thereafter.
>
> I have had the privilege of polling some of the major tympanocentesis
> centers. Some of those people are in this room. Over 10,000
> tympanocentesis in primary care, no major complications reported by
> any of those in the survey.
>
> I am now ready to show you another video. We will need the lights
> down.
>
> \[Video.\]
>
> There will be a lot of discussion about the causal diagnosis of otitis
> media. This video is shown during our workshops, and it has taught me
> a lot and the other faculty a lot about what we should know a lot
> about.
>
> This video was developed in cooperation with Drs. Hoberman and Kaleida
> at the University of Pittsburgh, and we are very grateful for their
> cooperation. They actually took video with an otoendoscope. It is a
> lot like a laparoscope that you put in the ear, and you simply take
> pictures, and they have made some beautiful pictures, and during our
> course, we show examples of sclerosis, atrophy, retraction pockets. We
> won\'t have time for all of that today. I am just going to show you
> four ears.
>
> The first two are examples. Here is an example of a normal tympanic
> membrane. You will notice that all the wax has been removed, and here
> is an easy to-and-fro movement, which occurs with pneumatic otoscopy
> properly performed when there is an air-filled middle ear space.
>
> Here is the light reflex. Here is the malleus. Our participants
> actually vote and we record their diagnosis. You will notice that this
> eardrum is gray in color, it\'s in a neutral position, that is,
> neither bulging nor retracted.
>
> It\'s translucent. You can see right through it including seeing the
> malleus, and it has a nice normal landmark, notably light reflex in
> the malleus. This would be a null effusion, a normal ear diagnosis.
>
> Here, in our second example, this is acute otitis media. It is a
> bulging tympanic membrane filled with pus, limited mobility. Only with
> positive pressure do you get a little bit of backward movement of the
> tympanic membrane; with negative pressure, it is so bulging, it can\'t
> bulge further.
>
> This is what you might consider a severe acute otitis media, which
> includes a smattering of hemorrhagic area on the surface of the
> tympanic membrane. You will notice that it\'s kind of a mixture of red
> and white or yellow. It\'s bulging, it\'s opaque, you cannot see
> through it.
>
> There is some mobility, but only with positive pressure, and the
> diagnosis would be yes, an effusion is present this is acute otitis
> media.
>
> Now, if you were examining a child and you saw this ear, what would
> you think? Now, you are getting to look at this ear for 20 to 30
> seconds. All the wax is gone, the mother is not breathing over your
> shoulder, the child is not screaming. What is the diagnosis?
>
> Well, we could argue about that amongst ourselves, but although there
> is yellow fluid, this eardrum is retracted. We know that from the
> anatomical position of the malleus. You have got some air fluid
> levels; 88 percent of ENT physicians say that this is otitis media
> with effusion, but only 40 percent of pediatricians think it is otitis
> media with effusion. What is it?
>
> Here is ear number two. Again, all the wax is gone, all the time in
> the world to look at it and think about it. The average pediatrician
> looks at an ear for less than two seconds. You are looking at it for
> 30 seconds. Usually, the cerumen blocks more than 50 percent of the
> view. What did you think that was? Did you notice the bubbles?
> Eighty-two percent of ENT physicians thinks this is OME, about 60
> percent of pediatricians think it\'s OME. What do you think?
>
> Do you want to see another one or have you seen enough? One more. The
> chairman says one more.
>
> I am going to show you the ear. This is going to be a good one, Barth,
> because watch the malleus. At the beginning of the video, the tympanic
> membrane is gray. Then, the child starts screaming, and the eardrum
> turns red, first, a blush down the malleus, then, the whole canal
> turns red. By the end of the video, everything is red, but at the
> beginning of the video, everything was gray.
>
> So, when Dr. Giebink and Sylvan Stool and other leaders tell us that
> color is the worst\--there it is, it\'s gray, folks, but watch a child
> cry, watch the blush of the capillary bed down the malleus. Here is
> comes, boom, and then the whole eardrum turns red. What is that, is
> that otitis media? It\'s red. It\'s red.
>
> No, it is not otitis media. There was not even effusion behind that
> tympanic membrane. That child had a retracted tympanic membrane,
> probably had a cold or an allergy, and there is nothing wrong with
> that ear.
>
> That\'s otitis media again, by the way. Those white flecks are
> epithelial cells on the surface of the tympanic membrane, pealing off
> from the heat of the infection. The eardrum is so bulging that when
> you puncture it, pus explodes out of the tympanic membrane, and the
> child stops crying on the table from the relief of pain.
>
> Thank you very much.
>
> \[End of video.\]
>
> DR. RELLER: This has been choreographed by Dr. Soreth. Dr. Ron Dagan
> perhaps is the only person who would be willing to follow Dr.
> Pichichero.
>
> Ron.
>
> DR. DAGAN: If you think I am going to dance, I am not.
>
> \[Laughter.\]
>
> **Double Tympanocentesis Studies**
>
> **Ron Dagan, M.D.**
>
> DR. DAGAN: I was asked to talk today about the bridging between double
> tympanocentesis and clinical outcome studies.
>
> \[Slide.\]
>
> This is, as you see, a very bulging eardrum, and just to remind all of
> us, a double tympanocentesis means that before treatment, we do one
> tympanocentesis, as you saw now, and we take it for culture, and
> during treatment, and usually, after 3 days to 5 days, because this is
> really the middle, but at 72 hours of treatment, this is day 4 to 6,
> if this is day 1, and then you do another one, and you take for
> culture.
>
> The double tympanocentesis means that we are going to see whether the
> organisms that exist here, they disappear on the second
> tympanocentesis, and then you can compare to drugs or compare to virus
> MICs or whatnot.
>
> \[Slide.\]
>
> Now, I have a series of seven questions that I have tried to see
> whether we get answers in terms of bridging, and the first question,
> of course, in acute otitis media, is there any difference between
> drugs in regard to bacteriologic eradication of day 4 to 6.
>
> \[Slide.\]
>
> I am not going to show all the slides from all the studies, but I
> wanted to bring a summary from the recent studies, and this is, as you
> can see, cefaclor, cefuroxime-axetil, amoxicillin or amoxiclav at the
> regular doses, ceftriaxone, one dose, azithromycin, 3 to 5 days,
> trimethoprim-sulfa, ceftriaxone, 3 days, Augmentin ES-600, and the
> gatifloxacin. These are the recent studies that we have data for.
>
> If we look at placebo, you remember that 84 percent of the 3 to 4 days
> is still persisting, so this is percent of persistence, and you see
> they all times were quite nice days, whatever you gave had eradication
> that was significantly better than placebo. Hopefully, after the
> pneumococcal vaccination, we will see something more similar to this.
>
> However, the situation with the resistant era, is that you can see all
> drugs are affected somewhat, and you can see really much differences
> between the drugs. You can see that for those who are beta-lactams,
> when you have penicillin, no susceptibility for the macrolides or for
> the trimethoprim-sulfa, et cetera, you do see much difference between
> the drugs nowadays in eradication of the nonsusceptible organisms.
>
> We don\'t have data on quinolone nonsusceptible pneumococci yet, but I
> think that in a year or two, when we meet, I will bring you probably
> already resistant quinolones because that is the way it will go if the
> quinolones will be given to children.
>
> As you can see, there are drugs, such as cefaclor here, ceftriaxone
> one dose, and azithromycin as presented of the macrolides,
> trimethoprim-sulfa where really are not very much different than
> placebo in terms of eradication of the organisms. Others are sort of
> reasonable, and others may be good.
>
> \[Slide.\]
>
> If you look at the Hemophilus, remember 50 percent eradicated around
> these and 50 percent persist, and you can see again excellent drugs
> versus not so good drugs. Cefaclor is not too far from placebo.
> Azithromycin is in the range of placebo in terms of eradication rate.
>
> You have some sort of acceptable. With trimethoprim-sulfa, if it\'s
> resistant, it\'s not eradicated, but only 30 percent are resistant, so
> you still have some good results. Here, you can see better results,
> but there is a big variety.
>
> Now, with Hemophilus, when you have beta-lactamase, then, you have
> amoxicillin, of course, because then amoxicillin is placebo when you
> have beta-lactamase.
>
> With Hemophilus, there is much more experience that can be drawn from
> the past, because in the past, the differences in Hemophilus today and
> in the past are not as big as with pneumococcus.
>
> So, I took all the studies I could find, which is about 35 or 36
> studies all together with double-tap tympanocentesis, and compared to
> placebo, and you can see that there are two groups of drugs, one group
> that is ranging from excellent eradication rate to reasonable
> eradication rate, and this is the number of studies done, not
> necessarily by our group, but all groups all together, and these are
> what I think is not too acceptable, cefaclors are frozen of the
> beta-lactams and the macrolides.
>
> So, you can see that really there is a big difference between drugs in
> terms of potential eradication exactly on the same timing.
>
> \[Slide.\]
>
> The second question is can double tap studies determine an MIC
> concentration cutoff, above which a given drug is not
> bacteriologically efficacious, because now you get for licensure
> sometimes application which is hooked to an MIC.
>
> \[Slide.\]
>
> This is again one of our first studies looking at cefaclor versus
> cefuroxime-axetil. These are the placebo eradication rates as found by
> Howie in the past. Remember that both drugs are good for pneumococcus
> that are susceptible to penicillin.
>
> If you see a nonsusceptible, and this time we really didn\'t have
> resistance only to immediate you could see that both are effective,
> but you can see one drug that is more effective than the other, and
> this is sort of the gradual increase in MIC, you can find some
> cutoffs. Hemophilus is not relevant to this question here in this.
>
> \[Slide.\]
>
> Now, with trimethoprim-sulfa, for example, since MIC of 0.5 is
> considered to be the cutoff, we wanted to see whether MIC of 0.5
> really is associated with eradication failure. You can see that for
> both pneumococcus and Hemophilus here, you have 37 cases, 100 percent
> eradication with trimethoprim-sulfa, while if you have above MIC of
> 0.5, basically, for pneumococcus and for Hemophilus, you have a
> placebo.
>
> So, again, I think I mentioned last time with a question that will
> come whether we need placebo studies, we have some placebos here that
> we don\'t really need to give placebos, they are as good as placebos
> for eradication.
>
> \[Slide.\]
>
> With azithromycin, there is now a study where we did from 3 days and 5
> days, and pharmacokinetic/dynamic calculation predict a 0.25 or less
> than 0.25 actually than MIC, below which you should see a response,
> and above which you should not see a response.
>
> These two studies actually show that for pneumococcus that is
> susceptible to macrolide, you do have almost 100 percent response,
> while if it is above that, which is usually above 2, because you
> don\'t have really intermediate values, this is basically placebo rate
> of eradication.
>
> For Hemophilus, there is no Hemophilus of less than 0.25 MIC for
> azithromycin. Up to 4, it is susceptible, but you can see that for
> both studies, 3 and 5 days, at 5 days, even one at 0.5, which are not
> the majority of the cases, you have basically placebo eradication
> rate, the same goes, of course, if the MIC is higher. They are all
> acting about the same.
>
> So, definitely, here, in this case, and the previous slide, you could
> see that there is an MIC where we can really measure above which you
> are not going to see good results.
>
> \[Slide.\]
>
> This is the Augmentin ES study that was published. The data, you can
> see that again this is penicillin MIC, and this is pneumococcus, and
> the majority had an MIC of 1 or less, and you have 100 percent
> eradication, but you start to see increasing failures with MIC, and as
> far as I know, the FDA did not approve it for MIC maybe because of
> this.
>
> For Hemophilus again, 0.5 or less, you don\'t have all those failures,
> and then you start to see more and more failures, and we need a little
> bit more cases to know where it is starting to be unacceptable, but
> definitely with a double tympanocentesis, you can go down to talk
> about MICs and for which MICs you start to see problems in
> eradication.
>
> \[Slide.\]
>
> The third question is, of course, is there a relation between
> bacteriologic eradication on day 4 to 6 and clinical outcome? I think
> this is maybe the most important question.
>
> \[Slide.\]
>
> We have two studies actually, only two studies that looked at this
> because in order to look at this, you need to do double
> tympanocentesis and to be able to follow clinically, otherwise you
> cannot correlate those.
>
> One is a study that was mentioned by Carlin, et al, and the other one
> is ours. This is the cases where you did eradicate the organism. You
> start with positive culture in cases you eradicate the organism, you
> see that there is about\--no, I am sorry\--you don\'t eradicate. This
> is culture-positive, about 40 percent would be clinical failures.
>
> If you eradicate the organisms, you get less than 10 percent clinical
> failure, so I think there is no argument that most of the clinical
> failures will be those for whom you did not eradicate the organisms
> after 3 to 5 days. This is very clear.
>
> But if you really want to see how the children feel, you have to start
> to use some scoring. This was the scoring we use, giving from each one
> of those from zero to 3, and this was evaluated by an independent ENT
> who did not know what the children were receiving and what the
> organism was.
>
> The maximum score is 15, the minimum is zero, and if you look on day 4
> to 6, and you try to see how the kids feel by scoring, this is the
> culture-negative, this is the children that responded to treatment
> bacteriologically on that time, and you will see that 45 percent have
> zero or 1 score, and very few have 4 or more. This would be equal or
> above.
>
> Those who are still culture-positive, you see the difference, a highly
> statistically significance, very few with zero to 1, and one-third
> above 4. So, the children in this group definitely feel better than
> children in this group, and this is the group where you eradicated the
> organism.
>
> So, there is a correlation, there is no doubt about that, between
> bacteriological eradication and how you feel after a few days, and how
> you feel at the end of treatment and whether you fail or not.
>
> \[Slide.\]
>
> The fourth question is can we determine by double tap studies if an
> organism is not important in acute otitis media?
>
> \[Slide.\]
>
> This is very important actually, because there are some authorities
> and some manufacturers and some clinicians who think this H.
> influenzae is not important, and the Hemophilus is relative or
> absolutely is going to be more important after pneumococcal
> vaccination than it is now.
>
> There was already data to show replacement of Haemophilus influenzae
> that replaced some of the vaccine type that disappear in the Finnish
> study, and definitely now since the vaccine types are going to be
> reduced, you are going to see maybe less of pneumococcal resistance,
> but more Hemophilus, so this is a very important question.
>
> \[Slide.\]
>
> One of the studies that was done by our group and presented at ICAAC a
> year and a half ago was looking at the regular bug that we have now in
> Israel, which is not very different from what you had in the States
> before starting with vaccination.
>
> Pneumococci were mainly penicillin-nonsusceptible, Hemophilus with
> about a third that were beta-lactamase-positive, very few Moraxellas,
> 43 patients, 56 bugs receiving what is recommended in the status of
> first liner, 80/kilo amoxicillin, and 13 failed with 16 organisms.
>
> You can see that now we have very few pneumococci that are
> penicillin-susceptible, the susceptible went away, and you see very
> clearly that you have now lots of beta-lactamase, and actually, if you
> look at 13 here, 8 here, so basically what you have got is again this
> spontaneous eradication of the beta-lactamase production, which is
> still placebo effect and most of the beta-lactamase not producing went
> away. Most of the children have beta-lactamase producing organisms.
>
> So, it depends on what drug you have, but with amoxicillin, Hemophilus
> is definitely a very prevalent one. The question is whether it causes
> any symptoms.
>
> \[Slide.\]
>
> We have now quite experience with reading, giving a scoring. This is
> more objective without ear tapping, giving a scoring by the ENT that
> sees the child before the first attempt, which means it is sort of a
> blind reading because you don\'t know what the organism is going to be
> when you tap, and you score the child.
>
> We have now about 1,000 cases like that where we can start to
> summarize those. You can see we have 762 that are culture-positive,
> 240 that are culture-negative, and the mean score is here, and the
> culture-negative, of course, has lower score despite the fact that all
> are involved as acute otitis media cases.
>
> \[Slide.\]
>
> Now, if you look at the organism, this is a negative, this is mixed
> pneumococcus and Hemophilus, pneumococcus alone, Hemophilus alone. You
> see the numbers are quite big, and you see that the culture-negative
> has a different score than the culture-positive, and because of the
> big numbers here, the P is significant between Hemophilus and no
> growth, and really not different from the others. If anything, this is
> a little bit higher, not significantly.
>
> So, basically, you can see that Hemophilus really does not have a
> different score when you see the child, when you look at the tympanic
> membrane and the fever than pneumococcals when they come to you, and I
> think that these big numbers really makes it more accurate than the
> few small series that characterize 1 or 2 or 5 or 20 patients.
>
> Even more important, if you look at eradication, what happened to the
> score after you give antibiotics. This is just an example of a score
> that was given before antibiotics. This is day 4 to 6, another score,
> and what is really important is the delta, and we want to see whether
> the delta is the same if you did not eradicate and did eradicate
> pneumococcus and Hemophilus.
>
> What you get is first when you eradicate, the organism is gone, the
> second test, you see quite a nice big delta, which is no difference
> between Hemophilus and pneumococcus from mixed infection.
>
> When the organism was not eradicated, the delta is much smaller, and
> again, not different between those three, and definitely it means that
> if you did not eradicate the organism, Hemophilus is as bad as
> pneumococcus, but remember that within 3 to 5 days, you have more
> eradication of Hemophilus compared to the pneumococcus, so all in all,
> there will be more cases that will look better with Hemophilus than
> pneumococcus, but the 50 percent of where you do not eradicate the
> Hemophilus, are going to look as bad as pneumococcus, and think this
> is proof that Hemophilus is not negligible at all in otitis media.
>
> \[Slide.\]
>
> This is the next question. Can we bridge between double tap studies
> and studies with clinical outcome? This is the main question coming
> from the previous questions.
>
> \[Slide.\]
>
> I use here an example of the one study of the previous dose of
> amoxicillin or amoxiclav, or the regular dose, if you will, of 45
> mg/kg compared to azithromycin, 5 days, and here you see the placebo
> rate again of eradication, and you remember that, or I am not sure I
> showed it, but basically, the results were that you have 87 percent
> eradication rate.
>
> Now, this is not persistence, this is eradication rate with Augmentin
> and 40 percent with azithromycin, and all together it is high
> statistically significant. Now, this is bacteriological eradication.
>
> \[Slide.\]
>
> If you look at this, this is what I show now, this is bacteriological
> eradication of pneumococcus alone. There was some difference, which
> was not statistically significant, and the overall bacteriological
> eradication rate was significant.
>
> \[Slide.\]
>
> But when you look at the clinical outcome now, you could see that
> here, there is no difference, significant difference in clinical
> outcome. Here, here is a significant difference in clinical outcome,
> and all in all, you have here 16 percent difference, which is
> statistically significant clinical outcome.
>
> Now, by doing the double tympanocentesis, this is the clinical
> outcome, but by doing the clinical tympanocentesis, you know that the
> main difference that accounts for this 16 percent between the two
> drugs is coming from the Hemophilus eradication, not really much from
> the pneumococcus.
>
> So, by doing this, and then doing clinical studies, you are going to
> see that the clinical studies don\'t say much different that we have
> here, but you can know that this is not because of pneumococcal
> problems, but because of Haemophilus influenzae issues.
>
> \[Slide.\]
>
> Now, if I take this, again, I am surprised, I am the fifth speaker or
> so, and nobody mentioned yet the Pollyanna phenomenon, but this is
> what I call\--I don\'t call it anymore Pollyanna phenomenon\--I call
> it the Colin Marchant drum, because this diagram was shown first by
> Colin Marchant.
>
> Remember, this is the eradication rate after 3 to 5 days. Placebo is
> very low. One hundred percent is best. You heard from Scott that even
> if you have 100 percent eradication, you are not going to see 100
> percent clinical response here. With placebo, you get up to 70 percent
> clinical response just because some and most of the organisms go away
> within 10 days.
>
> The difference is that small here. I take the data that I showed in
> the previous study, and I try to put them here. So, for pneumococcus
> with Augmentin, a regular dose, you have about almost 90 percent
> clinical success rate, which is well located.
>
> With azithromycin, you have 80 percent. It might be a difference or
> not, it is an issue of sample size, but they are located in the upper
> 50 percent. If you look at the amoxiclav, Hemophilus, it is here, 87
> percent bacteriological eradication, it is well located here.
>
> If you look at the azithromycin, it is located basically in the range
> of placebo.
>
> So, this is what we saw with clinical response. This is what we saw
> with bacteriological response. This is just to show you how we
> are\--and I am trying to take this diagram, it\'s the bridging diagram
> for clinical studies\--and try to see what happens if I put clinical
> studies on that.
>
> \[Slide.\]
>
> In order to choose that, I took the only one, the only FDA meeting I
> was in was the previous one, which now it says 7/11, the other one was
> 11/7, in November, for licensure of one dose and three doses of
> azithromycin, and I took data from clinical studies that have one
> tympanocentesis, that were obtained, but clinical outcome, it was
> obtained by the people who wanted to have the best results because
> this was shown, this was presented by the people from Pfizer, and you
> can recognize those slides from work you can download from the
> Internet.
>
> \[Slide.\]
>
> What you can see here is\--I didn\'t find the slide with
> macrolide-resistant pneumococcus, but with penicillin-resistant
> pneumococcus, I could find one slide and, of course, the more
> penicillin resistant you are, the more it is enriched with macrolide
> resistance.
>
> They showed, the point was that even if you are susceptible
> intermediate resistant, although you have a little bit lower response,
> you still have quite a nice response for all three.
>
> \[Slide.\]
>
> Well, if I put this again in this, what I find here is that
> penicillin, pen-susceptible pneumococcus has 95 percent success, which
> is the best you can have, you cannot have better than that, which
> really is concordant with what we found in our studies on
> azithromycin.
>
> If you have penicillin, it is immediate, which is enriched with
> macrolide resistance, you already drop to not too nice results, and if
> you have penicillin resistance, which is even more enriched, you
> actually are within the placebo range.
>
> So, with the same drug, in the same study, clinical outcome only, if
> you put it here, you actually find a very nice distinction although
> the sample size is not sufficient, but if I bridge it with a double
> tympanocentesis study, then, this drug should not be approved for
> macrolide-resistant or penicillin-resistant pneumococci in the States
> why it was approved.
>
> \[Slide.\]
>
> Now, if I take the Hemophilus versus pneumococcus data for 3 days, 1
> day, this is post-treatment, this is EOT, this is after 28 days, and
> you can see that there is a difference between Strep pneumoniae and
> Haemophilus influenzae, the same here, the same here.
>
> Again, take those here, and I show 3 days pneumococcus 94 percent,
> excellent; one day pneumococcus, about the same. It is not a
> comparative study between those two, so I am not sure that you can
> deduce anything with the difference especially that it\'s a small
> size, but it might be that there is a difference between one day, but
> they are excellent, both of them are excellent.
>
> This is Hemophilus 3 days, this is Hemophilus 1 day. I think again,
> what they showed basically is that for pneumococcus, they get an
> excellent drug, if it is not pneumococcus that is macrolide resistant;
> for Hemophilus, in my opinion, it should not be approved because it
> falls into the placebo range.
>
> \[Slide.\]
>
> The next to last question is how do double tap studies help in
> understanding the best timing for clinical outcome?
>
> We heard end of treatment versus test of cure.
>
> \[Slide.\]
>
> You remember this? Basically, you have still a way to go until here,
> and we heard about the otitis-prone children, and many of these
> children are otitis prone, so what happens here?
>
> The FDA elected until now to look at test of cure here, and if there
> is a clinical relapse, to put it as a failure. What we have
> documented, and again, about 800 kids we have positive culture here,
> negative here, and we have clinical relapse, and the question that
> Scott was asking, do we have really eradication or it is just a
> suppression, and you get it back here.
>
> \[Slide.\]
>
> Of those kids, we have 108, of the over 800, that came with a clinical
> relapse, and we were able to do a tympanocentesis, 30 tympanocentesis,
> and see what happens compared to the previous bugs.
>
> In 20 percent of the clinical relapse, there was culture negative. In
> 54 percent, it was totally new infection with a different bug. That
> means, and I will tell you a second what it means. Only in 28 percent,
> it was a different organism.
>
> So, the real bacteriological relapse was only 28 percent, the majority
> just reflected the child\'s otitis-prone nature.
>
> Even if you had a pneumococcus that was replaced by a pneumococcus,
> when you do serotypes, you find that the majority are not the same
> pneumococcus. If Hemophilus is replaced by Hemophilus, the majority is
> not the same Hemophilus, so even if it\'s the same organism, sort of,
> it is not the same, it\'s a new infection.
>
> So, definitely, what I can say, that if you think about EOT versus
> TOC, definitely, what reflects more is EOT and not TOC, and I think
> this should be taken into consideration. Again, without the double
> tympanocentesis, you cannot determine the third one, of course.
>
> \[Slide.\]
>
> The last question. Are the patients that are studied in double tap
> studies different than those in purely clinical studies?
>
> Because the question is how can we extrapolate from them, and my
> question is do we need to extrapolate from them, and I will tell you
> why I ask this.
>
> \[Slide.\]
>
> First of all, yes, they are different. As Scott alluded a little bit
> to you, in order to be able to get kids for double tympanocentesis,
> they usually have to be less than 2 years. Older kids are less
> cooperative despite the nice kid that Mike was showing. I believe this
> child was deaf, because you heard all those things about the
> tympanocentesis, and he was smiling.
>
> \[Laughter.\]
>
> Tympanic membrane bulging plus pus is not the rule for every single
> child with otitis, but these are the ones that we take really to
> tympanocentesis.
>
> Positive culture, you only take the ones with positive culture, and
> also, as Scott said, they are enriched for more complex acute otitis
> media, so, of course, they are different kids than the rest, but in my
> opinion, these are the ones who need antibiotics.
>
> You cannot extrapolate to the majority of kids that get antibiotics
> because those are diluted by older kids, mild disease, those who
> don\'t have otitis at all, and other things, and if I have to really
> say I don\'t want them to reflect what is usual to get patients given
> antibiotics, I want them to reflect the ones that need antibiotics,
> and I think therefore, these are the appropriate patients to study
> despite that they don\'t reflect the rest.
>
> \[Slide.\]
>
> So, in conclusion, double tap studies clearly demonstrate a
> considerable difference between drugs in regard to their ability to
> eradicate the pathogens with 3 to 5 days.
>
> Double tap studies can determine an MIC concentration cutoff above
> which a given drug is not bacteriologically efficacious.
>
> Bacteriologic eradication within 3 to 5 days and clinical outcome
> correlate.
>
> \[Slide.\]
>
> Double tap studies demonstrate that Haemophilus influenzae is an
> important pathogen in otitis media.
>
> We can bridge between double tap studies and studies with clinical
> outcome.
>
> Double tap studies help in understanding that the best timing for
> clinical outcome determination is EOT rather than TOC.
>
> The patients that are studied in double tap studies are those who need
> antibiotics more often than patients enrolled in purely clinical
> studies.
>
> DR. RELLER: Thank you very much, Dr. Dagan, for a succinct, focused
> delivery and an early arrival.
>
> I should like to have our 10-minute break now. We will begin promptly
> at 10:50.
>
> \[Break.\]
>
> DR. RELLER: Dr. Marchant.
>
> **Limitations of Clinical-only Studies**
>
> **Colin Marchant, M.D.**
>
> DR. MARCHANT: Good morning. First of all, I would like to thank Dr.
> Soreth and her colleagues for inviting me and for allowing me to
> speak.
>
> I have spoken several times before and I am not going to repeat all of
> that, but perhaps take it a little bit further. As you can see, I am
> from Boston University, and the teaching hospital affiliated with
> Boston University is Boston Medical Center.
>
> We have had a number of talented chief residents, but one in
> particular had an unusual talent. He was an amateur cartoonist, and
> during grand rounds, conferences, meetings, he will sit with a piece
> of paper and draw cartoons pertinent to what is going on.
>
> On a morning like this if he were in the audience, he would have at
> least six cartoons floating around the audience making cryptic
> comments about what had gone on.
>
> So, I am fortunate to have some of his cartoons and I am going to use
> them loosely as a metaphor as we talk about some of these things.
>
> \[Slide.\]
>
> Here is his first cartoon. Some people can\'t see the forest for the
> trees.
>
> \[Slide.\]
>
> The next cartoon, some people can\'t find either the forest or the
> trees. Maybe the cell phone will help.
>
> \[Slide.\]
>
> Some people get lost in the forest.
>
> \[Slide.\]
>
> And some people find a path through the forest, and it is our task to
> find a path through the forest here, of all this data and all these
> ideas, all these concepts, et cetera.
>
> \[Slide.\]
>
> This is the slide that Dr. Dagan already showed you. What is important
> about this earlier was raised the question what is the correlation
> between bacteriologic outcome and clinical outcome.
>
> Well, the answer, we have facts. We have two studies, and they both
> came up with the same answer. It may not be the correlation you wanted
> to see, but this is what the data shows, and in addition to the
> comments and the details that Dr. Dagan mentioned, the importance of
> this data is that it validates the bacteriologic outcome. The
> bacteriologic outcome would not be important if it didn\'t result in a
> better clinical outcome when you kill those bacteria, eliminate them
> from the site of infection compared with when you don\'t.
>
> \[Slide.\]
>
> This data, specifically the Carlin data, but the Dagan data could be
> used in the same way, leads us to the Pollyanna phenomenon where
> excellent drugs look worse than they are, and poor drugs look better
> than they really are, and then that shows us that there is a very
> narrow difference at the clinical efficacy level between one drug and
> another.
>
> \[Slide.\]
>
> That leads to the next issue, which is the sample size issue if we do
> the double tympanocentesis, we don\'t need a lot of patients.
>
> Notice, this is in thousands. If we do a single tympanocentesis with a
> clinical outcome, we have trouble telling the difference between a 90
> percent effective drug and 70, we are getting near 2,000 patients
> here, and if we do clinical-only studies, then, at this end of the
> graph, we can\'t really do a study of 15,000 or so patients or
> particularly to see fine differences, but we even need hundreds or
> thousands of patients just to do that.
>
> \[Slide.\]
>
> The next issue that comes from this same data is the issue raised by
> Dr. Giebink, and that is, he said that because there is so many
> millions of children treated with otitis, we need to think about it
> because there is just such a large number, and this data allows you to
> calculate what that burden is with various levels of bacteriologic
> efficacy, and obviously, the perfect drug, there aren\'t going to be
> any children who have persistent symptoms on days 3 to 6 who otherwise
> would have been better, but even at 90 percent, there is going to be
> 20,000 per million, 60,000 per million, 100,000 per million, 140,000
> per million, and so this data allows us to put some numbers of what is
> the cost of not finding out whether a drug is efficacious or not
> efficacious.
>
> \[Slide.\]
>
> So, I am going to cover some design issues. I have put up here that
> they are all important, yes, they are all important. This is just my
> preference, order of the day, if you will, but they are all important.
>
> In the IDSA guidelines, they covered these general issues, that trials
> should be randomized, double-blind, should measure compliance, et
> cetera, et cetera, but the place that the guidance has fallen down, in
> my judgment, is where the issues are otitis media specific, which
> means you have to go to the data on otitis media to get properly
> designed studies for industry.
>
> I noticed in Dr. Powers\' talk that statistical issues will be talked
> about later, but I say you can\'t divorce yourself from the
> statistical issues, you can\'t divorce yourself from the sample size
> issues because the sample size is so affected by the outcome, because
> the sample size, in fact, is affected by the patient selection factor,
> and the sample size, if you use poor diagnostic criteria and put a lot
> of non-otitis, we saw Dr. Pichichero\'s illustrations, it is really
> not always easy if we don\'t have good diagnostic criteria, then, we
> will also drive up the sample size, decrease the power of our trials,
> so even when we spend time talking about these, they all have sample
> size statistical implications, and we can\'t get away from them.
>
> \[Slide.\]
>
> So, I am going to talk in the next few slides about four trials
> designs - a double tap, a tap at entry to the trial where you then do
> a tympanocentesis on the clinical failures, a tap at entry with
> clinical outcome only, and then clinical criteria at both entry and by
> outcome.
>
> \[Slide.\]
>
> This is just for reference because these slides are in your handout or
> end up on the web site or what have you. These are the statistical
> parameters used in the tables that I am going to show you.
>
> Here, in this table, I am showing you if we compare a drug that is
> very good, 90 percent bacterial efficacy versus tap water or placebo
> at 30 percent, we look at the number of patients we have got to
> recruit, the number of taps we are going to do, the number of patients
> that we analyze.
>
> At this lowest level, we see that the double tap study shows us was
> small numbers, but also notice that amongst the three studies with the
> tap designs, we also do fewer tympanocenteses. Yes, they are repeated
> on the same children, but actually is fewer tympanocenteses that are
> done.
>
> \[Slide.\]
>
> Now if we do these calculations for a poor drug, the numbers are going
> to rise in each column. We are now close to 100 with the double tap
> study. We are close to 300 with a tap and tap of failures, we are
> already over 1,000 with the clinical outcome.
>
> This relationship remains the same, fewer tapes in the double tap than
> the tap and tap of failures and respectively the initial tap only.
> Then, when we get up to a 20 percent difference, and that is
> equivalent to 40,000 children per millon remaining symptomatic at the
> time of this second tap, who otherwise would have been better, that
> difference is going to take you near 300, near 1,000, and up at 4,000.
>
> \[Slide.\]
>
> So, sample size clearly depends on the outcome, the population, even
> diagnostic criteria, and the minimal standard should be that the trial
> is large enough to have shown that an antibiotic that was no better
> than placebo, that it, in fact, was efficacious, so the sample size
> should really be that large.
>
> Let\'s think of the high jump. In the high jump, you jump over a bar.
> If you jiggle the bar and it shakes, it may fall off. When you do a
> trial, you would like to be jumping over the bar, but, in fact, most
> of the trials have been ducking under the bar. When you look at the
> result, the bar is still standing, but you didn\'t jump over it, you
> ran under it.
>
> \[Laughter.\]
>
> In the November 11th meeting, people went under the bar. So, how large
> should it be? I am suggesting that perhaps a 20 percent difference in
> bacteriologic efficacy might be the standard. So, we need to move on.
> We need to find a path through the woods, if you will, so we need some
> recommended guidance for industry, so I am going to propose some for
> consideration in the sample size area.
>
> \[Slide.\]
>
> One of the main, as I look back at previous guidance, at the IDSA
> guidelines, et cetera, one of the big problems has been that guidance
> was based on general principles, on expert opinion, and not by going
> back and saying what does that data say, what does the best data tell
> you about how the disease behaves.
>
> Sample sizes, if you are going to calculate them, should not be based
> on assumptions or expert judgment, but based on data, and there is
> data in the literature that you can use from previous trials to make
> more informed projections of how you base your sample size.
>
> I have already said that we need to at least exceed the tap water
> standard proposed the 40,000 children is what we should look at, and
> we also need to consider the power of subgroup analyses for specific
> pathogens if we want to look at those.
>
> Previous guidance, the 1998 one had I think arbitrary 25 pneumos, 25
> Hemophilus, 15 Moraxella. Where do these numbers come from, how are
> they powered, what is the chance of showing them, are they going to
> show anything by looking at those?
>
> \[Slide.\]
>
> So, now let me shift to the outcome, which, of course, is linked to
> sample size, but the outcome should be directly meaningful like is the
> child better at 72 hours or 48 hours, as used in the Pittsburgh
> Kaleida study. That is a meaningful outcome, and the bacteriologic
> outcome is only meaningful because it has been validated by the data I
> showed you earlier, the data Ron showed you, the data that Scott
> showed you earlier.
>
> The outcome should be objective or at least reproducible. The outcome
> should be sensitive, that is, it has to be an outcome that is affected
> by antibiotic therapy, and there is data in the literature to tell you
> what outcomes have been affected by antibiotic therapy, and it should
> be timely. You have got to measure it at the time point when it is,
> according to the data, affected by antibiotic therapy.
>
> So, we have already pushed back the test of cure thing as being
> incorrect. We are now getting closer to the end of therapy, and the
> end of therapy guideline appears to me that it came from the general
> guidance in the IDSA recommendations or guidance, and not otitis
> specific, but just as a general principle that it is at the end of
> therapy that we are interested in, but many of the outcomes in otitis
> media, in fact, happen earlier, and if we are going to actually
> measure them, we need to measure them when they happen, and not at
> some time later. I have already been vigorous in looking at that
> issue.
>
> \[Slide.\]
>
> So, if we take the four designs\--your handout is incorrect here, it
> is incorrect here, as well, and this should read increases as you go
> from double tap to clinical outcome, the sample size increases\--but
> the other important point is we get more information as we climb this
> order.
>
> Dr. Dagan has showed you that if you do double taps, you can find out
> what MIC it takes to or what the relationship is for a specific drug
> and organism and MIC. Pathogen eradication rates, you can only get
> those if you tap the ears, and then there is the emerging area of
> PK/PD data, and that has become clinically relevant because Dr. Craig
> correlated the double tap outcome studies with the serum
> concentrations and MIC\'s of organisms, and Dr. Jacobs, in the public
> session, I believe is going to amplify that.
>
> So, one of the values of going up this hierarchy is that we find out
> more, it teaches us more, it will help us go in better directions to
> manage these children.
>
> \[Slide.\]
>
> So, here are the recommendations I would make. We should do double tap
> studies, and they are preferred for the reasons that I have just
> mentioned, and a tap and tap of clinical failures is an alternative
> that if large enough, will also provide useful information.
>
> If clinical outcome studies are going to be done other than
> symptomatic response, which, of course, will require thousands and
> thousands of patients, we need to use outcomes that are validated,
> that are against the clinical response to the clinical outcome.
>
> \[Slide.\]
>
> I didn\'t spend a lot of time on that, but this was mentioned. Dr.
> Dagan mentioned it, what should we say we should do for the
> recommended guidance on population selection and enrichment.
>
> It is these enriched populations, the young, those that fail
> treatment, those with prior antibiotic therapy in daycare, that are
> most challenging, and we need data. Clinicians want to have data on
> how our drugs behave in those groups. We should include those, not
> exclude them.
>
> \[Slide.\]
>
> Diagnostic criteria, I am just throwing these up into the mix. Yes,
> they should be symptomatic otitis because that\'s our goal, is to
> relieve those symptoms. Yes, we should use some good diagnostic
> criteria, the kind that have been championed by Dr. Paradise and
> others, and the other issue that Dr. Soreth has raised, that some
> folks doing these studies bat 80 percent and some bat 20 percent on
> their bacterial isolation rate, and those batting 20 percent, we are
> not sure what disease they are studying most of the time, and we would
> want to do better.
>
> \[Slide.\]
>
> I have deliberately left the ethical issues until later because I
> think if we are going to stay out of the woods, we have to think
> through the science first and then ask the ethical questions, because
> the ethical questions aren\'t show-stoppers.
>
> If the ethical questions were so large, we wouldn\'t even go here, but
> they are not that large, they are important, but they are not
> show-stoppers. So, think through the science first, we will get
> further, and then let\'s move on to the ethics, and there is more than
> one ethical question, there is broad ethical questions, as well as
> focused ones.
>
> Of course, is it ethical to perform tympanocentesis, is it ethical to
> perform double tympanocentesis? Those are two important questions, but
> these other questions are important also.
>
> Is it ethical to license, market and prescribe drugs without knowing
> that they are efficacious? Is it ethical to duck under the bar? Is it
> ethical to perform drug trials in humans that will not yield
> scientifically valid data? I suggest no, they aren\'t.
>
> With regard to tympanocentesis, the question in part is, well, the
> question about the ethics of it, we haven\'t really heard from anybody
> that there is a significant permanent damage.
>
> Dr. Pichichero talked to you about the case of the blood behind the
> eardrum for a week that made him nervous, but healed. It appears to be
> a fairly safe procedure, and every day in our country,
> otolaryngologists do a more extensive procedure. They put tympanostomy
> tubes in the ear, which stay there for months. They perforate the
> eardrum, and although there are issues of scarring, and so forth
> there, many eardrums heal and tympanocentesis is very much a lesser
> procedure than that.
>
> So, it is primarily the pain of tympanocentesis that is the objection
> here.
>
> \[Slide.\]
>
> So do the benefits outweigh the risks? I believe this to be true, and
> therefore, I believe that the benefits of the knowledge gained from
> properly done studies that are going to give us answers, do outweigh
> the risks.
>
> That, of course, is a judgment. However, tympanocentesis is still a
> painful procedure, and in order to move guidance for industry forward,
> in order to move forward clinical trial design and to get it right, to
> see a path out of forest and not stay back in the woods, we need to do
> something else, and that is we need more efforts to find ways to make
> this procedure less painful and less objectionable.
>
> Currently, it has been pointed out that many practitioners don\'t do
> tympanocentesis, and this is true, it is really a very small number of
> people that do this procedure, many more could, but when something is
> not familiar with people, they tend to fear it and many of the
> objections to tympanocentesis come from those who are really not that
> familiar who fear it, who aren\'t experienced, not solely, but in many
> cases. We have more work to do to do that.
>
> So, in summary, then, I offer up for consideration some, not a
> complete list, it doesn\'t cover all the issues, but some things that
> we should offer as a guidance for industry.
>
> One last comment. Dr. Soreth mentioned the problem where you have to
> be worried about making these things too expensive for industry, and I
> think that\'s right, but the first and foremost duty we have really is
> the public, and in this case, the public is the children, and it\'s
> all about how many have ear pain as a result of what our decisions
> are.
>
> That is what we need to do first. Industry, they are business people,
> and what they do is they negotiate. That is very much part of their
> culture and part of what goes on in business. So, when they tell you
> it\'s too many, it\'s too much, it\'s too expensive, that is part of
> their negotiating position.
>
> So, you need to judge them by their behavior, and when they stop
> coming around proposing new drugs for otitis media, then, we will know
> that we have gone too far in coming to high standards, which are going
> to get us the data that will help us make clinical decisions and
> license-effective drugs for this indication.
>
> Thank you.
>
> DR. GIEBINK: Colin, could I ask a quick question of fact here? Okay.
> On your first recommended guidance slide, the last bullet says, \"If
> clinical outcomes other than symptomatic response are to be used as
> outcomes, they should be validated.\"
>
> Do you mean externally validated, internally validated, validated
> against tympano? I just would like a definition for that word.
>
> DR. MARCHANT: Let me give by example. If you were to propose acoustic
> reflectometry or tympanometry, or the appearance of the drug on
> otoscopy as important outcomes, then, those important outcomes have to
> relate back to what the child care is about, which is whether it hurts
> or not, just as the bacteriologic outcome has been shown to be
> important in terms of whether there are persistent symptoms or not,
> that is the validation that I would be speaking about there, or any
> other new measure that somebody came up with.
>
> DR. RELLER: Dr. Soreth.
>
> DR. SORETH: Very briefly, a point of clarification for Dr. Marchant. I
> did not say that we need to be worried about the cost, but rather
> cognizant that any particular set of recommendations for clinical
> trial design has implications at the end of the day for cost, and it
> is just one of many, many factors that are taken together as we are
> all on the same page about caring for the public, in this case, caring
> for children who have acute otitis media, and that at times, not
> necessarily for otitis, but that at times, one can conclude that a set
> of recommendations in the ideal world are best, but that in the
> practical world, sometimes cross some line of practicality and
> doability.
>
> That was really my only point, that in some measure, it is also part
> of the overall complex equation of what can be done, should be done in
> an ideal world or in the real world, and that was my only point.
>
> DR. MARCHANT: I didn\'t mean to put any words in your mouth, and
> really, what I did, was I extended the issue that you raised with my
> own view of it is what I did.
>
> DR. RELLER: Dr. Rochester will present for the FDA, Study Designs for
> Acute Otitis Media Trials: What Can Each Design Tell us?
>
> Thanks, Dr. Marchant. We will have much discussion later on all of the
> important issues raised and perspectives given.
>
> **Study Design for Acute Otitis Media Trials:**
>
> **What Can Each Design Tell Us?**
>
> **C. George Rochester, Ph.D.**
>
> DR. ROCHESTER: I am George Rochester. I am a mathematical statistician
> in the Division of Biometrics III, and I am co-located with Division
> of Anti-Infective Drug Products.
>
> The purpose of my talk today is to discuss the topic briefly, study
> designs for acute otitis media, and what can each design tell us.
>
> I would like to begin with just a couple of opening works in the sense
> that when we start thinking about acute otitis media, as well as any
> other kind of infectious disease, we must have some clarity about what
> exactly is the question that we want to answer with our study.
>
> Until we have clearly articulated our hypotheses and ensure that we
> are going after the correct populations that we are studying, we tend
> sometimes to go amiss in terms of the value and interpretation of what
> we get out of each study. So, I want us to bear that in mind as I move
> through these.
>
> \[Slide.\]
>
> The outline of my talk essentially will address three main areas. One
> will be the role of tympanocentesis, which I abbreviate as TAP, and
> will speak of as TAPS in acute otitis media trials, and then
> advantages and disadvantages of each design, and I will speak
> primarily of two types of designs, the superiority design in which we
> will refer to placebo-controlled, and the non-inferiority design,
> which has been the design that we have used mostly in the last
> probably decade or so.
>
> \[Slide.\]
>
> Acute otitis media represents a spectrum of illness, and I think that
> has been nicely described by other speakers already. In order to
> demonstrate the efficacy of a new drug, one needs to provide both
> clinical and microbiological proof of efficacy.
>
> We must be cautious. We need to guard against post-hoc subset analyses
> as proof. We have all been confronted with a situation where at the
> end of a trial, when our data has been analyzed, we get this kind of
> ah, oops, I think I should revise my protocol here in order to restate
> my hypothesis for what I wish I had studied now that I have found
> something.
>
> We have seen where people do become very enthusiastic and very excited
> because we have seen something that looks really wonderful in a small
> group of patients that we didn\'t otherwise anticipate when we started
> the trial.
>
> I get excited about that, accept that in the context that that
> generates a new hypothesis that I would like to see studied in a
> future trial. It may offer certain important reassuring information,
> but it is not enough for me to call it solid clinical or microbiologic
> proof.
>
> Then, we want to also guard against extrapolating to populations not
> directly studied. In the era of evidence-based medicine, where we want
> to really provide a good, solid foundation upon which to make medical
> decisions, it is imperative that we understand that having completed a
> study, having generated the data, that we are very careful when we
> make extrapolations to populations we did not actually study.
>
> Now, those extrapolations need to have solid scientific pinnings and
> underpinnings for what we are doing. The temptation is very easy to
> just say, well, we have studied, you know a group of children from age
> 5 to 12, and that\'s just as good for the ones that are under 2, I
> don\'t see any reason why not, pain is pain, and so on, and so on.
>
> These generalizations, really, one needs to be careful and very
> cautious about that.
>
> \[Slide.\]
>
> The current state of affairs, what is the evidence that we are getting
> now, that we are looking at in terms of a dossier for registration. We
> tend to get a clinical-only study, comparative in nature,
> non-inferiority in design, in which we are comparing a new versus a
> standard therapy.
>
> Dr. Dagan\'s statement, this actually nicely concurred with our
> thoughts on this, back and at the November 2001 Advisory Committee,
> where he said, \"Most of the acute otitis media trials with clinical
> outcome as currently conducted are virtually guaranteed to show no
> differences between agents, dosing, or duration of treatment.\"
>
> I would like us to think about this within the context of Dr.
> Marchant\'s ethical framework that he just provided, that if we are
> going to make a study in which we really do not have a real high
> probability of successfully answering our question, that may call into
> question our ethics in human trials.
>
> Then, we get another study, which is a baseline bacteriology study,
> some baseline bacteriologic information at study entry, followed by a
> clinical outcome at some later time point, usually at end of therapy
> or at some test of cure, which we might agree on should be different.
>
> That is often non-comparative although not required to be
> non-comparative, but we often see that people take the path of least
> resistance.
>
> \[Slide.\]
>
> Why do some trials fail to detect differences among treatments? Well,
> for one, differences among these different treatments may, in fact,
> truly not exist. These drugs probably are not different.
>
> We also may have the issue of \"noise,\" and noise in statistical
> jargon probably means kind of all these things that are confounders
> that you are probably not controlling very well, things you are not
> measuring very well, imprecision in terms of how you are carrying out
> your study.
>
> Sources of noise in AOM studies include enrollment of subjects without
> bacterial infection at baseline, an example, they have got viral
> infection, or they probably just have some sort of situation in which,
> for example, effusion leads to diagnostic confusion.
>
> We have got loose case definitions. We have seen a situation where you
> have spontaneous resolution even with a bacterial infection, and we
> have just heard about the tympanocentesis, for example, that it, in
> and of itself, has some therapeutic value.
>
> So, we are not even sure, that we may go in, perform a TAP, pull out
> fluid. We have nicely cleansed this nice little pocket of pus, and
> maybe that, in and of itself, has some clinical benefit to the extent
> that we are now attributing that benefit to a drug, I am not sure.
>
> Determination of treatment response includes both subjective
> components, as well as objective components, but the subjective
> components, in fact, may be subject to significant inter-rater
> variability.
>
> So, strategies for handling noise would include designing
> placebo-controlled trials, and for differences observed in the
> placebo-controlled trial, we know that we can say we have demonstrated
> a clinical benefit.
>
> We may also have a non-inferiority trial in which we could have either
> a baseline TAP, which reduces noise in terms of at the diagnostic
> phase, and we may have a repeat TAP, which actually reduced some
> noise, as well, in terms of our outcome assessment.
>
> \[Slide.\]
>
> Should TAPS be performed? I think we have heard many other speakers
> address this issue.
>
> Placebo-controlled trials, in general, will provide clear evidence of
> clinical benefit, but if you add TAPS to a placebo-controlled trial,
> then, it does add efficiency to the trial.
>
> Baseline TAP is probably a little bit more critical if we are thinking
> of the non-inferiority design where \"noise\" sometimes may lead to a
> false proof of efficacy.
>
> Then, a follow-up TAP in which we have bacteriologic outcome becomes
> more objectively determined.
>
> The optimal time and number of TAPS to perform may need further
> research. I have heard several speakers may use timing of day 3 to 5,
> some people say day 4 to 6. We do know that if we tap probably too
> early, it may not be as helpful to differentiate differences between
> drugs; if we tap too late, it may not be ethical, the children are
> actually cured, their fluid has gone away, they are fine, they are
> happy, and so on. People do not feel that may be a good to tap.
>
> However, tapping all failures has always been encouraged, it seems, in
> all the guidances I have read, however, there is also a difference
> between clinical trial and clinical practice.
>
> What I have seen in a lot of the studies that come to us for review,
> is that physicians sometimes forget the difference between practice
> and a trial. A clinical trial is an experiment in which a protocol has
> been designed and agreed to, and should be followed.
>
> It ensures uniform documentation and it ensures that we can interpret
> our data with a certain rigor. In clinical practice, however, a
> patient appears to a health care provider for care, and that care
> means that physician has a wide latitude of discretion in the way the
> patient is ultimately managed.
>
> If, in a trial, you have a protocol and the investigators are not
> following the protocol, it actually becomes very difficult in order to
> really interpret and understand the information.
>
> \[Slide.\]
>
> A single TAP at baseline. You have got bacteriological diagnosis and a
> clinical outcome assessment, that is the standard trial we have been
> talking about in a non-inferiority setting.
>
> The baseline TAP ensures that patients in he primary analysis have
> baseline pathogens. It is better than having no TAPS, but the
> bacteriological outcome is presumptive if we are going on a clinical
> outcome assessment to determine success or failure.
>
> In practice, failures do not usually get follow-up TAP regardless of
> what the protocol specification is. A non-inferiority with baseline
> TAP may allow a wider non-inferiority margin which leads to a smaller
> sample size, and Dr. Marchant did speak about sample size actually
> quite nicely, so I won\'t go further into that.
>
> \[Slide.\]
>
> Repeat TAPS provide objective bacteriological outcome. Blinding in
> this situation is not as critical for the bacteriologic endpoint, but
> it is essential to reduce bias during study if the clinical outcome is
> the ultimate goal.
>
> Study is successful, though, if efficacy is shown at both the
> microbiological and the clinical assessment time points.
>
> \[Slide.\]
>
> Fundamental question regarding the utility of a microbiological
> endpoint. Bacteriological endpoint is a surrogate and the correlation
> with clinical endpoint sometimes may be less than satisfactory given
> current data.
>
> So, I think until we are really certain of whether or not we can truly
> predict the clinical course or the ultimate clinical outcome of this
> patient from the bacteriologic data, bacteriologic endpoint, then, it
> needs to be seen as probably a co-primary kind of information with the
> clinical outcome.
>
> I am not sure if we are at the point in the literature where we can
> say we can substitute one for the other.
>
> Much uncertainty still remains about the bacteriological endpoint.
>
> \[Slide.\]
>
> The Agency for Healthcare Research Quality Evidence document,
> published in 2001: Management of Acute Otitis Media, makes the
> following quote that I find very useful:
>
> \"There is still a need to adequately address he role of antibiotics
> in the initial treatment of acute otitis media in children compared to
> placebo or observational treatment especially in terms of various
> influencing factors such as age and otitis-prone status.
>
> \"Close monitoring of patients in these studies with a priori plans
> for appropriate intervention should allay any concerns about
> suppurative complications and should also be a focus of research.\"
>
> So, when we are talking about any trial in a pediatric population,
> children fall within a group that we consider vulnerable populations
> who deserve significant additional protections.
>
> So, whether you are doing a placebo-controlled trial or a
> non-inferiority trial, it is important that we have an ethical
> framework, such that children are monitored carefully and all
> strategies that are important to protect them from any harm is
> actually in place and followed.
>
> \[Slide.\]
>
> The randomized, double-blind, placebo-controlled trial is kind of what
> I am thinking of when I say placebo-controlled trial, and that is the
> gold standard. It is efficient and easy to interpret, it provides
> direct evidence. We may consider a three-arm trial in which we have a
> new drug, a standard drug, and a placebo.
>
> We want to have certain features of blinding, randomization, all of
> which ensure that we are minimizing the bias that can be present
> during study conduct, and, of course, the placebo helps in terms of
> giving us direct estimate of the treatment benefit, and the
> placebo-controlled information is what becomes the scientific
> foundation on which to plan future trials.
>
> \[Slide.\]
>
> So, advantages and disadvantages are that the placebo-controlled trial
> will provide clear evidence of a clinical benefit. If TAPS are added,
> it will improve the efficiency of the trial and provide direct
> bacteriological information and obviously may help with a smaller
> sample size than a non-inferiority design. Once we add TAP into the
> design, it also improves upon efficiency of one that wouldn\'t have
> had a TAP.
>
> A disadvantage would be that one treatment group is untreated, and
> that could be taken two ways. You may say one group did not get
> treated, they ultimately could have not reaped the benefit that it
> could have otherwise had if it turns out to be useful, but they also
> were not exposed to any of the toxic effects that they could have
> experienced on drug, so to some extent, that could be an advantage or
> a disadvantage. If no TAPS are done in the placebo-controlled trial,
> certainly an additional microbiological study would be necessary and
> preferably in a comparative study.
>
> \[Slide.\]
>
> Non-inferiority trials. You are comparing a new drug against a
> standard. Your estimate of the treatment benefit will depend
> intricately upon knowing the benefit of the standard over placebo.
>
> Efficacy here is indirect and is demonstrated only if we actually knew
> that the control itself would have had a benefit over placebo. The
> choice of non-inferiority margin will depend upon microbiologic rigor,
> as well.
>
> \[Slide.\]
>
> Advantages of this one include acceptability, all patients get
> treated, so parents probably may sign up for this one more readily. It
> does provide some comparative clinical information.
>
> But I couple of the disadvantages I want to point out are that
> bacteriologic infection may not clearly have been established at
> baseline if you have no baseline TAPS, and over time, the magnitude of
> the initial benefit of the control may not be maintained.
>
> So, this one may not give us real good assurance that the new drug
> could actually beat placebo.
>
> \[Slide.\]
>
> In a non-inferiority design with a baseline TAP added, then your
> additional advantages would be that you have better microbiologic
> diagnosis, setting your non-inferiority margin becomes a little bit
> easier, but a clear disadvantage is that determination of efficacy is
> still indirect and relies upon clinical judgment, because the outcome
> is being measured as a clinical response.
>
> \[Slide.\]
>
> Certainly, with a repeat TAP, we now can assess two endpoints. We can
> assess a delta for a micro, which is our overall microbiologic
> response, we can assess for clinical response, and certainly a
> combination of clinical and micro endpoints would be what we would
> call a successful trial.
>
> \[Slide.\]
>
> So, which design to use? If you want to demonstrate absolute efficacy,
> and a placebo-controlled is your design, if you want to demonstrate
> absolute and relative efficacy, then you can consider a three-arm
> trial in which you can compare new drug to placebo, new drug to the
> old drug. We get relative efficacy and, of course, we have a placebo
> arm there.
>
> Now, if the magnitude of the advantage of the active control over
> placebo is known for the primary endpoint, then, we could consider a
> non-inferiority design, and the ICH E-10 gives us some advice probably
> on how to consider setting those non-inferiority margin.
>
> The basis idea is be conservative if our historical information is
> poor or if it is not relevant. Do not extrapolate beyond the strength
> of your data.
>
> \[Slide.\]
>
> So, what does each design really tell us?
>
> In a placebo-controlled setting, we know that the new drug beats the
> control and so it shows a clear clinical benefit among the patients
> studied.
>
> If have a non-inferiority design and with no TAPS, then, all we are
> saying is a difference in clinical success rates is less than some
> non-inferiority margin delta that we set.
>
> If we have a baseline TAP, then that difference is within the delta,
> but with patients with baseline pathogens.
>
> If we have one in which we have repeat TAPS, then, we have an
> observable difference in both a microbiologic endpoint and a
> difference in the clinical endpoint.
>
> \[Slide.\]
>
> So, in summary, TAPS do improve the efficiency of AOM trials. Repeat
> TAPS provide objective microbiologic information in which to judge not
> only the subjects who are successful at the end, but it also helps us
> to understand why subjects are failing.
>
> Placebo-controlled trials are efficient, easy to interpret, provide
> direct evidence, and the non-inferiority design, microbiologic rigor
> can improve the quality of those trials if the benefit of the standard
> over placebo is known.
>
> Then, we come to the real question, when we are setting all these
> studies up, what it is we really are interested in, is the
> microbiological or the clinical endpoint more desirable to patients,
> what it is that we really, truly are interested in at the end of the
> day? So, bear that in mind as we proceed with the discussion for
> today.
>
> I just want to thank the other members in our Division of Biometrics
> III, who contributed to this presentation.
>
> Thank you.
>
> DR. RELLER: Thank you, Dr. Rochester.
>
> Dr. Smith. Lessons Learned from Past Approvals.
>
> **Lessons Learned from Past Approvals**
>
> **Thomas Smith, M.D.**
>
> DR. SMITH: Thank you.
>
> In this presentation, I am planning to use some examples from recent
> approvals to highlight specific areas of the current draft guidance
> where we have had problems and where we would like to get the
> committee\'s advice as we prepare to make revisions.
>
> \[Slide.\]
>
> The current draft guidance speaks of two clinical trials. The first
> one of these is a statistically adequate and well-controlled
> multicenter trial that uses rigid case definitions with specific
> subjective and objective diagnostic and effectiveness parameters
> clearly defined.
>
> We have heard from Dr. Pichichero\'s presentation and from some of the
> other speakers today of some of the difficulties with these rigid case
> definitions and the fact that the diagnosis is not always so easy to
> make.
>
> In these studies, baseline tympanocentesis need not be performed, and
> as a result, in fact, most of the trials that are submitted to us are
> clinical-only trials. Tap of failures is strongly encouraged to
> document inadequately treated pathogens.
>
> Again, the taps of failures are rarely performed in studies even
> though the guidance recommends it and, in general, the protocols that
> are submitted also strongly encourage the tapping of failures.
>
> \[Slide.\]
>
> The second trial is a tympanocentesis trial. The guidance actually is
> silent on whether this trial should be comparative or non-comparative
> and, as a result, most of the trials that are submitted are
> non-comparative in design.
>
> These trials should establish acceptable outcome in at least 25
> patients with Haemophilus influenzae, 25 patients with Streptococcus
> pneumoniae, and 15 patients with Moraxella catarrhalis.
>
> Tap of failures is strongly encouraged. Again, even though baseline
> tympanocentesis is done in this studies, failures rarely get tapped.
>
> \[Slide.\]
>
> This is an example from our most recent approval, which was actually
> for a labeling change in which the applicant very closely followed the
> recommendations of the current draft guidance and submitted as the two
> major trials, a clinical-only trial and a non-comparative
> tympanocentesis trial.
>
> The clinical-only trial was a double-blind, double-dummy, randomized
> trial that enrolled 350 patients from 9 United States sites. The ages
> of the children eligible for the trials were 6 months to 12 years, and
> 60 percent of the children turned out to be over 2 years of age.
>
> \[Slide.\]
>
> The clinical outcomes from this study are presented here. I have shown
> both the end of therapy and test of cure results. Although the current
> guidance uses the test of cure, which is at day 28 to 32, in this
> study as the primary outcome, the committee recently voted unanimously
> that the end of therapy clinical outcome was of greater value.
>
> These results are typical of most of the clinical-only studies in
> acute otitis media in that you have high end of therapy success rates,
> which are somewhat lower at the test of cure visit. The other thing to
> notice here is that there is no difference between the drugs. There is
> a satisfactory confidence interval around the treatment difference.
>
> \[Slide.\]
>
> The second trial submitted as part of this package as a
> tympanocentesis trial, which was an open-label, non-comparative trial
> with baseline tympanocentesis. 248 patients were enrolled from 22 U.S.
> and Latin American sites.
>
> The ages of the eligible children were 6 months to 12 years, and in
> this study, 65 percent of the children were over 2 years of age with a
> mean of 3.4 years. Fifty-one percent of the children who had
> tympanocentesis had positive cultures.
>
> \[Slide.\]
>
> Clinical outcomes by pathogen are presented here, and I simply
> presented them for the end of therapy visit. The overall success rate
> at the end of therapy was 89 percent, which is consistent with what
> was seen in the earlier study that was presented.
>
> For the individual pathogens, the point estimates for successful
> clinical outcomes ranged from 71 percent for Haemophilus influenzae to
> 100 percent for Moraxella catarrhalis.
>
> \[Slide.\]
>
> These data were presented before the Advisory Committee in November
> 2001, and there was a great deal of discussion that was generated.
> Much of it centered around the limitations of clinical-only trials,
> the fact that you are relying on a clinical diagnosis of otitis media,
> and that this necessarily includes a lot of patients who do not have
> bacterial disease.
>
> There were issues raised with the microbiologic data, questions about
> some of the point estimates presented and about the non-comparative
> nature of this data. There were comments made also concerning the age
> distribution of the patients and the fact that the population in this
> study was not representative of the population where the incidence of
> acute otitis media is greatest.
>
> Finally, there were several calls from the committee members for the
> revision of our draft guidance.
>
> \[Slide.\]
>
> A couple of months later, in the Pediatric Infectious Disease Journal
> Newsletter, there was a comment by Drs. Nelson and McCracken to the
> effect that, \"The supporting studies for these two regimens have
> shortcomings, similar to studies of other therapeutic agents in acute
> otitis media. It is time for the FDA to establish strict criteria for
> conducting clinical trials in patients with acute otitis media if a
> new antibiotic is to be approved for therapy.\"
>
> \[Slide.\]
>
> \"Such clinical trials should include a predominance of children
> younger than 2 years, a tympanocentesis at diagnosis to establish
> etiology, a repeat tympanocentesis at 4 to 5 days in a subset of
> patients to establish bacteriologic cure or a repeat ear tap in
> patients who are considered clinical failures, and follow-up
> evaluation at 10 to 14 days as the primary clinical endpoint.\"
>
> \[Slide.\]
>
> I think the example of this recent approval raises a couple of the
> major issues that we would like the committee to address in the first
> question for discussion today. These issues are the value of
> comparative studies with diagnostic tympanocentesis, and these studies
> might be single tap, double tap, or some combination, and also the
> issue of the future role of clinical-only studies.
>
> \[Slide.\]
>
> Now, another area of the study considerations of the current draft
> guidance talks about the listing of pathogens, and it states that
> pathogens listed in the label should have acceptable eradication
> rates.
>
> These rates are not otherwise defined in the guidance. It does state
> that if a product fails to have acceptable clinical and microbiologic
> effectiveness against all three major pathogens, it should be listed
> only for those it has eradicated. This would take the form of a
> restricted listing as not a product for first-line therapy.
>
> This restriction is based on the empiric nature of treatment and the
> need for first-line therapies to be effective against all common
> pathogens.
>
> \[Slide.\]
>
> I have here a couple of examples of pathogen labeling in which
> products have not achieved approval for Streptococcus pneumoniae.
>
> This first one is for otitis media caused by Haemophilus influenzae,
> Moraxella, and Group A Streptococci. The clinical study section states
> that the response rate of Strep pneumoniae to this drug is
> approximately 10 percent lower and that of Haemophilus influenzae or
> Moraxella catarrhalis approximately 7 percent higher than rates of
> these organisms to the active control drugs.
>
> \[Slide.\]
>
> The second label is for a product, which again is approved for acute
> bacterial otitis media due to Haemophilus influenzae, Moraxella
> catarrhalis, or Group A Strep. There is a note here that although this
> drug used empirically was equivalent to comparators in the treatment
> of clinically and/or microbiologically documented acute otitis media,
> the efficacy against the pneumococcus was 23 percent less than
> control. Therefore, this drug should be given empirically only when
> adequate antimicrobial coverage against Strep pneumoniae has been
> previously administered.
>
> The clinical study section of this label contains a table showing
> bacteriologic eradication rates for the pneumococcus for this drug of
> 65 percent versus 88 percent for the active control.
>
> This example demonstrates two important points. First, it shows some
> of the problems with restricted labeling in situations in which a drug
> is approved when it lacks acceptable efficacy versus all three major
> pathogens.
>
> This is labeled as a second-line drug which is indicated empirically
> for treatment failure only when adequate coverage against the
> pneumococcus has been previously administered.
>
> In an era of increasing pneumococcal resistance, however, many
> formerly adequate therapies no longer are adequate and the treatment
> failure population for whom this drug is prescribed actually had a
> disproportionate share of resistant Strep pneumoniae compared to the
> general acute otitis media population.
>
> I think the second important point from this example is that it
> demonstrates the importance of having comparative rather than
> non-comparative microbiologic data in evaluating pathogen-specific
> efficacy.
>
> \[Slide.\]
>
> Among the issues for discussion then related to the microbiology of
> acute otitis media are whether it is important for a drug to
> demonstrate efficacy against all the major otitis pathogens in order
> to obtain approval, whether per-pathogen efficacy should be
> demonstrated using comparative as opposed to non-comparative data, and
> whether it is feasible to have objective criteria for the inclusion of
> individual pathogens in the label.
>
> \[Slide.\]
>
> I would like to talk briefly about some issues with inclusion and
> exclusion criteria. The draft guidance states that among the inclusion
> criteria, clinical-only trials ordinarily should not enroll children
> less than 6 months old.
>
> There is no recommendation, however, in the guidance about the actual
> distribution of the children in these studies. This lack of guidance
> has resulted in several instances of submissions that contain
> unrepresentative study populations.
>
> I have a couple of examples here of products where one product in the
> 90s, although the tympanocentesis study that was submitted had 44
> percent of the children under age 2, the large clinical-only study had
> less than 20 percent of the enrolled population that was under age 2,
> and had a median age of 4 1/2 years.
>
> We have other approvals from the 90 of products where another product,
> as part of the package submitted, one clinical-only and two
> tympanocentesis trials, all of which enrolled only children from 2 to
> 15 years of age.
>
> Even the most recent supplement that I have described for you in the
> two major studies that were submitted, 60 to 65 percent of the
> children were over 2 years of age.
>
> We have heard from the speakers today and from previous committee
> meetings that when you consider that the peak incidence of acute
> otitis media is between 6 and 18 months of age, the fact that these
> children have lower rates of successful treatment, it seems that we
> should be considering whether the future guidance should include some
> type of recommended age distribution for future trials.
>
> \[Slide.\]
>
> Under exclusion criteria in the current guidance, children with
> tympanostomy tubes, children with acute otitis externa are excluded.
> Recent systemic anti-infective therapy for clinical-only trials,
> children treated within the 7 days prior to enrollment are excluded,
> and for clinical and microbiologic studies, children receiving
> systemic therapy 3 days prior to enrollment are excluded.
>
> The guidance also recommends exclusion of children who are receiving
> antimicrobial prophylaxis for recurrent otitis media. I think we have
> heard today and particularly for studies in which baseline
> tympanocentesis is going to be done, and you will have bacteriologic
> confirmation of the etiology of the acute otitis media, that it
> certainly seems reasonable to allow for the inclusion of these
> children in acute otitis trials.
>
> \[Slide.\]
>
> The issues for discussion then related to these inclusion/exclusion
> criteria issues are the age distribution of children enrolled in
> trials and whether there are other methods of capturing populations of
> greatest interest, where the exclusion criteria, as I mentioned, the
> issue would be to permit enrollment in clinical/micro studies of
> recently treated patients and patients receiving prophylaxis.
>
> \[Slide.\]
>
> The final topic regarding recurrent guidance, and this, the committee
> has already voted on, is the timing of outcome assessments. The
> current guidance recommends study evaluations at entry, on-therapy,
> which is 3 to 5 days into therapy, there is a visit strongly
> recommended.
>
> The end-of-treatment visit is actually optional in the current
> guidance, and the recommended test-of-cure visit is 2 to 4 weeks after
> study entry with an optional late post-treatment visit.
>
> The current guidance uses, as the primary endpoint for both clinical
> and microbiologic assessments, the test-of-cure visit at 2 to 4 weeks
> after entry.
>
> \[Slide.\]
>
> The committee recently has voted on this issue, and in regards to
> clinical outcomes, the committee unanimously voted that the relevant
> clinical test of cure is at the end of therapy, with the later
> follow-up visit, meaning the one that we currently use as the test of
> cure, being an important secondary endpoint.
>
> Furthermore, in studies that contain a repeat tympanocentesis
> component to assess microbiologic response, the committee voted that
> the most informative repeat taps were on therapy, followed by those
> obtained at the time of clinical failure.
>
> \[Slide.\]
>
> In summary, then, regarding the general indication of acute otitis
> media, we would like to get the committee\'s comments during today\'s
> meeting, and we would also appreciate other comments in the form of
> written comments to the docket, regarding some of these issues here -
> the value of comparative studies with diagnostic tympanocentesis, the
> role of clinical-only studies, how best to demonstrate efficacy
> against all the major pathogens, and issues regarding the inclusion of
> pathogens in the label.
>
> \[Slide.\]
>
> Changes in recommendations for the age distribution of children who
> are enrolled in these trials, and limiting the exclusion criteria to
> permit enrollment of recently treated patients, and patients who are
> receiving prophylaxis for children who are in tympanocentesis studies.
>
> The next speaker will be Dr. Rosemary Johann-Liang, who will be
> talking about design issues for studies targeting acute otitis media
> in special populations, particularly as it relates to recurrent otitis
> media in kids with treatment failure.
>
> **Study Considerations:**
>
> **Recurrent/Treatment Failure AOM**
>
> **Rosemary Johann-Liang, M.D.**
>
> DR. JOHANN-LIANG: I am delighted to speak before the committee one
> more time, although today\'s topic is very different from yesterday,
> and I had the pleasure of being the last hurdle before all of us and
> lunch.
>
> \[Slide.\]
>
> Today\'s topic is on recurrent and treatment failure acute otitis
> media. As we consider revisiting the current guidance, we have heard
> quite a lot this morning about clinical trial designs.
>
> I would like to draw your attention now to the types of children who
> will populate these clinical trials. Specifically, we will be
> discussing the proposal for an additional indication that will study
> the population of children with recurrent and/or treatment failure
> acute otitis media.
>
> I will be following this outline. The relevant sections in the current
> guidance will be first shown, then, the rationale and proposal for
> change will presented. This will be followed by the discussion of
> definitions and the types of trials for the indications. I will end
> with some issues we hope will be included in the committee\'s
> discussions this afternoon.
>
> \[Slide.\]
>
> The 1998 draft guidance taken after the 1992 Points-to-Consider lays
> out study considerations for one all- comers indication of acute
> otitis media. There is no differentiation of different populations,
> however, there are exclusion criteria and they include the following:
> children who have received systemic anti-infective drug product in the
> previous 7 days prior to enrollment in the clinical-only study,
> systemic anti-infective drug product in the previous 3 days prior to
> enrollment in the clinical micro study, and patients receiving
> antimicrobial prophylaxis for recurrent otitis media.
>
> Various beta-lactams and macrolides have been approved thus far under
> one indication by studying all-comers population with these
> exclusions.
>
> \[Slide.\]
>
> You all have been telling us that changes need to take place to the
> current guidance. Of the various recommendations for change by the
> committee, these are a few of the advice we have heard regarding
> populations to study.
>
> Dr. Leggett\'s statement from last year\'s November meeting - \"There
> was a thing about not being able to use antibiotics within the last 7
> days of the last month. I think that would be another way to actually
> enrich the resistant population because isn\'t that who we have the
> trouble with, the more severe illness and the more resistant
> pathogens?\"
>
> Dr. Wald\'s comment - \"I think that groups of children that we should
> be studying are children with severe disease.\"
>
> You have also heard Dr. Giebink and the other experts this morning so
> wonderfully discuss population issues.
>
> \[Slide.\]
>
> So, in thinking about this in picture format\--and I would like to ask
> for your indulgence at this point, all my PowerPoint diagrams are
> conceptual in design, and not proportional and not drawn to scale\--we
> have the all-comers population for acute otitis media in the large
> green oval.
>
> You are telling us that the recently treated population should not be
> excluded, in fact, they should be perhaps studied more in depth. You
> are also telling us that the population with severe disease should be
> especially studied.
>
> What is the driving force behind these proposals for change? I think
> you will all agree with me that the underlying factor is resistant
> pathogens, specifically, at this point, PRSP. PRSP is a critical
> factor for otitis media disease in general, but a problem of greater
> magnitude in these subpopulations.
>
> \[Slide.\]
>
> Rising to meet the challenge of resistant pathogens in otitis media
> disease, drug development programs are already ongoing. I would like
> to spend the next several slides briefly reviewing with you the
> lessons we have learned and are continuing to learn from looking at
> these examples of drug development programs.
>
> I want to share with you this morning two examples, the high-dose
> formulation of Augmentin and the development of fluoroquinolones in
> pediatrics.
>
> \[Slide.\]
>
> High-dose Augmentin, the 14 to 1 formulation was presented to this
> committee in January of last year. As you are aware, the high-dose
> formulation was developed with PRSP in mind, and enrichment strategies
> were used in its clinical trials to maximize patients with bacterial
> disease especially PRSP.
>
> However, the restricted subpopulation that this formulation is
> currently labeled for was not prospectively defined and therefore not
> the defined population studied during development.
>
> How does this label currently read? It says, \"Augmentin ES-600 is
> indicated for the treatment of pediatric patients with recurrent or
> persistent acute otitis media, characterized by the following risk
> factors: antibiotic exposure for AOM within the preceding 3 months,
> and either of the following - age less than or equal to 2 years,
> daycare attendance.\"
>
> This recurrent or persistent indication was inserted post-development
> following this committee\'s advice that this 14 to 1 formulation
> should be differentiated from the 7 to 1 formulation, and should not
> be used for routine acute otitis media.
>
> The lesson learned here was that the population that the indication
> will be labeled for needs to be pre-defined.
>
> Next, I would like to walk you through a time line of a series of
> recommendations by this Anti-Infective Drugs Advisory Committee on the
> development of fluoroquinolones in pediatrics.
>
> \[Slide.\]
>
> The story starts in 1989 where the committee recommended that mainly
> due to safety concerns, fluoroquinolone development in pediatrics
> should be restricted to older children with severe underlying diseases
> of cystic fibrosis and cancer needing therapy for gram-negative
> resistant pathogens.
>
> The committee met again in 1993 regarding this matter and recommended
> expanding the types of diseases and age, but again unanimously voted
> that this class of drugs was not for investigation in routine
> indications.
>
> By 1997, there is a change. There was again the recommendation to
> continue the pediatric study of these drugs for severe indications,
> however, the committee began to discuss the development of these drugs
> to treat the sick subpopulations of generally well children due to the
> increasing emergence of gram-positive resistant organisms.
>
> \[Slide.\]
>
> This is a statement by Dr. George McCracken from that committee
> meeting. \"The fluoroquinolones could then be evaluated in
> hospitalized pediatric patients with community or hospital-acquired
> pneumonia and possible middle ear or sinus infections caused by
> resistant pathogens, PRSP, i.e., recurrent or persistent otitis
> media.\"
>
> Currently, the development of fluoroquinolones for use in pediatrics
> is ongoing, and it is not just for severe indications, but also for
> the sicker subpopulations in routine indications, such as acute otitis
> media.
>
> One example is the gatifloxacin development program, parts of which
> were presented at the 41st ICAAC last year. That sicker subpopulation
> within the acute otitis media being studied with gatifloxacin is
> called recurrent and/or non-responsive otitis media.
>
> Clearly, the committee has pointed out throughout the time line that I
> have just presented to you that fluoroquinolones are not for study in
> routine cases for routine indications due to the safety issues
> especially the arthrotoxicity, the fact that many other alternative
> drugs are available for routine use, and the worry of more resistance
> if this class of drugs are to be used widely in pediatrics.
>
> \[Slide.\]
>
> To summarize what we have heard from you and the lessons learned
> regarding populations for study in acute otitis media, you have told
> us to enrich the populations for study for better yield of patients
> with bacterial disease especially those with PRSP, and that this may
> be accomplished in part by studying the subpopulation of children with
> recurrent and/or persistent disease, and not to exclude children
> recently exposed to antibiotics.
>
> Furthermore, you have told us that the drug development programs
> geared towards treatment of resistant pathogens, especially PRSP,
> should not be pooled together for study in routine use. This is due to
> safety issues at the individual level and the judicious use of drugs
> to curb more resistance at the public health level.
>
> All in all, what we have learned is that this not for routine
> subpopulation of acute otitis media need to be precisely defined as we
> move forward in developing drugs for resistant pathogens.
>
> \[Slide.\]
>
> So, bringing together all that you have told us through multiple
> advisory meetings, we have a possible solution to propose. The
> proposal is for an additional indication termed recurrent and/or
> treatment failure acute otitis media.
>
> This is a population-driven concept. I think it is fair to say that we
> would all agree that the child coming into the office with an
> occasional episode of acute otitis media is a distinct entity in
> comparison to the child that is constantly in the office with multiple
> and frequent episodes of acute otitis media requiring repeated and
> cycling of therapy.
>
> The proposal for change then is that we go from the one all-comers
> indication that is currently in guidance to two indications relevant
> to the targeted populations, one for routine acute otitis media, and
> one for the recurrent treatment failure AOM.
>
> This would, in turn, facilitate drug development programs by
> pre-defining the appropriate populations for clinical trials. For
> example, a regular dose beta-lactam being studied here for routine
> AOM, going on to be labeled for this indication at the time of
> approval, while high-dose formulations or fluoroquinolones being
> studied here, will eventually be labeled for the indication of
> recurrent treatment failure at the time of approval.
>
> It is also possible for a drug without particular safety or resistant
> pattern concerns and having necessary efficacy parameters, may be able
> to pursue both indications concurrently with data from both programs
> complementing and supporting that overall development program.
>
> \[Slide.\]
>
> A simple illustration of this concept may be as follows: In choosing
> the clinically distinct populations as the basis for separating out
> the indications, we will be able to clinically distinguish the
> population that will be studied under routine acute otitis media here
> in the large pretty pink color from the recurrent and/or treatment
> failure disease here on the smaller green oval.
>
> The resistance factor will overlap both populations, but will have a
> greater overlap for the not-for-routine indication.
>
> \[Slide.\]
>
> With that change in general concept in mind, let\'s spend a few
> minutes on defining the elements of the additional indication, so that
> as we revise the guidance, we can reflect the consensus that was
> reached on this concept and be precise with our definitions. Defining
> exactly what we mean by the terminology used will provide a clear
> channel for communication by all interested parties and avoid
> confusion.
>
> \[Slide.\]
>
> First, the definition for recurrent. Are we correct in hearing from
> you that recurrent otitis media should be part of the not for routine
> population for study? The generally accepted and used definition for
> recurrent AOM is shown here: greater than or equal to 3 episodes of
> AOM over the last 6 months or greater than or equal to 4 episodes of
> AOM over the past year.
>
> This population of children includes children with various underlying
> and predisposing factors to acute otitis media including young
> children with anatomical immaturity. Clinically, this definition would
> encompass the children thought of as a distinct entity.
>
> Microbiologically, however, when the literature is carefully
> scrutinized, this population defined exactly and precisely, as shown
> here, may not have significantly higher rates of PRSP when compared to
> age-controlled children with routine AOM.
>
> \[Slide.\]
>
> Next, the definition of treatment failure. Are we correct in hearing
> from you that children recently treated with antibiotics or early
> treatment failure should not be excluded from clinical trials for AOM,
> but rather be studied vigorously since this is the population that
> microbiologically appears to have higher rates of resistance?
>
> One definition, then, one definition that we may be able to propose
> here is this. During therapy: No improvement observed in signs and
> symptoms of acute otitis media after at least 48 hours of antibiotic
> management, or post-therapy: Presentation with signs and symptoms of
> acute otitis media within 7 days of completing a course of antibiotics
> for acute otitis media.
>
> This definition is inclusive of the accepted definition of persistent
> acute otitis media, signs and symptoms continuing on the third day
> after start of therapy, while being exclusive of the time point beyond
> 1 week after end of treatment, where it becomes very hard to
> differentiate reinfection from new infection.
>
> \[Slide.\]
>
> Now that we have proposed some definitions for what the elements of
> the new indication might be, I want to clarify what the new indication
> is not synonymous with.
>
> Some terms that we have been seeing in recent protocols that are used
> as names for subpopulations of otitis media are: difficult-to-treat
> otitis media, otitis-prone children, hard-to-treat otitis media, and
> children \"at risk.\"
>
> For example, we have been seeing protocols wanting to study the
> hard-to-treat or difficult-to-treat acute otitis media with high-dose
> formulations or fluoroquinolones that has the listing under the
> inclusion criteria of less than or equal to 2 years, daycare
> attendance, or 3 or more siblings, et cetera.
>
> This would mean that even with the first-time otitis, just by being a
> 6-month-old infant, that infant will be exposed to drugs like
> fluoroquinolones, for example, which I don\'t think is what anybody
> wants at the moment.
>
> \[Slide.\]
>
> These listings are then not the elements of the proposed new
> indication, but rather enrichment strategies to yield patients with
> bacterial otitis media especially PRSP otitis media for both
> indications.
>
> Again, the two distinct populations are shown here in the pink and
> green ovals with the resistance factor overlapping both populations.
> The enrichment groups are overlaying both indications and the
> resistance factor.
>
> Now, taking into account all the definitions that have been discussed,
> I would like to walk through a series of possible scenarios in the
> next slide.
>
> \[Slide.\]
>
> This is an illustration of a hypothetical AOM drug development schema.
> Having used enrichment strategies to increase the chance of having a
> patient with bacterial otitis media, a 6-month-old infant in daycare
> full time is identified.
>
> If this baby is in the office with his first episode of AOM or has now
> grown to be a 9-month-old and is having a second episode of AOM, for
> both of these scenarios, the infant will be studied under the
> indication of routine AOM, enrolling in drug trials seeking first-line
> therapy.
>
> If this baby has treatment failure OM meeting the predefined
> definitions or is now a 12-month-old and is always in your office
> because this is the fourth episode of acute otitis media, this infant
> will be studied under the indication of recurrent/treatment failure
> AOM, enrolling in drug trials seeking not-for-routine therapy.
>
> \[Slide.\]
>
> So, I have presented to you what you have told us about targeted
> populations and have laid out for you our responsive proposal of
> relevant indications corresponding to appropriate drug development
> programs that can move forward with prospectively defined populations
> that needs consensus on precise definitions.
>
> In the next slide, I would like to highlight some particulars about
> the types of trials that would be part of the drug development program
> for this additional indication.
>
> \[Slide.\]
>
> We would be looking for well-controlled single or double tap
> tympanocentesis trials with non-inferiority or superiority design with
> pathogen-specific diagnosis by tympanocentesis at entry.
>
> For single tap studies, the primary outcome assessment will be
> clinical at end of therapy, and for double tap studies, the primary
> outcome assessment will be on-treatment micro and end of therapy
> clinical.
>
> I might mention here that if the claim for PRSP is being sought for
> the label, it may be particularly valuable to include a double tap
> trial in the drug development program.
>
> These two types of trials may be supplemented by empiric or actual use
> therapy trials to increase the safety information for the product.
> This type of trial is particularly encouraged for new molecular
> entities, drugs with specific safety issues, or drugs with limited
> safety data and should be inclusive of children with various
> underlying conditions.
>
> Non-comparative double tap trials may be another supplemental study in
> cases where efficacy data on a specific organism, for example, needs
> more support. Relevant studies from \"other\" indications may also
> provide supplemental information.
>
> \[Slide.\]
>
> Finally, I would like to show a broader schema for our considerations
> regarding the types of trials for acute bacterial otitis media
> overall.
>
> \[Slide.\]
>
> As we consider revisiting the guidance on acute otitis media, this is
> a summary overview of our overall proposal.
>
> We have heard from you that acute otitis media should be studied in a
> microbiologically-driven, comparative manner with populations enriched
> to yield the patients having bacterial disease under the indication of
> routine acute otitis media, drug development programs for regular
> beta-lactams, macrolides, et cetera, or new drugs can proceed.
>
> The types of trials for study in this indication would include single
> tympanocentesis trials, double tympanocentesis trials,
> placebo-controlled trials, and other supplemental studies.
>
> Under the indication of recurrent and treatment failure otitis media,
> drug development programs for high-dose formulations,
> fluoroquinolones, or other new drugs can proceed.
>
> The types of trials for study in this indication include single
> tympanocentesis trials, double tympanocentesis trials, empiric therapy
> safety trials, and other supplemental studies.
>
> We have arrived at this overall conceptual proposal in response to
> your recent recommendations for change by incorporating what you have
> told us and the lessons that we have learned.
>
> \[Slide.\]
>
> We would like to turn this proposal back to you now for discussion and
> further advice. Some items for discussion are listed here for you. We
> would like to know if you agree with the definitions for recurrent
> AOM, the definitions for treatment failure AOM. Do these two groups
> fit the population to pre-define for \"not-for-routine\" drug
> development programs with PRSP emphasis?
>
> Is it reasonable to have these two groups be placed together in the
> new indication?
>
> Are the types of trials for this indication appropriate? Can you
> suggest any other types of studies?
>
> Thank you so much for your attention and we look forward to listening
> to your discussions this afternoon.
>
> DR. RELLER: We have had a packed and informative morning. It is just
> after 12:15. This is the plan for the afternoon with a reward for
> promptness and punctuality.
>
> At 1:15, we reconvene. There will be a 20-minute open public hearing.
> Dr. Jacobs is the only speaker. When you look at your schedule, that
> would bring us to 1:35. Thereafter, if you take one-half hour off all
> the listed times, we will finish at 3:30 p.m. Stick on schedule and we
> will be done at 3:30 for the people meeting the commitments for
> flights including international ones.
>
> Thank you.
>
> \[Whereupon, at 12:15 p.m., the proceedings were recessed, to be
> resumed at 1:15 p.m.\]
>
> AFTERNOON PROCEEDINGS
>
> \[1:20 p.m.\]
>
> DR. RELLER: We will begin the second half with the open public
> hearing, actually presented by a colleague of all of ours in the
> field, Dr. Michael Jacobs from Case Western Reserve University.
>
> Michael.
>
> **Open Public Hearing**
>
> DR. JACOBS: Mr. Chairman, committee members, advisers, guests, I am
> pleased to have this opportunity to give my thoughts on this complex
> area and while I will be giving you a lot of information, I will try
> and make the points that I want to make clear about the issue of what
> the problem is with respiratory tract infections and using
> antibiotics, and validity of evidence for using those.
>
> One of the points I wanted to make is that otitis media is a very good
> example and we probably have the best data on respiratory tract
> infections for otitis media, but most of what I am going to say
> applies to other respiratory tract infections as well.
>
> \[Slide.\]
>
> Now, one of the big limitations we have with respiratory tract
> infections is there is a high rate of spontaneous resolution that
> makes it difficult to show differences between agents.
>
> Bacteriologic outcome studies are not often performed due to necessity
> for invasive procedures, and you have heard a lot about those. Most
> studies are therefore designed to show equivalent clinical outcome
> between established and new agents, and what that means is that if
> there are inadequacies of agents, they are often not apparent.
>
> \[Slide.\]
>
> I found this slide that Dr. Soreth showed very interesting and very
> informative. In the absence of culture of middle ear fluid, no
> specific claim can be made regarding the effectiveness of any
> anti-infective drug. This statement was in force in 1977, and this was
> a very important year for me because that was the year I started
> working on the pneumococcus and found the multi-resistant
> pneumococcus, and I hope that we can go back to this statement.
>
> \[Slide.\]
>
> Now, some of my objectives are to define pharmacokinetics and
> pharmacodynamics because this gives us a basis for predicting the
> activity of most antibiotics certainly against extracellular
> pathogens, and if we just look at these basic parameters, we can see
> where many of our problems are.
>
> I want to show you how we can correlate pharmacokinetic parameters
> with outcome of infection, show examples in animal models and in
> humans, and apply these to otitis media.
>
> \[Slide.\]
>
> Now, we need to be able to accurately predict efficacy. We need newer
> dosing regimens, we need newer antimicrobials, we need revised
> susceptibility breakpoints, and we need statistically valid clinical
> studies, and many of these points were discussed extensively this
> morning.
>
> \[Slide.\]
>
> I am going to try and bring this into focus by looking at what
> pharmacokinetics and pharmacodynamics do for us, and basically, you
> are all familiar with oral ingestion of a drug. We talk about oral
> drugs, and the drug is absorbed through gastrointestinal tract,
> distributed through the bloodstream, and this is where we can
> conveniently measure drug concentrations and kinetics, but we must not
> lose sight of the fact that what we are looking at is the actual
> effect of the drug in the extracellular compartment of tissues.
>
> However, what is driving the concentration of drugs there is the
> concentration in serum, so that even though the serum concentration
> doesn\'t correlate with what is going on in tissues, it does drive
> what is going on in tissues certainly in instances where you have
> acute inflammation. This is why blood concentrations are so important,
> not only in antibiotics, but in many areas of therapeutics.
>
> \[Slide.\]
>
> Now, looking at the serum pharmacokinetic profile of a drug, we can
> measure this very conveniently, we can time it, whereas, measuring
> this at the site of infection is very difficult and very difficult
> particularly to do over time.
>
> \[Slide.\]
>
> As you can see here, we can look at various parameters, the
> concentration of the drug present for various percentages of the
> dosing interval, we can look at the peak serum concentration, we can
> look at the area under the curve.
>
> \[Slide.\]
>
> For time-dependent agents, time above MIC correlates with outcome. For
> concentration-dependent agents, either area under the curve to MIC
> ratio or peak to MIC ratio.
>
> \[Slide.\]
>
> For beta-lactams, this needs to be 25 to 35 percent of the dosing
> interval for penicillins and 35 to 40 percent for cephalosporins. The
> presence of neutrophils decreases this by a further 5 to 10 percent,
> and free drug levels of these drugs therefore need to exceed the MIC
> for between 35 and 50 percent of the dosing interval to produce
> maximal survival.
>
> \[Slide.\]
>
> This is showing an animal model, as you have all seen this figure of
> Dr. Craig, and I would like to acknowledge Dr. Craig and the other key
> people who work in this field for teaching me about this area.
>
> You can see here it shows the value for cephalosporins, and I have
> tried very extensively to apply these principles to respiratory tract
> infections and also see if I can find examples of where these
> principles don\'t work, and I can find very few.
>
> \[Slide.\]
>
> For concentration-dependent agents, it is the area under the curve to
> MIC ratio or the peak to MIC ratio. From the data that I have seen,
> either of these parameters works equally well.
>
> \[Slide.\]
>
> This again shows the animal data at 25 to 30 ratio for immunocompetent
> animals.
>
> \[Slide.\]
>
> At dosing comparable to dosing in humans, looking at a rat pneumonia
> model with both pneumococcus and Hemophilus published last year,
> azithromycin and clarithromycin were able to reduce the inoculum for
> macrolide-susceptible pneumococci, but not for macrolide-resistant
> pneumococci with either of the common resistance mechanisms, the
> efflux or the ribosomal methylase, and it could not do this against
> Haemophilus influenzae either.
>
> \[Slide.\]
>
> This is another study showing the same thing, and I am quoting
> directly from the paper. \"This is a chinchilla otitis media model.
> After administration of azithromycin at 30 mg/kg as single daily doses
> in our chinchilla model of experimental otitis media due to
> non-typeable Haemophilus influenzae, we were able to achieve levels in
> serum and AUCs approximately twice those observed in children treated
> with the dosing regimen given, and concentrations in the middle ear
> fluid comparable to those found in children, as well.
>
> \"Our observations provide evidence that current doses of azithromycin
> administered to children are likely to have a modest antibacterial
> effect on otitis media, characterized by a reduction information
> density of infection, but not eradication of infection. Maximizing the
> dosing of azithromycin in children has the potential to improve the
> microbiologic outcome.\"
>
> However, I also want to point out that even going to 4 times this
> dose, which would be equivalent to about 8 times the dose we give in
> humans, the high dose still did not eradicate Hemophilus from the ears
> in 15 percent of the animals.
>
> \[Slide.\]
>
> Looking at human data, Dr. Dagan has shown you this data in different
> format, and you can see here that when you get to above 40 percent of
> the dosing interval, you get greater than 80 percent bacteriologic
> eradication. Note also the cluster of Haemophilus influenzae around
> about the 40 percent point here. This is not 40 percent eradication,
> this is spontaneous resolution of disease. These are drugs with no
> activity against Haemophilus influenzae. Similarly, this point here of
> 20 percent is a drug with no activity against pneumococcus.
>
> \[Slide.\]
>
> There is very much less data in sinusitis, but when this data is
> available, it shows exactly the same thing.
>
> \[Slide.\]
>
> This is a very interesting study that was done on community-acquired
> pneumonia, predominantly in patients treated with intravenous
> levofloxacin. In 134 patients, predominantly with pneumonia, you can
> see here how well the PK/PD correlated with outcome.
>
> When these parameters were optimal area under the curve to MIC ratio
> greater than 100 or peak to MIC greater than 12, then, there was
> almost 100 percent clinical and bacteriologic success. This is based
> on clinical outcome in these patients. There was only one patient
> judged to be a clinical failure. This patient was not a bacteriologic
> failure.
>
> When your parameters were below those which have been shown to work in
> animals, in other words, area under the curve to MIC ratio of less
> than 25, then, there was a 43 percent clinical failure, and the
> successes were due to spontaneous resolution.
>
> When the values were between these, you got an intermediate value of
> 12 percent clinical failure, so you can see this is one of the best,
> although one of the few, pharmacodynamic studies ever conducted in
> humans, and it shows how well these parameters correlate.
>
> \[Slide.\]
>
> When you take these parameters and for beta-lactams and macrolides,
> you then determine\--and Dr. Dagan discussed how to do this\--the
> microbiological, the MIC breakpoint, this is what you come up with,
> values between 0.1 and 2 mcg/ml depending on the mechanism of action
> and the actual concentrations you get with these drugs.
>
> \[Slide.\]
>
> However, when you look at what the regulatory agencies have come up
> with, this shows the same PK/PD breakpoints, you can see for the
> pneumococcus, these values as of the year 2000 were changed, and are
> very similar to those that are predicted, whereas, those of
> Haemophilus influenzae with the exception of cefixime are all
> considerably too high and are based on four clinical studies that were
> not adequate to show differences.
>
> \[Slide.\]
>
> When you look at susceptibility of our pathogens, you see that these
> agents vary considerably in achieving pharmacodynamic breakpoints, and
> if you believe that these pharmacodynamic breakpoints are correct,
> then, would believe that this information is correct, and you can see
> here there are very few agents that cover the majority of all three of
> our major pathogens in otitis media and other respiratory infections.
>
> You can see, in fact, if you go by this, our choice for empiric
> therapy in both primary disease, as well as recurrent disease or
> complicated patients is really pretty limited, and we have a great
> need for new drugs.
>
> Hopefully, the situation with the pneumococcus, we are expecting the
> resistance to decrease because of the vaccine, but we started to see
> evidence of this, but we don\'t know how extensive this is going to
> be. We don\'t know whether replacement is going to be by susceptible
> pneumococci or by Hemophilus, and we don\'t know whether replacement
> organisms are going to develop resistance.
>
> Just to mention one point also which disturbed me considerably when I
> was hearing many of the presentations this morning, I was hearing many
> of the speakers refer to PRSP, penicillin-resistant Streptococcus
> pneumonia, as an acronym for drug-resistant organisms in these
> respiratory tract infections.
>
> To me, that is a very bad terminology and particularly when you are
> discussing non-beta-lactams to try and describe a drug being active
> against a totally different class where you have resistance, to me,
> that makes absolutely no medical and scientific sense.
>
> If you want to use a macrolide for pneumococci, you need to use it for
> macrolide-susceptible pneumococci. There is cross-resistance with
> beta-lactams, but macrolide resistance is the reason for the macrolide
> working or not working in those agents, not the penicillin resistance.
>
> \[Slide.\]
>
> Now, let\'s look at a couple of drugs in more detail, starting off
> with amoxicillin-clavulanate. As you saw from the data Dr. Dagan
> showed, it has activity against Hemophilus, but its activity is pretty
> close to the breakpoint of 2 mcg/ml, and by extending the dosing
> regimen to the new dosing regimen, if we have such, is 90 mg/kg of the
> mass component, you can bring the concentration that you are going to
> achieve up to 4 and possibly even 8 mcg/ml.
>
> The way I have colored these graphs is the green area shows you the
> pharmacodynamically achievable breakpoint, the yellow area that can be
> achieved with higher doses, and the red area are strains which you
> would expect to be in the resistant range.
>
> When you look at the pneumococcus, when you go back to strains that we
> had 20 years ago, they were all at 0.03 mcg/ml or less, but now 30 to
> 40 percent or even more of our strains have higher MICs, but you can
> see that amoxicillin still covers the majority of our pneumococci.
>
> When you look at Moraxella catarrhalis, almost all of these would be
> lactamase producers, so we need the clavulanate, but again, those are
> all well within pharmacodynamically achievable concentrations.
>
> You can see that the breakpoints we have with H. flu are maybe a
> fraction too high, but otherwise the breakpoints are correct.
>
> \[Slide.\]
>
> Looking at cefaclor, not a very active drug against Haemophilus
> influenzae, and, in fact, as Dr. Dagan showed you, acts as you would
> expect a placebo to in otitis media. As far as bacterial eradication,
> not a very good drug even against penicillin-susceptible pneumococci,
> and not a very good drug against Moraxella catarrhalis.
>
> When you look at the breakpoints that we have for cefaclor, the
> pneumococcal breakpoint is reasonably correct, the H. flu breakpoint
> is totally incorrect.
>
> \[Slide.\]
>
> Looking at cefuroxime, reasonable, pretty similar parameters to
> amoxicillin-clavulanate against Haemophilus influenzae, fine against
> penicillin-susceptible pneumococci, but doesn\'t cover the
> nonsusceptible strains because of dosing limitations, and also not a
> very good drug against Moraxella catarrhalis.
>
> Again, you can see the Haemophilus influenzae breakpoint that we have
> is too high.
>
> \[Slide.\]
>
> Cefprozil, not a very good drug against Haemophilus influenzae, and if
> you remember, Dr. Dagan showed you bacteriologic outcome with
> Haemophilus influenzae, which was very poor, not a very good drug
> against penicillin nonsusceptible pneumococci, and not a very good
> drug against Moraxella catarrhalis.
>
> You can see here the breakpoint for pneumococcus is reasonably
> correct, that for Hemophilus is way too high. Also, just to make the
> point that no one has official breakpoints for Moraxella catarrhalis.
>
> \[Slide.\]
>
> Looking at cefixime, very good drug for Haemophilus influenzae, okay
> for penicillin-susceptible pneumococci, it doesn\'t cover
> nonsusceptible pneumococci, and is adequate for Moraxella catarrhalis.
> Breakpoint, there is no breakpoint for pneumococcus, the breakpoint
> for Hemophilus is correct.
>
> \[Slide.\]
>
> Looking at macrolides, azithromycin, pharmacodynamic breakpoint is 0.1
> mg/ml, covers virtually no Haemophilus influenzae, and as you saw from
> the bacteriologic outcome studies, acts accordingly.
>
> About 30 percent of our strains are macrolide resistant, and we see
> two resistance mechanisms, the efflux strains which have MICs in the 4
> to 16 range, and you can see even these are nowhere near the MICs you
> need for being able to treat this organism, and obviously, the strains
> with ribosomal methylase are way out of any kind of reasonable range,
> but even these strains here, you can see it is not surprising that you
> don\'t get any response with these strains here even though the MICs
> are not very high, and, in fact, they are fairly similar to those in
> Haemophilus influenzae. They are way above the breakpoint.
>
> Even going to 4 times the dose of azithromycin, as I showed you in
> experimental animals, has great difficulty in covering Hemophilus. So,
> the breakpoint you have for pneumococcus is too high, but it doesn\'t
> make much difference because we don\'t get many pneumococci in that
> range. That for Hemophilus is way too high.
>
> \[Slide.\]
>
> Clarithromycin, very similar, very poor against Haemophilus
> influenzae, covers only macrolide-susceptible pneumococci, however,
> does cover Moraxella catarrhalis. The breakpoint again for Hemophilus,
> much too high.
>
> \[Slide.\]
>
> Clindamycin, a drug that is not often talked about and is difficult to
> administer in children because of taste, but is used in some patients,
> again is well known it doesn\'t have Hemophilus activity, but its
> activity again Hemophilus is no worse than macrolides, and also is
> only active against pneumococci, but it is active against pneumococci
> with the efflux resistance mechanism, so as opposed to macrolides,
> which cover 70 percent of pneumococci, clindamycin covers 90 percent
> of them. The breakpoint is correct.
>
> An experimental drug, telithromycin, I am mentioning because that is
> one of the next drugs on the horizon for use. It has already been
> approved in Europe. Its Hemophilus activity is very similar to that of
> azithromycin potency-wise, but again, the pharmacodynamic breakpoint
> has now been fairly well established to be 0.5 mcg/ml, and this makes
> Hemophilus pretty much resistant to this drug. Some strains will come
> up as intermediate if you use one as the intermediate range.
>
> Pneumococcus, it does have an advantage over macrolides and
> clindamycin even though it is in the same group, it does seem to be
> active against all resistance mechanisms at the moment, but there is a
> lot of potential for resistance to emerge. With Moraxella catarrhalis,
> it is also active. The breakpoint that has been approved
> pharmacodynamically, is 0.5, and that was the breakpoint, in fact,
> that was approved in Europe.
>
> \[Slide.\]
>
> Doxycycline is not applicable to pediatrics, but in my remarks, if you
> remember, I said were going to be applied to all respiratory diseases.
> It is fairly commonly used, but not much is known about it, and it is
> not a very active drug against Haemophilus influenzae even though
> there is no specific tetracycline resistance mechanism.
>
> It has greater potency against pneumococcus, but we have about 25
> percent of strains that are resistant, and it is active against
> Moraxella catarrhalis.
>
> \[Slide.\]
>
> Going on to the quinolones, as these are now starting to be used more
> in pediatrics and some of them are being tested, starting off with
> ciprofloxacin, one of the original quinolones, very active against
> Haemophilus influenzae, but inadequate activity against the
> pneumococcus, but I note that it is still approved for pneumococcal
> infections to this day in its product insert, and also very active
> against Moraxella catarrhalis.
>
> With the quinolones, there is no breakpoint problem. The breakpoints
> are all correct.
>
> \[Slide.\]
>
> Levofloxacin, MICs against Hemophilus remain extremely low, better
> MICs against pneumococcus in relation to the breakpoint, so that all
> strains or pretty much all strains are susceptible. We only have a few
> percent of strains that are resistant, currently less than one, and
> also highly active against Moraxella catarrhalis, also no problem with
> the breakpoints.
>
> \[Slide.\]
>
> Looking at trimethoprim-sulfa, an old drug, but one that was mentioned
> several times this morning, what is not well appreciated is that
> approximately one-quarter of the strains of Hemophilus are resistant
> to trimethoprim-sulfa, and probably slightly more than that of
> pneumococci are also resistant, and also Moraxella catarrhalis is
> intrinsically resistant to trimethoprim-sulfa, as well.
>
> So, again trimethoprim-sulfa is not nearly as useful as it was 10 or
> even 20 years ago.
>
> \[Slide.\]
>
> So, my conclusions are antibacterial choice for empiric use in
> respiratory tract infections, most clinical studies do not show
> clinical differences between agents. Pharmacodynamic parameters
> correlate with bacteriological and clinical outcomes in animal models
> and, where we have the data, in humans.
>
> These parameters can be used to select agents with maximal potential
> for bacterial eradication, and currently available agents very
> significantly in achieving these parameters.
>
> Going back to the 1977 statement, I want to make the following
> statements. We need new FDA guidance on AOM. Do we admit there is a
> problem? Do we admit that we were right in 1977? What does it take to
> fix the problem, and hopefully, that is being addressed today.
>
> Will we fix the problem? I certainly hope so. And when will this be
> achieved? I think that is a crucial point because some of the
> discussion that we are having today goes back, in fact, to 1977, and a
> lot of it, in fact, goes back to 1998, and not much has happened
> between 1998 and now.
>
> Thank you for your attention.
>
> DR. RELLER: Thank you, Dr. Jacobs.
>
> I would next like to call upon Dr. Jack Paradise for some
> supplementary comments to this morning\'s presentations.
>
> Dr. Paradise.
>
> DR. PARADISE: These are just a few random, not necessarily connected
> thoughts that I had about what was discussed this morning.
>
> The evidence report on acute otitis media that was issued with the
> sponsorship of AHRQ, I think is based in many instances on studies
> that I think are questionable in terms of methodology, and I think
> many of the studies that were included were studies in which
> diagnostic criteria were not satisfactory, much too loose, and allowed
> for the admission of children with OME or perhaps even children
> without otitis at all.
>
> With respect to tympanocentesis, the point was made earlier today that
> tympanocentesis may, in itself, be therapeutic, and if that is the
> case, and I think we don\'t know with certainty whether or not it is,
> but if it is the case and it seems likely to be true, then,
> incorporating tympanocentesis may have one of two effects in a
> clinical trial.
>
> One effect, and the likeliest one, would be to blur the distinction
> between efficacy of the two drugs being compared, but another
> possibility, a little more far-fetched, would be the possibility of
> enhancing apparent effectiveness through interaction, because how
> tympanocentesis affects an infection due to Hemophilus may differ from
> that of how it affects an infection due to pneumococcus. The group in
> Denmark under Dr. Toser\'s \[ph\] direction has recently shown, and I
> think it has been shown in other studies, that there are distinct
> microscopic differences between changes in the epithelium when the
> infection is due to pneumococcus as compared with Haemophilus
> influenzae.
>
> The issue of double taps and ethics, I certainly would agree that no
> research is justifiable that doesn\'t stand a reasonable chance of
> producing new information no matter what the activities of the
> research consist of, but I think that it is questionable.
>
> The issue of ethics was raised earlier, and I think it is questionable
> ethically to perform a painful procedure on a child who is doing well
> symptomatically and who is apparently improving in all respects from a
> clinical standpoint, and I believe irrespective of my opinion on the
> subject, that my experience with our own review board suggests that
> they will not tolerate that as a study procedure.
>
> Colin\'s comments that fewer tympanocenteses would be done, I think is
> entirely accurate if studies were restricted to double tap studies,
> overall, fewer procedures would be done, but all of the procedures
> that were done in a tap failures-only study, which is what I would
> personally like to see as the usual type of study, all of the children
> who got tympanocenteses initially at baseline and then, if failure
> occurred, would stand a chance of benefitting from the procedure
> itself, and I think that is the issue rather than the number of
> procedures that are done.
>
> On another vein, I think that it may be artificial to try to
> dichotomize patients into two categories, those with ordinary garden
> variety AOM and those with persistent or recurrent AOM.
>
> First of all, I think persistent and recurrent may be different
> animals in some cases, and, secondly, I think there is such a
> multitude of variety of presentation of children with otitis, that a
> child on one occasion may have a mild episode, a sporadic episode that
> you think is not likely to be problematic, but then, in fact, turns
> out to be persistent or problematic, and one is dealing with histories
> based often on information that is of questionable reliability. Lots
> of studies have shown that parental recall is not necessarily adequate
> for demonstrating what actually has happened with children.
>
> So, I would be inclined to have studies be fairly inclusive of
> children with bona-fide acute otitis media and to collect as much
> information as possible about their past histories and particularly
> about the degree of severity of the episode, which could be greater in
> a clinical rating scale similar to the one that Ron used this morning
> or using other parameters, as well.
>
> One last point, and that is, it seems to me that the emphasis has been
> on bacteriology and on the organism, but in categorizing children as
> likely to have resistant organisms or not, it is also important to
> take into account the host.
>
> Children vary a great deal I think in their susceptibility to the
> disease and in their ways of responding, and the problem may not
> always be a resistant organism, but rather the child who anatomically
> or immunologically is performing less well than his peer with the same
> infection.
>
> Thank you.
>
> DR. RELLER: Thank you.
>
> The open public hearing has been closed, and we will now hear from Dr.
> Renata Albrecht with a Summary from the FDA and Charge to the
> Committee.
>
> After, we will have the discussion, may or may not have a break, and
> vote.
>
> Dr. Albrecht.
>
> **Summary and Charge to Committee**
>
> **Renata Albrecht, M.D.**
>
> DR. ALBRECHT: Thank you. I think I will address this group from the
> podium, so that I may advance my slides. Before I begin, let me
> apologize. I made these summary slides during the lunch break, and
> therefore, I do not have copies of them. However, I believe they will
> be posted on the FDA web site should anyone need to gain access to
> them.
>
> \[Slide.\]
>
> My responsibility is to provide a summary and a charge to the
> committee. As I do that, I stand here feeling truly privileged having
> been able to listen to these august group of presenters that we had
> today, both the distinguished external consultants and truly even our
> FDA colleagues.
>
> I think I am quite humbled by the expertise in this room on this
> topic, and I feel I have got a daunting task to try to summarize that,
> but I will give it a try, and cover some of the issues that we would
> like to have you deliberate on, and a couple of questions that we
> would specifically like you to vote on.
>
> \[Slide.\]
>
> With that, and at the risk of introducing yet another term today, I
> have inserted the word \"bacterial\" into the indication of acute
> otitis media, and I have done that intentionally really to focus us on
> the fact that within the Divisions of Anti-Infective and Special
> Pathogen and Immunologic Drug Product Divisions, we are responsible
> for regulating the drugs for bacterial infections, as well as some
> others, and it is bacterial pathogens that are responsible for otitis
> media and the morbidity associated with it that have been discussed
> today. Parenthetically, we acknowledge that some of these bacterial
> etiologies do cause self-limited disease.
>
> I have mentioned that the drugs that we are reviewing do involve
> treatment of bacterial pathogens and equally, importantly, as has been
> included in several presentations today, the product labeling that is
> written as a result of review of these drugs, does include the listing
> of bacterial pathogens for the indications.
>
> Dr. Giebink reminded us that viruses also contribute to morbidity in
> otitis, however, those are generally self-limited and we certainly
> have not yet had any drugs to treat viral otitis.
>
> \[Slide.\]
>
> Let me go ahead and talk to some of the categories that were covered
> today, as Dr. Powers indicated during the opening presentation this
> morning.
>
> The first of these, the diagnosis of acute bacterial otitis media, as
> we have heard, the current guidance talks about clinical signs and
> symptoms as the basis of diagnosis. It talks about using a strict or
> rigorous case definition. I think we have heard what may or may not be
> some of the limitations of using a clinical diagnosis.
>
> We have also heard about the use of tympanocentesis at baseline to
> establish the diagnosis of a bacterial etiology of otitis media, and
> actually, I guess the third bullet, if you will, is perhaps the
> diagnosis can best be established by using a combination of both
> clinical and tympanocentesis results to make the diagnosis.
>
> \[Slide.\]
>
> Let me turn to another category that has been discussed, which is
> endpoints, and I have added timing as part of those endpoints, and, in
> fact, parenthetically say this is relating to the baseline
> characteristics that were documented, because again I think what we
> recognize is that we look at the endpoints and compare them to the
> baseline to come to the conclusion of whether the child, in fact, did
> get better or did not as a result of the intervention be it treatment
> tympanocentesis or some other management.
>
> The endpoints that we have essentially used consistently before \'77,
> since \'77, and today, are clinical, and the one that I think we have
> heard repeatedly recommended is probably the one that we should be
> focusing on, is the end of therapy assessment. I have put in
> parentheses that we actually don\'t mean the last day of therapy, we
> tend to be thinking in terms of 2 to 7 days after the last dose.
> Again, those dates could vary depending on the drug used and the
> half-life and perhaps other parameters.
>
> I have used a softer font to just remind me to mention that an
> on-therapy clinical assessment has not been used rigorously. I think
> we recognize clinically it is used to make a decision whether a
> patient is responding to therapy or not, but from a regulatory
> perspective, it has not been a major evaluation time point.
>
> However, perhaps we might consider whether in the future we could use
> it to assess time of resolution of patients as supported by some of
> the information that Dr. Dagan presented to us this morning.
>
> An endpoint that I think has been a topic of much discussion today,
> that we might consider looking at a new way of evaluating is the
> microbiological endpoint. What we have done in the last decade or so
> as far as the microbiological endpoint is in clinical-only studies, we
> didn\'t have it in studies where a tympanocentesis was performed at
> baseline. We would look at the clinical outcome and extrapolate that
> the organism was eradicated if the outcome was successful, and the
> organism was presumed to be persistent if the outcome was not
> successful.
>
> I think we have heard that there may be limitations to that kind of
> interpretation. I think the newly proposed say of looking at
> microbiology that we are hearing or have heard actually in several
> Advisory Committees and again today, is the possibility of using a
> tympanocentesis on therapy, and this would be day 3 to 5. Some have
> suggested 4 to 6 days, or 48 hours into therapy, to be able to
> actually compare the pathology of the otitis at baseline and on
> therapy, again, just for sake of discussion, is perhaps one of the
> options to get both of these.
>
> \[Slide.\]
>
> We have heard today about populations. The studies over the past
> several decades have focused primarily on patients with acute otitis
> media, and the drugs like in the penicillin, cephalosporin, macrolide
> classes have been developed for that indication.
>
> You have heard today the proposal that we consider recurrent acute
> otitis media and treatment failure, also sometimes referred to I guess
> as persistent or nonresponsive otitis media, as a separate category.
>
> For example, I think we have seen studies looking a fluoroquinolones
> for these kind of indications and also high-dose beta-lactams. As was
> brought up earlier today, I think one of the reasons to consider this
> is, is this a population likely to predict patients with PRSP or
> otherwise resistant organisms. A corollary of that is whether this
> would be a way to encourage a more limited use of agents that we would
> feel should be reserved for treating organisms that are resistant.
>
> \[Slide.\]
>
> Then, we heard several presentations about clinical trial designs. The
> two that have been discussed are active control, normally, a
> non-inferiority design although I think the possibility could exist
> that one could even do a superiority design in an active controlled
> trial, and then placebo-controlled studies.
>
> \[Slide.\]
>
> Putting these three elements together, clinical trial design,
> diagnosis, and endpoints, I have tried to summarize sort of the
> categories of studies that could be done, and I was going to say in
> the interest of time, let me skip them, so that I think I will get an
> opportunity to go over them during the questions, as I read those.
>
> \[Slide.\]
>
> Let me just mention one thing. We have been talking clearly about the
> science of otitis media and treating children, but as regulators, I
> just did want to mention that there are certain constraints under
> which we operate, and the rules and regulations that are relevant in
> this particular context is the Code of Federal Regulations, Title 21,
> 314.126, which defines adequate and well-controlled studies. These are
> relevant because our approval of drug products should be based on
> adequate and well-controlled studies. The different choices allowed us
> are placebo-controlled, dose-ranging, no treatment control, active
> control, or historical control.
>
> There is another part in this section that I thought is also
> important, which is that these adequate and well-controlled studies
> should be conducted in patients who have the disease, and in
> quotations is the definition of that, which is that, \"the method of
> selection of subjects provides adequate assurance that they have the
> disease or condition being studied.\"
>
> In this case, we would assume that what we are looking for is patients
> with acute bacterial otitis media in contrast or just to compare them
> to patients who may be managed clinically as patients with otitis
> media.
>
> \[Slide.\]
>
> I just wanted to briefly then refer back to some of the remarks made
> by Dr. Powers earlier this morning, about the practical issues that
> face us. I think as we talk about tympanocentesis, this is not the
> first meeting that this topic has been brought up, the question is
> really what are the barriers to performing tympanocentesis in clinical
> trials in the United States.
>
> Another issue or question is that are placebo-controlled trials
> practical in the United States at this point in time. We have heard
> from Dr. Rochester and others that sample sizes could be smaller if
> placebo-controlled studies are undertaken.
>
> How acceptable are these procedures to patients and to their parents?
> Can we perform trials more efficiently while still obtaining useful
> data?
>
> With that overview, let me go ahead and turn to the questions.
>
> The first question before us is:
>
> Should a comparative trial incorporating tympanocentesis be
> required\--and that word I think is used in context of what the Code
> of Federal Regulations requires that we do adequate and
> well-controlled studies\--should it be required for demonstrating the
> effectiveness of drugs for acute otitis media?
>
> As you deliberate this question, I think we would like you to keep in
> mind some of the topics that have been discussed today including
> clinical-only studies, single tympanocentesis trials, double
> tympanocentesis trials, and placebo-controlled trials.
>
> Consider also how predictive is a strict case definition of clinical
> otitis media to the pathogenesis of a bacterially documented acute
> otitis media. Consider also the relative value of comparative versus
> non-comparative studies and the use of tympanocentesis in these.
>
> The second question we would like you to consider is whether you agree
> with the proposed definitions for recurrent otitis media and treatment
> failure in otitis media, and that this actually represents a separate
> population that we should study.
>
> As you deliberate this question, consider whether the use of this
> definition is helpful in identifying patients who are more likely to
> have penicillin-resistant Streptococcus pneumoniae or perhaps other
> resistant pathogens, as well.
>
> Consider the likelihood of differences in treatment response in this
> population versus the general population, and consider this as
> possibly a means to suggest that agents developed for this population
> might not be used in the same wide range of patients as drugs
> developed for acute otitis media.
>
> I am sorry, we have provided for you the definitions that Dr.
> Johann-Liang reviewed with you earlier.
>
> The final question is: Do double tympanocentesis trials have a role in
> demonstrating effectiveness of drugs for general otitis media, acute
> otitis media, and all-comers, or for the subset of patients or the
> population of patients that have recurrent or treatment failure in
> acute otitis media.
>
> In considering these questions, consider the timing of assessments,
> both clinical and microbiologic. Consider the importance, the relative
> importance of clinical and microbiological assessments.
>
> Consider the ability of the on-therapy tympanocentesis results to
> predict clinical outcome, and whether practically, there are adequate
> sites within the U.S. and other parts of the world to perform the
> double tympanocentesis studies.
>
> If we are so fortunate as to have time, you could perhaps also give us
> some advice on alternative methods of clinical outcome assessment,
> such as I mentioned earlier, the time to resolution, the expected
> activity against the major pathogens, the role of other results, such
> as PK/PD, in vitro susceptibilities, age distribution within placebo
> and active controlled trials, and other factors, daycare attendance,
> prior antibiotic use, exclusion criteria, and seasonality.
>
> DR. RELLER: Thank you, Dr. Albrecht.
>
> **Committee Discussion and Vote**
>
> DR. RELLER: In the ensuing discussion, I would like to encourage all
> of the persons at the table, both voting and non-voting consultants
> and guests, to express their viewpoint. There is much expertise here.
> Some individuals we have not heard from as yet. This is your
> opportunity, as well as responsibility, to speak up.
>
> Secondly, to get a vote on these questions, I think it may work well
> to have a discussion of the subcomponents, then hearing that, which
> will be captured for the record as has been delineated earlier, some
> of you have seen remarks from past meeting portrayed on the slides,
> captured going back even decades, so don\'t be intimidated that you
> will be quoted in perpetuity.
>
> On the other hand, everything is not captured in the vote alone, but
> also the discussion is captured for the Agency\'s consideration in
> carrying forth the next steps.
>
> Then, on the specific questions 1, 2, and 3, we will actually have a
> show of hands to see how strong the consensus is on the individual
> questions posed.
>
> Then, we will conclude with some additional discussion on the
> important but secondary fine points that Dr. Albrecht alluded to at
> the end of her discussion.
>
> Dr. Dagan had a couple of points of clarification in terms of
> terminology, so we are all talking about the same thing.
>
> DR. DAGAN: There are four points where people don\'t always mean the
> same thing, and I think we have to have it at least very clear. When
> you say \"post-therapy,\" I mean some drugs are given for 3 days, some
> are given for 10 days, some are given for 5 days.
>
> That is the point that I want to raise. My opinion is that we have to
> have one time for everybody because if you start to give 3 days, you
> don\'t want to be in fewer than 10 days, so probably 10 days would be
> the time when you end therapy by definition, even if you give 3 days.
>
> That could be discussed or not, but this is the point where we have to
> at least know that it might be controversial.
>
> The second point is day 4 to 6 or day 3 to 5, it depends how you
> actually start to count. In our studies, and this is came to 4 to 6,
> we counted the first pretreatment day, I mean the first day of
> involvement is day 1. Now, we want to test the second tympanocentesis
> after 72 hours at least, so that is why it comes day 4 to 6, which is
> after 3 to 5 days of treatment.
>
> So, I don\'t think that day 3 to 5 is appropriate if day 1 is the
> first day. So, that is another clarification. We want to have 72 hours
> of treatment before we assess bacteriological outcome.
>
> Then, people have used PRSP as a synonym to antibiotic resistance,
> Strep pneumonia, which is inappropriate. It is RSP. If you give
> macrolides, you really want to look at macrolide resistance, and if
> you quinolones, you want to look at quinolone resistance.
>
> A secondary question could be penicillin resistance and how you
> promote those. So for the summary slide, one of the summary slides
> uses PRSP, but should be actually resistant Strep pneumonia, not PRSP.
>
> The fourth point is that when you do one-arm, say, Augmentin high
> dose, whatever, gatifloxacin, it could be still a comparative study,
> it depends what is your question.
>
> If you establish a drug that is appropriate, penicillin-susceptible or
> whatever, pneumococcus is susceptive to that drug, you still do a
> comparative study, actually, it\'s a double-blind sort of study,
> because you don\'t know what is going to grow there, comparing the
> resistant organism to the established already treatment of the
> susceptible, so it could be still a comparative study, and then you
> have to site it appropriately, but it could be something that sounds
> like one arm, but it could be actually a very nicely non-comparative
> study looking at exactly cutoff of MICs and all others.
>
> So, not necessarily you don\'t have a comparative drug, it\'s a
> non-comparative study, and that is another point that I wanted to
> make.
>
> DR. RELLER: Thank you.
>
> The first question, should a comparative trial incorporating
> tympanocentesis be required for demonstrating the effectiveness of
> drugs for acute bacterial otitis media?
>
> Let\'s have then the discussion on the bullets below that would enable
> us to vote on this question, in essence, the centrality, if that is
> the conclusion, or complementary, what is the positioning of
> tympanocentesis in the regulatory requirement for rigorous, adequate
> clinical trials.
>
> Discussions in the context of the bullets and the relevant issues.
>
> Dr. Giebink.
>
> DR. GIEBINK: Dr. Reller, I think that we should be aware that if the
> committee accepts the FDA\'s suggestion that the word \"bacterial\" is
> inserted into the title, then, we can skip over this bullet, because
> there would have to be tympanocentesis for middle ear culture, and we
> would be automatically then accepting the 1977 guideline that absent a
> middle ear fluid culture, no claim could be made regarding the
> effectiveness of the anti-infective.
>
> So, I think that point that was made by both FDA speakers slipped in,
> and perhaps we should decide are we measuring antibiotics and
> developing indications for their use in clinical otitis media or in
> bacterial otitis media.
>
> This gets to the issue of do you do scientific studies of antibiotics
> for the treatment of a particular infectious disease, or do you try to
> replicate clinical practice. I will express my bias right now for the
> former, and not the latter, because you can\'t get to clinical
> practice unless you have done the scientific study.
>
> So, I favor doing tympanocentesis to define the bacterial nature of
> the infection, so that we can then measure the outcome, and we will
> talk about double taps later on. I have some other thoughts about
> that.
>
> DR. RELLER: I purposely slipped that word in to get exactly what you
> hit on, because from the discussions presented, if other phenomenon,
> apart from bacterial infection, are self-limited, then, no matter what
> you were saying about acute otitis media, how would you know what
> category you were in without a microbiological confirmation of either
> the presence or the absence of an agent.
>
> Additional discussion. Dr. O\'Fallon.
>
> DR. O\'FALLON: I think that there are some other ethical issues that
> haven\'t actually been expressed here explicitly, they are implicit,
> but they have been bothering me throughout this whole two or three
> years that we have been at this.
>
> We have underneath this the fact that there is a large percentage of
> patients who are misdiagnosed as having \--well, they don\'t have
> bacterial otitis media. Something like 25 percent is the data that we
> are seeing from these guys.
>
> So, if there is no tap upfront, what we have is a bunch of patients
> who are being treated with something that isn\'t going to do them any
> good, and I think there is an ethical issue there.
>
> Secondly, there is the ethical issue of we have been struggling with
> the creation or enhancement of the fast development of resistance, and
> if we are treating people with antibiotics that don\'t need them, I
> think my understanding is that that is going to increase the
> development of resistance.
>
> So, I think that those two issues really need to be addressed when we
> try to argue that it is not fair to do the taps on the children.
>
> Also, if we don\'t do a tap, there is inability to identify the
> subsets that would benefit from that particular treatment. We have
> seen a lot of information that has been given here. I think that is a
> very important scientific and again ethical issue, because what we
> realize is that with so many children or in so many people, but mostly
> children, who have these acute otitis media, that we are looking at
> thousands, hundreds of thousands of people that are going to be
> treated based on these studies, and if we don\'t get the answer right,
> that is going to have a tremendous impact on the future of treatment
> of an awful lot of people.
>
> I think this is a big stakes\' game that we are dealing with here, and
> we need to get the answers right.
>
> If we do a single tap versus a double tap, there is talk about it is
> not fair to the patients, but as they pointed out, I thought that was
> a very interesting thing. Because of this Pollyanna effect, if you do
> the double tap, you use so many fewer patients that actually, the
> number of taps administered is fewer. You are tapping fewer kids if
> you do a double tap study.
>
> So, if you are going to argue on the tap business, I think that that
> is an important piece of information to think about, again, as a
> critical issue.
>
> I do think, again, placebo or not, the question is what are you trying
> to do. If you are trying to prove the effectiveness of a new drug, if
> you are trying to show that is has any activity, then, it really
> should have a placebo.
>
> Again, the fact that 25 percent or better, even the ones that have
> pathogens there, treatable pathogens, the fact that some high
> percentage, 75 to 80 percent of them are going to resolve without any
> treatment means that we are not being unfair. It is not like they have
> leukemia or something.
>
> The ethical issue of not treating them, of giving a placebo, is not
> the same as it is, say, in a leukemia study. So, I think there is an
> ethical issue there.
>
> I think that I will quit there because I have other points, but I
> can\'t read them.
>
> \[Laughter.\]
>
> DR. RELLER: Dr. Bell.
>
> DR. BELL: I want to congratulate Dr. O\'Fallon. She has said probably
> better than I could exactly what I wanted to say. I totally agree that
> for the clinical studies in the future, clinical diagnosis at entry is
> not acceptable. I am in favor of tympanocentesis at entry. We have to
> make sure these antibiotics work, not just for the patient, but also
> to minimize the selective pressure that is exerted on favoring
> antimicrobial resistance.
>
> I would be very interested in seeing placebo-controlled trials and I
> would also just to say we need to know which bacteria are in the ear
> and whether they are sensitive to the antibiotic being studied,
> because it could turn out in the future that those incidence rates of
> bacteria etiology might change, and we need to know that information
> for that drug.
>
> So, I just want to totally agree.
>
> DR. RELLER: Dr. Nelson and Dr. Pichichero.
>
> DR. NELSON: What has impressed me here is the devil is very much in
> the details of all of this information. Personally, I found the most
> helpful presentation to me and sorting out from the perspective of
> someone who chairs an IRB is Dr. Pichichero\'s presentation of
> benefits, risks, and the like.
>
> I would like to present what I see as perhaps a way of getting through
> the forest. It would bother me if we started tapping kids, which
> everyone says we diagnose poorly, in order to use that as an
> enrichment strategy to make sure that we have the right group to go
> into a study.
>
> The thought that occurred to me is given the 80 percent response rate
> and the percent viral etiology, that you could argue quite
> convincingly that a three-arm placebo trial is appropriate for a
> clinical diagnosis and a clinical endpoint, and that you actually
> could use that as a first phase of an enrichment strategy defining
> failure, which could be defined in a way similar to the indications
> for doing a tympanocentesis that was presented by Dr. Pichichero.
>
> You could also have an arm that goes in, which could be into that
> second phase, which could be a severity of illness, toxic, bulging,
> febrile child, perhaps other things, to where they would go in
> immediately to the second phase, which would be a double tap
> comparative trial.
>
> I think the whole issue of the efficacy of the tap itself, I think
> raises an interesting question of how you would design that, does that
> really mean it\'s an add-on trial of antibiotic on top of tap, or
> should you have a tap alone arm.
>
> So, in listening, I think I would hope ultimately that FDA would begin
> to list 50, 51, 52, 53, and 54 as part of their regulatory constraints
> besides just the desire to have good science.
>
> I think there is equipoise if you are in the clinical setting, and so
> that fits in 50-52, which is the direct benefit. If the tap is being
> done by someone who has done 1,000, and teaches others to do it, it
> looks to me like it fits in a minor increase over minimal risk, and
> the second tap wouldn\'t necessarily have to meet a constraint of
> providing benefit.
>
> The first tap would provide benefit, but I would also be worried that
> those taps would be done by people without sufficient expertise unless
> they are privileged or certified in some way to be able to perform it.
>
> I have never done one, and I work in an intensive care unit. I have
> never actually seen one done until today. So, you know, it is not out
> there being used a lot.
>
> So, I guess to summarize, what I began to sort of think about is a way
> that the Phase I, the clinical diagnosis could be enriched by not
> using the tap, but by using basically a three-arm, randomized phase to
> get into it, and then, at that point, take the non-responders, the
> recently treated, and the severe ones immediately that could bypass
> that first phase and put them into a double tap trial at that point.
>
> A company that wants to do that through both phases could end up
> potentially with labeling either for the general indication or for the
> specific limited indication, because their motivation obviously is to
> want to have the general indication, so it might be able to kill a
> bunch of birds with the same stone.
>
> DR. RELLER: Dr. Pichichero, Dr. Chesney, and Dr. Sumaya.
>
> DR. PICHICHERO: I wanted to comment on the notion of
> placebo-controlled trials before there gets too much of an
> enthusiastic endorsement of that idea by the committee or the FDA.
>
> Several of you are quoting a rate of 75 or 80 percent placebo response
> rate. As Dr. Paradise briefly alluded, if you look at the actual
> studies of placebo-controlled trials, there are not many. The entry
> definition of otitis media is so vague or nonexistent that I would
> question whether many of those children had otitis media, and if they
> did, whether they had otitis media fusion rather than acute otitis
> media.
>
> So, I think at this time we really don\'t know what the placebo
> response rate of children with otitis media might be, but my suspicion
> is if you use a bulging tympanic membrane as the single most important
> criteria, it is not going to be 75 or 80 percent spontaneous cure.
>
> Secondly, it was mentioned in Dr. Rochester\'s presentation that if we
> were to do placebo trials, we would need careful follow-up. Does that
> mean that you are going to follow the patient and see them every day,
> and even if you do, how many cases of meningitis or mastoiditis that
> you pick up early would be a tolerable level in the United States?
>
> In my own practice, one would be intolerable. Therefore, as an
> investigator in the field, I would be very reluctant to participate in
> a placebo-controlled trial to ask my patients to accept a placebo in
> what I think is bona-fide otitis and to accept a risk in my community
> that I would cause one child to get meningitis or mastoiditis.
>
> My last point about the tympanocentesis is that in my experience, this
> procedure causes no more pain than a venipuncture, which we do
> routinely, for example, in vaccine trials multiple times to children,
> and what I see in terms of the amount of pain that it induces, the
> amount of change in heart rate on the pulse oximeter, the amount of
> times it takes a child to recover, in experienced hands, it is the
> same as a venipuncture.
>
> Those are my points for the moment.
>
> DR. RELLER: We will stick with our rotation, so that everyone gets a
> chance. Then, we will come back to Dr. Marchant. Dr. Chesney.
>
> DR. CHESNEY: Just three brief comments. Dr. Paradise\'s comment that
> we have all wondered about whether a tap is therapeutic, and if we
> limit our studies to those involving tympanocentesis, that is not
> going to apply to the real world, because most people are not going to
> do taps before they treat otitis media, so can we really extrapolate
> studies that involve tympanocentesis to the real world.
>
> The second point, I think we do need tympanocentesis studies for sure,
> and again we have all talked about this now for a number of years,
> particularly now that we have the pneumococcal vaccine, because we
> really don\'t know that PRSP is going to persist.
>
> We don\'t know that other strains are going to pick up the resistance
> organisms, so I think we really don\'t know what the future of otitis
> media with respect of PRSP is, I don\'t think, or RSP.
>
> The third point that I wonder about is if we really do placebo
> controls, and a year down the road that child turns out to have
> hearing deficit or developmental delay, where are we going to be at
> that point legally, and do we know enough about the relationship
> between acute otitis media, no treatment, and hearing and
> developmental delays following that.
>
> DR. RELLER: Dr. Sumaya, then, Dr. Marchant.
>
> DR. SUMAYA: I am reaffirming what Dr. Pichichero has just said,
> because I was very worried about the discussion on the 70, 75 percent,
> up to 80, of spontaneous resolution, because I think it is very
> unclear how that relates to specific pathogens in the ear, whether
> they are viral or if it\'s a pneumococcus or whatever.
>
> The other part of it was the complication rate that may be related to
> that, and, thirdly, is clinical manifestations that the child may have
> on day 1, 2, 3, 4, that may be different depending on the pathogen.
>
> Secondly, on the tympanocentesis, again, I would refer to what he just
> said. When an RFP eventually comes out, I would assume that there is
> going to be some very good requesting of experienced people who do
> tympanocentesis, because I think in experienced hands, it is a simple
> procedure; in non-experienced hands, I wouldn\'t go for that.
>
> I am in favor of the tympanocentesis on entry.
>
> DR. RELLER: Dr. Marchant.
>
> DR. MARCHANT: The first thing I would like to do is comment on the
> issue of placebo trials. I think there are some placebo trials in the
> literature that are instructive. None of them are completely ideal.
> The one that was done in Pittsburgh is an interesting case in point.
> There is also some European trials that were reasonably well done,
> although typically on selected populations.
>
> In terms of what do the best placebo trials say or what do the
> meta-analyses of placebo trials say about the response of otitis media
> antibiotics, it is that children get better a little bit faster
> perhaps by a day, a day and a half, if you use antibiotics than if you
> don\'t. There is a benefit.
>
> So, if we are going to do a placebo-controlled trial, then, we are
> going to withhold a therapy that might have some benefit to that
> child. I think that, yes, as Dr. O\'Fallon pointed out, they are going
> to get better, most of them, fairly quickly.
>
> That doesn\'t preclude doing a placebo-controlled trial, but I would
> want to see a placebo-controlled trial that was going to really teach
> us something new, and not just be a placebo-controlled trial for the
> purposes of new drug B that we are now testing for licensure, but
> rather that if we are going to do the placebo group, that we do it to
> identify a group of patients that don\'t need treatment because they
> are milder or something of that sort.
>
> The other thing, I know I sound a little bit like a broken record, but
> it keeps coming up, and that is, if you do a clinical-only trial at
> entry with a placebo arm, et cetera, you just drive that sample size
> issue back up again, and it always needs to come back into the
> conversation.
>
> Those are my comments.
>
> DR. RELLER: Dr. Dagan.
>
> DR. DAGAN: Again, going for a second to the placebo issue, it is very
> nice to talk about placebo, but if you really read those articles, and
> I promise you I read them much more than once, all the placebo except
> the one that was done by Howie, which I use all the time as my
> reference point, they have limitations because they don\'t want to put
> into that study, patients that are going to be actually in danger if
> they get placebo.
>
> So, the one that you cite, of 1 day out of 14, or whatever, took away
> those with high fevers, took away those with real bad bulging, took
> away those who were looking a little bit more sick, et cetera, so
> eventually, you will come down to those who don\'t really need
> antibiotics, then, it is only 1 day out of 14, so the real placebo
> study that enrolls all patients with otitis including those who need
> antibiotics the most is nonexistent for the moment except Howie\'s
> study.
>
> So, I think this is one very important point. I don\'t think the
> Ethics Committee will approve us, or ourselves will approve ourselves,
> to do a study with placebo without a priori ruling out those who need
> antibiotics the most. So, this is a point, and I think therefore, it
> is not feasible to do it.
>
> The other point is talking about Dr. Nelson\'s remark. He works at the
> ICU, and he rarely sees these because this is not an ICU procedure,
> this is a very benign procedure, you don\'t do it in ICU.
>
> Actually, my ICU people, it is very difficult to convince them to take
> blood cultures, they are so busy doing the big stuff. This is the
> small stuff. A second blood culture in study to go to ICU to get it,
> which is totally benign, they always forget to do it.
>
> My point is that Dr. Paradise mentioned the word \"dangerous.\" Now,
> we were talking about this last time, and people have talked about
> this time. I don\'t think it is dangerous, I didn\'t see any real
> complication out of the dozens of thousands of tympanocentesis we do
> in our center, and it is one center for the whole region. If we had
> this complication, we would have seen them.
>
> I think that the point again and again and again, otitis media is a
> disease with complications, inappropriate treatment is procedure with
> complications. Giving drugs that act similar to placebo is much worse
> than placebo because they promote resistance, and therefore, knowing
> what you do is the most ethical thing, and therefore I don\'t see any
> danger of doing tympanocentesis.
>
> I think this is a very, very important point, and I would like
> everybody who says it is dangerous to justify why he or she says it is
> dangerous.
>
> The last point that I want to make is that Ethics Committee, like all
> of us, like the FDA, they are subject to continuous education, and
> what is ethical and what is not ethical, 10 years ago it would be
> unheard of.
>
> Dr. McCracken is the editor of his journal, sent me back a case report
> of quinolones in children with a letter, which I keep, saying that he
> would never publish a study on such drug that would never be used in
> the United States.
>
> So, what is ethical now and what is not ethical changes. If FDA thinks
> this is the most appropriate study to do, together with the Advisory
> Committees, and together with experts, it is going to become ethical
> slowly but surely as people would never believe that we can move the
> FDA to do again bacteriology, and it is now moving.
>
> Don\'t take a snapshot of what is ethical now, convince the Ethics
> Committees how dangerous it is to treat without knowing what you do,
> and therefore, it will become slowly but gradually ethical.
>
> DR. RELLER: Dr. McCracken.
>
> DR. McCRACKEN: Well, one thing I have learned in medicine, never say
> never, so I don\'t think I said never in that letter I wrote.
>
> The comments I want to make, obviously, my bias is well known, it has
> already been on the screen a couple of times, but it harkens back to
> the very simple principle, what is an antibiotic for. Why are we
> giving an antibiotic for otitis media? It is not a decongestant, it\'s
> an antibacterial, and if you are going to be evaluating a drug for
> otitis media, for meningitis, which happens to be my real love, you
> have got to know whether it works, and you don\'t know unless you can
> show bacteriologic eradication. That is the only thing that drug does.
>
> Now, it has secondary benefits obviously, but its primary benefit is
> only for the eradication of that organism either with the help of the
> host or not, but it is the eradication.
>
> So, not only am I in favor of an initial tympanocentesis for the
> reasons stated, and I think Scott did a good job in doing that, but I
> am still in favor of a second tympanocentesis at least in a
> substantial subpopulation to demonstrate exactly what this drug is
> doing, does it eradicate it in a timely fashion.
>
> This is true in many bacterial diseases - sepsis, meningitis, otitis,
> urinary tract, it is all the same. You just have to pick the time when
> you want to demonstrate that.
>
> Two other points. It has been stated that tympanocentesis probably may
> improve outcome, and that could be true to a certain extent, but I
> just remind you of Ron\'s study that he showed already, with
> azithromycin versus Augmentin, the regular formulation of Augmentin
> where both groups got double tympanocentesis, and yet there is still a
> difference, both in the clinical scores and in the outcome.
>
> So, if it does help improve symptoms to whatever the modest degree
> might be, it doesn\'t obscure the clinical outcome, which is very
> important.
>
> The final point about placebo. Mike Pichichero is concerned about
> meningitis, and I will just say that in the British Medical Journal
> placebo study, published in 2000, in the placebo group was a case of
> meningitis, so it is not a far-flung possibility.
>
> DR. RELLER: Dr Wald has a comment, but just to follow up on that
> point. It seems to me this issue of placebo and the requirement for
> tympanocentesis are related. Accepting, I think all would agree that
> the rare, but potentially devastating complications are related to
> bacterial infection, the abscess in a closed space, I mean it was
> described earlier.
>
> So, the need for placebo, it seems to me is related to showing a
> difference, tap water, if you have got a study population that is so
> diluted by people who don\'t have the real thing, that you might come
> up with not being able to show a difference, but if you have a
> tympanocentesis, and you know where you are to start with, as Dr.
> McCracken has just mentioned, one can show differences in efficacy of
> agents that would otherwise be obscured for the reasons that Dr.
> Marchant has emphasized earlier.
>
> Dr. Wald.
>
> DR. WALD: I would comment on that, as well, the need for
> placebo-controlled trials, and that is, that there is tremendous
> enthusiasm now among physicians, as well as the lay public, to not
> treat acute otitis media. Now, there don\'t seem to be too many of
> those folks in this room, but there is a tremendous enthusiasm for a
> no-treatment policy, and I think it is essential that we show, in
> fact, that this is an acute bacterial infection that benefits
> substantially from the antimicrobial therapy, and the only way that we
> can do that is with a placebo-controlled trial that is very tightly
> monitored.
>
> Although I share concerns about meningitis, I would say two things
> along those lines. One, there has never been very good evidence that
> otitis leads to meningitis. They occur in some patients together, but
> I think that one leads to the other is not clear, and that we were
> never in a better position to do this study than we are now because of
> the availability of pneumococcal conjugate vaccine, which is really
> going to protect the meninges of the majority of children who we will
> be studying who have been immunized.
>
> In fact, you could make it a requirement that anybody who entered a
> placebo-controlled trial had received the pneumococcal conjugate
> vaccine, and I think that would provide a lot of protection.
>
> I think there is a general consensus in the room that tympanocentesis
> is appropriate for a lot of patients who are going to be studied, and
> it is essential, I think, in terms of establishing the microbiology,
> which is an ever-changing phenomenon.
>
> I would like us to require that when investigators submit cases or
> when industry submits cases, that there be a certain minimum level
> that investigators achieve in order to enter patients into those
> studies, you know, whether that be a 75 percent positive culture or an
> 80 percent positive culture, I think we need to insist on some minimal
> level, and that those very same investigators who achieve competency
> at that level, be the people who can do clinical-only studies where we
> know that they have established their expertise in the diagnosis of
> acute otitis media.
>
> Just one word about double tap studies. It is true that you will tap
> fewer children and do fewer taps if you do double tap studies, but you
> will not be benefiting all the children when you do that.
>
> When a child is symptom-free on the 4th or 5th day of therapy, I think
> it is very hard to ask permission of that patient to tap that child,
> whereas, at least at the entry points, there is some thought that
> every child who undergoes tympanocentesis will benefit from that
> procedure.
>
> DR. RELLER: I don\'t know who was first here, but Dr. Marchant and Dr.
> Soreth.
>
> DR. MARCHANT: I am having a little trouble understanding here. If we
> withhold antibiotics from children in a placebo-controlled trial, and
> they have symptomatic otitis media, even the mild variety, such as the
> one in the Kaleida trial, I think we are using a study design which is
> going to result in more discomfort and more pain for those patients.
>
> So, my earlier comment was motivated we need to learn something good
> from doing such a trial because if we are going to have a trial that
> has more discomfort or pain, we should at least get something
> scientific about it.
>
> On the flip side of that, when you talk about tympanocentesis, the
> second tympanocentesis, in my mind, is justified even in an
> asymptomatic patient because we are getting the data that we need to
> know whether the drug is going to work for all those children out
> there, and for that reason, it is justified.
>
> Now, there are other design approach, tap and tap of failures, but it
> has other implications in order to get that information, but I think
> there needs to be some consistency about how much discomfort we are
> going to design into trials and for what benefit for patients, and be
> clear about what those are.
>
> DR. RELLER: There will be additional discussion about double tap. We
> will be voting on whether tympanocentesis is essential for any trial
> that would claim to show efficacy for the treatment of acute otitis
> media.
>
> Dr. Soreth, Dr. Leggett, Dr. Ramirez, and Dr. Nelson.
>
> DR. SORETH: I think a comment that pertains either to active control
> trials or to the prospect of a placebo-controlled trial is that in the
> development of a novel compound for any infection and this one, acute
> otitis media, we can\'t forget that part of the equation involves
> safety.
>
> So, whether we have an active-controlled trial with some standard
> agent that we feel we know a lot about or a placebo-controlled trial,
> we can\'t assume that the new drug is completely safe or safe enough,
> so part of what we might get out of a placebo-controlled trial is
> information about safety, and similar information can come in an
> active-controlled trial, but we can\'t assume that we have all the
> data to say absolutely the way to go in every case of acute otitis
> media is antibiotics because we know that a day\'s difference is the
> end-all and be-all.
>
> It may be, but I don\'t know that we have enough data to say that
> definitively, it is, so we can dismiss completely placebo-controlled
> trials as an issue.
>
> I think I had a second point, but my thought train may have been
> derailed.
>
> DR. RELLER: We will hear from Dr. Leggett and Dr. Ramirez. It is very
> important for the continuity, the togetherness of the session that we
> all here to the end, so after comments from these two, and there will
> be time to have throwbacks to some of these issues because they are
> all interconnected, we will vote after these two comments on Question
> 1, move on to Question 2.
>
> Dr. Leggett.
>
> DR. LEGGETT: I had two questions to bring up along the lines of the
> tympanocentesis and the single or double, in the sense as follows. If
> we are going to try to include folks who have recurrent otitis or who
> have recently received therapy, and therefore, are more likely to have
> the more severe disease, and we tap them, and because they have just
> been on antibiotics, the tympanocentesis is negative, what do we do
> about that?
>
> The second question is presumably one of the purposes of the guidance
> is to improve upon some places where the FDA recognized that there
> were some problems as in the recent azithromycin case. Without a
> double tympanocentesis study, I would like to hear some comments about
> how we avoid doing the exact same thing again.
>
> Those are two questions.
>
> DR. RELLER: Dr. Ramirez.
>
> DR. RAMIREZ: I just want to make a general comment regarding the first
> tap. It was already mentioned, it seems to me that the clinical
> symptom of acute otitis media involved a large number of patients that
> may not have the disease or less number of patients may have a viral
> infection, and when we design clinical trials for infectious diseases,
> we never say, okay, I want to see what happened with these antibiotics
> against meningitis, because we don\'t take the meningitis syndrome and
> try an antibiotic, because we know there are plenty of patients who
> have a viral meningitis.
>
> We always design antibiotics for bacteria meningitis, we don\'t
> discuss antibiotic for chronic extravasation of chronic bronchitis, we
> discuss antibiotics for acute bacterial extravasation of chronic
> bronchitis.
>
> I think that this is supposed to be a discussion of antibiotics for
> acute bacterial otitis media. Now, how do we know if the meningitis is
> bacterial? We put a needle, and we figure out is this a virus or is it
> a bacteria.
>
> I think that we have the possibility to make a microbiological
> diagnosis, it is not just to define the etiology, it is to define the
> disease because we don\'t put needles in the lung to define if the
> patient has a bacterial pneumonia, because then the complications are
> a bit high, but otherwise, if we all of a sudden find a way to put a
> needle in the lung without complications, we would put needles to
> figure out what is there.
>
> I think that was already explained clearly by the experts that this is
> a very simple procedure, and if have the possibility to eliminate all
> the known bacterial cultures of otitis media, to me it is a no-brainer
> that if I decide on a study to study acute bacterial otitis media, I
> need to make the right diagnosis at least in a significant number of
> patients.
>
> Now, where we are mixing those, we discussed yesterday in this
> committee, one thing is a clinical trial for the right indication, and
> the other thing is clinical practice. Now, we know that what we get
> approved here for these 20 percent of acute bacterial otitis media is
> going to be used in the other 80 percent that have viral disease, but
> this is a different discussion, because this is because the general
> practitioner, it seems to me, they use the clinical syndrome for
> diagnosis, they are not going to be doing the tap.
>
> The antibiotic is going to be overused in some patients with viral
> otitis media, but I don\'t think that we are going to be able to
> prevent this unless we have a very, very simple way to define these
> are bacterial or viral with a needle, and this is why we have an
> overuse of antibiotics, but still, it is going to be justified overuse
> from the clinical point of view.
>
> To me, to define that antibiotic that is well expressed, it needs to
> kill a bacteria. This is the only thing that we ask for the
> antibiotics. First of all, we need to figure out is there bacteria
> there.
>
> DR. RELLER: Thank you.
>
> From the voting consultants, Drs. Chesney, Giebink, and Nelson, and
> the current members of the committee, a vote. We will start to my
> right.
>
> Basically, should the FDA require a study that incorporates
> tympanocentesis, not necessarily as the only evidence, but as one
> criterion for the approval, looking forward, of a drug that would be
> claimed to demonstrate efficacy in the treatment of acute otitis
> media?
>
> Dr. Nelson, yes, no?
>
> DR. NELSON: I have not heard enough information for me to vote, and I
> had a specific question which I wanted to ask to get that information.
>
> DR. RELLER: Excuse me?
>
> DR. NELSON: The question I was going to ask if you said we would vote
> before, I wanted to ask to get the information so then we would vote,
> so I am happy to abstain and wait, or whatever, but I am not going to
> vote yes or no based on what I have heard.
>
> DR. RELLER: Okay. So, that\'s an abstention.
>
> Dr. Glode.
>
> DR. GLODE: Yes, I think a comparative trial incorporating
> tympanocentesis should be required.
>
> DR. BELL: Yes, I think that tympanocentesis should be required
> initially. I do not believe it should be required for follow-up. I am
> not sure it is ethical. I think too many parents will not consent, and
> it will make subjects too hard to enroll.
>
> DR. RELLER: Thank you, Dr. Bell.
>
> I vote yes, I think we need to know what is there to be able to judge
> efficacy.
>
> Dr. Patterson.
>
> DR. PATTERSON: I think tympanocentesis studies should be the standard.
> I think many of those may be single tap studies, which should be
> accepted because they will be done over a wider geographic range, and
> I think we need the information about the microbiology and
> susceptibility over a broad geographic range.
>
> The double tap studies will be useful in subsets in centers where
> those are the standard of care. Placebo trials, I have some concerns
> about. Even with the Prevna \[ph\], which is I think of interest,
> would we be selecting then for less severe disease, making
> pneumococcal disease less common in this group, and therefore, less
> sick or severe population.
>
> The clinical-only studies in the setting of safety or placebo trials,
> which I have a little discomfort with, and I am going to throw in age
> distribution. I think at least 50 percent should be 6 to 24 months.
>
> DR. RELLER: Thank you.
>
> Dr. Wald.
>
> DR. WALD: Yes.
>
> DR. SUMAYA: Yes.
>
> DR. GIEBINK: Yes.
>
> DR. O\'FALLON: Yes, and I enthusiastically endorse what Dr. Patterson
> said.
>
> DR. RELLER: Dr. Chesney.
>
> DR. CHESNEY: Yes, also without qualification.
>
> DR. RELLER: Dr. Ramirez.
>
> DR. RAMIREZ: Yes.
>
> DR. EBERT: Yes, although I think that we need to be clear on entrance
> criteria for patients to enter a study involving a tap.
>
> DR. RELLER: Dr. Leggett.
>
> DR. LEGGETT: Yes, a comparative tympanocentesis trial should be the
> pivotal trial. I wanted to address one of the other points we were
> supposed to, and I haven\'t heard yet, about the non-comparative
> versus comparative.
>
> If we use non-comparative data, it should be used for gathering more
> safety data or for boosting the N for efficacy purposes, but I think
> that is where we can incorporate PK/PD things with MICs to give us
> more information about the breakpoint while we are doing the trial.
>
> DR. RELLER: Dr. Cross.
>
> DR. CROSS: My answer is yes, but since I didn\'t have the opportunity
> to make a number of comments earlier, I will take this opportunity to
> say that if we do encourage comparative trials of drug A and drug B,
> it seems that we almost have to invite either a placebo trial or ask
> the FDA to come up with a response if drug B is 70 percent and drug A
> is 90 percent, what happens in terms of judging the 70 percent of
> there is no placebo, will the FDA accept that for approval, that is,
> is that 70 percent drug sufficiently effective for approval even
> though it is inferior to another approved antibiotic.
>
> So, I think that the question is kind of in a way tied into the issue
> of placebo-controlled, and in terms of addressing the point of a
> placebo control, that Dr. Dagan made, I mean I think it is really
> incumbent upon us if we include placebo-controlled, that we would have
> to really tighten up the clinical definitions in a way that would
> really incorporate who are the people who were excluded out of all
> those other \"placebo-controlled\" trials.
>
> Then, lastly, in terms of the issue of double tap, I would like to
> return to an issue raised by Dr. Giebink, where he showed the cells,
> and there were certain people who were bacteriologically cured, but
> were clinical failures.
>
> I think by doing a double tap in those patients, it really affords us
> the opportunity to say are there any inflammatory media that may have
> resulted from the bacteriologic cure which may account for the
> clinical failure, which may at least lead us into other therapeutic
> areas.
>
> DR. RELLER: Thank you.
>
> Question 2. Does the committee agree with the definitions below of
> recurrent acute otitis media and AOM treatment failure, used to
> identify a separate population of patients for study?
>
> There are some additional things that we are to address in the
> discussion, but the two definitions are listed below, and I think it
> would be helpful to take these individually.
>
> So, first of all, does the committee\--and maybe a brief discussion on
> this\--does the committee feel comfortable with, feel it is
> appropriate to define recurrent acute otitis media with the numbers
> given, that is, 3 or more episodes of AOM over the last 6 months, and
> 4 or more episodes of AOM over the past year?
>
> Those have been used earlier in slides from the experts in the field.
> Are these pretty well accepted? Do they need to be modified?
>
> Yes, Dr. Hoberman.
>
> DR. HOBERMAN: One additional comment. There is two different groups of
> children that will not be included if those two definitions are used.
> One is children that have early infection during the first six months
> of life, but we can argue whether it should be nine months, may not
> have had enough time because they did not live through the previous
> winter to have declared as otitis-prone, so an early in life otitis
> media would probably be similar to more than 3, and children that have
> had an otitis media within the previous month might be at a similar
> risk as somebody that had 3 episodes over the past 6 months or 1 year.
>
> So, those two additional groups of children may enrich the population
> at risk.
>
> DR. RELLER: Dr. Paradise, Dr. Giebink.
>
> DR. PARADISE: I would just want to add the qualifier of documented
> episodes, because it has been our experience, and that of many other
> people, that situations don\'t always pan out as they had been
> forecast.
>
> DR. GIEBINK: I would feel more comfortable with a definition that
> embraced the high risk and the low risk child, and to not try to
> wordsmith the definition of high risk at this kind of a setting.
>
> The beauty of the schema that was proposed by Rosemary is that this is
> the exact scheme that came from a CDC consensus discussion about five
> years ago, published by Scott Dowell \[ph\] in George\'s Journal.
>
> So, it is a scheme that is being used now in clinical practice, and in
> terms of meeting the pragmatic threshold for industry to develop
> trials, it has a relatively large hoop to jump through.
>
> So, I think that high risk and low risk, good idea. I share Dr.
> Hoberman\'s worries about age and number of episodes, and I think that
> just needs a lot more discussion to define what is a high risk
> episode.
>
> DR. RELLER: Dr. Marchant.
>
> DR. MARCHANT: In terms of the reasons why in a single episode, a child
> will not do well, one is resistant bacteria, which is mostly related
> to prior antibiotic use and daycare exposure, thereby prior antibiotic
> use by their mates in daycare.
>
> The other one is young age. Dr. Paradise earlier talked about the host
> and the clear factor we have that predicts bacteriologic failure and
> clinical failure in Pittsburgh trials and double tap trials, and so
> on, is young age, and so the age factor, if you are going to enrich a
> population in terms of their risk for not doing well on antibiotics,
> age is an important issue, and you can cut it at 1, you can cut it at
> 2, or 18 months, or whatever, but that is a factor.
>
> The recurrent otitis media definition per se, I believe that it is
> enriching the population mostly because those kids have already been
> on a lot of antibiotics, and maybe daycare, et cetera. On its own, I
> am not aware of it being a predictor for poor response inside a single
> episode of acute otitis media, so I am not sure it, on its own merits,
> is critical here, and I would be interested in the other folks that
> know the otitis literature, what their comment would be.
>
> DR. RELLER: Dr. Wald and then Dr. Ramirez. I have asked Dr.
> Johann-Liang to bring up the definition that Dr. Giebink alluded to,
> because to the extent that there are vetted definitions that might not
> as a necessarily definitive statement, but close to the mark, it might
> save us a lot of time if we have a target for trying to reach some
> degree of consensus.
>
> Dr. Wald.
>
> DR. WALD: I agree with the definitions, but I think that sort of
> categorizing children according to risk is more helpful, however, most
> children, the peak age incidence for acute otitis media is under 2,
> and we know that age is a risk factor.
>
> So, most of the children that we will be entering into these studies,
> by definition, have an important risk factor. Although some of them
> may not attend daycare, we know that that is an increasing trend among
> U.S. children, and even those who don\'t attend daycare, go to church
> on Sunday morning, in the play group, or they go to mother\'s exercise
> class, and they are in a play group, or they go to McDonald\'s once a
> week, and they are in that little playground.
>
> So, I think that a daycare equivalent is almost universal, as well. I
> think most children are in the high risk category, and maybe what we
> want to create is a low risk category for children who are over 3 or
> 4, and who never had an episode of otitis media before, but the
> majority of children are really in a high risk category.
>
> DR. RELLER: Dr. Dagan.
>
> DR. DAGAN: Some risk studies looked at daycare center versus age
> versus previous antibiotic treatment, and they found each one to be
> independent risk factor, so what you say is correct, but probably if
> you go every day for 5 hours together with kids, it is different than
> if you see them on Sunday morning for whatever, 3, 4 hours at the play
> group.
>
> So, I think that so far, the evidence tells us that each one is
> independent, and if you have all the 3, you multiply each risk by the
> other, and you get enormous risk. So I still think that this should be
> taken into account as for risk factors.
>
> The other point is that when we take our 1,000 cases with double
> tympanocentesis, and we look at those who have, first, otitis media or
> at least did not have otitis media in the last three months, or those
> who have clinical nonresponsive/recurrent otitis media, and you look
> at the MIC of the bug, this is the number one thing that counts, and
> not the previous episode in terms of bacteriological eradication.
>
> If you don\'t see lower bacteriological eradication, what you see is,
> in general, you have lower bacteriological eradication because you
> select for more resistance, but if you break them by MICs, you
> actually find exactly the same. Not only this, even if you have mixed
> infections, each of the bugs behave according to what they were
> supposed to behave according to the MIC.
>
> So, I think that if you look at bacteriological eradication, it
> doesn\'t really matter. There are two slides that you want us to
> consider in this Question 2. One is in relation to whether you do to
> groups or one group, and I think that bacteriological eradication,
> what counts is the MIC and the dose of the drug.
>
> For clinical responses, for the second group that has recurrent,
> relapsing, et cetera, they returned immediately, during treatment, to
> get to the next complication, then, the clinical outcome is going to
> be worse in one group than the other.
>
> So, if eventually, this group here decided they want double
> tympanocentesis study, and look at bacteriological outcome, it
> doesn\'t really matter which kids to take, and we have the evidence,
> and I can send these tabulated.
>
> If you look for clinical outcome, it makes a lot of difference if you
> accept this\--I am not sure you need two groups, but you need to
> analyze them separately.
>
> DR. RELLER: Dr. Glode.
>
> DR. GLODE: I don\'t see that there is two distinct populations, and I
> think it is very confusing to have them as two indications, so I am
> doing the study for group 1 indication, but not group 2, because it\'s
> a spectrum.
>
> Recurrent otitis media, as an enrichment issue, is just a selection
> for people who have gotten antibiotic courses. So, if they got it for
> sinusitis, then, they are in group 1. Because they didn\'t have
> recurrent otitis, they are still going to have a higher risk of
> resistant pneumococci.
>
> So, I think you can look at that by having the bacteriology and
> analyze that way, and I just think this is, I don\'t know, more
> confusing and suggests that there is two distinct populations when I
> don\'t think there really are.
>
> DR. DAGAN: I think this was invented because some drugs are intended
> not to be given to all children. Nobody mentioned that, but this is
> the main justification for me to put it in two groups.
>
> If I don\'t want to give quinolones to every child, only to those that
> don\'t respond, then, I take this group and study this group as an
> indication for the specific study in order to limit the drug, not in
> order to get the better information.
>
> DR. GLODE: Then, you do that as your Phase II of your bacteriologic
> failure, and you have no other choice, and so you must go now to this
> less safe antibiotic, but I think to use it as an excuse for testing
> those kinds of drugs is also a wrong reason to make these two groups.
>
> DR. RELLER: I think we are making some progress here. The last two
> comments, and then we are going to have a vote, and maybe, given what
> is heard, I mean we will see whether people think this is crucial to
> have this, not that it couldn\'t be incorporated, but crucial to have
> it, or is it the real issue is part (b), namely, treatment failure and
> what might be appropriate approaches there.
>
> Dr. Bell, Dr. Ramirez, and then we must take a stand on 2(a).
>
> DR. BELL: Drs. Giebink and Dagan are correct in that this was
> developed some years ago by a group, some of which are in the room,
> that CDC convened to try and identify episodes where second-line
> treatment was not needed, at least empirically.
>
> I guess the question is does this refer to clinical trial designs
> only, or is it what I think is the intention is the practical use by a
> practicing pediatrician, who is not going to do ear taps, and this is
> a nice, convenient category, and the clinical trials, the
> pharmaceutical companies might find it attractive to have this
> admittedly rough distinction. I am inclined to support it.
>
> The final comment I want to make is that I guess I was a little
> surprised to see fluoroquinolones appear on the FDA slides and be kind
> of mentioned glibly as options. I think that requires a lengthy
> discussion in its own right, and I just would hate to see a message go
> out that that is a done deal.
>
> DR. RELLER: Dr. Ramirez, do you have a comment?
>
> DR. RAMIREZ: Yes. If I remember right, we discussed this a lot. In
> this committee, we discussed the amoxicillin-clavulanate. The idea was
> trying to enrich the population. If you have an antibiotic that you
> want to get approval for penicillin resistant Streptococcal pneumonia,
> you don\'t want to get 1,000 children and get only 10 penicillin
> resistant. The idea was just study in a specific group that we call an
> enriched population, that you have a very high chance that you want to
> get penicillin resistant Streptococcal pneumonia.
>
> I would say that for a drug company that is looking for this
> indication, for PRSP, then, this may be a good possibility for them
> just to select these populations.
>
> Now, this is different to say that because in this population, you
> have the greater chance for getting pneumococcal resistant, but as
> already mentioned, because all children or most children with this
> disease are less than 2 years of age, I would not use the same
> criteria to say to the clinician, now, you have a child with this.
> Without these risk factors, the penicillin resistance is not going to
> be there, because by definition, these are disease where penicillin
> resistance is going to be prevalent, and if one of the risk factors is
> less than 2 years of age, it is going to be very difficult to make an
> algorithm for clinical practice to say you have these risk factors,
> use second line, you don\'t have these risk factors, use the first
> line, because you have to put less than 2 years of age as a risk
> factor, and he is going to read the first line only for patients that
> are 3, 4, 5 years of age.
>
> I think the intention here is to separate populations for a study, to
> identify patients with higher risk for penicillin resistance, then, I
> would say yes for these, but not for empiric use of antibiotics, you
> know, first line, second line, as it seems to me that was the
> intention of the presentation.
>
> DR. RELLER: One has heard some of the major points of discussion, so
> the vote is do you agree that it is important to differentiate into
> high risk, low risk, or are these particular categories not
> necessarily limited to those, in other words, to differentiate the
> population, and perhaps that is less necessary, although it could be
> part of the analysis if one has a tympanocentesis and knows whether
> you have got the organism in the first place, if these are tools to
> get at the surrogate for knowing what you have, because of the
> likelihood of having a bacteria.
>
> We are going to start over here this time. Alan, do you think it is
> crucial to incorporate these or it is part of trial design, but not
> essential to separate them into two categories, whatever the
> definition?
>
> DR. CROSS: I am not a pediatrician, but from the discussion I have
> heard, the frequency is not sufficient to define the population at
> risk, and high risk/low risk has its problems for what we have heard.
>
> It seems to me the most logical is that if we truly want to focus on
> the resistant population, that after our tympanocentesis, of the
> failures, those are the folks who are the most highly enriched for
> failure by definition, and would be a good population to study the
> antibiotics, which we don\'t want used for initial therapy.
>
> So, the answer is that I don\'t think we have enough information to
> simply use the definitions as proposed here, and I think that the best
> information will come from the double tap studies.
>
> DR. RELLER: Thank you.
>
> Dr. Leggett.
>
> DR. LEGGETT: I am not sure that the use of these two definitions per
> se will help us delineate well enough to make it worthwhile to
> industry or anyone else, especially if our guidelines are now going to
> be tympanocentesis at the baseline and the inclusion of lots of kids
> under 2. So, we will have so much overlap between the kids under 2
> with everything we have heard about all the other things that is going
> to happen, that these are no longer going to be very useful.
>
> DR. RELLER: Dr. Ebert.
>
> DR. EBERT: I think overall I believe that the age group under 2 should
> be a broad focus regardless of other risk factors, that even in
> simple, uncomplicated cases of otitis media, increasing the percentage
> of children that are under 2 would be useful.
>
> Having said that, I think that using other factors, such as recurrent
> infections, may be of benefit because they may enrich the likelihood
> of having more resistant organisms, and I think they also parallel in
> many ways the clinical stepwise approach that many physicians take to
> treating recurrent cases, that you tend to up the ante, if you will,
> as far as the types of antibiotics that you are using with recurrent
> cases.
>
> DR. RELLER: Thanks.
>
> Dr. Ramirez.
>
> DR. RAMIREZ: I agree with the definitions. I think that these plus
> other risk factors can be used to identify patients that are more
> likely to have penicillin resistant Streptococcal pneumonia for
> clinical trials of enriched populations. We are looking for this
> indication.
>
> DR. RELLER: Dr. Chesney.
>
> DR. CHESNEY: Could you restate the question again?
>
> DR. RELLER: Basically, the question is do we agree with these
> definitions, and we are taking them in two parts. The way I interpret
> it is should clinical trials, the patients necessarily be categorized
> as being recurrent or non-recurrent, or is the population that you
> really want to study, the under 2\'s, the ones that are at higher risk
> because of daycare, the children under 6 months of age, in effect,
> that this becomes a component, but not a critical one that really you
> are talking about studying the patients who really have the disease,
> but this as a tool to get there alone is either not enough or is too
> restrictive, I mean however you want to look at it.
>
> Basically, I know how I am going to vote. I am going to vote that it
> is not crucial. I was convinced by Dr. Glode\'s comments and Dr.
> Wald\'s comments earlier.
>
> DR. RAMIREZ: More than the two definitions, I would like to see what
> are the risk factors for penicillin resistant Streptococcal pneumonia,
> and mostly because we know that having two or three risk factors is
> different to having one. I would like to see at least risk factors for
> otitis media produced for penicillin resistant Streptococcal
> pneumonia, and then incorporate in the trial, and then you can see
> these, you have a population with five risk factors or three or none
> of the risk factors. These may help.
>
> DR. CHESNEY: I think I understand the question, and I think my answer
> is no, and what I think it is saying is would we break down this into
> a separate population, and my answer would be no to that, but I think
> it is a much more complex question in terms of when you rephrased the
> question, you complicated the issue for me even more, because you
> brought in age.
>
> I am not sure that I wouldn\'t use age in some way, but to be very
> concrete, my answer is no, I wouldn\'t use recurrent acute otitis as a
> discriminating factor.
>
> DR. RELLER: We are actually in agreement. I mean you want to use age
> as an additional thing, Dr. Hoberman brought that up, as well, and I
> think that this is not sufficient to identify the patients that you
> want to study, or that is an adequate separator, if you want to look
> at it that way.
>
> Dr. O\'Fallon.
>
> DR. O\'FALLON: As a statistician, I have to answer as if I were your
> statistician working with you on developing a study. After listening
> to the discussion here, what I would say is the factors that you have
> identified, I think age has to start out as being the most important
> one.
>
> So, where I am going is we are going to go for stratification. Okay.
> Statisticians do that. I would say we are going to have to be able to
> stratify the population. How that will be done is a whole discussion
> but the principle is we have got to stratify by age to start with.
>
> But it seems to me, listening to your discussion, there ought to be
> something like has this patient ever had antibiotics before, and so
> there will be a class of patients that have never had antibiotics
> before. That is one group.
>
> Then, there is the group that have. Now, there seems to be levels of
> that, and how you break that down, it sounds like that is a topic for
> discussion that you guys have to duke it out, but it sounds like that
> there ought to be some sort of a prior treatment history factor.
>
> So, I think that they sound like the two things, an age factor and a
> prior antibiotic therapy factor that ought to be involved, and this
> one isn\'t it.
>
> So, I vote against this one.
>
> DR. RELLER: Dr. Giebink.
>
> DR. GIEBINK: I will tell you what I believe, but I don\'t know, given
> the question, whether to say yes or no.
>
> DR. RELLER: Well, we are actually more interested in the comments and
> what you believe than a yes or a no.
>
> DR. GIEBINK: Let me tell you what I believe. As long as the trial
> includes entry tympanocentesis, the whole business about enriching for
> antibiotic-resistant organisms is moot, because it will be addressed.
>
> So, just leave that aside. There is a concern about heterogeneity of
> the subjects with regard to ear chronicity. So, I do believe you have
> to stratify for ear chronicity and probably the best parameters are
> recurrence and age.
>
> So, I would stratify based on recurrence and age, and I would leave
> the rest of this aside, and not try to enrich for resistance.
>
> DR. RELLER: Thanks.
>
> Dr. Sumaya.
>
> DR. SUMAYA: Again, I am not totally clear on the question, but what I
> was interested in is in having some identification of the patients
> that would be a proxy of sorts for a complicated case, and so
> recurrence and treatment failure fall under that category, and there
> could be others.
>
> I would use that as my indication of why I would favor a second
> tympanocentesis. This would be the subgroup that I would be in favor
> of having that done, because I am not favorable to doing a double
> tympanocentesis on all who would enter a study.
>
> DR. RELLER: Dr. Wald.
>
> DR. WALD: Essentially, I agree with Scott. I think that it is
> important to collect all the information, such as age at first
> episode, number of occurrences, recent antibiotic use, attendance at
> daycare, and then either take that into account by stratification or
> in your ultimate analysis. I don\'t think we need a separate study for
> those children.
>
> DR. PATTERSON: I agree with Dr. O\'Fallon and Dr. Giebink that some
> stratification of high risk versus low risk would be very useful to
> physicians in delineating the role and hopefully conservation of
> broader spectrum antibiotics.
>
> DR. RELLER: I agree.
>
> Dr. Bell.
>
> DR. BELL: I agree with Dr. Giebink that as long as ear taps are
> required for entry, this is moot, and so these people don\'t need to
> be targeted. I do think that we want to be sure that there is a
> sufficient group of penicillin non-susceptible or other drug resistant
> organisms in the study population to draw conclusions on them, but if
> the ear taps are done, this doesn\'t need to be required.
>
> The only final comment is that these are common clinical problems, and
> somehow in the guidance to physicians, these concepts might be useful,
> because they are not going to do ear taps routinely.
>
> DR. RELLER: Dr. Glode.
>
> DR. GLODE: I don\'t think we need these separate groups and having
> companies go for separate indications. I do think that one could
> modify their exclusion criteria to eliminate the issue of not
> including children who have had recent antibiotics again if you want
> to enrich.
>
> So, I favor stratification on the front end and analysis on the back
> end, and the microbiology.
>
> DR. RELLER: Dr. Nelson.
>
> DR. NELSON: In listening to this, I guess I would support if the goal
> is to move to riskier antibiotics that would be stronger and therefore
> deal with issues of resistance. It would concern me that you have
> narrowed your population, and a bacteriologic diagnosis, to narrow
> that population would be important.
>
> I would like to clarify what I think was a misinterpretation of my
> earlier remarks. The reason why I felt I could not address the tap was
> because I hadn\'t heard clear diagnostic criteria for what acute
> otitis media is.
>
> If, indeed, it meant bulging eardrums, I would have no problem with
> that. The difficulty I have is the bouncing back and forth that is
> going between what pediatricians do in their office, which we are all
> admitting is haphazard, and what actually happens in a trial.
>
> I think the reluctance of IRB to deal with this issue is that when
> someone says can you tap acute otitis media, they are thinking of what
> happens in the pediatrician\'s office, and to the extent the tap is
> used to compensate for faulty diagnosis, I think that is a problem.
>
> To the extent the tap is used in a narrow population defined by good
> criteria, that is not a problem.
>
> DR. RELLER: Thanks for that clarification.
>
> In my positioning the microbiology, I mean there is a clinical
> presentation, an examination that Dr. Pichichero went over, and
> others, and then there is the tap, which is the only way to establish
> etiology in what has been a targeted for clinical trial definition of
> who would be appropriate for tap in the first place.
>
> DR. NELSON: But the key there is the skilled diagnostician who says
> this is an ear worth tapping, which is what I heard in his
> presentation as opposed to this is maybe otitis media and an ear worth
> treating with a drug that might not be any better than tap water or
> placebo, and not tapping and not going into trial.
>
> DR. RELLER: I think we are actually in agreement and related to some
> of the remarks you made earlier about the IRBs, there are additional
> requirements that all of us face in terms of minimal training to
> participate in NIH grants and other things. It seems to me that
> clinical trials\--and I think everybody in this room would agree\--are
> far more complex that meets the eye, and if you do not have
> appropriate training and education to do whatever is necessary to
> participate is a clinical trial, you have no business gathering data
> on those patients because it is just going to end up with stuff that
> is devilishly difficult to interpret in the end.
>
> So, it all comes together in terms of people who are appropriate
> candidates for entering into study in the first place by the criteria
> that have been discussed, having them entered by people who know what
> they are doing in clinical trials, and know what they are doing for
> procedures that might be required for an objective assessment.
>
> We must go on because the down side, I mean we have tried very hard to
> have everyone have an opportunity to speak, but we are going to start
> losing members unless we have at least some comments on all three
> questions.
>
> When the turn comes around, anything that people want to say that they
> missed before, that will be the opportunity.
>
> Dr. Nelson, to finish Question 2(b), treatment failure. There is a
> definition of treatment failure that has been put forth here, and I
> would like to ask you and around the table do you agree with this as a
> definition that would be acceptable, not final necessarily, but is it
> a reasonable definition of treatment failure, and if you would change
> it, how would you change it.
>
> DR. NELSON: I will confess that this is probably not in my area of
> expertise, but I will just say that I was impressed by the correlation
> between bacteriology and the symptom scores that I think were
> presented earlier from some of the clinical studies, and whether 48
> hours was sufficient to see those changes or not would be an open
> question, but it would look to me like you could potentially use some
> of those symptoms, if you will, appropriately. The signs, I will
> defer.
>
> DR. RELLER: Thanks.
>
> Dr. Glode.
>
> DR. GLODE: I think one has to distinguish between clinical treatment
> failure and bacteriologic treatment failure, so in Dr. Marchant\'s
> study of the 40 bacteriologic failures, 62 percent were clinical
> successes.
>
> So, I think it is very important, so treatment failure, you will have
> to ask me whether\--I want bacteriologic failure or success I think is
> my definition.
>
> DR. RELLER: We will get into this a little more with the double tap
> issue, but basically, if a child had persistent symptoms after 48
> hours or 72 hours, whatever you want to say, or had it all over again
> within 7 days after finishing treatment, is that a child that, in
> general, in the context of a trial, that you would want to know
> whether the organism was gone or not gone.
>
> DR. GLODE: That would be a clinical failure, which then would raise
> the question of\--
>
> DR. RELLER: Trigger a microbiological confirmation.
>
> DR. GLODE: Yes, which may or may not be a bacteriologic failure.
>
> DR. RELLER: Exactly.
>
> DR. GLODE: Right.
>
> DR. RELLER: These are basically, if you want to get right down to it,
> that if you were a double tap believer, would these be children that,
> at a minimum, you would want to re-tap?
>
> DR. GLODE: Except I would change 48 to 72.
>
> DR. RELLER: Thanks. That\'s exactly what we want to hear. I mean what
> you would do.
>
> David.
>
> DR. BELL: I agree. I don\'t have anything more to add.
>
> DR. RELLER: The 72 hours has been mentioned earlier. I think that is
> what I would do is I would give them 72 hours, and by that time, it
> should have done what it is going to do or not.
>
> Dr. Dagan mentioned about what to call day 1, and it is sort of like
> tertian malaria. I mean it gets very confusing. There is 40 hours
> between the cycle, but day 1 is day 1, day 2, day 3, it is actually
> only 40 hours between, so 72 hours of treatment it would be if you
> start at day 1, and then day 4.
>
> Dr. Patterson.
>
> DR. PATTERSON: I agree.
>
> DR. WALD: I think there are two issues. There is no improvement by 72
> hours, with which I agree, there is worse at any time, so if a child
> deteriorates in 24 hours, that\'s a failure.
>
> I don\'t think I would call it a treatment failure, I would call it an
> early recurrence for what you are calling post-therapy, because that
> could be anything. It could be a brand-new infection. So, it\'s a
> second early infection.
>
> DR. RELLER: Would you like to know microbiologically what the status
> is?
>
> DR. WALD: I would.
>
> DR. RELLER: Good.
>
> DR. GIEBINK: I would use 72 hours after initiating treatment for the
> during, and 1 to 5 days after the end of therapy.
>
> DR. O\'FALLON: This is hardly my area of expertise. What I am hearing,
> I agree with what you have said before, and I just want to make the
> comment that I was not all that impressed by the correlation between
> the clinical and the microbiological points.
>
> That is very debatable from a statistical point of view, and it needs
> more discussion.
>
> DR. CHESNEY: I like Dr. Wald\'s comment of worse at any point, and I
> would defer the 48 to 72 hours to the experts. I also would agree with
> Dr. Giebink that 1 to 5 days after completing the course.
>
> DR. RELLER: Dr. Ramirez.
>
> DR. RAMIREZ: I agree. In most respiratory infections, we use 72 hours.
> We need to give at least 48 to 72 hours to the antibiotics to start
> having some killing or bacteria decrease to see clinical response in
> at least 72 hours, I want to take the chance now to go back to the
> prior question, because I think that some members of the committee are
> missing or at least I consider that the enriching population, what we
> discussed here before, was that yes, you want to do a tap, eardrum
> tap.
>
> Then, you say, well, I look for the resistant organisms, but you have
> in the population, 20 percent of resistant pneumococci, and 50 percent
> of otitis media is caused by pneumococcus, and then you have 10
> percent of all the bacterial otitis are going to be resistant
> pneumococci.
>
> They will say to a company go ahead, do 100 taps to get the 10 percent
> resistant pneumococci. What we are saying is that in enriched
> population, we are saying we have these inclusion criteria, if you
> don\'t meet this inclusion criteria, you don\'t get into the study.
>
> Then, we are going to need probably 30, 40 taps to get this. They were
> worth doing, we increased the population, not to enroll 100 patients,
> again, only 10 patients for the study, just from those 40, I get 10
> patients for the study. To me, the idea of enriched population in
> clinical trials looking for penicillin resistant is very valid.
>
> DR. RELLER: Thank you.
>
> Dr. Ebert.
>
> DR. EBERT: I agree with the treatment failure during therapy being at
> 72 hours or after 72 hours of therapy. As far as post-therapy, I am
> reading within 7 days as meaning 1 to 7 days after therapy, and I will
> defer to the experts whether it should be 1 to 7 or 1 to 5.
>
> DR. RELLER: Dr. Leggett.
>
> DR. LEGGETT: Ditto.
>
> DR. RELLER: Dr. Cross.
>
> DR. CROSS: And the same.
>
> DR. RELLER: Question No. 3. Do double tympanocentesis trials have a
> role in demonstrating effectiveness of drugs for general AOM, for
> recurrent/ treatment failure AOM?
>
> Then, you can see all of the related issues about timing, relative
> importance of clinical and microbiology assessments, et cetera.
>
> I think lest we lose some members, it is now 3:30. We can continue on
> as long as there is a healthy number. There has much discussion, some
> allusion to this before, but let\'s start with you, Alan.
>
> Dr. Cross, what do you see as the role, if any, for double
> tympanocentesis trials for demonstrating effectiveness of drugs?
>
> DR. CROSS: I think they are essential. I think we saw some data early
> on that showed a very good correlation on some limited data, on
> clinical outcome after doing studies with a single tap. Perhaps at
> some point in the future, we will reinforce that data. If after an
> initial tap, a patient does well clinically, we might not need a
> second tap, but that\'s in the future. We still have to firm up that
> correlation. I think it\'s essential we do double taps.
>
> The timing of the second tap, whether it\'s during therapy or at the
> end of therapy, I am not sure. We heard positions at both ends, that
> perhaps end of therapy is better than during therapy, obviously unless
> a patient is worsening.
>
> I am not sure if there are any other issues in this last question that
> you would want us to address.
>
> DR. RELLER: Thank you. This is great. The comments like Dr. Cross has
> made for or against, and then the additional discussion points we had
> scheduled until 4 o\'clock, so let\'s go around on Question 3, the
> central issue about double tympanocentesis, and then we will fit the
> remainder of the discussion in the time allotted, and then that\'s it
> for this meeting.
>
> I think from an optimist\'s standpoint, that there has been clear
> demonstration of the Agency\'s commitment to pursue and revisit these
> issues for however many times and however many decades it takes to get
> it as close to right as possible, and to revisit it to keep it right.
>
> Dr. Leggett.
>
> DR. LEGGETT: In talking about this, I go back to the question I had
> before, how are we going to avoid another azithromycin problem without
> some sort of confirmation that it actually works. So, whether you call
> it a double or a single, and then with failure as long as you actually
> see somebody at day 4, or whatever it is, and decide at that point to
> do the double tap or not, I will leave to the experts and people
> arguing with IRBs, but we need to have some confirmation that the drug
> is actually working against the bacteria, against what it is supposed
> to be doing.
>
> DR. RELLER: Dr. Ebert.
>
> DR. EBERT: I think double tympanocentesis does have a role. I am very
> strongly in favor of second taps in patients who have clinical failure
> based on the data that Dr. Giebink presented, as many as 50 percent of
> those patients will have a positive culture.
>
> I am also supportive of double taps in a smaller number of patients
> where you may still see clinical response, but still looking for
> recurrence or persistence of the organism, but I a hoping that that
> will not need to be as large of a patient population as the primary
> descriptor of where you have just a single tap.
>
> I am hoping that our earlier suggestions of assessing clinical
> response at the end of therapy as opposed to at a later time point,
> will help us to delineate some of the issues that Dr. Leggett
> mentioned.
>
> DR. RAMIREZ: I think it was mentioned in the presentations that the
> use of an antibiotic, that you may decrease the inoculum of bacteria
> to the point that the patient clinically respond, but without clinical
> cure.
>
> In these group of patients is when we may see a relapse. I think that
> is going to be necessary to ask, that we are asking the antibiotics to
> kill the bacteria, it is going to be necessary to have repeat taps in
> as many number of patients as the statistician requires to see if
> there is any difference between one antibiotic and the other.
>
> I totally agree with Dr. Dagan regarding the education of the IRB,
> because if we are convinced that a poor antibiotic that doesn\'t
> stabilize the middle ear, is going to be on schedule with relapse, and
> repeat the tap is going to be necessary, and repeat tap is no good
> even though the patient may be doing clinically better, still is going
> to be an indication to see if this antibiotic is really going to
> prevent relapse.
>
> It may be even beneficial for this patient, and be beneficial for the
> future to see what is the best antibiotic to use for otitis media. I
> don\'t think there is an ethical issue to repeat a tap when you are
> really defining what is going to be the best antibiotic that you need
> to use in this disease.
>
> DR. RELLER: Dr. Chesney.
>
> DR. CHESNEY: Could I have another day or two to think about this?
> Let\'s see. Double tympanocentesis trials, I feel definitely have a
> role in both (a) and (b). The timing of clinical assessments and of
> microbiologic I think should be between that 48 to 72 hours, and I
> think the clinical should be obviously end of therapy and even beyond
> that.
>
> On-therapy tympanocentesis in a child who is clinically improving, I
> think that is what we are all having trouble with, and that is the one
> that I feel like I would need more time for, but I think we probably
> do need to do some number who are clinically improving.
>
> In order to answer the third bullet, which is can we predict clinical
> outcome based on the on-therapy tympanocentesis, so to me you would
> have to do double studies in order to answer the third bullet, and the
> fourth issue is I don\'t think there would be any problem finding
> enough study sites in the United States.
>
> DR. RELLER: Thanks.
>
> Dr. O\'Fallon.
>
> DR. O\'FALLON: Yes, obviously, I think that the double tap is
> essential. Now, my reason is a little different. Everybody is worrying
> about the ability of the tap to predict the clinical response, which
> is important, but I am more worried about the clinical response being
> used to predict the microbiological one, and I am not impressed with
> the\--well, let\'s put it this way\--I am impressed with the
> misclassification rates between the success and failure in those two
> endpoints. I think you had better go back and take a look at them and
> see if you really think that is such a good idea.
>
> So, yes, I think double taps are needed in both kinds of studies.
>
> DR. RELLER: Dr. Sumaya.
>
> DR. SUMAYA: I would favor the double taps for the treatment failures
> of acute otitis media. Presumably this would occur at around 72 hours
> after initiation of therapy.
>
> I would also advocate for a tighter clinical evaluation at entry and
> then at 72 hours and probably at the end of therapy, as well, and very
> interested in the scale that is used, but more particularly in the
> criteria that are used within the scale of clinical assessment and if
> it could be made into a semi-quantitative type of an assessment, I
> think would be of value.
>
> I am not in favor of a double tap in general acute bacterial otitis
> media unless there is some type of complication.
>
> DR. RELLER: Dr. Wald.
>
> DR. WALD: I certainly agree with doing second tympanocentesis in any
> treatment failure, and while I think the microbiologic data on repeat
> taps, even where there isn\'t treatment failure is of interest. I like
> to look at microbiologic data, and I think it teaches us something.
>
> I don\'t think it is essential for judging outcome in the majority of
> patients because, in fact, there is a reasonable correlation between
> the bacteriology and the clinical outcome.
>
> Some of the differences that we may see in children who are
> bacteriologic failures and clinical successes may be a function of the
> fact that we don\'t stop there beyond day 4 or 5 or 6, in fact, we
> continue treating the majority of those patients until day 10, and by
> that time, they may be a bacteriologic cure.
>
> I think when we look at the data that exist, we need to look at that
> precisely were they children tapped on day 4 or 5 or 6. I think we are
> going to see differences according to the duration of therapy.
>
> DR. PATTERSON: I think double tap studies have a role in efficacy
> studies as a subset in some centers where they are routinely done. I
> don\'t think the efficacy studies should be exclusively double tap
> studies because I think we need probably a broader geographic range
> for pathogens and susceptibilities for where those might be done.
>
> I think that in single tap studies, the second tap is useful for
> therapeutic failures particularly with regard to the resistance issue
> and how to direct the use of broader spectrum agents.
>
> DR. RELLER: I think there is an important role for double taps.
> Perhaps the only exclusion would be a patient who at the appropriate
> time of follow-up, who is doing well, and on examination by an
> experienced investigator, is so fortunate to have no evidence of the
> signs and symptoms that caused them to be enrolled in the study in the
> first place.
>
> Dr. Bell.
>
> DR. BELL: I think double taps are nice, but in terms of an FDA
> requirement, I do not think they should be required for the patient
> who is clinically improving. For treatment failures, I want to see the
> information. Whether it should be required, I guess I would like some
> more input from people who have done these studies as to how feasible
> this is and how much information it provides, but I would very much, I
> would like to see it for treatment failures. I don\'t think it should
> be required for people who are improving.
>
> DR. RELLER: Dr. Glode.
>
> DR. GLODE: I think they do have a role and I agree with what most
> other people have said here, that for treatment failures they have a
> role, and I think in a small group of children, the double tap studies
> are also important. If you don\'t do them, it looks to me from the
> information provided you will overestimate the efficacy of the drug if
> you believe in bacteriologic eradication.
>
> Now, it could be as Dr. Wald said, that if we were doing quantitative
> cultures, we would find that when you tapped them on day 3, they are
> still positive, but it\'s a 2 log kill, and that is why they are a
> clinical success, but in the absence of that knowledge right now, I
> think in a small study that there should be smaller studies of two
> taps.
>
> DR. RELLER: Dr. Nelson.
>
> DR. NELSON: I will give an IRB answer to this. First of all, I think
> we all need to be better educated about the ethics of our pediatric
> rules in addition to IRBs as well. In a treatment failure, I would
> presume the tap is potentially of benefit, so that doesn\'t sound to
> me like that would be terribly controversial to do a second tap.
>
> In a child who has already had the first tap, if we had that
> population appropriately defined, what you would need is the tapping
> down by someone with the skill to be able to argue that it is only a
> minor increase over minimal risk.
>
> It certainly is an experience that is reasonably commensurate\--this
> is the language from the regulations\--with that child\'s experience
> because they just had one, four or five, six, seven days ago.
>
> But then the other threshold is it has to be of vital importance for
> understand or ameliorating the child\'s condition, and I have heard a
> mixed message on that point, some saying it is vitally important,
> others not so sure, particularly for the children that are improving.
>
> So, from my point of view, I would remain agnostic on that vital
> importance, but if you want to convince your IRB, that is what they
> have to be convinced that it is, in fact, vitally important and that
> may demonstrate the variability from institution to instruction
> depending upon what the investigators actually believe ought to be
> done for that population.
>
> DR. RELLER: Thanks. We have 15 minutes or so for additional
> discussion, and I would like to pose a question related to Dr.
> Nelson\'s important comments.
>
> For Dr. Pichichero, Dr. Hoberman, Drs. McCracken, Paradise, others,
> would we more often see clinical failures, that is, the symptoms that
> were microbiological successes, or if you had double taps, the flip
> side of that, because there was perhaps if quantitatively done, it
> would be a decrement, but not enough, and when the treatment is
> completed, if it\'s one of the courses that is longer in treatment,
> that it would eventually improve, and what about the issue of the
> proportion of children in the population that goes to daycare, I mean
> the higher risk patients, of the probability of having fluid that can
> be tapped at 3, 4, 5 days into\--let\'s just assume that it is an
> effective drug, how long does the fluid last, and is there something
> to tap safely.
>
> Comments please.
>
> DR. PICHICHERO: On a number of the items you just voted on, you
> didn\'t ask the opinion of the consultants before you voted. I just
> wanted to give a few sobering facts.
>
> Regarding the diagnosis of otitis media, for example, to define
> recurrent otitis media, you rely, as Dr. Paradise alluded to, it was a
> correct diagnosis in the past. Physicians, pediatricians who come to
> our CME course and see that video miss the correct diagnosis 50
> percent of the time. When we have taken the course abroad, they miss
> the diagnosis 65 percent of the time.
>
> So, Dr. Nelson\'s comments about a skilled operator to do the tap are
> well stated, and similarly, skilled people to make the diagnosis. The
> practicality is today that many of the centers enrolling children are
> not like our center, they are referral centers. They rely on diagnoses
> coming in to them for the background history, which may or may not be
> reliable, and I would submit that they are not reliable.
>
> Dr. Chesney said there should be no problem getting such a number of
> sites. I was recently at an investigative meeting, two of them, in
> fact, which called for a double tympanocentesis in the protocol
> design.
>
> There were 30 sites sitting approximately in each of those audiences.
> Three of those sites were in the United States, 27 sites were outside
> the United States. Dagan was at both of them. The other sites, which I
> chatted with Dr. Hoberman about, many from Latin and Central America,
> they have never done tympanocentesis double tap, so I don\'t know
> whether they are going to do it or not.
>
> I don\'t know about their diagnostic capability. I don\'t know whether
> they have a certificate from outcomes management or somewhere else
> that they are killed in tympanocentesis, and I have a lot of concerns
> about some of those issues the practicality of what you might be about
> to mandate here.
>
> I think double taps definitely need to be done, but I am concerned
> about those issues of accurate diagnosis, and for me, the ear needs to
> be bulging, and we don\'t know so much about symptoms. We don\'t know
> whether that ear tugging really means they are in pain or not, if they
> are irritable. Children get irritable, but if that ear is not bulging,
> it is not otitis media in my opinion, and if it is bulging, it still
> is otitis media, and it deserves to be tapped because there will be
> pus there, and there are two papers to say that more than 90 percent
> of the time, if they have not been on an antibiotic, you will get
> bacteria.
>
> DR. RELLER: Drs. Chesney and Hoberman.
>
> DR. CHESNEY: Just to make a correction. I didn\'t mean to imply that
> there were plenty of centers already set up, but I think that I am
> already planning to send all our house staff to your course and
> including all of the general ambulatory faculty, and I think that if
> this came out as being a requirement, then, we would become skilled at
> a technique probably we should all be skilled at.
>
> Maybe that\'s your fault for making it look so easy.
>
> DR. RELLER: Dr. Hoberman.
>
> DR. HOBERMAN: I could not agree more with Dr. Pichichero with regards
> to the accuracy of diagnosis. I think we went by the definitions of
> otitis media, and they were not addressed today but they need to be
> more stringent than what you had as stringent in the last draft
> guidelines.
>
> The repeat tympanocentesis in the case of clinical failure, I
> absolutely agree with it, and there has to be some limitation. It
> needs to happen at the end of treatment basically, but there is no
> need to repeat a tympanocentesis at day 25 if the child is failing
> because the odds of that being related to the antibiotic treatment
> that was used, it is nil.
>
> The other key point is that after recent visit of Dr. Nelson to
> Pittsburgh, the IRB has become very, very stringent with regards to
> the criteria for a repeat tympanocentesis, and I think I heard\--I
> wasn\'t at your presentation, but I watched the video, and I agree
> with the concepts that were raised there, but one thing came up which
> was the 13 tympanocentesis.
>
> I was asked the question based on this protocol, whether there was
> going to be a 13 tympanocentesis. There should not be 13
> tympanocentesis in any child. Either they get re-tapped at day 4 to 6
> and the criteria that we are debating with the IRB are bulging of the
> tympanic membrane of 2 or 3+, or 1+ plus ear pain. Those would be the
> instances in which we may be allowed to repeat a tympanocentesis, of
> course, in anybody that has clinical failure, but not in a child that
> is failing at 28 days.
>
> So the point, and you raised the question today about greater than
> minimal risk with no prospect of benefit to the patient, which will
> put us in the category 3 that requires vital importance and hoops that
> nobody will be able to jump over.
>
> We still feel like the repeating tympanocentesis is greater than
> minima risk, but of prospect of benefit to the patient if we identify
> children with bulging of the tympanic membrane at day 4 to 6.
>
> DR. RELLER: Dr. McCracken and then Dr. Bell.
>
> DR. McCRACKEN: The point raised by Ellen, and Dr. Nelson actually
> also, about the rate of kill of bacteria and whether, at 3 or 5 days,
> it is sterile or at least nothing grows because you can\'t be
> completely certain that it is not suppressed and would grow, or
> whether at 8 days, it would be okay, too.
>
> Well, there are several things about that. First, the rate of
> bacteriologic kill is different than the rate of eradication. Time to
> eradication is one thing, rate of kill is yet another, and where the
> comes into focus, and hasn\'t been done yet, but I think Ron has
> started to do this, is to determine the concentration of bacteria,
> because we know in meningitis if you have 10^8^ organisms, and your
> kill is the same as for two drugs in 10^5^, it is going to take
> longer. Time to eradication depends on those two factors.
>
> However, when you look at the data and at bacteriologic eradication at
> 3 to 5 days from several of the studies I have already mentioned, it
> does correlate with clinical outcome and the argument has been with
> the macrolide, while they may not tell it 3 to 5 days, but they
> probably do at 7 to 9 days. Well, that could be because no one is
> going to be probably tapping at that time in the normal child, but
> nevertheless, the positive culture at 4 days correlates with a poorer
> clinical outcome, both in score and just globally.
>
> This has come up with meningitis, too, they say why do you do 18 hours
> and not 30 hours?
>
> Renata and I have talked about this. I think 30 hours is the way you
> do it, so that you get away from the impact of the higher
> concentration in some children, because by 30 to 36 hours, that has
> dissipated, and I suspect by 3 to 5 days, it has also.
>
> DR. RELLER: Thank you.
>
> Dr. Bell.
>
> DR. BELL: I was happy to hear Dr. Pichichero\'s comments because
> underlying my hesitation has been the concern that double taps,
> although scientifically justifiable, practically, just may not get
> done, and we don\'t have anybody from the pharmaceutical industry
> commenting on that here, but I am cognizant of Dr. Soreth\'s comments
> this morning about something to the extent that, you know, we have to
> be sure that what\--I am paraphrasing it\--but if we set the bar too
> high, then, the studies won\'t get done, so I think we have to keep
> that in mind.
>
> DR. RELLER: Dr. Soreth.
>
> DR. SORETH: I think an important experience that we discussed here in
> January of 2001, was that of GlaxoSmithKline\'s trials with Augmentin
> ES, the 14 to 1 formulation in which double taps were done in children
> who had, on the first tap, penicillin resistant Strep pneumoniae.
>
> As I recall\--and Dr. Winn can correct me\--there were between a dozen
> and 2 dozen centers all told within those trials, and I think roughly
> half were in the United States, perhaps, and half not. I mean there
> were a goodly number of centers that were U.S. based that were
> inexperienced hands, and the percentage of positive cultures at the
> baseline tympanocentesis was quite high.
>
> When I look back over many different applications that we have had in
> the past dozen or 15 years, there is a great range, low to high, of
> even in what I would submit to you on paper would be a tight clinical
> case definition.
>
> They checked off the box that said bulging TM, they checked off that
> box. I don\'t know what that child\'s eardrum looked like because that
> data we don\'t get, we don\'t ask for pictures as yet, but perhaps we
> should.
>
> But the box is checked off that there is a bulging TM, the box is
> checked off that we did acoustic reflectometry. The boxes are checked
> off that there is an effusion there and that the child meets the
> definition of AOM, presumably ABOM, and not OME, and then when you
> look across centers, at the rate of positive cultures on that baseline
> tap, it might be as low as 20 percent or as high as 90 percent even
> with the tight clinical case definition, so there are limits to who
> tight you can make it.
>
> There probably are things that we could do in terms of assessment of
> one\'s level of training, expertise, competence, so that if you were
> batting .200, maybe you shouldn\'t be an investigator in these trials
> and that maybe you bat something at a minimum to be such a learned
> investigator.
>
> DR. RELLER: Drs. Hoberman and Marchant.
>
> DR. HOBERMAN: There are ways of getting pictures of tympanic
> membranes. We are using those systems and Dr. Smith has copies of the
> computer system we are using to capture pictures every time we enroll
> a child in an acute otitis media trial.
>
> With regards to they are batting too low or batting to high, I
> absolutely agree that the batting high should be the ones entered in
> patients in clinical trials.
>
> On the other hand, with regards to encouragement of re-tap of clinical
> failures, when clinical trials, pharmaceutical companies, quote, end
> quote, \"encourage\" investigators to do it, it doesn\'t happen, so
> there has to be some mandated proportion of children that have a
> clinical failure that need to be retapped.
>
> I frequently encounter our site and a few other sites being the only
> sites as part of clinical trials or retapping the clinical failures.
> So, i would suggest a 75 percent of clinical failures if we want to
> learn something about it, will need to be retapped as part of the
> design of the study.
>
> DR. RELLER: Dr. Marchant.
>
> DR. MARCHANT: I think Dr. Nelson\'s concern about training is well
> taken. At our hospital, we got our pediatric ER physicians to learn
> tympanocentesis, and we had each on of them do a minimum of 6 taps in
> the OR while the patient was under anesthesia, as the otolaryngologist
> put in tubes as a way that they became competent, and there are
> available practical ways to get people to be competent in the
> procedure and that can deal with the issue that you raised.
>
> DR. RAMIREZ: May I ask a question?
>
> DR. RELLER: Yes, Dr. Ramirez.
>
> DR. RAMIREZ: I get the feeling that sometimes we are thinking that in
> a clinical trial, we cannot go beyond clinical practice because it is
> unethical, because it seems to me that the second tape is never,
> unless it is a failure, is never clinical practice, but this make a
> definition of unethical, because when we do clinical trial for
> sinusitis, we require a tap. I would never tap any person with
> sinusitis when we see the patient in the office.
>
> We do always clinical type things that go beyond clinical practice,
> and if we want to see what is the base antibiotic to treat an
> infection, we may need to repeat the tap even though it may not
> benefit these children, but, yes, sometimes you discuss with the
> patient, you are doing a Phase II/Phase III antibiotic study, you
> don\'t even know the antibiotics are going to work.
>
> You may say to a patient, well, you know, this may not work, may work,
> but it may not benefit you, but in the future we are going to know
> what is the baseline antibiotic, and this is not just for you, it is
> for Dave, for future patients. I don\'t see why this would be such a
> big ethical issue.
>
> DR. RELLER: Thanks.
>
> Dr. Nelson.
>
> DR. NELSON: I think going beyond clinical interventions can be
> appropriate. The issue is, is the risk of going beyond roughly similar
> to the risks of the kinds of procedures that child would experience
> otherwise.
>
> The regulation specifically restrict exposing particularly a child to
> risk for others on that basis, but from what I have heard, it sounds
> to me like in experienced hands, tympanocentesis fits with something
> that could be done when it is not only clinical indicated for benefit,
> but the issue of experience and context is crucial to that decision.
>
> DR. RELLER: Thank you. Dr. Soreth, in the time allotted, we have tried
> our best to address the issues put to us. I think the points that have
> just been made about the standards of a clinical trial with
> appropriate design to demonstrate efficacy and safety within the
> confines of independent IRB review, adhering to the highest ethical
> standards that have been talked about.
>
> In my view, from summarizing the discussions, if you want to look at
> it, the bar needs to be raised, I think there are concerns about the
> stability of the bar and passing under it in the past, and this is
> coupled with a higher caliber of criteria as well for clinical
> investigators who are capable of carrying out the trials and adherent
> to all of the requirements including a rigorous review by
> institutional review boards.
>
> The potential end result of that is greater confidence in drugs that
> would be approved for specific indications by the FDA, in general use
> by practitioners that they would do what they are licensed to do.
>
> My final query, and this is for a future meeting , is what within the
> regulatory process would enable the Agency to reconsider looking
> backwards for drugs that may be approved now for indications that in
> our heart of hearts, we have grave questions about whether they do
> what they say they do.
>
> DR. SORETH: I can hazard an answer.
>
> DR. RELLER: Dr. Soreth, you got us\--and colleagues\--got us all
> together. You get the last word and then we will conclude the meeting.
>
> DR. SORETH: Quickly, we will publish in the Federal Register the
> appropriate docket number to which anyone and everyone is invited to
> send in written comments. I don\'t want to give you the previous
> number, because that may not be the best way to address this.
>
> We will publish it in the Federal Register and we will also put it on
> the web site together with slides and transcript from today\'s
> proceedings.
>
> Secondly, to try to answer your question about what do we have within
> the regulatory framework to address, that which we approve, at one
> point in time maintaining being safe and efficacious in current times,
> and I think there are a couple of mechanisms that we have and a couple
> of databases to try to answer that.
>
> We have with all of the caveats attendant to it a postmarketing
> spontaneous reporting system for adverse events for any and all drugs
> and for vaccines. That includes coding such reports for drug lack of
> efficacy for infections that one may get as a result of taking an
> antibiotic, in other words, there are codes and queries that you could
> do of this spontaneous reporting system and marry that information to
> usage data in a crude attempt to try to get a denominator to
> understand within a given drug, across drug class, within a given drug
> class or across drug classes, et cetera, whether or not something that
> used to work, might not still be working.
>
> Perhaps more rigorous than scientific, we have theoretically
> surveillance data that tell us with current isolates and current
> antibiotics and old antibiotics what theoretically should still be
> covered and what ought not to be covered from isolates and from real
> people who have real infection.
>
> I think that we are trying to be diligent in our efforts to embrace
> those two real big databases and get our hands around them to try to
> answer the simple question that you raised, which on inspection, is
> actually rather complicated.
>
> DR. RELLER: Thank you. The meeting is adjourned.
>
> \[Whereupon, at 4:00 p.m., the hearing adjourned.\]

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