ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

**ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE MEETING**

**OPEN SESSION**

> Wednesday, October 29, 2003
>
> 8:30 a.m.
>
> Holiday Inn Gaithersburg
>
> The Ballrooms
>
> Two Montgomery Village Avenue
>
> Gaithersburg, Maryland

PARTICIPANTS

James E. Leggett, Jr., M.D., Chair

> Tara P. Turner, Pharm.D., Executive Secretary

MEMBERS

> John S. Bradley, M.D.
>
> Alan S. Cross, M.D.
>
> Jan E. Patterson, M.D.
>
> Donald M. Poretz, M.D.
>
> Ciro V. Sumaya, M.D.
>
> Ellen R. Wald, M.D.

ACTING INDUSTRY REPRESENTATIVE (Non-Voting)

Kenneth R. Brown, M.D.

CONSULTANTS (Voting)

> Janet D. Elashoff, Ph.D.
>
> Thomas R. Fleming, Ph.D.
>
> Jack M. Gwaltney, Jr., M.D.
>
> Joan F. Hilton, Sc.D.,
>
> M.P.H. (Consultant-CBER)
>
> L. Barth Reller, M.D.
>
> Keith A. Rodvold, Pharm.D.
>
> (Acting Consumer Rep)

CONSULTANT (Non-Voting)

> Thomas A. Sydnor, Jr., M.D.
>
> Allan R. Tunkel, M.D., Ph.D.

FDA

Mark Goldberger, M.D., MPH

> Renata Albrecht, M.D.
>
> Edward Cox, M.D., MPH
>
> John Powers, M.D.
>
> Janice Pohlman, M.D.
>
> Carl Kraus, M.D.

[C O N T E N T S]{.underline}

> Call to Order:
>
> James E. Leggett, Jr., M.D. 4
>
> Introduction of Committee 4
>
> Conflict of Interest Statement:
>
> Tara P. Turner, Pharm.D. 6

**General Overview: Antimicrobial Development**

> **for ABS, Regulatory History**
>
> Renata Albrecht, M.D. 8

**Acute Bacterial Sinusitis: Overview**

> Jack M. Gwaltney, Jr., M.D. 19

**Description of Sinus Puncture**

> Thomas A. Sydnor, Jr., M.D. 61

**Statistical Considerations in Clinical Trial Design**

> **in ABS**
>
> Thomas R. Fleming, Ph.D. 65

**Clinical Evaluation of ABS: Diagnostic**

**Considerations**

> Carl Kraus, M.D. 100
>
> **Observations from Past Approvals for Acute**

**Bacterial Sinusitis**

> Janice Pohlman, M.D. 116

**Clinical Trial Design in ABS: Consideration for**

**Future Guidance**

> John H. Powers, M.D. 140

Open Public Hearing

> Jack Anon, M.D. 179
>
> Ron Jones, M.D. 189
>
> Charge to the Committee
>
> Edward Cox, M.D., MPH 194
>
> Committee Discussion 199

[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. LEGGETT: I would like to get started if we could. Today is October
> 29th. We are going to be discussing Clinical Trial Design in Acute
> Bacterial Sinusitis.
>
> We will first have the introduction of the Committee.

**Introduction of the Committee**

> DR. GOLDBERGER: Mark Goldberger, Director of the Office of Drug
> Evaluation IV.
>
> DR. COX: Ed Cox, Deputy Director, Office of Drug Evaluation IV.
>
> DR. POWERS: John Powers, Lead Medical Officer, Antimicrobial Drug
> Development and Resistance, in 04.
>
> DR. ALBRECHT: Renata Albrecht, Director, Division of Special Pathogen
> and Immunologic Drug Products.
>
> DR. POHLMAN: Janice Pohlman, Medical Office, Division of
> Anti-Infective Drug Products.
>
> DR. KRAUS: Carl Kraus, Medical Officer, Division of Special Pathogen
> and Immunologic Drug Products.
>
> DR. RODVOLD: Keith Rodvold, University of Illinois at Chicago.
>
> DR. FLEMING: Thomas Fleming, University of Washington.
>
> DR. ELASHOFF: Janet Elashoff, Biostatistics, Cedars-Sinai and UCLA.
>
> DR. HILTON: Joan Hilton, Biostatistics, University of California/San
> Francisco.
>
> DR. RELLER: Barth Reller, Infectious Diseases, Diagnostic
> Microbiology, Duke University.
>
> DR. TURNER: Tara Turner, Executive Secretary for the committee.
>
> DR. LEGGETT: Jim Leggett, Infectious Diseases, Portland, Oregon.
>
> DR. WALD: Ellen Wald, Pediatric Infectious Diseases, University of
> Pittsburgh.
>
> DR. PATTERSON: Jan Patterson, Infectious Diseases, University of Texas
> Health Science Center, San Antonio.
>
> DR. BRADLEY: John Bradley, Pediatric Infectious Diseases, Children\'s
> Hospital, San Diego.
>
> DR. PORETZ: Donald Poretz, Infectious Diseases, Fairfax, Virginia.
>
> DR. GWALTNEY: Jack Gwaltney, Infectious Diseases, University of
> Virginia.
>
> DR. SYDNOR: Austin Sydnor, Retired Otolaryngologist, Charlottesville,
> Virginia.
>
> DR. TUNKEL: Allan Tunkel, Infectious Diseases, Drexel University
> College of Medicine.
>
> DR. BROWN: Ken Brown, Infectious Diseases, University of Pennsylvania.
>
> DR. LEGGETT: Welcome, everyone.
>
> Tara, could you please read the Conflict of Interest.

**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 granted waivers to the following
> Special Government Employees which permits them to participate in
> today\'s discussions: Drs. Jan Patterson, Thomas Fleming, and Keith
> Rodvold.
>
> 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.
>
> Further, Dr. Jack Gwaltney and Dr. Donald Poretz reported financial
> interests in pharmaceutical companies covered under CFR 2640.202(b) de
> minimus exemption.
>
> The topics of today\'s meeting are issues 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 participants 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.
>
> We would also like to note for the record that Dr. Kenneth Brown is
> participating in this meeting as an acting industry representative,
> acting on behalf of regulated industry.
>
> 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.
>
> 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.
>
> Thank you.
>
> DR. LEGGETT: Thank you.
>
> Dr. Albrecht, could you please give us a general overview.

**General Overview: Antimicrobial Development**

> **for ABS, Regulatory History**
>
> DR. ALBRECHT: Good morning, everyone. I would like to welcome you to
> the second day of the Anti-Infective Advisory Committee meeting. I
> would also like to thank the members of the advisory committee, as
> well as our invited consultants, for being with us today to help us on
> a number of scientific issues.
>
> This morning you are going to hear a series of presentations on
> various aspects of clinical trial design in acute bacterial sinusitis,
> and then we are interested in the committee\'s and our consultants\'
> advice on several aspects of clinical trial issues in antimicrobial
> drug development for the indication of acute bacterial sinusitis.
>
> So, to start, I would like to provide a general overview on the
> antimicrobial development for acute bacterial sinusitis, highlight
> some regulatory milestones, and talk about the goals for today.
>
> \[Slide.\]
>
> The first drug that received labeling for the indication specifically
> of sinusitis was Augmentin, which was approved in 1984, and the
> labeling at the time stated \"Sinusitis infections caused by
> beta-lactamase producing strains of Hemophilus influenzae and
> Branhamella catarrhalis.\" That is the former name of Moraxella
> catarrhalis.
>
> Other drugs that were approved at that time or before that time had
> more nonspecific wording in the Indication Section, such as for
> Amoxicillin, \"Infections of the ear, nose, and throat,\" and other
> products carried a broader sort of indication of upper respiratory
> tract infections, which may or may not have included infections of the
> nose or sinusitis, as well.
>
> Approval in those years was based on clinical data and patients on
> both arms of the study\--these were comparative studies\--had sinus
> puncture and aspiration for microbiologic documentation of a bacterial
> pathogen at entry.
>
> \[Slide.\]
>
> So, as I mentioned, approval was based on demonstration of efficacy,
> which included clinical outcome and also microbiological data from
> baseline pathogens, as well as safety.
>
> The approval took into consideration other relevant data which
> invariably included in vitro activity on the target pathogens and
> pharmacokinetic data on the product in question, and at least on one
> occasion, there was also tissue and sinus fluid drug levels available
> in the application.
>
> Again, the indication was not sought in isolation. It came typically
> in an NDA where the applicant, the sponsor was looking at multiple
> indications for approval including a number of respiratory
> indications, for example, community acquired pneumonia, AECB, acute
> bacterial otitis media, and non-respiratory indications, such as skin
> or urinary tract infection.
>
> \[Slide.\]
>
> As I mentioned, microbiology was a component of the data available on
> patients and, in fact, baseline pathogens were sought in all patients
> on both the tests and the control arm.
>
> Now, to document the presence of a bacterial pathogen, a sinus
> puncture with aspiration was involved, and the agency started hearing
> fairly early that there was concern about patient acceptance of this
> procedure. It was invasive, it did involve discomfort, and sometimes,
> even despite anesthesia, apparently there was some pain.
>
> \[Slide.\]
>
> So, the FDA, actually in consultation with IDSA in an effort that was
> going on in the 1992 era, did consider an alternative approach, and
> this was documented in 1992, what is known as the Points to Consider
> document that was put out at that time by the Division of
> Anti-Infective Drug Products.
>
> To very briefly summarize, what the 1992 Points to Consider document
> did is put forth two clinical trial designs that could be used to
> support this indication. The first has become known as the \"Clinical
> only\" trial design. This was a comparative study where rigid criteria
> clinical and radiographic were used to select a patient population
> with the expectation that these patients had bacterial sinusitis.
>
> Microbiologic diagnosis was not required and the delta that was used
> for this comparative study was determined by a step function, which
> was summarized in the document.
>
> A second study, referred to as a \"microbiologic-driven\" study, was
> stated to be open in that document, which was translated to mean
> non-comparative, and the majority of these studies were not
> comparative, and patients on the test drug had sinus punctures
> performed to document the bacterial pathogen at entry.
>
> The purpose of the second study was to try to reduce the number of
> patients who would need to undergo the invasive procedure, but despite
> that measure, there was still continued concern about the procedure.
>
> \[Slide.\]
>
> As a result of that, in 1994, the agency asked the advisory committee
> to consider whether endoscopic sampling of the sinus to obtain a
> specimen for culture would be acceptable as an alternative to sinus
> puncture and aspiration.
>
> During that advisory committee, we heard presentations from FDA
> consultants, and two of our consultants are actually with us today,
> Dr. Gwaltney and Dr. Wald, and industry.
>
> After deliberation, the committee actually recommended that sinus
> puncture should continue to be considered the gold standard, that
> studies to compare endoscopy to puncture have not really been done.
> Dr. Talbot did present some preliminary data from his trial at that
> advisory committee meeting, but other data were not available from the
> published literature.
>
> Also, the observation was that in 1994, endoscopy was not considered a
> precise, reproducible and standardized procedure, so the suggestion
> was that endoscopy continue to be evaluated to see whether it perhaps
> in the future could have a role in this diagnosis.
>
> \[Slide.\]
>
> As a result of that, the agency, in putting together the draft
> guidance documents that we have available now, in 1998, adopted the
> trial designs initially put in the 1992 Points to Consider document.
>
> At the present, there are two clinical trials recommended - one, the
> clinical-only comparative trial where an active control is used as the
> comparator. In this trial, rigorous case definitions based on signs
> and symptoms, as well as radiographic findings, should be used to
> select the patient population.
>
> The recommendation is that patients have more than 7, but less than
> 28, days of signs and symptoms of an upper respiratory tract
> infection. The signs and symptoms are listed in your handout and also
> in the document.
>
> Radiographic evidence of mucosal thickening, air fluid levels,
> opacification is also requested, and no microbiology is requested in
> this particular study, and evaluations at baseline, as well as outcome
> assessments at 1 or 2 weeks post-therapy are based on the clinical
> criteria.
>
> \[Slide.\]
>
> The second study, the so-called microbiologically-driven study, is
> often a non-comparative study, still a clinical trial looking at
> clinical outcome, as well as microbiological data in each patient.
>
> In this trial, the idea is that again the clinical and radiographic
> criteria ideally would be similar to what was used in the comparative
> trial, and that the microbiology of the maxillary sinus be obtained
> through puncture and aspiration at baseline.
>
> That specimen should be examined for the presence of bacteria, as well
> as WBCs. It should be sent for isolation, culture, and quantification
> of the pathogen, and although the recommendation of 10^4^
> colony-forming unit/ml is made for Staph aureus, the thought was to
> actually try to make it easier to find the common three pathogens.
> Those, in fact, the agency will consider as pathogens regardless of
> colony count.
>
> There is a quantitative number of organisms that is being looked for,
> 25 Strep pneumo, 25 Hemophilus influenzae, 15 Moraxella catarrhalis,
> and if Staph aureus is being sought, about 10 to 20 isolates should be
> available.
>
> Again, evaluation is made at baseline and the outcome is assessed at 1
> to 2 weeks post-therapy, and the microbiologic outcome or eradication
> is presumed based on the clinical outcome of the patient.
>
> \[Slide.\]
>
> So, why are we here today? What is it that we hope to get your advice
> and guidance on?
>
> We have experience with about 10, perhaps a dozen, NDAs since 1990
> where the applicant was looking for the indication of acute bacterial
> sinusitis, and it is time to consider whether the advice in the draft
> guidance to industry on acute bacterial sinusitis that we have is
> useful and sound, or is it perhaps time for us to revisit this
> guidance document.
>
> Specifically, the clinical-only trial, while it is more acceptable to
> patients, have we actually lost diagnostic specificity by using that
> approach?
>
> As far as the microbiologically-driven study, are fewer patients
> really undergoing sinus puncture, which was one of the implied goals
> in putting forth this study design?
>
> Is the non-comparative data that we are obtaining from this study
> informative or adequate? Are there other diagnostic procedures that
> could perhaps be now used in lieu of the gold standard to obtain
> specimens for microbiology?
>
> As I mentioned, the two trial designs recommended in this guidance,
> are they yielding reliable data on drug efficacy, or is it time for us
> to consider other trial designs, as well?
>
> \[Slide.\]
>
> To address these issues, we have a series of presentations, and we are
> privileged this morning to have Dr. Jack Gwaltney, who will start the
> presentations with an overview of acute bacterial sinusitis.
>
> Then, Dr. Austin Sydnor will actually show us a video of a sinus
> puncture procedure, and Dr. Fleming will talk about Statistical
> Considerations in Clinical Trial Design in Acute Bacterial Sinusitis.
>
> \[Slide.\]
>
> Then, you will hear a series of presentations by FDA staff. Dr. Kraus
> will talk about Clinical Evaluation of ABS: Diagnostic Considerations.
> Dr. Pohlman will review past approvals of drugs for this indication
> and talk about lessons learned from the clinical trial designs.
>
> Dr. Powers will conclude the presentations with Clinical Trial Design
> in ABS: Consideration for Future Guidance.
>
> \[Slide.\]
>
> As you listen to these presentations, keep in mind the questions that
> we will be asking you to address this afternoon. Dr. Cox will
> elaborate on these.
>
> Very briefly, the questions will be: How to ensure that patients in
> clinical trials of acute bacterial sinusitis have bacterial disease,
> and in that, we will also be asking you to think about how to obtain
> the microbiological data, whether sinus puncture and endoscopy or
> other procedures may be useful.
>
> \[Slide.\]
>
> The second question will be ask you to discuss the clinical trial
> design for acute bacterial sinusitis. Some of the areas include
> strength and limitations of placebo-controlled trials, non-inferiority
> trials, and also the non-inferiority margin in non-inferiority trials
> for this indication.
>
> We will also ask about the strengths and limitations of comparative
> microbiological data.
>
> \[Slide.\]
>
> The final question that we would like you to keep in mind is to
> discuss the issue of measuring outcomes in patients in trials of acute
> bacterial sinusitis. Include in your discussion measuring
> time-to-resolution of symptoms as an endpoint compared to fixed
> endpoints.
>
> Now I will turn it back to you, Dr. Leggett.
>
> DR. LEGGETT: Thank you.
>
> Could I have the two other members of the committee please introduce
> themselves.
>
> DR. CROSS: Alan Cross, University of Maryland.
>
> DR. SUMAYA: Ciro Sumaya, School of Rural Public Health, Texas A&M
> University.
>
> DR. LEGGETT: Thank you.
>
> I think we will continue and have Dr. Gwaltney present to us an
> overview of acute bacterial sinusitis. As we did yesterday, we will
> have a timer to let the speakers know when it is about time to close
> up.

**Acute Bacterial Sinusitis: Overview**

> DR. GWALTNEY: Thank you for the invitation to be here today.
>
> Most cases of acute community-acquired sinusitis arise in the setting
> of a patient that has got either a common cold-like illness or an
> influenza-like illness.
>
> \[Slide.\]
>
> When a physician is faced with the management of one of these
> patients, there are several questions that need to be addressed in
> order to deal effectively with the problem, and these questions also
> are relevant to the discussion today because they are important in
> terms of designing clinical trials of antimicrobial therapy in
> sinusitis and in selecting a patient population which would be
> appropriate for use in those clinical trials.
>
> The questions are as you see here. Is disease present in the sinuses?
> If it is present, is it viral or bacterial? What are the bacteria and
> the clinician wants to know what antibiotic to select. Here today, the
> question might be what antibiotic to test and what criteria to use to
> determine that valid results have been obtained from testing of that
> antibiotic.
>
> \[Slide.\]
>
> The first question, is disease present in the sinuses, this question
> in the past was somewhat difficult to answer because the sinuses are
> difficult or impossible to examine, they are difficult to sample in a
> non-invasive way, so the most specific diagnostic test was thought to
> be some type of imaging procedure.
>
> \[Slide.\]
>
> This, I think has changed, and it changed because we now know that
> patients that have common colds and flu-like illnesses also have
> sinusitis, that this disease is not just a rhinitis, but it is a viral
> rhinosinusitis.
>
> If patients with early common colds, in this particular study, colds
> of duration 2 to 4 days, are examined by CT scan of the sinus, these
> are the kind of findings that you see.
>
> I don\'t know with the lights, if you can see those CT scans very
> well, perhaps it is possible to dim the lights up here in the front of
> the room.
>
> \[Slide.\]
>
> These are taken from the same patient early in the illness, at
> approximately 2 weeks later. Some of you may be not be familiar with
> CT scans. This is a coronal view cut down through the front in this
> plane. This is a normal examination. The sinus is normally full of
> air, which is black. Of course, the bone is white.
>
> In this instance where the patient has the acute cold, this gray
> material in both maxillary sinus cavities and also here in the
> anterior ethmoids.
>
> I also want to point out these black areas here, and these are air
> bubbles. This tells you that this is not thickened mucus membrane
> which you might suspect from looking over there, the way this is
> distributed around the lumen of the sinus, but that indeed this is
> some kind of fluid material because of the presence of the air
> bubbles.
>
> This patient received no antibiotic treatment and, as I said, had
> recovered from these abnormalities in the sinus in 10 days to 2 weeks.
>
> \[Slide.\]
>
> Just another example. This patient has disease here in the ethmoids
> again, a little bit in this maxillary antrum again, clear after the
> cold is resolved.
>
> \[Slide.\]
>
> Here is another patient. This slide is in backwards, I am sorry. This
> sinus has a lot of this material in here. This sinus is completely
> clear. There is an accessory ostium present in this patient. You can
> see this material kind of oozing up here as it is transported out of
> this sinus cavity by the mucociliary transport and again returned to
> normal. This again is evidence that that is not mucosal thickening.
>
> The distribution of that would also be unusual I think to have so much
> mucosal thickening here, nothing here, and nothing here. The erratic
> distribution of these abnormalities was something that was puzzling
> when they were observed.
>
> \[Slide.\]
>
> In this study, the summary of the results were that the maxillary
> infundibulum, the passage that drains the maxillary sinus, was
> occluded in 77 percent of these patients. The denominator here is 31.
> There were abnormalities like I showed you in the various sinus
> cavities - 87 percent maxillary, 65 ethmoid, 32 frontal, and 39
> sphenoid.
>
> \[Slide.\]
>
> So, the answer to the first question is disease present in the sinus
> really does not require any specific diagnostic test. One can assume
> that in the patient with an upper respiratory illness like a cold or
> flu, there is a very good probability that there also is some disease
> in the sinus cavity. As I said, really, we should look at these
> diseases as cases of viral rhinosinusitis.
>
> \[Slide.\]
>
> Now, just a word about what is going on in this process, because when
> it was seen that the sinuses were involved, the question obviously
> arose what is this abnormality, what does it represent, and how does
> it occur.
>
> Here is another patient with a common cold and you see the
> distribution, quite unusual, here in the upper part of this sinus and
> down here in the bottom here, again, this ethmoid disease.
>
> \[Slide.\]
>
> Just a kind of graphic representation of what we think this material
> is. This is material obtained from a patient with an early common cold
> in which we fished out the mucus, not the thin stuff, but we went and
> got the good glob of mucus, which I am sure you are all familiar with
> if you have children or have colds.
>
> We split the specimen and we put it in a syringe, as you see here.
> Now, the diameter at the end of this syringe is about 3 millimeters.
> It is about the same diameter as what the infundibulum of the
> maxillary sinus is. This specimen was left as it was, and in this we
> put some N-acetylcysteine, a mucolytic, and we left it overnight.
>
> As you can see, with the mucolytic, the material did drain, but when
> left alone, it was not able to get out of the syringe, and we think
> this is very similar to what we are seeing happen in the sinus cavity.
>
> \[Slide.\]
>
> Now, the sinus cavity is lined with goblet cells. There is a very high
> concentration of goblet cells and not many seromucous glands. The
> original thought was that maybe by some triggering mechanism, the
> goblet cells were exocytosing the mucus, but a couple of years ago we
> saw a patient that had again acute common cold and the sinus was full
> of this frothy material. You can\'t see well on the slide, but there
> are bubbles all the way up through the entire cavity of the sinus.
>
> This is the same patient, a few days later when it is coalesced, you
> still see there are some bubbles here. This led to the idea that the
> only thing that made sense was this fluid and the bubbles had gotten
> into the sinus cavity by being blown down the infundibulum, and that
> led to the question of what types of actions would lead to the
> expulsion of material from the nasal passage into the sinus cavity.
>
> We looked at the three most likely types of activities, which were
> nose blowing, coughing, and sneezing, and working with some engineers
> who measured intranasal pressure, determined that\--and this is
> intranasal pressure in millimeters of mercury, not water, so this is
> up in the level of a diastolic blood pressure\--nose blowing does
> elevate intranasal pressure consistently to these ranges, and the
> engineers calculated that if the middle meatus is loaded with mucus,
> one nose blow would have the capacity to propel approximately 1 ml of
> mucus into the maxillary sinus cavity. Coughing and sneezing did not
> elevate the intranasal pressures much above baseline.
>
> \[Slide.\]
>
> We pursued this one step further and took more volunteers, put
> contrast medium in the back of the throat, again had them cough,
> sneeze, or blow their nose, and every time they blew their nose, we
> would find the dye here in the anterior ethmoid, here in the
> infundibulum of that maxillary sinus, here, and here is some in the
> base of the maxillary sinus with a bubble in the posterior ethmoids
> and in the sphenoid.
>
> So, it appears that at least one mechanism or maybe the most important
> mechanism for introducing material into the sinus cavity during these
> upper respiratory infections is nose blowing.
>
> Of course, nasal fluid during a cold contains not only the virus that
> caused the cold, it contains inflammatory mediators, and it contains
> bacteria, and to me, it is really somewhat surprising that the
> instance of bacterial sinusitis is not higher than it is if the nasal
> fluid reaches the sinus on such a regular basis.
>
> \[Slide.\]
>
> Now, the second question is if disease is present in the sinus, is it
> viral or bacterial. This, of course, is one of the major questions
> being addressed today is how do you make that determination.
>
> \[Slide.\]
>
> There are not ideal studies that address this question. The ideal
> studies would involve sinus puncture of patients with colds at various
> stages in the illness, and that has never been done.
>
> Probably the two best sets of data that we have, one comes from the
> Cleveland Family Study, the old study done in the fifties and sixties
> of some 11,000 patients based on clinical diagnosis. It was thought
> that 53 or half a percent had developed a secondary bacterial
> sinusitis.
>
> This is a more recent study by Berg done in ENT patients who were in
> the clinic, and these patients did have sinus puncture, however,
> cultures were not done on the material. The diagnosis was based on the
> observation of the character of the material, and if it looked
> purulent, then, the diagnosis of bacterial infection was made and 2 of
> 89 or 2.2 percent of these patients were thought to have bacterial
> sinusitis.
>
> This I think is probably in the range of what does occur. You have all
> had colds and you know that fortunately, most of the time they don\'t
> turn into a bacterial sinus infection, but this also presents a major
> problem in terms of diagnosis, because with this great disproportion,
> 98 percent viral, 2 percent bacterial, diagnostic tests have to have
> high specificity in order to have accurate predictive value.
>
> \[Slide.\]
>
> Now, the fact that bacterial infection does occur is certainly well
> established by sinus puncture studies that go back to the late forties
> and fifties beginning in Scandinavia, and they have been continued in
> the United States and elsewhere, so there is no question to the fact
> that it does occur.
>
> \[Slide.\]
>
> Now, in terms of diagnosis, though, problems remain and when
> individuals have looked at the sensitivity and specificity of the
> clinical findings in patients with acute sinusitis\--this is a study
> by Williams and this is a study by Berg\--the findings are that these
> several things that have been considered characteristic of bacterial
> sinusitis, the individual signs and symptoms, none of them have both
> high sensitivity and high specificity.
>
> For example, colored nasal discharge where there is quite a bit of
> sensitivity, the specificity is only 52 percent.
>
> Maxillary toothache, which occurs in the patients in which the
> pathogenesis of sinusitis begins with the infection of the tooth root,
> not a cold or flu-like illness, this has quite high specificity, but
> only a very low sensitivity because most patients develop the
> sinusitis from the cold and flu, and not from the dental infection.
>
> The same thing was seen by Berg, who again was using sinus aspirate
> and looking at the purulent character of the material.
>
> \[Slide.\]
>
> Another diagnostic approach has been the use of x-ray. That slide
> apparently didn\'t fall the way, but this is from a study, that was
> the first study that was done by the Charlottesville group in 1975, in
> which punctures were done and x-rays, not CT scans, were compared.
>
> This led to the findings which were described earlier, that the air
> fluid level, the thickening of the mucous membrane, quotes thickening
> of 3 ml or more, I think that is all right, or a complete opacity.
>
> As you can see, the number with positive culture here with the air
> fluid level was relatively high, and I want to talk about that in just
> a second.
>
> The number with positive culture, here is the denominator and the
> numerator. It was not as good with quotes mucosal thickening or
> complete opacity. I also want to point out that these patients had
> been through a filter. They were in the ENT clinic, so they had been
> ill probably for a week or longer in most cases. This would not be
> what you would find if you did this study in patients that were early
> in a cold-like illness.
>
> \[Slide.\]
>
> This is just an x-ray from back at that time, and here is an air fluid
> level right here, and this is what we are talking about. This is a
> very flat meniscus, and this is characteristic of patients that have
> thin fluid in the sinus cavity. If you put this patient in a different
> position, that fluid would move, unlike the material I showed you with
> the viral rhinosinusitis.
>
> What may happen in these patients is that the thicker material with
> the viral infection is degraded by bacterial enzymes\--this is just a
> speculation\--and you get this thin material, and that is why that is
> more specific for the bacterial infection.
>
> \[Slide.\]
>
> Another approach that has been looked at more recently is to do
> endoscopic sampling of the nose, and I want to emphasize that this is
> the nose, not the sinus cavity. It is not possible to insert an
> endoscope into the sinus cavity because of the protected nature of the
> infundibulum and the acute angle that occurs.
>
> So, the best that can be done is to put the endoscope into the area
> where the sinus cavities drain. In this comparative study, which was
> mentioned earlier, if all cases were looked at\--the new technology is
> overriding my old horse and buggy slides, I am sorry, but if it
> doesn\'t work, I can show you the slides and you can pass them around.
>
> These are just the data I talked about earlier.
>
> \[Slide.\]
>
> This is the Talbot study. This was a head-to-head comparison, the same
> patients that had both endoscopic sampling and sinus aspiration,
> sensitivity 65 percent, specificity 40 percent, positive predictive
> value 38, negative 67, accuracy 49, which is obviously not very good.
>
> If only the three organisms were examined, then, the accuracy was 85
> percent. By doing this, one leaves out other important pathogens, such
> as the anaerobes, the alpha-hemolytic Strep like Strep milleri, Strep
> intermedius, or pus-producing alpha-Strep, beta-Strep, and Staph
> aureus.
>
> \[Slide.\]
>
> So, there are problems in establishing a diagnosis of acute bacterial
> sinusitis, and these are that the signs and symptoms do not have a
> desirable degree of specificity for making the diagnosis, and the
> standard that has been used in those studies, or in Williams\' study,
> was imaging. This is a very important point - the correlation was not
> made with sinus puncture, and as I have said, neither has imaging been
> correlated with the results of sinus aspirate culture.
>
> So, there are two problems with trying to understand the results of
> that study, and it was certainly a well done study in the sense of
> what it was possible to do under the conditions of the study, but
> there are problems because of the lack of what would be an acceptable
> diagnostic standard for bacterial sinusitis, which is a positive sinus
> aspirate culture. That is the way we diagnose infectious diseases, and
> it is for other types of infections, and the same should be true for
> sinus infection.
>
> The signs and symptoms have not been correlated. This study has never
> been done with pretreatment of bacterial sinus aspirate culture. Signs
> have not been correlated with post-treatment bacterial sinus aspirate
> culture.
>
> We don\'t know whether this assumed bacteriologic cure based on the
> clinical course really has any validity, because there are no data to
> show that such a correlation exists. Neither has imaging been
> correlated with pre- and post-treatment sinus aspirate culture, and
> diagnosis of bacterial sinusitis in clinical trials have been based on
> these signs and symptoms of imaging.
>
> Now, I might also say that in terms of the endoscopic sampling, as far
> as I know, there are no data on whether that correlates with the
> result of bacteriologic cure after treatment. So, that also is a
> problem.
>
> \[Slide.\]
>
> Well, now, in order to help the clinician to make a diagnosis, these
> three categories have been proposed of patients presenting who may
> have acute bacterial sinusitis.
>
> One is an emergent category, which fortunately is quite rare, which is
> sinusitis that has become complicated by bacterial meningitis or brain
> abscess. These patients present with either orbital or periorbital
> infection. The attention of the more serious illness usually is what
> brings these patients in.
>
> There is a second category here termed \"urgent.\" Patients that have
> what has been the classical description of acute bacterial sinusitis,
> fever, erythema over the cheek, true pain, real tenderness, and
> maxillary toothache in those patients that have dental infection that
> is the initiating factor.
>
> These patients, if presenting this way, should be diagnosed as having
> a bacterial infection of the sinus cavity, in most cases, don\'t have
> this, and therefore, they are in what would be called an elective
> category here, and these are patients that have a cold or flu-like
> illness which is no better or worse after 7 to 10 days.
>
> This is currently pretty much the standard that has been proposed by a
> number of expert groups to be used by clinicians in the diagnosis of
> bacterial sinusitis. What is this based on? It is based on indirect
> evidence.
>
> I guess the best evidence is that in studies which we did in
> Charlottesville, in patients that were in this stage of the illness,
> about 60 percent of them would have a positive aspirate culture. They
> would have bacteria growing in the aspirate culture and frequently in
> titers of 10^5^, 10^6^, or 10^7^.
>
> \[Slide.\]
>
> The other piece of information or the other inference that could be
> made is that if you look at the duration of patients with known viral
> colds, and this bar graph is from patients in an insurance company,
> 139 patients who had proven rhinovirus colds by viral culture, and
> this is the duration of illness, you see that the majority of these
> patients have gotten over the illness, they are completely well by,
> say, 8 to 12 days, so the great bulk of patients with an uncomplicated
> cold will be well and certainly an even higher percentage will be
> better at the end of the 7 to 10-day period.
>
> The other reason to believe this is Dr. Ellen Wald thinks it is true,
> and I give her great credit for being an authority in this disease, as
> well. I kind of came up with the same belief.
>
> \[Slide.\]
>
> The third question, what are the bacteria, and this is a question that
> is easy to answer, based on the sinus puncture studies that have been
> done over the last 50 years, the etiology is as shown here, it hasn\'t
> changed, pneumococcus, Hemophilus influenzae, and about 50 to 60
> percent, sometimes more than one pathogen is recovered in the aspirate
> culture.
>
> The anaerobic bacteria in the patients that have dental disease, and
> then Moraxella, and I am sure this percentage is too low, because in
> more recent studies when Moraxella was recognized as a pathogen,
> usually, these were discarded and called Neisseria as you heard Dr.
> Albrecht say, and then Group A Strep, and then other Strep species
> that I mentioned, and again I think this is an underestimate, these
> are an important cause also.
>
> Staph aureus does cause acute community-acquired bacterial sinusitis,
> but a relatively small percentage, absolutely a small percentage.
>
> Finally, what antibiotics to select.
>
> \[Slide.\]
>
> Well, the question that I think should be addressed before that
> question, and really I won\'t get into that today because that is not
> appropriate for this group, is this question here. Should cases of
> acute community-acquired bacterial sinusitis be treated with
> antibiotics?
>
> If the answer to that is no, then, really, there is no reason for us
> to be here today, and there are people around the world who would
> substantiate that, who would support this proposition.
>
> That has fairly recently been raised. I have to say that I wonder why
> sometimes these kind of ideas are proposed, but I think you cannot
> argue with the fact that without there ever having been a
> placebo-controlled clinical trial with pre- and post-treatment of
> sinus aspirate cultures, you really can\'t criticize somebody who
> would raise that question.
>
> \[Slide.\]
>
> Well, to answer that question, one has to answer two other questions:
> Is acute community-acquired bacterial sinusitis a disease? If it\'s
> not a disease, then, obviously, you don\'t need to treat it, and if it
> is a disease, is antimicrobial treatment effective?
>
> \[Slide.\]
>
> Well, the question of is it a disease, there were a number of studies
> done in rabbits in which the sinus cavities were artificially infected
> and then histopathologic studies done, and they showed damage to the
> sinus cavity, particularly to the epithelium.
>
> More recently, as far as I know, really, one of the first or maybe the
> first study that was done in humans was published in 2000, and in this
> study, the epithelium was intact in most sections, but pathologic
> changes were found in the lamina propria, and these include edema,
> massive infiltration of neutrophils, increased lymphocytes and plasma
> cells, microabscesses, thrombosed blood vessels, and necrotic foci.
>
> So, I think this is pretty sound evidence that this process is a
> disease, these are not normal histologic findings.
>
> \[Slide.\]
>
> In summary, one could say that there are several things that support
> the idea it\'s a disease. Number one, the sinus is normally sterile
> and during this condition, there is loss of sterility and bacteria are
> present in high quantities in association with evidence of
> inflammation in the form of white blood cells.
>
> Pathologically, there is destruction in the lamina propria, not the
> epithelium. This is in the rabbits. Physiologically, there is
> impairment of sinus clearance, so the sinus is not doing what it is
> supposed to do, whatever that is, and then the risk status\--and this
> is never discussed by people who talk about not treating
> patients\--but there is an increased risk of susceptibility to the
> central nervous system and orbital infections, as I mentioned, and
> although it is small, when it does occur, this is a serious and
> sometimes catastrophic illness.
>
> \[Slide.\]
>
> So, if one assumes that it is a disease, and the theoretical reasons
> to treatment patients with antibiotics would be to restore sterility
> to the sinus cavity, reduce duration of illness, prevent the
> complication, and prevent progression to chronic sinus disease.
>
> I have to say that I don\'t think there is good evidence to expect
> that this might occur because the pathogenesis of chronic sinus
> disease is certainly not understood, and I think some people think
> that maybe it is an entirely different process and that acute sinus
> infection may not be a risk factor.
>
> On the other hand, we don\'t know that it is not a risk factor and so
> I certainly think it needs to be considered in the deliberations.
>
> \[Slide.\]
>
> Well, now, what would be the features of a clinical trial that would
> be desirable? This is my attempt to list what I think would be
> important.
>
> Content validity. Ideally, a positive pre-treatment of sinus aspirate
> culture and a quantitative culture would be preferred because there
> are some bacteria where there might be some question about whether
> they were actually pathogens or not, although with the Big 3
> mentioned, if you grow them at all, then, I think it is reasonable to
> accept them as being pathogens. It would be nice to have simultaneous
> Gram stains.
>
> In the absence of this, probably the next best thing that could be
> obtained would be a positive history of a common cold or
> influenza-like illness that is no better or worse after 7 or 10 days,
> the clinical criterion, not the gold standard, but at least something
> that seems to have some validity.
>
> The other things are pretty standard. You would like the sample size
> calculations to be done and reported, and be adequate for the effect
> size as specified, randomization of the patients, blinding, patients
> and investigators, look at the completion rates, look at compliance.
>
> \[Slide.\]
>
> And then the endpoints. Bacterial eradication, and ideally, this would
> be based on post-treatment sinus aspirate culture again with
> quantitative culture because some patients, their culture may not be
> entirely sterile, but if the titer is dropped a number of logs, one
> could assume that the patient is going to undergo a cure.
>
> Clinical response based on pre- and post-treatment standardized
> measurements, and this has been done in a number of trials. It would
> be nice to have imaging evaluations, as well, and then nowadays it is
> always important to put on the functional status of work, daily
> activities, things like this, and, of course, proper analysis of the
> data.
>
> \[Slide.\]
>
> This is a review of nine studies that were done and are in a paper
> which I think is material you have received and will be published in
> the journal Clinical Infectious Diseases in January.
>
> You see the studies listed here. They were evaluated for content
> validity, sample size, calculations, randomization, double blinding,
> standardized measurements pre- and post-imaging evaluations.
>
> As you can see, five of the studies did have imaging as part of the
> experimental design. All were randomized, all except one had double
> blinding. All except one had randomization. So, in terms of the
> quality of the experimental design, you would I think say that this
> part was handled very well.
>
> \[Slide.\]
>
> Again, the same, going backwards now. Sample size calculations were
> done in only 3 of these 9 studies, but, of course, if you have a
> positive finding, then, that would be less of a problem. But when you
> get to the first of these criteria, the content validity, then, the
> studies fall down badly.
>
> Looking at the clinical standard of duration of illness, the only
> study that probably meets that is Lindbaek study, and although that is
> not in the paper, in discussions with him, he did say most of his
> patients had been sick for a week or longer.
>
> In this study, the patients had had symptoms for five days. None of
> the studies had sinus aspirate cultures although the old study by
> Rantanen did take sinus aspirates, but there were no post-treatment
> culture results reported in that particular study.
>
> So, this obviously is an important point now that we know of the
> existence of viral rhinosinusitis because if you are not really
> studying what you think you are studying, then, obviously, you can\'t
> hope to get valid results from your investigation.
>
> \[Slide.\]
>
> Well, what information is available from non-controlled studies?
>
> \[Slide.\]
>
> First on the question, does antimicrobial treatment eliminate
> infection, a number of pre- and post-sinus aspirate culture
> uncontrolled studies have been done. We did a number of these, here
> through \'75, and that should be 1997, not 77, number of antibiotics.
>
> When these studies were done, resistance had not developed in
> Hemophilus and Moraxella, so these were appropriate antibiotics. They
> were given for a 10-day course, and if you look down the list, you see
> that the resolution rate was in the range of 90-95 percent.
>
> I want to point out that is the wrong word up here. I made the slide,
> but it really should not be cure, we can\'t claim that these were
> cures because we had no control group to make any comparison to, and
> all we can say is a resolution rate. But I think you can say that if
> patients with this disease, which is proven by bacterial culture from
> the sinus, are given antibiotics, that approximately 90 to 95 percent
> will no longer be infected after 10 days of treatment.
>
> \[Slide.\]
>
> Now, is there any control information on this? There is an old study
> by Carenfelt done in 1975, in which patients were evaluated based on
> whether the antibody concentration in the sinus aspirate was greater
> than that of the causative bacteria, and if that were so, the
> eradication rate was 90 percent compared to those in which the
> concentration of the sinus aspirate was less than that of the MIC of
> the causative bacteria and a cure rate of 45 percent. This is a
> significant difference.
>
> We did a study a number of years ago in which we were looking at
> clindamycin, which is not effective for Hemophilus influenzae, and we
> stopped the study because that was obviously not a good idea, but we
> had zero of 6 cures in patients receiving clindamycin who had
> Hemophilus influenzae. You compare that to the rate that I showed you
> earlier. This is a significant difference.
>
> \[Slide.\]
>
> Two other studies that are published that I know of, again, a study
> from Scandinavia, an appropriate antimicrobial and dose, and a
> suboptimal dose, and in all three studies\--this was cefaclor at a
> dose of 500 milligrams either b.i.d. or t.i.d.\--and a cure rate 91
> percent versus 74, and 90 percent versus 20, and 71 percent.
>
> So, there is limited data on bacteriologic eradication based on pre-
> and post-sinus aspirate cultures.
>
> \[Slide.\]
>
> This is just a Gram stain from one of the patients that had H. flu and
> got clindamycin, and after 7 days, you can see this is still a very
> diseased sinus with all the Hemophilus influenzae and the pus in the
> sinus.
>
> \[Slide.\]
>
> Does antimicrobial treatment reduce disease? Looking at the papers
> that I showed earlier, and there are only eight here because in one of
> them, it was difficult to extract the clinical information, this is
> the improvement of illness, and this is not necessarily resolution,
> but improvement in patients on placebo.
>
> We have no studies of the natural history of this disease in untreated
> patients with acute community-acquired bacterial sinusitis the day of
> evaluation from one to two weeks, and this is the number improved over
> the number observed. As you can see, the range was from 37 percent to
> 79 percent, and this had a mean improvement rate of about 60 percent.
>
> \[Slide.\]
>
> I think the best study or at least the only study that did try to use
> a criteria of duration of illness was the one by Lindbaek, which is
> published in the British Medical Journal. This was a double-blind,
> controlled trial. This looks at the proportion of sick patients, and
> this is days. This is a placebo group, and this is the two groups
> treated with antibiotics.
>
> This was with high-dose penicillin and with amoxicillin, and here, at
> about two weeks time, the improvement or actually the resolution rate
> is in the range of about 50 percent, similar to what was seen in the
> studies I just showed you.
>
> \[Slide.\]
>
> So, in summary, in my opinion, the current status of testing the
> effectiveness of antimicrobial treatment for bacterial sinusitis is
> not satisfactory, and it is due to the problems in making a
> bacteriologic diagnosis and determining bacteriologic cure.
>
> I don\'t think this is surprising, it is certainly understandable. The
> use of sinus puncture has been considered invasive and has, in many
> people\'s minds, been considered not an appropriate thing to do even
> in the investigative setting.
>
> Also, information on clinical response in relation to bacteriologic
> response is lacking.
>
> Thank you.
>
> DR. LEGGETT: Thank you, Dr. Gwaltney.
>
> Does any of the panel have any questions regarding his talk? Yes, Ken.
>
> DR. BROWN: Dr. Gwaltney, I think this is a fantastic presentation.
>
> Is there good evidence that treatment with antibiotics, whether
> approved or not, is better than a sinus puncture for relief?
>
> DR. GWALTNEY: You are saying is the old treatment of sinus puncture
> and washing, which was done for centuries, is that better than
> antimicrobial treatment?
>
> DR. BROWN: No, I am saying is antimicrobial treatment better than
> that?
>
> DR. GWALTNEY: Either way. I don\'t know.
>
> DR. BROWN: I know, as a person who has had a puncture repeatedly, I
> will take the puncture any day for relief.
>
> DR. GWALTNEY: Well, Dr. Sydnor is sitting next to you, and you can
> certainly call him if you need him. That is certainly a very good
> question, and it has never been investigated, so we don\'t know the
> answer.
>
> I personally believe that washing is very effective, and in patients
> who fail a course or two of antimicrobial treatment, I would send them
> for that immediately because if it is a risk factor for chronic sinus
> disease, I would like to eliminate that because that can be a very bad
> and life-long condition.
>
> So, a good question. We don\'t have the answer.
>
> DR. LEGGETT: Dr. Gwaltney, looking at different lengths of therapy,
> recently, there have been antibiotic trials in community-acquired
> pneumonia giving five days of therapy. There have been approvals with
> one dose of a drug or three days of a drug versus what we have always
> used as sort of the 7 to 10-day course.
>
> Do you know of any data about different lengths?
>
> DR. GWALTNEY: All the data I showed you are based on 7 to 10 days.
> That is what we have the information on. It wasn\'t too long ago that
> people were saying you ought to treat for 21 days, and that was based
> on the fact they said, well, you washed the sinuses when you took the
> specimens out, and you were giving the added therapeutic benefit of
> the sinus wash, so you probably should treat longer because all the
> patients had not had complete resolution of infection. Sometimes we
> would still find some bacteria there.
>
> Things suddenly changed. It is a lot cheaper to give 3 days than 21
> days, so now, driven by these economic concerns, people are talking
> about short-course therapy. As far as I know, there are no data based
> on double tap studies to support that.
>
> In some of the studies that have been published, there was one in JAMA
> a few years ago, trimethoprim sulfa. I have a strong suspicion that
> that patient population was contaminated with cases of viral
> rhinosinusitis, so I don\'t think it would be proper to change what is
> an established state of the art in terms of duration of therapy
> without scientific evidence or research studies to support the fact
> that the short course of therapy may be better\--I mean may be
> sufficient, and it may be.
>
> I think we are going to hear something about that later in the
> afternoon, which is interesting in that regard.
>
> DR. LEGGETT: Dr. Cross.
>
> DR. CROSS: We know that in cases of pneumonia, resolution of the chest
> x-ray often lags behind the cure of the disease. What do we know about
> the case of \"adequate\" therapy of sinusitis?
>
> DR. GWALTNEY: There is one study, I didn\'t put it in today, but I
> think it\'s a pretty good study in which patients with what seemed to
> be bacterial sinusitis, although it wasn\'t a puncture study, were
> followed by serial MRI.
>
> What was seen was that the changes that are there resolved fairly
> rapidly or started to resolve over about 10 days, but they didn\'t
> clear for up to a month.
>
> So, it looks like that the duration of illness in bacterial sinusitis,
> in terms of the sinus returning completely to normal status, may be
> quite prolonged, as long as one month, and that is one of the reasons
> that some of these studies that I have reviewed, some of them had
> findings of patients that a large proportion had cleared within, say,
> 10 days, and that tells you that wasn\'t bacterial sinusitis, that was
> viral rhinosinusitis.
>
> DR. LEGGETT: Dr. Reller.
>
> DR. RELLER: Dr. Gwaltney, in your design of clinical trials, you had
> two options of microbiological criterion or 7 to 10 days of symptoms.
>
> Would there be utility of combining those to increase the likelihood
> of having a positive culture, or alternatively, could you sample too
> early in the process and before the bacterial infection had been fully
> established on top of a viral rhinosinusitis?
>
> DR. GWALTNEY: I think in a study in which sinus aspirate culture was
> part of the design, it would be desirable to have, as an entry
> criterion, that the illness had been present for at least 7 to 10
> days, something in that range.
>
> I feel pretty confident it would increase the yield of patients that
> were positive for bacteria, but we would also learn something about
> the validity of this clinical criterion which we are currently using
> today, bacterial sinusitis. I think we have to start saying bacterial
> and viral.
>
> DR. RELLER: The second question is rendering an expert opinion. Many
> people use the change in color, persistence and changes colors to say,
> oh, that is where the transition has gone to bacterial infection and
> what triggers antibiotic therapy.
>
> Is that of any utility or is it worthless, and that is just the
> natural history of resolution of the disease when one blows this stuff
> out?
>
> DR. GWALTNEY: I think the general opinion is that it is not a useful
> criterion because we say, well, colds can give you colored nasal
> discharge, but to be perfectly honest, until the study is done where
> that is correlated with the results of sinus aspirate culture, we
> really don\'t know.
>
> When that criterion is correlated with radiographic positivity as a
> standard, it has poor specificity, so it probably is not very
> specific, but the real answer has never been determined.
>
> DR. LEGGETT: Don.
>
> DR. PORETZ: For the purpose of designing future studies, should the
> sinusitis or acute maxillary sinusitis associated with viral
> respiratory infections be separate and distinct from those of dental
> origin when you are planning studies? Are they different diseases?
>
> DR. GWALTNEY: I think, well, I think it might be very useful to
> analyze the results of a study. I am not sure I would exclude those
> patients because I think it would be worthwhile to know what they look
> like.
>
> They have, as you know, very complicated mixtures of anaerobic
> bacteria. We have had cases that had four different species of
> anaerobes and four of microaerophilic species, and that really in many
> ways is a different kind of infection, and they really respond pretty
> well to antibiotic treatment and also making sure that the dental
> disease is corrected with a root canal or something like that.
>
> So, I think that would be a good thing to do. It is a question of
> getting enough numbers of those kind of cases to have meaningful
> results.
>
> DR. LEGGETT: Ciro.
>
> DR. SUMAYA: In the information you presented on I believe it was the
> CT scans of the viral or rhinosinusitis, and you showed a number of
> changes early in that diagnosis.
>
> Do you have a sense of the frequency of those same CT type scans at 7
> to 10 days?
>
> DR. GWALTNEY: Well, in the patients with the common colds, at 7 to 10
> days, most of the time those findings had improved or resolved.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: If there were an easy procedure to actually tap the sinus
> to give you the bacteriology that you are asking for, and you had the
> ability to do these follow-up taps, do you think that the best time to
> do a follow-up tape in a study for purposes of documenting
> microbiologic evaluation of eradication would be at 3 to 5 days after
> therapy, 5 to 7, or 7 to 10?
>
> DR. GWALTNEY: Dr. Jack Anon is here in the audience and is going to
> talk about what I think is a pretty ingenious approach to this problem
> after lunch, and I don\'t want to steal his thunder, but maybe\--Jack,
> should I go on and say what you are going to talk about? I am not
> going to go into details, or shall we just wait? Save it, he wants to
> surprise you. He wants you to come back.
>
> DR. BRADLEY: The question is the timing.
>
> DR. GWALTNEY: Well, he is going to address that, and that is a very
> good question, and they have come up with I think kind of an ingenious
> way to address that problem.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: Just a comment in response to Barth\'s question about the
> timing of the sinus aspirate and maybe in part to John\'s comment.
>
> I think for patients who represent the majority of patients, those who
> present with protracted respiratory symptoms as a signal that they
> have bacterial infection of the sinuses, then, I think you want to do
> that tap not ever before 7 and maybe as close to 10 as possible.
>
> For patients who present with a more urgent, even though they are not
> emergent, then, I think you need to do the tap earlier because you
> need to treat earlier. One question would be whether you want to
> include both of those patients simultaneously in clinical trials,
> because they do represent somewhat different populations although I
> think the bacteriology is the same and their response to antibiotic
> would be the same.
>
> Just one comment on the color. I mean my supposition is that probably
> many viral upper respiratory infections go through a phase of
> transient bacterial infection, but it is transient and we don\'t need
> to know about them.
>
> Maybe that is what correlates with the color change, but they go from
> clear nasal discharge to colored nasal discharge to clear again in the
> course of a viral URI and maybe what that represents is this transient
> period of some partial obstruction of the sinus ostia, so there is a
> replication of organisms to an important height, but then the
> inflammatory response in the mucosa begins to resolve, the sinus opens
> again, and drainage is facilitated.
>
> DR. LEGGETT: John.
>
> DR. POWERS: I certainly want to make a comment relative to what Dr.
> Wald just said. As Dr. Gwaltney said, there is no data on correlating
> what color actually means in this disease, the color of the discharge.
>
> If you look at other diseases, there are some natural history studies
> on acute bronchitis and what this actually means, and if you look at
> people that have a viral acute bronchitis, they do exactly as Dr. Wald
> said.
>
> They go through this, the first two days they have no sputum at all,
> and then it becomes clear, and then it becomes green, and if you eat a
> purple popsicle, it turns purple, so correlating the color with what
> is actually going on is very problematic without the bacteriologic
> diagnosis to go along with it.
>
> DR. LEGGETT: For what it is worth, a lot of the cells in AECB turn out
> to be eosinophils when the color changes.
>
> DR. ANON: Jack Anon, Clinical Professor, University of Pittsburgh
> School of Medicine. Jack, as always, you raise questions and bring
> things to our attention that are key in our understanding of the
> disease.
>
> There are a couple of things, one of which is your slide, in the
> beginning, which had your emergent, urgent, and then your third
> category of sinusitis, I think that for the committee, that may be
> very important because as we did in our sinus guidelines that you were
> involved with, Ellen Wald was involved with in some early work, what
> we believe is that there are those patients\--the emergent disease, I
> don\'t think we need to talk about\--but those patients with the group
> of symptoms in your urgent category, the ones that are ill, the ones
> that will undergo a sinus tap for relief, those of us who have family
> members or ourselves who have had this problem, those are the patients
> where we really ought to be looking at directing antibiotic therapy
> aggressively.
>
> I think most of us would have no reservations about treating those
> patients, and it is the third patient, that mild group, that viral in
> between, gee, is it viral or bacterial, where a lot of the issues are
> clouded because we can\'t differentiate at times readily those
> patients.
>
> So, those are I think important categories that you went over quickly,
> but may be more important here.
>
> The second thing is with regards to color, we actually have developed
> a color slide kit similar to what was done in the acute bronchitis
> study that Dr. Powers was mentioning, and actually I think that it is
> probably odor that may be a key here.
>
> We actually did a study where we did gas chromatograph studies of
> Strep pneumo, H. Flu, M. cat, and we have plots showing that they have
> their individual odor characteristics on chromatography.
>
> So, when the patients say, gee, it is starting to really smell, my
> breath stinks, we actually proposed to this company that we could
> develop a small mask. They could actually a portable gas chromatograph
> unit that would fit in an office. You can actually breathe through it
> and it would give you peaks showing whether or not the bacteria they
> are producing, their characteristic signatures.
>
> DR. LEGGETT: Dr. Anon, could I please ask you to reveal any potential
> conflicts of interest as part of speaking here at the meeting?
>
> DR. ANON: Oh, yes, sir. I do consulting work and we are involved with
> drug companies, such as GlaxoSmithKline, Ortho McNeil, Bayer, Aventis.
> These are groups that, as an otolaryngologist, we are frequently asked
> to do consulting work like this with them.
>
> DR. LEGGETT: Thank you.
>
> The next speaker and presenter is going to be Dr. Sydnor, who is going
> to describe a sinus puncture to us.

**Description of Sinus Puncture**

> DR. SYDNOR: Thank you for asking me to make this presentation. It will
> date my age and training, but I was trained in the era in which sinus
> puncture and lavage was really the standard therapy for acute
> maxillary sinusitis. The amoxicillin and ampicillin had not been
> marketed by the time I was in my training to give you an idea of how
> far back that goes.
>
> Therefore, to wash a sinus or to aspirate it was a relatively simple
> procedure that was done by almost all otolaryngologists in private
> practice back until the advent of endoscopic sinus surgery and the
> insurance reimbursement thereof.
>
> What we used to do, and still do, and I did a lot of the sinus
> punctures in Jack Gwaltney\'s study, would be, the mechanics of it,
> simply spray the nose with ponocaine \[ph\] and a decongestant, Afrin
> or neosynephrine, and then put a topical anesthetic into the inferior
> meatus of the side of the nose you are going to wash, and we used to
> use 10 percent cocaine. That has fallen out of favor and now is a
> combination of lidocaine and phenylephrine, which really I think is a
> good anesthetic.
>
> We do not inject the mucosa directly with the needle, but then put a
> needle through the inferior meatus of the nose, directing it
> posteriorly and superiorly until you feel it go through the bone, and
> generally up high in the antral sinus, the superior medial wall of the
> antrum is very thin and you generally can go through without any great
> deal of difficulty and without pain.
>
> I have had my sinuses washed several times, I have done my own family,
> and it can be done without any significant discomfort to the patient,
> certainly no worse than having a dental filling done even under local
> anesthesia.
>
> The complication rate is negligible. You probably with forceful\--not
> probably, I know I have done it, anybody who has washed enough sinuses
> is bound to have some complications. You can go through into the
> orbit, can come out in the cheek, but that instance is extremely low
> and in all of our studies, we have had none of this happen.
>
> In the studies that we have done with Dr. Gwaltney, when you put the
> needle in, we would aspirate it, and if you get pus back, don\'t wash
> the sinus because we are trying to test the efficacy of antibiotics,
> and not the lavage itself, and then get the cultures and the Gram
> stains, that sort of thing.
>
> If you can\'t get anything back, then instill about a cc or 2 of
> normal saline in, kind of stir up the sinus, and aspirate that back.
>
> We have got a video now done from Sweden, an instrument called a
> SinoJect, that Dr. Anon will talk about later, and that shows
> basically how the sinus puncture and aspirate is done.
>
> We can go on with that now.
>
> \[Video.\]
>
> DR, SYDNOR: That is through now. That is basically how previous
> studies have been done without the SinoJect, but the principle is
> absolutely the same without using the forceful instrument itself.
>
> Thank you.
>
> DR. LEGGETT: Dr. Sydnor, what is the variability in the size or the
> shape of the maxillary sinuses, and is this procedure usually done
> without any radiographic technique before doing it?
>
> DR. SYDNOR: I think the capacity of the maxillary sinus is about 30
> cc, I may be wrong there, but you can use it with or without
> radiographic evidence if you are treating someone clinically. If you
> are in a study, it depends on what the protocol calls for.
>
> DR. LEGGETT: Jan.
>
> DR. PATTERSON: Is the puncture enough in some cases to treat the
> patient, or do you have to do irrigation, as well, if you are going to
> use that as therapy?
>
> DR. SYDNOR: That depends clinically again if you are treating the
> person, and also again if you are in a study, what does the protocol
> call for, repeat aspirate or not, post-therapy aspirate. But prior to
> any study being done, you could use your clinical judgment as to
> whether it needs to be repeat aspirate or not.
>
> DR. LEGGETT: Dr. Gwaltney.
>
> DR. GWALTNEY: I think the question is in order to get therapeutic
> benefit, do you need to wash in addition to just do the puncture.
>
> DR. SYDNOR: No, no, I don\'t think so.
>
> DR. GWALTNEY: The old therapeutic procedure was once you got the thing
> in there, then, you washed it out.
>
> DR. SYDNOR: Yes, I think clinically, that improves the resolution of
> the disease certainly from the patient\'s standpoint. Any of you who
> have had sinuses washed, know it actually feels good when you leave. I
> don\'t mean to compare it to a thrombosed hemorrhoid, but it is not
> unlike that.
>
> DR. LEGGETT: Thank you, Dr. Sydnor.
>
> Our next presentation will be by Dr. Thomas Fleming, who will discuss
> Statistical Considerations in Clinical Trial Design in Acute Bacterial
> Sinusitis.

**Statistical Considerations in Clinical**

> **Trial Design in ABS**
>
> DR. FLEMING: Good morning. I would like to discuss some design issues
> in acute bacterial sinusitis trials and my statistical colleagues on
> the committee were criticizing me for not preparing a video for the
> statistical issues, but I will do the best I can here.
>
> \[Slide.\]
>
> What I will do here is actually just begin with a very brief review of
> some issues that we discussed yesterday given that we have a number of
> people here today that weren\'t here yesterday, talking about issues
> surrounding criteria of endpoints and surrogates, and the then focus
> more on discussion of non-inferiority issues and time to event
> analyses for resolution of symptoms to lay some background for some of
> the issues that we will be discussing in the questions later on today.
>
> \[Slide.\]
>
> So, very quickly, criteria for study endpoints. Indeed, whereas
> endpoints should be measurable and interpretable and certainly
> sensitive, one of the critical criteria here is they should be
> clinically relevant and clinical efficacy endpoints, endpoints that
> unequivocally reflect tangible benefit to the patient would be very
> important measures to have in pivotal studies.
>
> In acute bacterial sinusitis, resolution or improvement of ABS
> symptoms or reducing time to resolution would be examples of clinical
> efficacy endpoints.
>
> \[Slide.\]
>
> Frequently in trials, replacement endpoints are considered surrogate
> endpoints, and often the approach is to look biological markers that
> are correlated with clinical efficacy endpoints and then establish
> effect on those markers.
>
> \[Slide.\]
>
> However, if we establish treatment effects on markers, such as
> microbiological and radiological outcomes, whereas those provide very
> important insights about the biologic activity at intervention, it may
> not follow that the clinical efficacy measures have also been
> impacted.
>
> \[Slide.\]
>
> We discussed this paradox yesterday at some length and let me just
> briefly review one of the slide to give some insight into this paradox
> as to why it may be that effects on a marker may not reliably predict
> the effects on a true clinical endpoint.
>
> \[Slide.\]
>
> We noted, first of all, that a disease process could have several
> pathways through which it actually influences the clinical endpoint,
> and the surrogate may only be in one of these pathways.
>
> For example, if the intervention affects a different pathway, we could
> miss the effect of the intervention. We talked about chronic
> granulomatous disease yesterday with gamma interferon, which did, in
> fact, have a positive effect on preventing infections, reducing the
> rate of infections, and yet didn\'t have an effect on the expected
> marker, which was bacterial killing and superoxide reduction, which
> was a case of a false negative conclusion by reliance on a surrogate.
>
> If the intervention has an effect on the pathway through which the
> surrogate is capturing effect, we still could get false positive
> conclusions. We may have decolonization through that pathway, but not
> other pathways, and so the endpoint may, in fact, not be affected, the
> infection endpoint may not be affected.
>
> Also, the intervention may have unintended pathway or effects directly
> on the clinical endpoint, and by being unintended, often would be
> undetected unless one actually establishes directly the effect on the
> clinical outcome/
>
> \[Slide.\]
>
> As one example, we were looking at the example of AIDS patients with
> MAI bacteremia. A study in 1994 showed that clarithromycin at higher
> doses had a very clear effect on bacterial loads, substantially lower
> bacterial loads at higher doses, and yet, the mortality rates were
> much higher at those higher doses.
>
> So, clarithromycin, in fact, did have a beneficial effect or had a
> positive effect on bacterial load, but the ultimate effect on
> mortality was adverse, presumably through unintended mechanisms, that
> were also existing.
>
> \[Slide.\]
>
> So, how does one validate a surrogate?
>
> \[Slide.\]
>
> In essence, just to remember the key for a valid surrogate is we would
> want the effect of the intervention, of the antimicrobial intervention
> on the true clinical endpoint to be reliably predicted by the effect
> of the intervention on a microbiological or surrogate endpoint.
>
> \[Slide.\]
>
> We had noted that there were two sets of criteria. One of the
> criteria, both of which must exist, is that the surrogate is
> correlated with the clinical outcome, but that it, in itself, while it
> is the necessary condition, it is not sufficient in its own right. One
> must also show that the surrogate endpoint fully captures the net
> effect of the treatment on the clinical outcome.
>
> In fact, this is must more often a much more difficult condition to
> show and, in essence, what we have noted is that a trial of sufficient
> size to directly show the effect of the treatment on the clinical
> outcome is, itself, not sufficient information.
>
> \[Slide.\]
>
> One, in essence, needs a meta-analysis of multiple trials typically to
> have the information required to be able to show that the surrogate is
> fully capturing the effect of the intervention on the outcome.
>
> Clinical insights are also critical. It is important to have a
> comprehensive understanding of the causal pathways of the disease
> process and of not only the intended, but what is the likelihood of
> unintended mechanisms that could also directly influence the outcome.
>
> \[Slide.\]
>
> So, an acute bacterial sinusitis, one example of a clinical endpoint
> would be from a patient\'s perspective, to have timely resolution or
> improvement of symptoms. Potential markers or surrogates would be
> radiological and microbiological outcomes, and these certainly provide
> very important evidence of biologic activity.
>
> We saw in Dr. Gwaltney\'s presentation that the symptoms themselves
> are not correlated with pre-treatment or post-treatment bacterial
> sinus aspirate cultures. A separate question is whether or not the
> bacterial eradication is, in fact, correlated with resolution of
> symptoms.
>
> I understand from his presentation and other data that there is rather
> limited data on that. Even if, however, we had conclusive data showing
> that if we had bacterial eradication, we have correlation with
> resolution of symptoms, that itself still is not adequate information
> to justify or validate the correlate.
>
> We would have to know that the antimicrobial intervention effects on
> resolution of symptoms are fully mediated through that bacterial
> eradication, and that is much more challenging conclusion to be able
> to reach.
>
> Well, let\'s suppose that we are proceeding then with endpoints of
> resolution of symptoms.
>
> \[Slide.\]
>
> What I would like to do now is turn to the issue of how do we assess
> efficacy in a non-inferiority trial. Essentially, if we are looking at
> a new antimicrobial against a standard antimicrobial, I think we are
> all fairly clear how we would show superiority.
>
> We would want to see a higher rate of success on this new
> antimicrobial. A non-inferiority trials says, well, it is adequate to
> be the same or better. We just want to rule out that we are
> meaningfully worse.
>
> So, if we have known rates of success on our standard antimicrobial,
> let\'s say 80 percent success of resolution of symptoms at 7 days, we
> want to be able to rule out that the experimental antimicrobial has a
> meaningfully worse rate.
>
> Now, of course, what is meaningfully less? Five percent less, 10, 20?
> That is the essence of the margin. How do we determine the margin,
> which is critical if we are going to do a non-inferiority assessment?
>
> \[Slide.\]
>
> Well, let me begin before getting to the specific issue of the
> determination of the margin, just to step back and say there really
> are dual goals that exist if you do a non-inferiority trial.
>
> The first goal is to be able to obtain a direct evaluation of the
> relative efficacy of the experimental antimicrobial against the active
> control. So, if we have a standard antimicrobial, we surely would like
> to know just from the perspective of which of these should I use, what
> is the relative efficacy of these two.
>
> A non-inferiority trial is excellent in giving us a direct insight
> into that relationship. But the non-inferiority trial also, from a
> regulatory perspective, provides other key insights and it contributes
> to the evidence of the efficacy of this experimental antimicrobial
> against a placebo.
>
> But in a non-inferiority trial, that placebo doesn\'t exist, so we
> have, in essence, what is called an imputed placebo. What we get from
> the non-inferiority trial is direct evidence of the experimental
> antimicrobial\'s efficacy against the active control, so we need to
> know something about how the active control would compare to a placebo
> to ultimately understand how the experimental would compare to a
> placebo.
>
> So, that means there are certain important conditions that must be
> satisfied by the active control to be able to do a non-inferiority
> assessment.
>
> \[Slide.\]
>
> The ICH guidelines provide some insights into these conditions.
> Basically, the ICH guidelines say that a suitable active control must
> have efficacy that is clearly established and quantified, and where
> that efficacy in the active comparator trial is similar to what you
> would have estimated it to be in the historical superiority trials.
>
> Those historical superiority trials could be either add-on trials
> looking at the standard against the standard plus the experimental, or
> more frequently, placebo-controlled trials.
>
> \[Slide.\]
>
> I have reworded this to say these requirements on the active
> comparator are essentially that the active comparator should be a
> standard of care intervention whose efficacy is of substantial
> magnitude that is precisely estimated where these estimates are
> relevant to the setting in which the actual non-inferiority trial is
> going to be conducted. The statisticians at FDA often call the
> constancy assumption, and I will talk a little bit later about the
> importance of that assumption.
>
> \[Slide.\]
>
> Let\'s illustrate this. Let\'s say in the context of ABS, where we
> have a standard antimicrobial intervention, let\'s say the endpoint is
> resolution of symptoms at 7 days, and let\'s suppose that with the
> placebo, that resolution rate would be 45 percent, and let\'s say the
> standard is very effective, it raises that resolution rate to 70
> percent.
>
> If that is the case, if I am plotting along this axis where placebo
> resides relative to the active control, then, what we see is placebo
> has a 35 percent lower resolution rate at 7 days in the active
> control.
>
> Now, we don\'t know that it is exactly 35 percent, it is 35 percent
> plus or minus the standard errors, and if we had a study with 175
> patients per arm, 2 standard errors would be plus or minus 10 percent.
> Basically, that would mean that the active comparator has anywhere
> from a 25 to a 45 percent better resolution rate at 7 days.
>
> One approach that has been taken is to then say we will take the
> conservative estimate of the efficacy and argue that the margin is
> set, so that we preserve at least half of the benefit of the standard
> antimicrobial.
>
> If we take that approach, then, the margin would be minus 12 1/2
> percent, and then when we do our non-inferiority trial to estimate
> where is the efficacy of this new experimental antimicrobial against
> that of the standard, the estimate has to be high enough, such that
> the lower limit of the 95 percent confidence interval rules out that
> it is 12 1/2 percent worse. That would be one approach.
>
> Now, it might be argued, well, why am I preserving half of a
> conservative estimate of efficacy, why not take the actual point
> estimate, and that is where this issue of the constancy assumption
> comes into play.
>
> I actually don\'t know what the efficacy of the active comparator is
> in the non-inferiority trial. I only know what it was in the
> historical studies.
>
> Well, for example, to take an extreme case, suppose these historical
> studies were conducted where a large fraction of these or a larger
> fraction of these infections were bacterial rather than viral, and
> suppose the assessment was cure rate at 7 days, so that there is a
> substantial effect of antimicrobial in that setting, but suppose the
> non-inferiority trial is done in a context where it is much more viral
> infection and I am looking at cure rates at 14 days rather than 7 days
> where the placebo itself would have a much higher cure rate.
>
> Well, in that setting, we wouldn\'t have a 35 percent efficacy of the
> active comparator when we are predominantly looking at viral
> infections and we are looking at resolution of 14 days, efficacy might
> be very low.
>
> If we are using a margin of minus 12 percent, when the actual active
> comparator has a placebo that is very close to zero, we wouldn\'t even
> be able to conclude we are better than placebo. So, uncertainties
> about the validity of this assumption or of this evidence for the
> effect of the active comparator historically for what it would be, for
> what the effect would be in the non-inferiority trial is critical and
> it is one of the reasons for having more caution here.
>
> \[Slide.\]
>
> The margin here should not only, though, be chosen based on these
> considerations, they should also be chosen based on clinical relevance
> issues. If we are saying we can\'t be meaningfully worse, we need to
> be thinking about from a clinical perspective how important is it to
> be somewhat worse, and that should guide the decision about size of
> margin, as well.
>
> \[Slide.\]
>
> So, for example, if we have a new antimicrobial that has an improved
> safety and tolerance profile, easier a administration or allows us to
> more effectively address resistance issues or drug-drug interaction
> issues, that might allow us to choose a somewhat larger margin.
>
> On the other hand, if we have a setting where reducing efficacy has a
> very substantial clinical effect, if it was efficacy and fungal
> infection or efficacy in HIV transmission, then, that would lead us to
> choosing a smaller margin.
>
> \[Slide.\]
>
> All things considered, the ICH guidelines say determination of the
> margin in a non-inferiority trial needs to be based on both
> statistical reasoning and clinical judgment issues that I have just
> been discussing, and should reflect the uncertainties and the evidence
> on which the choice is based, and therefore should be conservative,
> one should be cautious about how big a margin one chooses.
>
> One of the additional motivations for this caution comes from the
> realization that what if I do a non-inferiority trial today for a
> second generation antimicrobial comparing it to a first generation,
> and then I do another one several years from now, the third generation
> against the second, and then a fourth against the third, where I keep
> trying to rule out I am meaningfully worse, but I am very lenient in
> what it means to be meaningfully worse, how many of these do I do
> before I realize I have a clue no longer about what the actual
> efficacy is.
>
> \[Slide.\]
>
> This is not entirely a hypothetical. Two years ago, the Anti-Viral
> Drugs Advisory Committee was asked to consider Voriconazole as empiric
> anti-fungal therapy for febrile neutropenic patients. Essentially,
> their evidence was based on three series of studies: an original study
> looking at Amphotericin B, then, a second generation study looking at
> the liposomal version against amphotericin, and then the third
> generation looking for Voriconazole against Ambisome.
>
> What was the essence of the challenges that the Anti-Viral Committee
> had to face? Well, first of all, the endpoint here, failure was
> considered to be either death, fungal infection, breakthrough fungal
> infections or persistent fever, so success is one minus that.
>
> The amphotericin B evidence was actually based on studies from EORTC
> and Peizo studies that were more than 25 years old and were based on
> extremely small sample sizes that basically showed there was a
> positive trend, but didn\'t even achieve statistical significance for
> evidence of benefit.
>
> The Mycosis Study Group did then the second generation Ambisome
> against amphotericin comparison and showed similar success rates.
>
> The third generation study, looking at Voriconazole against Ambisome
> came up with some interesting results from a couple perspectives.
> First of all, the success rate on Ambisome was 30 percent compared to
> the 50 percent success rate in the non-inferiority trial that
> established efficacy of Ambisome, in essence in large part because a
> different definition of success was used. It used a different duration
> of persistent fever when defining what was failure.
>
> So, the question is would Ambisome have been adequately effective
> under that different definition. We don\'t know the answer.
>
> The other issue is that Voriconazole was actually, by point estimate,
> 6.5 percent less effective, and with a lower confidence interval
> indicating it would be as much as 12 percent less effective. So, using
> a more conservative lower limit as a guideline, the Anti-Viral Drugs
> Advisory Committee did not approve Voriconazole, believed that these
> data were not sufficiently reliable.
>
> But suppose it had approved by taking a more lenient criterion here
> for the margin? Then, if a fourth generation antifungal therapy came
> along, might you compare it to Voriconazole, and then what margin
> would you use and at what point would you really know whether or not
> these therapies are truly causally influencing or positively affecting
> the success rate.
>
> \[Slide.\]
>
> What about in acute bacterial sinusitis? I will just be very brief
> here because I think there will be more discussion of this data later
> on by FDA. There was a meta-analysis showing that there were 14
> placebo-controlled trials of antimicrobials that have been conducted
> since 1969, interestingly, 9 of these 14, though, just in the last 7
> years.
>
> The outcome in these studies were antimicrobial effect on resolution
> or improvement of symptoms assessed at some fixed day that was some
> time between 7 and 14 days.
>
> \[Slide.\]
>
> This plot then shows the antimicrobial efficacy for these studies, and
> essentially, it looks at the difference in success rates in resolution
> of symptoms on intervention versus control. Actually, if you are
> looking at the 16 datapoints, but 2 of these, this one and this one,
> are actually subgroup analyses, so if you take those out and look at
> the remaining 14, what you see here is that there is some
> heterogeneity in the efficacy estimates we get against placebo, but
> two-thirds of these really show rather trivial differences.
>
> There are many issues as to why that may be the case, I won\'t get
> into those right now, but the general sense is if this is the type of
> data that we would have, does this put us in a position that we can
> justifiably define a margin if we were to use any of these
> antimicrobials as a standard against which we were going to compare an
> experimental antimicrobial. How could we define a non-trivial margin?
> We would need to know that that standard had a substantial level of
> efficacy that was reliably and precisely estimated.
>
> \[Slide.\]
>
> So, essentially, following the ICH guidelines, if we are suitably
> conservative, there are situations where it really wouldn\'t be
> possible to justify a non-trivial margin, and, in fact, is that not
> where we are at least at this point in time in ABS.
>
> If one is in that circumstance, then, certainly it is reasonable to
> consider placebo-controlled trial as one approach that would be
> ethical and certainly quite scientifically reliable in assessing the
> actual efficacy of an experimental antimicrobial.
>
> \[Slide.\]
>
> Briefly, the last point I want to turn, the issue that has been raised
> in our questions that we have to discuss today, which is time to event
> analyses.
>
> In a self-resolving disease, it is entirely possible if what we are
> looking at or looking for is resolution of symptoms, we might miss an
> effect if, for example, we are looking too late in time where, in
> fact, the control itself has substantially high levels of resolution.
>
> The effect may be that we are actually getting clinically meaningful
> benefit to patient by resolving those symptoms sooner. So, as is noted
> in the briefing document, it may be more appropriate to measure time
> to resolution or improvement of symptoms.
>
> \[Slide.\]
>
> I just wanted to do a quick calculation to show that this, in fact, is
> a viable approach. If one was looking at time to resolution of
> symptoms as the primary endpoint, and one had a 7-day average or 7-day
> median time to resolution with a placebo, a no-treatment situation,
> the placebo had 7 days, if an antimicrobial would reduce that to 5
> days, it would only take 200 patients per arm to have a very high
> power to pick up this 2-day reduction, and you would actually achieve
> statistical significance if your estimate was only slightly more than
> 1 day, so it would be a very viable approach to take.
>
> \[Slide.\]
>
> In summary, certainly there are a number of criteria to consider in
> choosing endpoints. One of those criteria that is very key is clinical
> efficacy measures or measures that unequivocally reflect tangible
> benefit are measures that need to be assessed. We need to understand
> whether or not the intervention truly is providing improvement to the
> patient in a tangible way.
>
> Microbiological measures are very important. They tell us about
> mechanism of action and biologic activity. If we are using those
> microbiologic measures and we show that bacterial eradication is
> correlated with resolution of symptoms, that result alone does not
> allow us to conclude that we actually have a treatment effect on
> resolution on symptoms.
>
> What we have to be able to show is the antimicrobial\'s effect on
> resolution of symptoms is fully mediated or fully captured by the
> bacterial eradication, and that is much more difficult conclusion to
> achieve.
>
> Non-inferiority trial designs provide us one approach to assessing
> efficacy of a new antimicrobial, but to use a non-inferiority trial
> approach, one needs to have standard of care antimicrobial that has
> substantial efficacy that is precisely estimated in a context or in a
> setting that is relevant to the setting in which we are actually going
> to be doing the non-inferiority trial.
>
> That is going to be necessary for us to be able to justify a
> non-trivial margin. In settings where non-trivial margins can\'t be
> justified, placebo-controlled trial provide us one alternative in
> general superiority trials, which placebo-controlled trials are one
> type of trial, would be alternative approaches, and in self-resolving
> diseases, in order to avoid missing true benefit, it may be that
> looking at time to resolution is, in fact, one effective way of
> getting sensitivity to an important clinical benefit.
>
> DR. LEGGETT: Questions for Dr. Fleming? Don.
>
> DR. PORETZ: Actually, I wanted to ask Dr. Sydnor a question. Can I ask
> him?
>
> DR. LEGGETT: I think so.
>
> DR. PORETZ: With the benefit of statistical analysis, you have been in
> practice a long period of time, have a wealth of experience in
> treating sinusitis. Over the years that you have taken care of
> patients with sinusitis, the antimicrobics that have been developed
> have been significant.
>
> Tracing the history of these antimicrobics and the development of
> third and fourth generation drugs, have you, based on your experience,
> noted a difference in the outcome of patients as these drugs have been
> developed clinically? Do patients in your experience get better
> quicker with these newer antimicrobics as compared to years ago?
>
> DR. SYDNOR: Yes, very definitely so. Just based on the fact that we do
> not have to do lavage many times again in a nonclinical trial study,
> but to have to wash your sinus at the end of therapy is somewhat
> unusual now, when it was very, very common back in first generation
> antibiotics.
>
> DR. PORETZ: What about the other complications, after someone had an
> episode of acute sinusitis, and those individuals several years ago
> who did not have access to antimicrobics, and you had to wash their
> sinuses out, were there other significant complications except for the
> localized sinus disease?
>
> DR. SYDNOR: Yes. Again, the numbers are fairly rare, but we used to
> see orbital infection and intracranial complications which are
> extremely rare now in people that have an acute episode, it is much
> more common in people with chronic sinusitis.
>
> DR. LEGGETT: Dr. Fleming, we can\'t really expect antibiotics to make
> people feel good. The only thing we can clinically, relevantly expect
> is that they eradicate bacteria. Your talk was about self-resolving
> diseases and coming up with endpoints.
>
> How do we get at this question of rare nonself-resolving disease stuck
> in the midst of all this multiple of patients with the self-resolving
> disease in terms of the comments you made?
>
> DR. FLEMING: That is certainly an important question. I am looking at
> two domains here. One domain is bacterial eradication, which is a key
> biologic effect, and we are hoping through bacterial eradication that
> we are going to achieve outcomes which would be tangible to the
> patient.
>
> So, as a patient, what I would want to have would be resolution of my
> symptoms, and as you point out, one aspect then of that clinical
> benefit would be whether I have a higher rate of resolution of my
> symptoms or shorter time to resolution.
>
> A separate benefit would be, if I am understanding your question,
> potentially a reduction in the rate of much more serious but much more
> rare outcomes, and this is a particularly difficult issue because the
> clinical trials that we would typically do, unless we went to enormous
> sample sizes, are not going to be powered to be able to show those
> types of effects.
>
> Can we presume those types of effects? Well, I would ask how do we
> know, what is the scientific evidence that even if there is a
> correlation between the existence of those side effects or those
> long-term effects with ABS, that a certain type of effect on bacterial
> eradication wouldn\'t necessarily lead to an effect on those more rare
> endpoints.
>
> Then, what I would have to say is if the benefit isn\'t in the largest
> fraction of people having a discernible improvement in resolution of
> their symptoms, the benefit is only in these very rare instances,
> then, I have to say at what price are we paying to achieve those, are
> there issues of resistance that arises from frequent use of
> antimicrobials that would also need to be used in other settings, and
> if we are inducing resistance, the complications and the prices that
> we are paying could also then be substantial when you are adding all
> this up.
>
> So, it is certainly a relevant issue, but I would argue that it is not
> even necessarily clear that bacterial eradication will necessarily
> influence the rate of those rare outcomes.
>
> DR. LEGGETT: Joan.
>
> DR. HILTON: When Dr. Gwaltney presented criteria for a clinical trial,
> he included that the patients should be 7 to 10 days into their
> disease course. It seems like if you are evaluating patients at that
> time point, you might have a pretty good idea of which cases are
> self-resolving and which ones are not, and you might be able to
> exclude the less severe cases from the protocol all together.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: If I just might make a comment to that, I think one of the
> very important things about distinguishing a child or an adult who has
> an uncomplicated cold from someone with sinusitis, is that not only
> are they symptomatic at 7 to 10 days, but they are not improving, so
> there will be many patients with colds who still have symptoms at 10
> days, but they have clearly turned the corner, and those are patients
> that you really don\'t want to include in a clinical trial.
>
> I think this concept of time to clinical cure is really extremely
> important, because as was said, in any self-resolving illness, I think
> the major benefit that you are going to see is that patients are going
> to get better faster, as well as hopefully more often, so this is one
> approach which I think is very important.
>
> One thing I just would worry about is that patients are sometimes
> loathe to say they are completely well. You know, they will just keep
> saying they have one persistent residual symptom, so I think one of
> the things that might be important for us is some kind of scoring
> system, so that we can say that some very modest residual symptom will
> not count against a patient being considered a cure.
>
> An alternative might be to use as an endpoint something early in the
> course of disease. What I have done in the past is to do an outcome at
> 3 days, as well as an outcome, say, at 10 days. But I think if you
> could do this kind of analysis of time to cure with some kind of a
> scoring system, it would be extremely valuable.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: I have got a few comments on overall clinical trial
> design that we are trying to get around this morning. Obviously, the
> microbiologic evaluation is critical in the assessment of whether the
> antibiotics are effective or not, and I think everyone pretty much
> agrees with that.
>
> Hearing the statistical considerations with bio-creep, which we
> certainly have gone into in other diseases, and the need for
> placebo-controlled trials, it brings up the ethics of doing
> placebo-controlled trials here in the United States.
>
> In terms of my enrolling young children with sinusitis in a
> placebo-controlled trial, it would be very difficult for me to talk
> any parent into that at this point in time.
>
> However, many of the clinical trials are done in many different
> countries in the world, sponsored by companies with protocols that go
> through the FDA, and a trial on the efficacy of pneumococcal conjugate
> vaccine in the prevention of otitis idea was done in Finland where, at
> birth, it seems that the parents were signed up and randomized and
> agreed to allow their children to have their ears tapped anytime they
> subsequently got an ear infection, which is a trial design that would
> be very difficult to do in the United States.
>
> So, as we struggle with trial design considerations, trying to get the
> best data to arrive at statistically valid, clinically applicable
> conclusions, I am wondering how we should put this together, whether
> it should be just for the United States, the United States plus other
> countries, or look at perhaps doing some of the trials in other
> countries where it is ethically acceptable in other countries, but
> perhaps very difficult to do in the United States.
>
> Many of these companies that have antibiotics are multinational
> companies with investigators in many different countries.
>
> DR. LEGGETT: Ken.
>
> DR. BROWN: After listening to these presentations, I have questions
> about the gold standard issues. It seems that if we have only three
> products which are licensed for the treatment of acute bacterial
> sinusitis, and it didn\'t sound from our speakers that they were
> necessarily limited to those in their experience, and if the trial
> designs for those three\--is that correct?
>
> DR. ALBRECHT: Actually, we probably have about a dozen. You may be
> thinking of yesterday\'s topic.
>
> DR. BROWN: Right. But over the course of the time during which these
> have been developed, the study designs have not necessarily been the
> same. If I understood both the statistical issues in Dr. Gwaltney\'s
> talk, there have never been any studies which really meet an idea
> standard for defining this.
>
> So, how do you pick what would be useful legitimately and ethically as
> a gold standard?
>
> DR. POWERS: I think to sort of answer that, I am going to defer
> because that is what we are actually going to address. Dr. Pohlman is
> going to show this afternoon what we have actually been seeing in the
> clinical trials that have been submitted, and then we are going to try
> to go on and try to answer that question.
>
> DR. LEGGETT: Janet.
>
> DR. ELASHOFF: With respect to the comment about maybe
> placebo-controlled trials could be done elsewhere, the issue of
> whether we could really make valid inferences from that situation to
> the situation here is a major one, especially if you start to think
> about the bacteria that might be involved, the percent of patients
> that might actually have a bacterial infection, other aspects of
> treatment in a different place, I think one would have to be extremely
> careful about assuming that results from some other country would
> apply here.

DR. LEGGETT: Jan

> DR. PATTERSON: Well, it seems like a lot of this discussion is very
> similar to the acute otitis media discussions that we have had before,
> and some of the things that came up in that were that pneumococcal
> otitis media was easy to distinguish and was more severe than other
> bacterial types of acute otitis media which looked very similar to
> viral otitis and you couldn\'t really distinguish them without a tap.
>
> So, you might could justify a placebo-controlled trial for acute
> otitis media for other than pneumococcal presentations. But it seems
> to me, based on the information that Dr. Gwaltney gave us, that there
> is enough criteria to distinguish bacterial sinusitis from viral
> sinusitis, you know, make a placebo-controlled trial not really
> necessary in this instance.
>
> The concern I would have about encouraging other countries to do it if
> we are not willing to do it is, first of all, to me kind of an ethical
> concern, but also I think that in other countries, there would be
> different risk factors and maybe even different epidemiology of
> pathogens, different resistance patterns, and so forth.
>
> DR. LEGGETT: Alan Cross.
>
> DR. CROSS: I have a question for either Dr. Fleming or John Powers. We
> have talked about the time to event. Is it sufficient simply to show a
> statistically significant difference, of if not, what considerations
> ought we have?
>
> For example, I am thinking of the neuraminidase inhibitors which are
> approved here, but when evaluated in the UK, my understanding was that
> even though there was a difference, it was not sufficient for them to
> actually approve the drug.
>
> DR. LEGGETT: Tom.
>
> DR. FLEMING: Let me begin at least, then, Dr. Powers may have
> something to add.
>
> In thinking through the design of trials\--and I think Dr. Cross is
> raising a very key point\--I would start at the point of trying to
> identify what is really the most clinically relevant outcome that
> patients would want to achieve.
>
> Let\'s suppose we arrive at resolution of symptoms. In a
> self-resolving disease, in order to not miss a clinically meaningful
> effect, if we decide to go with trying to show we have a shorter time
> to resolution, I see that as being very relevant.
>
> Your point is well taken, though. You do need to see more than just a
> statistically significant change. That has to be judged to also be
> clinically meaningful. So, a one hour shortening is not clinically
> meaningful. So, what one has to arrive at in the design is what level
> of improvement on this clinically important endpoint will be
> clinically meaningful - is it a day, is it two days.
>
> Then, one needs to design the trial to be adequately powered for that
> clinically meaningful change. But you are absolutely right, it has to
> be ultimately an outcome that is simultaneously clinically important,
> as well as statistically established.
>
> DR. POWERS: I agree and I think the other thing Dr. Cross brings up is
> that it also depends upon that decrease in the time that you have
> symptoms, it may also be relevant as to when that decrease occurs. As
> a clinician, I would think a decrease from four days of symptoms to
> three days of symptoms, similar to what we saw with neuraminidase
> inhibitors.
>
> It would be a lot different if it went from 12 days to 11 days, even
> though it is the same absolute decrease, because if you are sick for a
> week and a half anyway, what difference does it make, as opposed to
> taking a short disease and making it shorter.
>
> So, I think one of the questions we are going to ask you today, and I
> am going to show exactly a slide about neuraminidase inhibitors and
> relate these two to each other, is what would you folks consider a
> clinically meaningful difference in this disease.
>
> DR. FLEMING: Just to add one additional thought to that, if you were
> reducing from 4 to 3, that is a 25 percent relative reduction. I had
> given the example of 7 to 5, which is almost exactly that same
> relative reduction.
>
> DR. LEGGETT: Any other questions, comments?
>
> We are only running 10 minutes late today. That is good, an
> improvement.
>
> Why don\'t we come back in 15 minutes.
>
> \[Break.
>
> DR. LEGGETT: I would like to ask Dr. Powers to respond to Dr.
> Bradley\'s query about doing placebo-controlled trials overseas.
>
> DR. POWERS: I sort of want to make a more general comment about doing
> trials overseas, period.
>
> First, a couple comments. One, we have been saying data in this
> disease and in others from overseas. The only thing that the Code of
> Federal Regulations says is that those diseases have to be similar to
> diseases that would occur in the United States.
>
> The data that we have seen shows this disease is very similar, and the
> degree of organisms that occur in the disease are very similar, as
> well, so we could do trials overseas and they would be acceptable.
>
> DR. LEGGETT: Thank you.
>
> The next speaker is Dr. Kraus, who will talk to us about Clinical
> Evaluation of Acute Bacterial Sinusitis and Diagnostic Considerations.

**Clinical Evaluation of ABS:**

> **Diagnostic Considerations**
>
> DR. KRAUS: Thank you.
>
> As Dr. Albrecht mentioned earlier today, the overriding goal will be
> to try and provide some literature context on the diagnostic criteria
> used for acute bacterial sinusitis and how that might relate to
> clinical trials inclusion criteria.
>
> \[Slide.\]
>
> Specifically, as Dr. Gwaltney has already mentioned, the percentage of
> patients that have sinusitis are exceedingly rare with a bacterial
> etiology based on the two studies that he presented, and the question
> I am going to try and address is how do we better hone on that
> individual that actually has bacterial sinusitis.
>
> \[Slide.\]
>
> One might hypothesize that there are a constellation of symptoms and
> imaging techniques that, when overlaid with cultured-proof punctures,
> would better populate the inclusion of patients with acute bacterial
> sinusitis in clinical trials.
>
> I guess the overriding question I am going to try and directly address
> is what evidence is currently present in the literature that
> correlates these specific diagnostic criteria for individuals that
> have acute bacterial sinusitis.
>
> \[Slide.\]
>
> The methodology that I am going to describe is going to be related to
> these four key elements that I used in looking at the literature,
> specifically, whether or not symptom duration actually is addressed in
> the literature as to what percentage of patients develop or have
> bacteria etiologies, whether there are specific symptom
> characteristics that best describe patients with bacterial sinusitis,
> or that there are radiographic criteria that can also delineate
> patients with bacterial sinusitis, and finally, I will also describe
> the two studies with regard to endoscopy that has been addressed at
> advisory committee meetings before this one.
>
> \[Slide.\]
>
> Specifically, the search strategy I used in looking at the literature
> was seeking those studies that specified inclusion criteria and had a
> sinus puncture with culture as part of the initial evaluation.
>
> Now, many of these studies that I looked at weren\'t specifically
> geared at trying to define these populations, but had embedded data
> that I pulled out, and many studies in the literature regretfully have
> many sinus punctures, but only have qualitative data describing
> purulence or non-purulence.
>
> There is a paucity of studies that actually have bacterial cultures
> performed at the same time. I think it is important to make that
> distinction because there is a handful of studies showing that even
> non-purulent disease have a large proportion of bacterial etiologies.
>
> Other line items that are worth noting here, that I looked at in the
> literature, were the type of study populations looked at in these
> various studies, the use of microbiologic cutoffs, and the specified
> inclusion criteria.
>
> \[Slide.\]
>
> The general methodology was to do medical subject headings search in
> the Medline database from 1966 to present, superimposed with that
> keyword searches for the specific disease entity, looked at the
> article references, evaluated the abstracts, and then did full article
> reviews for those that were thought to be relevant.
>
> \[Slide.\]
>
> Ultimately, what I found was no studies that could specifically
> describe symptom duration as how it correlates to acute bacterial
> sinusitis. There were 5 studies that described some symptom
> characteristics and how they related to culture-positive rates. There
> were 12 that I identified with radiography-included data, and there
> were 2 studies that I will discuss with regards to endoscopy.
>
> \[Slide.\]
>
> Initially, when it comes to symptom duration, Dr. Gwaltney went into
> this with some detail and I won\'t belabor the point, so suffice as to
> say that in patients with disease that has lasted for only 7 days or
> so, as you go out in the disease process, it is less likely that you
> are going to have a viral etiology for your process.
>
> \[Slide.\]
>
> I don\'t know what that is really going to say about bacterial
> etiologies, but you can probably guarantee that the risk of a viral
> etiology is diminished after 7 to 10 days.
>
> There was a comment in one article by Lindbaek, I think it was in
> Hickner\'s article, that stated that bacterial sinusitis is seen in
> only 20 percent of patients with symptoms less than 7 days although
> data wasn\'t provided with that citation.
>
> \[Slide.\]
>
> With regard to symptom characteristics, I want to underscore the point
> that much of what I am describing here is in some ways comparing
> apples with oranges, because the reporting that is described in many
> of these articles is disparate.
>
> \[Slide.\]
>
> What do I mean by that? I mean that patient-based reporting\--and I
> have just created an example here to sort of describe this a bit\--if
> one were to look at an article that had 30 patients included, and 15
> of those patients had at least 1 sinus that was considered to be
> positive, we would say that it has a 50 percent positive culture rate.
>
> However, if you took 30 patients on a similar study and reported it,
> instead of based on patient data, on sinus data, such that there were
> 60 maxillary sinuses that were potentially tapped, 40 were positive,
> you would say there was a 67 percent positive culture rate.
>
> Lastly, there are some studies that describe their database on
> aspirates, such that again you might culture more than even the 2
> aspirates from those 2 sinuses, such that you might have a higher or a
> lower culture rate depending on the type of reporting that was
> included just to underscore the fact that much of this data is
> disparate and must be taken with a grain of caution.
>
> \[Slide.\]
>
> So, what I have done in this initial slide is to pull or describe
> those five initial studies that tried relating symptom characteristics
> to positive culture data. I think the important thing to note here is
> that at the top of this slide, the positive sinus culture rate I have
> noted here is 34, 60, and 65 percent for the initial three studies I
> have remarked on.
>
> The initial studies that is in italics, 34 percent, I made it italic
> and I put it in italics because a large section of those patients, I
> think it was 40 patients actually, had radiographic data, as well, so
> it somewhat dilutes the study.
>
> The study 2 and 3, that really only had symptomatic criteria at the
> time of inclusion were somewhat pure in that sense, and down the
> lefthand column you can see that in the second study, only headache,
> purulence, and facial pain were needed for inclusion, which allowed a
> 2-fold increase sinus culture rate compared to the first study, with
> the inclusion of purulence and facial pain.
>
> In Savolainen\'s study, which is No. 3, he required 2 of any of these
> data for inclusion in the study, implying that perhaps with an
> increase in study inclusion, there is a modest increase in the amount
> of positive tap rate.
>
> I included Study 4, which is Berg\'s study, here because he states an
> 87 percent positive culture rate, but regretfully, when reviewing the
> article, there is no specific signs or symptoms denoted in the actual
> article.
>
> The other article that is quoted frequently at the same time period,
> from \'88, from Berg, only describes purulence versus non-purulence.
> It doesn\'t specifically describe positive culture rate data.
>
> So, these are 4 of the 5 that I am remarking on.
>
> \[Slide.\]
>
> The fifth one identified was Evans\' article in 1975, and specific
> signs and symptoms were not provided in the study, but he does quote
> that, \"Quality, radiation, intensity of facial pain, purulence of
> nasal discharge or presence of fever did not accurately predict the
> presence of infection as determined by aspiration.\"
>
> So, regretfully, there is no data to actually describe, but
> qualitatively, he at least describes that there is no direct
> correlation.
>
> \[Slide.\]
>
> Underscoring these three studies, as well, are some deficiencies in
> the three studies that I just outlined. There were no maximum symptom
> durations in Van Buchem\'s, as well as no minimum symptom duration.
> There was no exclusion secondary to antibiotic use, and it was based
> on patient-reported data as opposed to Hamory\'s, which was a
> sinus-based reporting of data.
>
> Savolainen\'s, which had the 65 percent correlation rate also had 18
> percent attrition, such that we don\'t know what happened to those
> patients, adding some element of doubt to the study.
>
> \[Slide.\]
>
> With regards to radiography and how that might impact the positive
> culture rate in patients that would be included for a clinical trial,
> there were 12 studies that were identified in the literature.
>
> \[Slide.\]
>
> I can say that the percentage of subjects with positive sinus puncture
> ranged quite broadly, from 30 to 77 percent, and there was an extreme
> heterogeneity of clinical inclusions used in these studies.
>
> \[Slide.\]
>
> For ease of reporting, I have divided them up into three groups. The
> first group, which showed a positive sinus culture of 30 to 54
> percent, had disparate reporting as well as inclusion criteria. As I
> have already stated, there is a difference between sinus-based
> reporting and patient-based reporting. There were two of each in these
> studies, three of which were adult, one which was pediatric.
>
> In broad strokes, there was a deficiency in antibiotic exclusion for
> these studies. There were many patients with confounding illnesses in
> these studies, such as allergic rhinitis and previous histories of
> sinus surgeries, as well as chronic sinusitis, and there was again no
> duration cutoff of the 7 to 10 days that was discussed earlier.
>
> \[Slide.\]
>
> In the second group of patients that were identified based on
> radiographic and clinical data, there was a positive sinus culture
> rate of 60 to 66 percent. Reporting again was disparate. There were
> three studies that were identified, all of which were adult. Three of
> them were sinus-based reporting.
>
> In one of the studies there was actually both types of reporting
> stated, and that was Camacho\'s study. What is interesting there, just
> to underscore the differences in yield, I think it was 62 percent of
> sinuses showed a positive culture rate, but only 24 percent of
> patients. So, depending on how you look at the data will markedly
> change how you can draw conclusions from many of these studies.
>
> Again, we have a slight heightening of inclusion criteria where now
> facial pain is part of the inclusion criteria. There are antibiotic
> exclusions noted in the methodologies, as well as purulence, but again
> no duration cutoff. I think it is worthwhile to make the distinction
> between the first three studies and these in that we have something of
> a heightened inclusion standard for the study evaluation.
>
> \[Slide.\]
>
> In the third group of studies evaluated, there were three, two of
> which were pediatric, and two were patient-based reported and one was
> sinus-based reported. The inclusion criteria were a bit more rigorous
> with some heightened radiographic criteria, certainly use of
> antimicrobial exclusion. There was use of microbiologic cutoffs, and
> there was a duration cutoff in one subgroup of one of the studies.
>
> As you can see, this group at least had a positive sinus culture rate
> in the 70s.
>
> \[Slide.\]
>
> I also think it is worth noting that there may be some benefit in
> specific types of abnormalities noted in radiography and how they may
> be related to positive culture rates.
>
> In Hamory and Gwaltney\'s study in \'79, it certainly looked like in
> those patients with positive cultures, if you try and heighten the
> inclusion criteria with radiographic criteria ranging from mucosal
> thickening to air fluid levels, you tend to enhance the number of
> sinuses with positive microbiologic findings.
>
> \[Slide.\]
>
> In looking at the literature, I could only find one study that seemed
> to have some evidence correlating CT findings with microbiologic data,
> and that was Hansen\'s study. The requirement for study entry was
> clinical impression.
>
> There were 174 subjects that completed this study 122 were found to
> have abnormal CT scans of the sinuses at 70 percent, and they had a
> definition for acute sinusitis by CT criteria, which was mucosal
> thickening and fluid in the sinus. Ninety-two subjects met criteria
> for that, and 61 were found to have pathogenic bacteria or 66 percent
> of these sinusitis-defined CT scans.
>
> I think it is worth noting here that if you use a denominator of all
> patients that were included in the study, 35 percent of patients
> enrolled had positive pathogenic bacteria, but now if you superimpose
> the filter of a positive CT scan, you can double the positive findings
> to 66 percent.
>
> \[Slide.\]
>
> Lastly, endoscopy.
>
> \[Slide.\]
>
> Endoscopy has been addressed in this advisory committee before, I
> believe.
>
> \[Slide.\]
>
> There were two studies that I found in recent literature addressing
> this issue, Vogan and Talbot study. The Vogan study is exceedingly
> small, 13 patients with 16 sinuses that are addressed in his
> conclusions.
>
> Thirteen sinuses had previous antimicrobial use. Diagnostic criteria
> for acute sinusitis was not stated in the article. Only patients with
> their fluid level, on radiography, were included, and no dilution was
> noted on semiquantitative microbiology, such that any colony that was
> counted on the zero plating would be counted as a positive as opposed
> to Talbot\'s study which was very well described with positive minimum
> symptom durations, positive antimicrobial exclusion, positive chronic
> sinusitis exclusion, positive dilutions noted on semiquantitative
> microbiology with specific radiologic findings noted.
>
> \[Slide.\]
>
> If we look at the two studies in tandem, what you see is that with
> Vogan\'s study, there was a sinus puncture that was found to be
> positive, 14 of 16 sinuses, but if you used more stringent criteria of
> what constituted positive microbiologic findings from 1+ denoting just
> a few bacteria, that you would only have 4 of 16 sinuses positive if
> you were raising the bar above 1+.
>
> So, overall, 8 of 14 sinuses was positive ipsolateral endoscopy, had
> sinus puncture with the same pathogen.
>
> In Talbot\'s study, which was a very well defined patient population,
> there were 31 of 46 patients with positive endoscopy, and overall, 12
> of 31 patients with positive endoscopy had sinus puncture. I think it
> is important to remark here that on the left, we are talking about
> sinuses, and on the right we are talking about patients, and that is
> something else that I think is not well standardized and hard to
> really compare in the literature.
>
> \[Slide.\]
>
> So, overall, the initial question, the specific question I tried
> addressing was does the literature adequately describe specific
> criteria for diagnosis of acute bacterial sinusitis, and I would have
> to say that with regards to symptom duration, there are no studies
> identified, but based on Gwaltney\'s initial data and the data you
> heard him describe earlier, that there is a high likelihood that you
> are not going to get viral dilution if you exclude patients who have
> had symptoms for less than 7 days.
>
> With regards to symptom character, there were 5 studies identified, 2
> of which had reasonable data with inclusion symptoms and signs, which
> gave you a 60, 65 percent positive culture rate.
>
> Radiographically, there was a broad range of studies comparing sinuses
> and patient-based reporting in their methods, and there was a broad
> range of inclusion criteria with positive culture rates ranging from
> 30 to 77 percent, and finally, with endoscopy, there is only the two
> recent studies that I just reviewed with positive results ranging from
> 30 to 57 percent, but again, sinuses versus patients.
>
> \[Slide.\]
>
> So, overall, I think we can say that symptoms are certainly necessary,
> but not sufficient for bacterial sinus diagnosis for the diagnosis in
> a clinical trial. Radiography is not necessary or sufficient, but may
> indeed help enrich a population for acute bacterial sinusitis as we
> saw with Hansen\'s study and certainly with the other studies and
> radiography data.
>
> Given symptoms, cultures are sufficient and since there is no
> validated or reproducible or standardized surrogate in the
> literature\--when I say \"standardized,\" I mean how do you report the
> findings whether they be based on sinuses, on patients, or on
> aspirates\--it is currently necessary for the specific diagnosis of
> bacterial sinusitis for clinical trials inclusion.
>
> Thank you.
>
> DR. LEGGETT: Thank you. Are there any questions for Dr. Kraus?
>
> \[No response.\]
>
> DR. LEGGETT: Thank you very much.
>
> Dr. Pohlman is now going to address us with Lessons Learned from
> Clinical Trial Design and Past Approvals.

**Observations from Past Approvals**

> **for Acute Bacterial Sinusitis**
>
> DR. POHLMAN: Actually, I think my titles of my talk in the agenda keep
> getting switched, and I think this was the first title before I
> switched it three times.
>
> Anyway, what I am going to talk about today is the observations that
> have been made from past approvals for acute bacterial sinusitis, my
> observations actually.
>
> \[Slide.\]
>
> What I am going to do today is talk a little bit. Dr. Albrecht
> actually went into detail about regulatory guidance that we give to
> industry in the form of our 1992 Point to Consider document, and the
> more recent 1998 guidance document. Basically, the 1998 guidance
> document is similar to the 1992. It maybe clarifies the language a
> little bit, but essentially, the points in the documents are similar.
>
> Then, what I did was a retrospective review of drug approvals of which
> there are 10 for acute bacterial sinusitis since 1990. The purpose of
> doing this is to sort of let everybody know what we are seeing from
> industry and in what we are processing in our reviews, and then
> hopefully to use the information obtained from this along with the
> discussion today and information that we may have learned to try to
> see if we need to revise those guidance documents.
>
> \[Slide.\]
>
> I am just going to go back to try to outline\--at the present time,
> two separate studies are done. The first study is what we refer to
> oftentimes as the \"clinical only\" study, statistically adequate and
> well-controlled, multicenter comparative trial where we want to use
> rigorous case definitions with specific clinical or radiographic entry
> criteria and where we also try to use rigorous clinical and
> radiographic endpoints as primary effectiveness parameters.
>
> Sinus puncture in these studies is not necessary, but is encourage in
> therapeutic failures.
>
> \[Slide.\]
>
> The second study that we asked people to do, often referred to as the
> \"micro\" study, or Dr. Albrecht referred to this as
> \"microbiologically driven\" study.
>
> It utilizes sort of the same inclusion criteria from a clinical and
> radiographic standpoint, but also requires sinus puncture at entry,
> and that is utilized in the diagnostic criteria of acute bacterial
> sinusitis.
>
> The purpose of this to establish successful microbiologic, clinical,
> and radiographic outcomes in at least 100 patients. Then, we come up
> with the numbers of 25 cases of Streptococcus pneumoniae, 25 cases of
> Hemophilus influenzae, 15 of Moraxella catarrhalis.
>
> Again, in these studies, post-therapy sinus puncture is strongly
> encourage in therapeutic failures. Although the overall diagnostic
> strategy look at microbiologic diagnosis along with the clinical and
> radiographic criteria, the guidance document actually states that
> outcomes on all patients should be reporter even those without
> pathogens at entry.
>
> \[Slide.\]
>
> Just a couple caveats in going through this. Basically, the guidance
> documents are established to serve as a guidance to industry. They are
> not absolute requirements. It is basically to try to level the playing
> field for everybody. The fact that the antibacterial agents are
> reviewed across two division, the fluoroquinolones being in the
> Division of Special Pathogens, and other antibacterials in the
> Division of Anti-Infective Drug Products.
>
> Another thing is that submissions for acute bacterial sinusitis are
> generally part of an NDA package and that there may be other
> respiratory indications that can be used in somewhat supportive
> fashion.
>
> This last point is important. I decided that this retrospective review
> of the work of others is equivalent to a chart review or put in
> something that Dr. Reller could relate to, sending his Clinical Micro
> fellows around to decide whether the Staph aureus that popped up in
> the blood culture bottle of the month is truly a true bacteremia.
>
> But at any rate, in a retrospective review, I can\'t tell whether the
> data was submitted in the NDA and the reviewer did not choose to focus
> on it, so nobody gets a grade, there isn\'t attribution for who is
> leaving out what, so we will proceed with that understanding.
>
> \[Slide.\]
>
> What I am going to try to do is go through with the particular
> language of the guidance document and then kind of take apart each of
> the particular criteria and look at what I found in my review.
>
> In terms of the guidance document for inclusion criteria, and these
> actually apply to both the clinical and micro studies, although they
> are separates studies, these inclusion criteria are pretty much
> consistent for both of them.
>
> The patient should have a clinical diagnosis of acute bacterial
> sinusitis based on history, physical exam, and radiographs. The
> diagnosis of acute sinusitis requires signs and symptoms or
> recommended signs and symptoms lasting for greater than 7 days.
>
> The signs and symptoms should include facial pain or pressure,
> purulent nasal discharge, nasal congestion, and cough.
>
> The radiographic documentation should include CT, sinus x-rays, or
> ultrasound and included comments about opacity, air fluid levels, or
> mucosal thickening.
>
> \[Slide.\]
>
> What I am going to do here, as I said, there were 10 drug approvals.
> Basically, if you say that there is two studies for each drug, that
> means one clinical-only trial and one micro trial. In some instances
> and in most cases, it happens in the microbiology arm because of the
> requirement for number of pathogens that have been considered,
> multiple trials may be done, but this is going go focus on the
> clinical-only trial, so we are looking at essentially 10 drug
> approvals.
>
> The first thing is focusing on signs and symptoms should include
> facial pain or pressure, purulent nasal discharge, nasal congestion,
> and cough.
>
> In kind of looking at sinus pain and purulent nasal discharge, it is
> perhaps major signs and symptoms in the definition. Both sinus pain
> and purulent discharge were required in 6 out of the 10 NDAs.
>
> One NDA required one or both of these signs to be present or symptoms,
> and two additional NDAs had listed sinus pain and purulent nasal
> discharge in a multiple symptom list. Basically, you pick two symptoms
> out of list, and other things could be nasal congestion, cough,
> headache, fever I guess was in there.
>
> In one NDA, purulent nasal discharge was not required to be included.
>
> \[Slide.\]
>
> Again, focusing on the clinical-only trials, in terms of the diagnosis
> of acute sinusitis where signs and symptoms have persisted for greater
> than 7 days, in 8 out of the 10 NDAs, there is actually no reported
> minimum duration of symptoms.
>
> One NDA did require 7 days minimum, and a second NDA required a 10-day
> minimum.
>
> \[Slide.\]
>
> Again, in the clinical-only trials, the radiographic documentation
> should CT, sinus x-rays or ultrasound and include comments about
> opacity, air fluid levels, or mucosal thickening.
>
> I would say the use of x-rays is pretty much universal in acute
> bacterial sinusitis, and it was in these applications. Use of opacity
> and air fluid levels was universal, as was use of mucosal thickening,
> but the extent varied among the NDAs.
>
> Six out of 10 NDAs used anywhere from 4 to 6 millimeters of mucosal
> thickening, and the extent wasn\'t reported in 4 out of 10 NDAs.
>
> \[Slide.\]
>
> So, to move away from inclusion criteria for right now, in terms of
> efficacy, what we are using as a clinical outcome definition. The
> guidance document definitions are that clinical cure should be
> resolution of signs and symptoms at test-of-cure visit and at least no
> worsening in radiographic appearance, clinical failure, persistence of
> one or more signs and symptoms of sinusitis or patients receive
> additional or new antibiotics.
>
> Then, there is an indeterminate category if people don\'t come back
> for follow-up, if they get an antibiotic for some other reason, but
> basically, the guidance document looks at the endpoint as a
> dichotomous endpoint.
>
> \[Slide.\]
>
> What are we seeing in the clinical-only trials? In terms of clinical
> cure defined in the guidance document as resolution of signs and
> symptoms at test-of-cure visit, 8 out of the 10 actually defined
> clinical cure as success, and I think this is getting at something Dr.
> Wald was indicating about earlier, where success actually incorporates
> categories of cure and improvement, where cure implies resolution of
> all signs and symptoms.
>
> Improvement, there are varying definitions for that. It is either all
> signs and symptoms at least improved or partial resolution. It is kind
> of a fuzzy zone.
>
> In terms of the use of radiographs in clinical outcome determination,
> the guidance document states that at least no worsening in
> radiographic appearance has to be present for a clinical cure.
>
> Five out of 10 NDAs explicitly used test-of-cure radiographic in the
> sponsor outcome definition, however, the medical reviewer generally
> discounted it as sort of lagging behind clinical progress.
>
> \[Slide.\]
>
> Turning to efficacy, another thing that has been discussed here is in
> terms of timing of test of cure. Outlined in the guidance document are
> the study visits that are necessary, and basically, there is a
> baseline or entry study visit, usually, an on-therapy visit which
> occurs about 2 to 5 days, an end-of-therapy visit which is an
> evaluation of patients near the completion of therapy, primarily to
> optimize patient care, and usually, these will occur anywhere from 24
> to 72 hours after therapy is completed.
>
> The guidance document says this visit should not be considered a test
> of cure.
>
> Then, there is the fourth visit that is outlined is this post-therapy,
> test-of-cure visit. The timeline for this, the guidance document says
> it should occur approximately 1 to 2 weeks after completion of
> therapy. This assumes a treatment duration for acute bacterial
> sinusitis that ranges from 10 to 14 days, therefore, the test-of-cure
> visit would approximate timing of the 3-week natural history
> resolution of acute bacterial sinusitis symptoms.
>
> At the post-therapy visit, notes made of results of clinical
> evaluation, including status of presenting signs and symptoms, as well
> as radiograph, but that is often discounted.
>
> \[Slide.\]
>
> In looking through the 10 drug approvals, in terms of timing of test
> of cure, when are they actually occurring, the actual outcome
> determinations, the sponsors used the end-of-therapy visit, the visit
> that is occurring 24 to 72 hours for test of cure determination in 5
> to 10 of the NDAs, and the post-therapy or later, 1 to 2 week post
> therapy follow-up in 5 out of 10 NDAs.
>
> The medical officers use the end-of-therapy visit for test of care
> determination in 2 out of 10 NDAs, and post-therapy visit in 7 out of
> 10 NDAs. Usually, there is a primary and a secondary endpoint, so I
> wouldn\'t say that they are not looked at, but the sponsors tended to
> use that early end of therapy determination, and the medical officers
> tended to concentrate on the later follow-up period.
>
> \[Slide.\]
>
> So, now, I want to turn a little bit away from the clinical-only
> trials and discuss in particular the microbiologic trials, and
> remember they have the same inclusion criteria that have been
> previously mentioned for the clinical-only trials, the same efficacy
> determinations and timing of test of cure.
>
> Indicated in the guidance document, the microbiologic dose diagnosis
> is based on isolation of a bacterial pathogen from baseline maxillary
> sinus punctures combined with the clinical and radiographic features.
>
> Documentation should include Gram stain with white blood cell and
> bacterial morphotype semiquantitation and quantitative bacterial
> cultures with susceptibility testing.
>
> For pathogen definitions, Streptococcus pneumoniae, Hemophilus
> Influenzae, and Moraxella catarrhalis are considered pathogens
> regardless of colony count. Staph aureus is considered a pathogen when
> isolated in pure culture with colony counts greater than or equal to
> 10^4^ colony-forming units per ml.
>
> \[Slide.\]
>
> So, now when we look at the microbiology trials in terms of pathogen
> definitions, what do we see? In terms of the major respiratory
> pathogens, Strep pneumo, Hemophilus Influenzae, and Moraxella
> catarrhalis, 6 out of 10 NDAs considered these organisms pathogens
> regardless of colony count.
>
> Three out of 10 NDAs had no reported definition of pathogen, and what
> I mean by this is that they could have included coagulation-negative
> staph as a pathogen. There was no particular list to get around or
> there may have some individuals with gram-negative rods that were in
> the aspirates, and they were considered to a pathogen.
>
> One NDA required quantity of greater than or equal to 10^3^
> colony-forming units per ml for the major respiratory pathogens.
>
> \[Slide.\]
>
> In terms of Staph aureus, 8 out of 10 NDAs considered Staph aureus as
> a pathogen and were pursuing Staph aureus in their labels. Only 3 of
> these applied Gram stain or quantitative measures to assess the
> presence of Staph aureus as a pathogen, however, information was
> available for the medical officer to apply Gram stain or quantitative
> requirements to Staph aureus pathogen definition, and 2 out of those 5
> NDAs didn\'t have that information utilized by the sponsor.
>
> \[Slide.\]
>
> Then, in terms of trying to talk about sinus puncture yields in our
> micro-only trials, this was a tough thing to get around. As Dr. Kraus
> indicated, the level of positivity of aspirates can vary depending on
> the reporting.
>
> The sinus puncture cultures were positive in 22 to 87.5 percent of
> patients enrolled in the microbiology clinical trials. I would say
> that is a wide range.
>
> However, the reasons for the rate of positivity are perhaps a little
> different than what Dr. Kraus indicated earlier. They seemed to be
> influenced and the analysis complicated by what the pathogen
> definition is. NDAs with pathogen definition, companies that were just
> looking for the major respiratory pathogens and maybe discounted other
> ones tended to focus on those as their positive aspirates.
>
> So, those where there was a pathogen definition, we had aspirate
> positivity rate or puncture positivity rate of 36 to 55 percent of the
> patients given the inclusion criteria that we had.
>
> NDAs with no recorded pathogen definition, meaning anything could be a
> pathogen, were positive in 66 to 72 percent of patients, and then
> there were actually 2 out of the 10 NDAs where puncture positivity
> rates appeared to be low, 22 percent and 42 percent, but they were
> likely underestimated by presentation as the microbiologically
> evaluable patients.
>
> Basically what happens is that you take your clinically evaluable
> patients, you know, people that have gotten drug for long enough and
> people that have had appropriate follow-up, and then you separate out
> the people that had a pathogen isolated on the baseline sinus
> aspirate, that\'s your population, your denominator, but people can be
> eliminated from the numerator for other reasons besides culture
> positivity. Perhaps they didn\'t have their follow-up visit, there is
> other reasons to take them out of the denominator.
>
> \[Slide.\]
>
> In terms of bacteriologic efficacy, how do we address that? In the
> approved NDAs, the majority of bacteriologic outcome determinations
> are extrapolated from clinical response. This was seen in 9 out of 10
> NDAs.
>
> There was a single NDA with relatively complete post-treatment
> follow-up sinus puncture. Sinus puncture is rarely done in cases of
> clinical failure. There was information in 4 out of 10 NDAs where
> there were some sinus punctures done, but it is not a consistent
> finding.
>
> \[Slide.\]
>
> I guess in summary, I just wanted to sort of restate the fact that at
> the present time we have the two separate trial. The micro trial
> utilizes the microbiologic data from the sinus puncture in addition to
> the clinical notification in the diagnosis of acute bacterial
> sinusitis.
>
> Although the clinical-only and micro studies are not directly linked,
> the inclusion criteria for both are often similar in the applications
> we receive.
>
> The rates of sinus puncture positivity varied widely, from 22 to 87.5
> percent, and are dependent upon the pathogen definition, method of
> collection. Although we require sinus puncture, there were a few
> studies where there were some endoscopy patients thrown in and sort of
> analyzed separately, but the method of collection as stated in the
> guidance document is the sinus puncture, and sinus culture positivity
> also varied depending on the population being reported on.
>
> \[Slide.\]
>
> My last little point, and I think Dr. Gwaltney touched on this a
> little bit earlier, although at the present time, x-rays are
> recommended at the end of therapy to document clinical cure, they are
> seldom used especially by the FDA as a basis for determining efficacy,
> recognizing that they may lag behind the clinical course.
>
> DR. LEGGETT: Any questions? Don.
>
> DR. PORETZ: Obviously, the microbiological data is critical. The
> laboratories used, I am sure varied all over the lot. I know studies
> that we have done in the past require different laboratories.
> Third-party payers are contracted to different laboratories. Transport
> may take hours and days before they are looked at.
>
> What is your experience in reviewing the microbiology laboratories
> that have participated in these studies?
>
> DR. POHLMAN: I am going to turf that to someone else. Actually, in my
> review, I didn\'t focus on what the mechanism for obtaining cultures
> was. Oftentimes the cultures may be done locally and then confirmed at
> a reference lab that is part of the study protocol.
>
> I will let Dr. Albrecht comment.
>
> DR. ALBRECHT: That is what I was going to say. We basically just
> specify in the protocol what are the parameters and criteria for
> diagnosis, and actually I don\'t know if our Microbiology staff may
> want to further elaborate on the protocol definitions, but then the
> sponsor actually makes the selections of the laboratories, both the
> local and the central, and follow their QC procedures. We don\'t
> actually go out and look at those laboratories.
>
> DR. LEGGETT: If you could address that issue.
>
> DR. SILVER: Harold Silver, Microbiology, Anti-Infectives. The
> microbiologists, what we do is we compare the methodology and all the
> information that is sent to us by the applicant or sponsor, to
> standardized methods and other information, and we compare it to what
> standardized out in the community.
>
> So, we do compare everything, and if there is a discrepancy, we
> mention it to the applicant or sponsor, but we ensure that the
> specimens, and so on, are guided by standardized methods and
> guidelines that are out there.
>
> DR. LEGGETT: Thank you.
>
> DR. TUNKEL: In terms of the two studies, the clinical-only and the
> micro, I guess in terms of specific antimicrobial agents studied, was
> the clinical cure the same in each study? That is, when you compared
> clinical to micro, did really your success rate make a difference in
> doing both studies?
>
> DR. POHLMAN: I would say they were not necessarily the same. I think
> Dr. Albrecht indicated earlier, too, about the fact that oftentimes
> the microbiology trials are non-comparative trials, they are not
> blinded. Cure rates could be higher, I don\'t want to generalize.
> There were about 30 studies that I looked at, so there is not a real
> good way to generalize that comment.
>
> DR. LEGGETT: Dr. Wald.
>
> DR. WALD: The idea of setting a specific colony count in the
> quantitative data is to try to ensure that pathogens that are
> recovered represent infection of the maxillary sinus, and not the
> nose, so I was a little surprised to hear that you take any colony
> count for Hemophilus influenzae, Strep pneumoniae, and Moraxella
> catarrhalis.
>
> Even though I know those are not regarded as normal nasal flora
> adults, when an adult has a cold, I would just wonder if you couldn\'t
> find those organisms in the nose, and if you wouldn\'t do better to
> ensure the validity of the culture representing again maxillary sinus
> disease rather than nasal colonization.
>
> In children, it is absolutely true that these are normal nasal flora,
> so for childhood studies, quantitation really would be essential. This
> was the same issue that we deal with in urinary tract infections. You
> know, we know the distal urethra is colonized, so we set our
> definitions of significant bacteria accordingly. I think for children,
> we absolutely have to do that.
>
> DR. ALBRECHT: I would say that I shared your surprise when I read the
> document again this time in preparation for this meeting, and as I
> mentioned in the introduction, I think this was really, again, we, as
> a regulatory agency, have parameters and criteria that we try to
> provide in our draft or finalized guidance documents, but we often
> hear concerns raised by companies about why that may or may not cause
> difficulties in enrollment.
>
> I think as I reflect back on sort of this work of a committee of
> experts internally and advisers from external sources, is that I think
> what must have happened, as we were considering this, we realized that
> in addition to having an aspirate with Gram stain predominant
> organisms, white cells, et cetera, that occasionally, the only that
> was quote \"wrong\" was that the colony count, it perhaps was not
> done, but in the setting where all the parameters were there including
> white cells and the predominant morphology of an organism on Gram\'s
> stain, so perhaps in the spirit of trying to be more inclusive instead
> of exclusive, we proposed that quantitation for the main three
> organisms not be mandated or not be really focused on completely.
>
> But I share your observation.
>
> DR. LEGGETT: Dr. Gwaltney.
>
> DR. GWALTNEY: As I understood those data, Ellen, those specimens were
> sinus aspirates, they were not nasal, they were sinus aspirates.
>
> DR. WALD: They are saying any positive culture from a sinus
> aspirate\--
>
> DR. GWALTNEY: From a sinus aspirate, yes.
>
> DR. WALD: \--equals a positive culture. You certainly didn\'t say that
> in your studies. You required 10^3^.
>
> DR. GWALTNEY: In our original, but I mean I think you can make the
> argument, which I tend to believe, is that the sinus clearly is
> sterile under normal conditions like bloodstream, the bladder, CSF, so
> that in this setting, if you do get any organisms of those three in
> that sinus aspirate culture, I have no trouble believing that they
> probably did come from the sinus cavity and you just caught the
> patient early in the infection, although you can never rule out the
> possibility that they might have been contaminants, but that more
> likely of proper care was taken in collecting the specimen, that they
> really do represent the fact that those bugs are in the sinus cavity.
>
> So, I don\'t see any problem with that. I would think that is the
> appropriate way to do it.
>
> DR. WALD: I would just worry about contamination. I think people are
> not always so careful and that nasal cultures can often be positive.
>
> DR. LEGGETT: Dr. Pohlman, did you see or does the FDA keep track of
> any adjunctive therapy?
>
> DR. POHLMAN: Adjunctive therapy, that is an interesting point because
> I think\--and I can\'t generalize because I didn\'t really pick that
> out for each of these particular categories.
>
> What I would say is that there are some that allow adjunctive
> therapies, decongestants, some that don\'t.
>
> DR. LEGGETT: Dr. Gwaltney, what would you say about the effect of any
> adjunctive therapy on resolution rates if we are going to be talking
> about floating end periods of resolution of symptoms?
>
> DR. GWALTNEY: Well, again, we have no data to start with. I think
> decongestant therapy theoretically makes sense, but I don\'t think it
> probably influences the outcome very much, and when you talk about
> things like steam, it is so difficult to get anything into the sinus
> cavity, because it is so sheltered behind the infundibulum and the
> inferior turbinate, and then you have got that tiny little opening
> with the angle, and it is hard to get steam or anything else in there.
>
> Then, on top of that, it is usually occluded with material, so I think
> we fool ourselves really when we think putting all this stuff up the
> nose is going to do much to sinus. It may help the middle meatus. I
> think that is what the decongestants do is they shrink that area.
>
> It would be nice to have randomized in terms of the adjunct therapy,
> but personally, I don\'t think that is a big issue.
>
> DR. LEGGETT: Dr. Reller.
>
> DR. RELLER: There is not as big a discrepancy here between the
> quantitative cultures and any organisms as might appear on the
> surface, because in reality, to get any organisms requires something
> about 10^3^ or more given the small sample size that is actually
> plated.
>
> There are published reports of what sounds very crude in terms of
> quantitation, but a properly streaked plate, you know, what grows in
> the first, second, third, fourth zones correlates actually quite well
> with 10^3^, 10^4^, 10^5^, 10^6^, and then if one couples, which I
> think should always be done, I think a culture should never be
> interpreted without a Gram stain of an aspirate or sputum specimen as
> far as that goes, because they are complementary and serve as a
> quality check each on the other.
>
> So, if one sees the organisms that are consistent with a Pneumococcus
> or Hemophilus influenzae, and then you grow, even it\'s only 1, 2, 3,
> 5 colonies, you have got a good case, and that is especially true in
> sputum samples.
>
> I mean anybody that would do a sputum culture without a Gram stain
> smear, I think is kidding oneself. So, I think they are complementary
> and I would like to see that, and, in fact, if one sees, to the extent
> that this material is liquid or semi-liquid, to see one organism per
> high-powered field, you are up in the 10^4^, 10^5^ range right there,
> so there actually is, I think, a correlation between the quantitation
> and what you are asking for I think is totally valid, and if the
> microbiology is done right with transport of organisms and they are
> not dying off, et cetera, things are going to match up pretty well.
>
> Unfortunately, in many situations, the state of microbiology is a
> sorry one.
>
> DR. LEGGETT: Thank you.
>
> The next speaker will be Dr. Powers, who is going to talk about
> Clinical Trial Design Considerations for Future Guidance.

**Clinical Trial in ABS**

> **Considerations for Future Guidance**
>
> DR. POWERS: What I would like to do is to answer Dr. Brown\'s question
> here, how we are going to pull together the information that Drs.
> Gwaltney and Sydnor have showed us this morning about the disease, and
> then what Drs. Kraus and Pohlman have showed us about our internal
> review of the medical literature as well as what we have been seeing
> in these clinical trials, and try to make some proposals for an some
> things to ask the committee about for what would go into a future
> guidance in this disease.
>
> \[Slide.\]
>
> The first issue I would like to address is why do we need to readdress
> the 1998 guidance, and you can see probably from Dr. Pohlman\'s
> presentation what we are getting and why we want to look at this
> question.
>
> The second one is something that anybody should do in research,
> whether it is clinical or laboratory research. What is the question we
> are trying to answer when we look at these trials, and then go into
> three points about considerations in clinical trial design and acute
> bacterial sinusitis, that is, defining the disease in the patient
> population, and you have heard a lot about that this morning, but how
> can we translate that into a guidance going forward.
>
> The types of studies that one might do and how one measures the
> endpoints, and even as importantly, how one evaluates those endpoints
> in patients with acute bacterial disease, and then finally make some
> proposals for discussion after lunch about going forwards.
>
> \[Slide.\]
>
> So, how did we get to this point where we wanted to talk about redoing
> this guidance? Well, discussions at previous advisory committees here
> in reference, as Dr. Patterson said earlier, otitis media, a workshop
> last November co-sponsored with the Infectious Disease Society of
> America, as well as PhRMA, an international meeting, such as the
> International Conference on Harmonization.
>
> All of these bodies have discussed selection of non-inferiority
> margins in clinical trials, is it just statistical or how does it
> impact clinically? It actually has a very important clinical
> significance, and that is lack of an adequate selection of a
> non-inferiority margin means one cannot ensure adequacy of any drug
> over placebo in that setting.
>
> IN other words, if you took one of our clinical-only trials and had
> added a third arm to that trial, which included placebo, would either
> the control or the test drug have been more effective than placebo in
> that trial design.
>
> \[Slide.\]
>
> So, the results of all those previous meetings led to an agreement
> that we would examine previous placebo-controlled trials in each
> disease to select the appropriate margin, also known as the delta, and
> we agreed that there was no 10 percent margin for all disease
> indications, but this entails reviewing all of the pertinent studies
> in a given disease, not just the studies which show a benefit, so that
> we can get an overall view of what the studies actually show for this
> disease.
>
> So, we internally did our review of the placebo-controlled trials in
> acute bacterial sinusitis, which revealed several issues, not only
> about the potential margin, but some other features about study design
> that we wanted to address today.
>
> \[Slide.\]
>
> So, what do we learn from looking at these previous placebo-controlled
> trials? Well, these trials provide some clues that antimicrobials may
> be effective in shortening the duration of symptoms in acute bacterial
> sinusitis.
>
> But relative to the question Dr. Poretz asked, we may all
> believe\--and I think we all think around the table here\--that
> antimicrobials do something for this disease as referable to the
> question that you asked of Dr. Sydnor earlier.
>
> What these trials don\'t allow us to do is to come up with an accurate
> assessment of the magnitude of that benefit in acute bacterial
> sinusitis. That remains unknown and may be actually small, so we need
> to discuss other study designs other than non-inferiority trials.
>
> We also want to discuss some other issues with acute bacterial sinus
> trials, which became apparent as a part of this review. So, this
> raises a very important question.
>
> \[Slide.\]
>
> What are we actually trying to measure in clinical trials of acute
> bacterial sinusitis? One could raise the point that what we really
> want to know is the, quote, unquote, \"true\" benefit of
> antimicrobials as sole therapy in bacterially defined disease without
> any other symptomatic therapies.
>
> Or one could make the case that what we really want to look at is what
> is the added benefit of antimicrobials above and beyond the effect of
> symptomatic non-antimicrobial therapies in patients with bacterially
> defined disease.
>
> Now, as Dr. Gwaltney just said at the end of the last session here, we
> don\'t even know what the benefit of symptomatic therapy is in this
> disease.
>
> But one might say that the second question is more appropriate because
> of decongestants, nasal saline, or anti-inflammatory agents are
> effective in and of themselves, there is no need for antimicrobial
> agents in this disease, and those other therapies do not result in the
> problem of antimicrobial resistance.
>
> As we know, acute bacterial sinusitis is the fifth most common reason
> for prescribing antimicrobials in the ambulatory setting, and
> therefore, may also be one of the major drivers of antimicrobial
> resistance, as well.
>
> \[Slide.\]
>
> Well, one could make the case that antimicrobials would logically have
> the greatest effect in patients with bacterial disease, and, in fact,
> the FDA has recently put out a labeling rule, so that each
> antibacterial drug will have, in their label, information informing
> clinicians that prescribing antibacterial agents in the absence of
> bacterial infection is likely to promote the spread of antimicrobial
> resistance.
>
> These previous placebo-controlled trials seem to confirm that there is
> lack of efficacy in the populations that are less likely to have
> bacterial disease, so given this issue of resistance, should we use
> anti-inflammatory drugs if what we are really looking at is an
> anti-inflammatory effect of antimicrobials.
>
> Use of antimicrobials in the non-bacterial disease-defined population
> would really seem to contradict current appropriate use guidelines,
> and clinical guidelines do recommend waiting 7 days specifically to
> try to address the issue of selecting the population most likely to
> have bacterial illness.
>
> \[Slide.\]
>
> In terms of a clinical trial, though, what is the effect of including
> patients with non-bacterial disease in a clinical trial? In the
> setting of a non-inferiority trial, what this actually does is bias
> the conclusion towards non-inferiority when, in fact, there may be
> true differences between drugs, and as I said, one way to look at this
> is if you added a third arm, which was placebo, into that trial, would
> either of those drugs have been more effective than placebo.
>
> On the other hand, including patients with viral disease in a
> placebo-controlled trials biases the conclusion toward no difference
> from placebo, when there may be important differences between the
> drugs and placebo.
>
> Including higher proportions of patients with non-bacterial disease
> results even so with less measured treatment effect of antimicrobials.
> So, even though you may observe a treatment effect, it is going to be
> less than what you would have seen if there were only people with
> bacterial disease in the trial.
>
> This may explain the minimal or no benefit in many of these previous
> placebo-controlled trials, as the inclusion criteria in many of these
> did not specify that the patients had to have bacterial disease, nor
> did they look for bacterial disease by means of sinus punctures.
>
> \[Slide.\]
>
> As you heard from Dr. Kraus this morning, our conclusions from the
> review of the literature on correlating clinical signs and symptoms
> and radiography with sinus puncture, showed that the more rigorous the
> criteria, that seemed to select for a higher proportion of patients
> who had bacterial disease based on sinus puncture.
>
> However, even the most rigorous criteria would still allow inclusion
> of maybe between 20 and 40 percent of patients who do not have
> bacterial disease into these trials.
>
> One of the questions that was asked yesterday was what happens when
> you include those people in the trial, what is the statistical effect,
> and I am going to show you that in a minute.
>
> There are no adequately sized prospective, reproduced studies that
> allow us to adequately select clinical or radiographic criteria which
> would select patients with bacterial disease. Even when we start
> looking at combinations of these, we still end up with perhaps, at
> best, 60 percent of people with bacterial illness.
>
> While 7 days of symptoms is a good way to select patients in clinical
> practice, I want to raise the question of whether you would want to
> think about this in a different way when evaluating a clinical trial.
>
> If one uses sinus puncture to define the patients at baseline, it
> wouldn\'t matter whether the patient had 7 days of symptoms or not,
> and I am going to reference this in a minute to trials, as Dr. Kraus
> said, with neuraminidase inhibitors.
>
> We know from those drugs that the antimicrobial agent has its effect
> earliest in the course of the disease. We don\'t know whether that is
> the case for acute bacterial sinusitis or not. Is it possible that if
> we waited 7 days in everybody and then gave them the drugs in the
> setting of a placebo-controlled trial, that the drugs may have less of
> an effect because they are on their way to getting better already, and
> remains unknown.
>
> \[Slide.\]
>
> Well, as you have heard from Drs. Gwaltney and Sydnor this morning,
> sinus puncture remains the gold standard. What has been the issue with
> using it? It is considered unpalatable by many people, but newer
> procedures may obviate some of this discomfort, and, in fact, are
> similar in performance to nasal endoscopy in that they are going
> through the nose instead of what people have described as going up
> through the gums.
>
> You saw the film this morning that shows that procedure, which is
> fairly the same as nasal endoscopy except, as the film showed, you go
> 10 mm further into the sinus instead of leaving the catheter up inside
> the nose.
>
> We have heard that there is less than optimal accuracy with nasal
> endoscopy especially for certain organisms like Staph aureus where the
> correlation was actually very poor, not surprising there since we know
> that the middle meatus is not normally sterile and you can find Staph
> aureus in the nose normally.
>
> Also, previous studies on nasopharyngeal and throat cultures showed a
> high level of discordance between the organisms found either in the
> pharynx or the throat and what was actually found in the sinus, and
> Dr. Wald\'s study looked at this in children, and Evans did this in
> adults, so in neither population was there a good correlation.
>
> \[Slide.\]
>
> Looking through the Advisory Committee presentations in 1994, 1997,
> and 1998, about this disease, several questions kept coming up again
> and again, and I wanted to address some of these here.
>
> Is sinus puncture therapeutic all by itself? Well, it may be
> therapeutic all by itself. We know that drainage of closed space
> infections in infectious disease usually is a good thing, however, in
> the clinical trial, this effect would be evenly distributed across
> arms of the trial.
>
> We would expect that perhaps the effect of puncture should be small
> relative to the effect of antimicrobials. We don\'t know that answer,
> but if the effect of puncture is so great, one could question whether
> puncture should be the treatment, which used to be the treatment in
> the pre-antibiotic era, and yet as you have heard this morning, we
> have never proven that antimicrobials are superior to just doing the
> puncture, so one could question the benefit of antimicrobials in this
> setting.
>
> The other issue is don\'t puncture and antimicrobials do two different
> things. We know if we want to reference otitis media, that
> antimicrobials don\'t make the fluid in the ear go away. We would not
> expect that antimicrobials would make the fluid in your sinus go away
> and really what we might be doing with antimicrobials is addressing
> residual inflammation caused by tissue invasion of the pathogens.
>
> \[Slide.\]
>
> So, here is another very big concern and that is that sinus punctures
> are not done in clinical practice, so if they are not done in clinical
> practice and we do trials based on sinus puncture, how does this
> replicate how people are going to use the drugs out in the community.
>
> Well, we could sort of put this in the era of been there, done that.
> Most of the prior placebo-controlled trials that use clinical entry
> criteria show minimal, if any, benefit for antimicrobials in acute
> bacterial sinusitis. If one is very concerned about this, we could
> stop now and say you don\'t use to use antimicrobials. We don\'t
> believe that is the case either.
>
> So, perhaps what we need to do is use better definitions out in
> clinical practice of who actually gets treated. So, we also need to
> make this distinction between clinical trials and clinical practice.
>
> In a clinical trial, one does blood draws, laboratory testing, any
> number of things that aren\'t done n clinical practice. So, because we
> want to be able to tell doctors how to use the drug appropriately once
> it gets out into clinical practice, so that gets to a difference
> between what the FDA does versus what doctors do out in clinical
> practice.
>
> What we want to do is approve safe and effective drugs for the disease
> under study. So, if we then approve a drug that we know is effective,
> then, somebody else can go out and do a trial that says how is this
> used out in the community, and we have referred to this as an efficacy
> trial versus a strategy trial.
>
> Other people in the epidemiologic literature have referred to that as
> an efficacy trial versus an effectiveness trial, with the
> effectiveness trial being sort of the strategy trial.
>
> So, if one does a strategy trial of how a drug is used out in
> practice, and it fails to show a difference over placebo, like many of
> the placebo-controlled trials in this disease have, there are two
> reasons why that trial may fail.
>
> The first is the drug isn\'t effective in the disease under study, or
> the second is that many of the patients studied didn\'t even have the
> disease you were trying to study.
>
> If you don\'t know that the drug is effective first, you don\'t know
> which one of these is the reason why the study may not have worked.
> So, what we are saying is we need to rule out number one first.
>
> We need to make sure we are approving that the drugs are actually
> effective in the disease under study and then translate that
> literature out into how clinicians can use these drugs in clinical
> practice.
>
> \[Slide.\]
>
> So, what is the actual effect? In your handout this is wrong, I was
> going through this, this morning, I had these flipped. The 65 percent
> viral is in the wrong place in your handout, but this slide is
> correct.
>
> So, what happens if you include a number of people in a clinical trial
> with viral disease, and what does that do the sample size of the
> trial?
>
> This is what happens in a placebo-controlled trial comparing drug to
> placebo if 65 percent of the people in the trial have viral disease,
> and only 35 percent have true bacterial disease?
>
> Let assume, and we have done this based on what we have seen in prior
> NDAs. The cure rate comes out to be about 80 percent in all these
> NDAs. Let\'s assume that the cure rate with viral disease is about 80
> percent at day 10, therefore, it is going to be 80 percent with
> placebo, as well.
>
> On the other hand, let\'s take the 35 percent of people with bacterial
> disease and let\'s assume, just for the sake of argument, there is a
> 15 percent treatment effect, so there is an 80 percent cure with the
> drug and a 65 percent cure with placebo.
>
> When you mush all those people into the trial and it comes out the
> other end, what you would end up with is an 80 percent cure rate with
> drug and a 75 percent cure rate with placebo.
>
> In a placebo-controlled trial, to show that magnitude of difference,
> you would need a sample size of 2,900 patients if you used
> clinical-only criteria in a placebo-controlled trial.
>
> On the flip side, if you defined the bacterial disease at baseline and
> all the people had bacterial illness, we then are left with the 80
> percent cure rate with drug, 65 percent with placebo, which requires a
> sample size of 370 patients.
>
> So, defining the bacterial disease at baseline also has huge
> implications for the sample size. Now, you could argue that not
> everybody you tap at baseline is going to have an organism, but even
> if you have to increase that by 50 percent, you can see that still
> does not approach what you would have to do in a clinical-only
> placebo-controlled trial.
>
> \[Slide.\]
>
> So, let\'s apply this to what the guidance says now. As you have heard
> already this morning several times, we suggest two studies, a
> microbiologically-based non-comparative trial with presumed
> eradication of the organism based on clinical outcome as the endpoint,
> and clinical-based non-inferiority trial with clinical inclusion and
> outcome criteria, which we referred to as clinical-only study.
>
> The guidance does say you can do a superiority trial in this
> particular setting. No one has chosen to do so.
>
> \[Slide.\]
>
> So, what are the issues with this previous guidance and what we have
> learned from looking at these placebo-controlled trials and what we
> have learned about the disease.
>
> Well, the micro studies presume that there is a correlation between
> microbiological and clinical outcome. As you heard this morning from
> Dr. Gwaltney, that has never been shown in this disease.
>
> There are examples of other diseases that have less than optimal
> correlations of microbiologic and clinical outcomes, and perhaps the
> one most referable to this illness is acute otitis media.
>
> We just published this in Pediatric Infectious Diseases where we took
> three of the so-called double tap studies in acute otitis media where
> children received a baseline tympanocentesis and an on-therapy
> tympanocentesis 24 to 72 hours into their treatment, and have shown
> that the correlation actually is less than optimal between
> microbiologic and clinical outcomes.
>
> Sixty-three percent of children who still have an organism in their
> ear, at that second episode, are clinically cured at that time.
>
> The pre- and post-therapy microbiologic data, however, are very
> helpful in ascertaining the contribution of drug to treatment effects,
> so we do want to be able to see this information.
>
> Where it becomes problematic is when one uses microbiologic
> information as the sole measure of efficacy in these trials, and you
> have heard enough between yesterday and today about the issue of
> microbiologic surrogate markers.
>
> The issue with clinical-only studies is again the issue was selecting
> a non-inferiority margin. They also may include significant
> proportions of patients with non-bacterial disease based on what we
> have heard today, and the issue with timing of measurements of
> outcomes may not be optimal But let\'s address this issue of
> non-inferiority margins.
>
> \[Slide.\]
>
> We did a Medline search for placebo-controlled trials plus we looked
> at the references of those trials. We actually came up with 16
> placebo-controlled trials, two of which I haven\'t included on here
> because one of them actually has uninterpretable results, a score that
> I can\'t actually even figure out, and it is a radiologic score, not a
> clinical one. So, we left that one off. The 16th one is off at the
> translator getting it translated from Swedish because I am a little
> rusty on that disease. So, we are going to evaluate 14 of these today.
>
> If you look at some of the meta-analyses performed on acute bacterial
> sinusitis trials, they look at things like blinding and randomization,
> and they come up with a Jedod score, but when we looked through these,
> it becomes very obvious you cannot do a meta-analyses on these,
> because the outcome measures are so drastically different across these
> trials regardless of the fact whether they are blinded or randomized.
>
> Three trials actually have some bacteriologic information. Two have
> nasal cultures and one does actually a puncture in a subgroup, but as
> Dr. Gwaltney said, they don\'t culture what they got out of the sinus
> puncture, so it is hard to know what that means.
>
> \[Slide.\]
>
> There is also widely varying methods of assessment of the outcomes.
> Again, as Dr. Kraus showed with the correlation literature, it is the
> same here. They evaluate sinuses instead of patients in some of these
> trials, which makes it very hard to figure out what the outcomes are.
>
> Some use the clinician\'s assessment so symptomatic cure, they just
> tell you the patient is better or the patient is not, but they don\'t
> tell you how they measured that.
>
> Some use ad hoc scoring systems for symptomatic cure, some use
> radiological scoring systems. My personal favorite was the osteal
> patency where you actually measured the pressure at the osteal meatus.
> What that means clinically we don\'t know, and the best is nasal
> cytology, and I would like to hear if Dr. Gwaltney can tell us
> afterwards what that actually means. How changes in that actually
> translate into clinical outcomes is unclear.
>
> The other thing is timing of assessment of cure varies widely. Most of
> them have used fixed time points, anywhere from days to weeks after
> the end of therapy. Two of them did use time to resolution of symptoms
> in a Kaplan-Meier curve analysis, but even those used different ways
> in which they did the Kaplan-Meier analysis.
>
> The one trial that is often quoted by Lindbaek because it shows an
> effect actually only used pain as the only symptom that they did in
> that time-to-effect analysis. The other one was the Kaiser trial which
> us a non-validated symptom scale to actually measure time to effect,
> as well, so there are two that do that.
>
> Several other trials used a sort of modified time analysis where they
> looked at day zero, day 3, day 5, day 7, at those fixed time points
> and then tried to draw a curve that way.
>
> \[Slide.\]
>
> What I am doing here on this slide is actually not scientifically
> appropriate. You should not put all these trials on one graph like
> this because they really can\'t be compared from one to the next.
>
> But to look at this, what we see is there are 14 trials all together.
> These lines in red are the bacteriologically evaluable subsets. This
> trial actually only used nasal aspirates through a plastic catheter,
> and this trial actually did the punctures, but didn\'t actually do the
> cultures. That is the one we were talking about, the Rantanen trial.
>
> So, as you can see, only two of these trials actually have a lower
> bound to the confidence interval, which is actually above zero, that
> actually show a treatment effect. All these others have lower bounds
> to the confidence interval, which are not above zero, so they do not
> show a treatment effect.
>
> The vast majority of these have very small treatment effects, and the
> mean is on the order of about 4 percent for those treatment trials. If
> we look at these trials and evaluate these in a little more aspect,
> this is a trial by Gananca. This trial, the symptom outcome
> measurement was a fixed time point measurement, which just told you
> whether the patients were very much improved, improved, or not
> improved, and don\'t tell you how that measurement was actually made.
>
> One can also call this trial into question because they did nasal
> cultures where the most common pathogens are Staph aureus, E. coli,
> Proteus followed by coagulase-negative Staphylococci. So, how one
> interprets this, which has a treatment effect of 30-some percent is
> really unclear.
>
> The second trial, which gets quoted often because it actually shows an
> effect, is the Lindbaek trial, which uses the time to event analysis,
> but again, that time to event analysis is based only on pain, no other
> symptoms, so we don\'t know how the other symptoms actually get better
> in that particular setting.
>
> \[Slide.\]
>
> So, as I went through this, the point estimates in the majority of
> these studies show a small benefit. Of the two trials that actually
> looked at the subgroups that had bacterial disease, one shows an
> effect of +25 percent, the other one goes in the opposite direction,
> -12 percent. So, again, they are going in vastly opposite directions.
>
> The other thing that is very interesting about these studies, they all
> have very small numbers of patients, which is why those confidence
> intervals are so wide, as well.
>
> \[Slide.\]
>
> So, what do we do with that information? We may believe that
> antimicrobials have an effect on this disease, and the point estimates
> all lean toward the positive, so that would support that hypothesis.
> What it doesn\'t allow us to do is to select an accurate margin.
>
> If you were going to pick it even just based on the point estimates,
> you would come with a mean average of 4 percent. The guidance, as it
> was done in the past, suggested what would end up being about a 15
> percent margin for these trials, which is clearly not appropriate
> based on what we know from the placebo-controlled trials and would not
> allow one to rule out any benefit over placebo in these illnesses.
>
> The ICH-E10 document suggests choosing trial designs other than a
> non-inferiority margin when the margin is now known, again, because we
> cannot ensure benefit of any drug over placebo in this setting.
>
> Again, we cannot scientifically justify saying, well, I know
> antibacterials work in this disease, so I think you should just pick a
> 10 percent margin. That isn\'t really scientifically legitimate to do
> that.
>
> So, are there other types of trial designs we could look at? Well,
> there is dose-response trial design or what we could call a
> placebo-controlled trial, which really is more accurately a
> superiority trial versus other symptomatic therapies, and this may be
> more palatable to patients because you are not just sending them out
> the door with absolutely nothing. You are at least giving them
> something that may make them feel better although again we don\'t know
> the effect of these symptomatic therapies.
>
> The other issue is that we could design a trial like this to be an
> early escape trial where, after so many days, if the patient is not
> improved, they could then be switched over to receive antimicrobial in
> that placebo arm.
>
> \[Slide.\]
>
> So, if we did a trial that looked at antimicrobials plus other
> symptomatic therapies versus other symptomatic therapies alone, there
> is no issue about selecting a non-inferiority margin since it\'s a
> superiority trial. The trial has its own internal validity since there
> is a direct comparison rather than an indirect comparison with no
> antimicrobial therapy, and placebo-controlled trials in this disease
> have been suggested by other independent reviews.
>
> A recent Cochrane review, and I quote it here, says, \"Given the small
> number of trials with heterogeneous results, additional
> placebo-controlled trials are needed to evaluate the efficacy of
> antibiotics in this disease.\"
>
> \[Slide.\]
>
> How about the ethical considerations of not giving people
> antimicrobials in this disease? Well, there are rare side effects, but
> they are serious that are associated with acute bacterial sinusitis.
> As Dr. Fleming answered when he was asked this question this morning,
> one must also balance the risk of adverse outcomes of sinusitis with
> the risk of adverse outcomes of giving the antimicrobial itself.
>
> We are actually doing an analysis right now of our database to
> actually look at what are the serious adverse events related to
> antimicrobials, and Dr. Albrecht pointed this out when we were doing
> our practice sessions. It seems like with every antimicrobial we see,
> we notice these bad side effects in the sinusitis group.
>
> That might just be because there are so many patients studied with
> bacterial sinusitis in NDA databases. Again, there is no data the
> antimicrobials actually decrease this risk of complications. That
> doesn\'t mean they don\'t. It means that the sample size for such a
> trial would be very, very large to actually prove that difference.
>
> The complications may be due, however, to altered host anatomy or
> other factors.
>
> When I looked at all these placebo-controlled trials, there is 1
> patient out of those 14 placebo-controlled trials who went on to get a
> brain abscess, and it was with Streptococcus anginosus, not with the
> usual organisms.
>
> \[Slide.\]
>
> Have we studied other infectious diseases that actually have higher
> mortality and complication rates in placebo-controlled trials? Yes, we
> have. Influenza drugs have been studied as placebo-controlled trials
> despite the availability of older drugs.
>
> The mortality in an influenza outbreak setting ranges anywhere from 10
> to 600 per 100,000 depending on whether they are healthy or
> chronically ill patients, much higher than what we would expect in
> outcomes with acute bacterial sinusitis.
>
> How do they do this? They select exclusion criteria to minimize the
> risk.
>
> Are there some ways we might be able to do this? Well, most brain
> abscesses associated with sinusitis seem to be from the frontal
> sinuses and cavernous sinus thrombosis may be from sphenoidal disease.
>
> \[Slide.\]
>
> So, could we exclude people who have frontal and sphenoidal disease?
> This is one of the questions we want to ask the committee after lunch,
> as this may be one way to do it.
>
> The other thing is if we are going to do bacteriology on all patients
> at baseline, could we exclude patients with certain organisms?
> Microaerophilic streptococci like those in the Strep anginosus group
> are associated with 70 percent of brain abscesses.
>
> Streptococcus pneumoniae and Hemophilus influenzae occur in less than
> 1 percent of brain abscesses, so the common organisms associated with
> this disease are not the common organisms associated with the
> complications.
>
> The other problem is excluding severe disease, but there is several
> issues with excluding severe disease.
>
> \[Slide.\]
>
> The first one is how do we actually define it, and we addressed this
> yesterday when we were talking about diabetic foot infections. No
> criteria exists such as that that exists for community-acquired
> pneumonia if one defines severity as predicting outcomes.
>
> Dr. Anon told me at the break that perhaps there is some validated
> scale, but in our search we didn\'t discover that, so if there is one
> out there, we would really like to see it.
>
> Patients with facial swelling may actually have a different disease.
> They may have periorbital cellulitis as a complication of sinusitis,
> and that is not sinusitis by itself.
>
> The exclusion criteria used in previous placebo-controlled trials has
> been something as minimal as fever. If you exclude people with fever,
> you may actually be excluding the people that have the bacterial
> disease, and that may explain why some of these results show such a
> minimal effect.
>
> So, the patients with what has been called severe disease in previous
> trials may actually be the ones most likely to benefit from
> antimicrobials.
>
> \[Slide.\]
>
> So, what are the implications for drug development? Well,
> clinical-only trials can be very attractive to drug sponsors because
> as they are currently designed, they afford a very low risk for
> failure.
>
> If you put a placebo arm into these trials, it would be unlikely that
> either the control drug or the test drug would be able to be more
> effective than placebo. So, proof from placebo-controlled trials that
> sinusitis does not need treatment in some proportion of patients would
> be a great public health advance by limiting antimicrobial use to
> those most likely to benefit, however, from the sponsor\'s point of
> view, this would decrease the market share.
>
> As we have heard at these discussions at ICAAC, that antimicrobials
> are already not very profitable relative to other drug classes.
>
> On the other hand, it would afford the opportunity for smaller trials
> and more streamlined development programs by using small numbers of
> trials and actually using supportive data from like community-acquired
> pneumonia trials and one rigorous sinusitis trial, which gets to what
> we have been saying about streamlined drug development, less data, but
> higher quality data.
>
> \[Slide.\]
>
> Let me show you some examples here of the sample size calculations one
> could do. We used this example of if you did a non-inferiority trial
> with a 5 percent margin\--and that is probably not correct because the
> mean margin, as we saw from the placebo-controlled trials is 4
> percent\--you would have to do a 2,700 patient non-inferiority trial
> to be sure that you were more effective than placebo.
>
> Placebo with a 10-day endpoint would be 780 patients, and placebo
> using a time-to-resolution endpoint would be 520 patients total in the
> trial.
>
> If you allow some more aggressive assumptions, such as a 10 percent
> non-inferiority margin, which is clearly not supported by the
> placebo-controlled trials, you could do a trial with 670 patients, a
> placebo-controlled trial in that setting would be 370, and placebo
> with a time-to-resolution endpoint would be only 250 patients.
>
> What are we seeing now? The current sample sizes of acute bacterial
> sinusitis databases from the 10 NDAs Dr. Pohlman presented have an
> average of 683 patients per drug in the clinical-only trials, and an
> average of 584 patients in the micro trials. That is about 1,100
> patients per database.
>
> \[Slide.\]
>
> Let\'s finally finish up with the appropriateness of timing in this
> disease. The most appropriate measurement would probably examine
> resolution of signs and symptoms as Dr. Fleming talked about this
> morning.
>
> Radiographic scores are not validated and we have heard this morning
> that they don\'t correlate with signs and symptoms anyway. The x-ray
> may resolve long beyond the time of signs and symptoms.
>
> The correlation with microbiological surrogate endpoints and clinical
> outcomes has not been demonstrated to date. I don\'t want to steal Dr.
> Anon\'s thunder, but hopefully he is going to tell us about some
> microbiologic information of how to obtain it in this disease, which
> we are very interested in, but we cannot accept micrologic endpoints
> as the sole measure of efficacy in acute bacterial sinusitis without
> knowing how that correlates or is validated actually with clinical
> outcomes.
>
> The time to resolution of disease may be most appropriate in
> self-resolving diseases. Have we used time-to-resolution endpoints in
> other infections? Yes, we have, the influenza trials and also trials
> in traveler\'s diarrhea, which are both self-resolving diseases, for
> the most part, use exactly this kind of analysis. This is what I
> wanted to show you.
>
> \[Slide.\]
>
> This is the time-to-event analysis in a clinical trial based for the
> approval of oseltamivir, a neuraminidase inhibitor. As you can see,
> even at 480 hours, almost everybody is better whether they received
> placebo, which is the solid line, or one of two doses of oseltamivir.
>
> If one were to evaluate the trial out here, and if you did a fixed
> time point in this influenza trial, this drug would never have been
> more effective than placebo. Even though this is still a small benefit
> out here of the drug compared to placebo, the sample size necessary to
> demonstrate that would have been exceedingly large.
>
> On the other hand, if you moved back here to an earlier time point,
> you can see the difference between drug and placebo is much greater
> and therefore you can use a small sample size, as well. So, doing an
> analysis like in acute bacterial sinusitis may be able to allow us to
> demonstrate a bigger difference between drug and placebo in a smaller
> sample size.
>
> Again, there is an issue with this and that is how do you measure
> this. In influenza trials, they measured this using twice daily
> patient diaries that were actually validated by the drug sponsor.
>
> This is one of the things I want to bring up for academic
> investigators to help us. What we have noticed is that when we look
> back through these trials, if the drug sponsor develops this scoring
> system, they keep it. It is proprietary information, and if you look
> back through this trial, it says that the sponsor has this on file,
> and there is a reason why, because if they spent all the money doing
> this validation program, they don\'t want their competitors having
> this validation scale.
>
> So, what we could really benefit from is if somebody out in academics
> gives us a validated scale that we can all use across these trials.
>
> \[Slide.\]
>
> So, what are our proposals for going forward? Well, we would like to
> propose defining the population with bacterial disease at baseline by
> sinus puncture. We would suggest\--and we would like some more
> discussion about this this afternoon\--that this not necessarily
> requires 7 days of symptoms, again because if the benefit of
> antimicrobials is early in the disease, we may miss that if we wait 7
> days into the treatment.
>
> This may actually result in fewer punctures. Our hope that doing the
> micro-only trials would result in fewer punctures did not pan out. We
> are tapping almost 600 people per drug right now. Perhaps this would
> improve the selection criteria for clinical practice, as well, and
> this is one of the things I think we feel strongly about. Rather than
> just using these trials to get a drug approved and on the market, can
> we use these trials to advance the science, analyze who has bacterial
> versus viral disease, and pick out the clinical signs and symptoms
> that may actually predict who clinicians need to treat.
>
> The second thing is superiority trial design of symptomatic therapy
> versus symptomatic therapy plus an antimicrobial, and we need to
> discuss appropriate exclusion criteria this afternoon.
>
> The other issue is it is very difficult for us to allow resistance
> claims for a given antimicrobial in acute bacterial sinusitis when one
> doesn\'t know the impact of any organism or any drug. You may give a
> drug and make the organism go away, which may be resistant to the
> original therapy, so optimizing pharmacodynamic parameters may make
> the bug go away, what we don\'t know is how does making the bug go
> away impact on the resolution of clinical symptoms in this disease.
>
> Thirdly, the endpoint of time to resolution of symptoms, again, we
> would like to suggest something to the previous influenza trial, but
> this would require a validation of some patient diaries and looking at
> those endpoints.
>
> Thanks.
>
> DR. LEGGETT: Dr. Wald.
>
> DR. WALD: I don\'t know if you want to reserve the discussion for this
> afternoon, but just in terms of the idea of puncturing early, I think
> again we have to take into consideration there are probably two
> populations of patients, one who have urgent disease or severe
> disease, or whatever we might want to call it, and then a second, much
> larger group which defines itself by the persistence of respiratory
> symptoms.
>
> In that group in particular, on the third day, those kids, those
> adults all look alike, they have a cold. At that point they have a
> cold, they don\'t have acute bacterial sinusitis. If we were to
> puncture them then, I think we would not identify a group of patients
> who are likely to benefit from antimicrobials.
>
> DR. LEGGETT: Thank you. Let\'s go to lunch. We come back at 1:15 for
> the open public hearing.
>
> \[Whereupon, at 12:25 p.m., the proceedings were recessed, to be
> resumed at 1:15 p.m.\]
>
> \- - -

[A F T E R N O O N P R O C E E D I N G S]{.underline}

> \[1:25 p.m.\]

**Open Public Hearing**

> DR. LEGGETT: We have one speaker, Dr. Jack Anon, who is from the
> University of Pittsburgh, who would like to speak on behalf of Paul
> Ambrose and Ron Jones for approximately 10 to 15 minutes maximum.
>
> Is there anyone else in the audience who would like to speak during
> this open session?
>
> \[No response.\]
>
> DR. LEGGETT: I would like to read the following for general matters
> meetings, such as this guidance document review.
>
> Both the Food and Drug Administration and the public believe in a
> transparent process for information gathering and decisionmaking. To
> ensure such transparency at the open public hearing session of the
> Advisory Committee meeting, FDA believes that it is important to
> understand the context of an individual\'s presentation.
>
> For this reason, FDA encourages you, the open public hearing speaker,
> at the beginning of your written or oral statement to advise the
> committee of any financial relationship that you may have with any
> company or any group that is likely to be impacted by the topic of
> this meeting. For example, the financial information may include a
> company\'s or a group\'s payment of your travel, lodging, or other
> expenses in connection with your attendance at the meeting.
>
> Likewise, FDA encourages you at the beginning of your statement to
> advise the committee if you do not have any such financial
> relationships. If you choose not to address the issue of financial
> relationships at the beginning of your statement, it will not preclude
> you from speaking.
>
> Dr. Anon.
>
> DR. ANON: Thank you.
>
> First of all, I paid for my own ticket and everything for the meeting.
> I have had consulting work, as I mentioned earlier, with
> GlaxoSmithKline, Aventis, Bayer, Bristol-Myers, and I think that\'s
> about it.
>
> If I left anybody, I apologize, but I have done work for a lot of
> companies, but basically, research and lecturing, et cetera.
>
> \[Slide.\]
>
> What I would like to do is present a new technique that we have
> developed called serial sinus sampling, and if anybody has a really
> cool name for this, we would appreciate it.
>
> \[Slide.\]
>
> Paul Ambrose is here in the audience, as well as Ron Jones, and the
> three of us are the main investigators for this.
>
> \[Slide.\]
>
> As we saw a little bit ago, there are different ways to look at the
> paranasal sinuses and acute bacterial rhinosinusitis. One technique is
> use clinical diagnosis alone, supplanted with plain film x-rays, or
> CT, or ultrasound, with observation and resolution of symptoms.
>
> \[Slide.\]
>
> Here we see again a plain film x-ray with near fluid level in the
> patient\'s left maxillary sinus, which is screen right.
>
> The other way to do it is to do an initial sinus puncture, get
> bacteriology, and we assume that resolution of symptoms implies
> resolution of bacteria. Finally, we can do follow-up puncture and
> culture, and as a matter of fact, Jack Gwaltney, as far as I know, is
> really the only one that has ever done that in the United States a few
> years ago in a study, one of the cephalosporins.
>
> \[Slide.\]
>
> So, what we have done is we have taken the indwelling catheter. This
> is the video that you saw earlier, the SinoJect, and what we realized,
> I saw this at a meeting a few years ago and I bought one, brought it
> back, and we were using it to irrigate the sinuses, and it did work,
> and then we started using it to take bacterial cultures during
> studies. So, we would tap the patient, take the culture, pull it out,
> and we were done.
>
> Paul Ambrose and Ron Jones, and some others, and I were sitting down
> talking one day, and we said, you know, rather than take the sucker
> out, why don\'t we leave it in and let\'s see what happens over the
> ensuing days.
>
> We will sure you that we are now able to get data from that regarding
> the bacteriologic time curve kills, as well as pharmacokinetic and
> pharmacodynamic data.
>
> \[Slide.\]
>
> This is a pilot study that we just presented at ICAAC recently and we
> have submitted for publication, and we look at a five-day course of
> gatifloxacin 400 mg. The patients were 18 years and older, and we
> looked at symptoms for more than 7 days. Again, this is what we were
> discussing this morning, and we did have radiologic evaluation to show
> maxillary air fluid levels, and this was sponsored by Bristol-Myers.
>
> \[Slide.\]
>
> We then put a catheter in on day one. We withdrew a small specimen,
> and in the ensuing five days, every day we would draw a small specimen
> for bacteriologic analysis, and on day 4, we did a
> pharmacokinetic/pharmacodynamic day where the patient stayed in the
> office, had movies, lunch, books, et cetera, we provided all that, and
> what we did was we would draw blood and we would draw out of this
> catheter, material, and we then analyzed it for the gatifloxacin
> concentrations.
>
> \[Slide.\]
>
> This is the catheter that we initially started to use and to show you
> that the future governor of California was our first volunteer. There
> is the specimen being taken. It was quite painful for him, no, but
> actually this is the catheters we saw this morning in the system, and
> it is called the SinoJect.
>
> \[Slide.\]
>
> What we do is we load the catheter onto the end, pull the stopcock as
> we showed, put it into lateral nasal wall, and push the button. Number
> one, we don\'t have to hold the patient\'s head as was alluded to this
> morning, and actually, this is very not uncomfortable. As a matter of
> fact, I will comment, I think having my tooth drilled is more painful
> than this.
>
> \[Slide.\]
>
> Then, we put the lavage tube in and just took a very small amount of
> material out. The key was not to take out much material each time
> because we did not want to use it for therapeutics, and also, we did
> put a small amount of saline in at the end of each time, but it was
> just enough to flush the tube out at the end. Again, we did not want
> to do anything that would like therapeutics.
>
> \[Slide.\]
>
> This is actually a picture of the catheter in the maxillary sinus on
> screen left, and on the right is the x-ray we had actually taken of
> patients, and it shows the catheter.
>
> By the way, in response to a question earlier, I happened to co-author
> a book on sinus anatomy a few years ago, and what we know is that 65
> percent of sinuses will be below the floor of the nose, 20 percent
> will be even, and about 20 percent will be above the floor of the nose
> and intermeatus, so when you do these taps, that is something you need
> to watch for.
>
> \[Slide.\]
>
> Here, we plotted out our gatifloxacin exposure of plasma versus sinus,
> and we see the curves here, which actually match very nicely in the
> group. If we look at our Cmax\'s and AUCs, we see our sinus aspirate
> versus plasma, and I won\'t go into all the pharmacokinetics of that
> which is not really important.
>
> \[Slide.\]
>
> This is our pathogen distribution. We can see here the historical
> distribution as quoted by Jack Gwaltney at 10:15 this morning,
> 1029.03. We see in our pilot study that our evaluable patients and the
> rest of our bacteriology very closely match what is historically seen,
> so that is of interest.
>
> \[Slide.\]
>
> If we focus in on our Strep pneumo patients, what we found was that in
> each of the study days, we were able to see the Gram stain, as well as
> cultures, dramatically drop. We found that our mean time to
> eradication was 50 hours, which is really the first time we have been
> able to follow the march of bacteriologic change over the course of
> therapy.
>
> \[Slide.\]
>
> So, when we ask the question how long do we need to treat,
> bacteriologically, in our pilot study, we have shown a median is about
> 50 hours. What we found was that all the bacteria were gone in 72
> hours if we took all comers in the study.
>
> \[Slide.\]
>
> This is just the 4 Strep pneumos. We got rid of the rest of the
> bacteria and just focused on what we consider to be the main
> pathogens. So, yes, the numbers are small, but we wanted to just focus
> it down.
>
> \[Slide.\]
>
> Now, the question is what is the relationship of symptoms versus
> bacteriology. So, what we did was we asked the patients all their
> symptoms, and we monitored the symptoms versus time to resolution of
> the bacteria, and what we found was the majority of patients, sinus
> pain resolved.
>
> Dental pain resolved in everybody, sinus tenderness resolved in
> everybody, purulent nasal drainage in the majority of patients, we
> still had 2 with persistent, headache in almost every patient, and
> facial pressure in almost every patient. Nasal congestion decreased in
> the majority, as well as postnasal drip.
>
> \[Slide.\]
>
> So, as we discussed this morning, this is really the first time that
> we can take the actual bacteriologic time curve kill and correlate it
> with symptoms as we used in our study. Obviously, as you were
> discussing this morning, we could look at a more complicated and more
> complex symptom scoring measure, et cetera, and apply it to make all
> the studies fairly even throughout if one would look at that.
>
> \[Slide.\]
>
> Cough and sore throat disappeared on everybody.
>
> \[Slide.\]
>
> As for our future studies, one thing we are looking at now is we are
> actually going to look at the inflammatory mediators. As we do the
> study, we are actually going to sample and send off for the evaluation
> of that, because as we mentioned this morning, there is a lot of
> up-regulation of the inflammatory disease process and acute bacterial
> rhinosinusitis.
>
> As an adjunct therapy, and actually I mentioned this to John Powers
> when I spoke to him recently, is I think that steroids actually do
> play a big role here. I will tell you clinically, in our practice, all
> patients who have acute bacterial rhinosinusitis, we do use steroids
> to treat, and feel in our hands that we do have improvement, but I
> don\'t have science behind that, and I am just throwing that out as a
> clinical observer, not as a scientist.
>
> That\'s it and I thank you very much.
>
> DR. LEGGETT: Thank you.
>
> Dr. Anon, a question. Can you tell me more about how long you waited
> before you chose these people, and how long you waited, did you wait
> to get a bacteria, or how did you initiate therapy?
>
> DR. ANON: What we did was initially, we took all the comers who had
> symptoms for more than 7 days and had the symptom complex that we
> equate to acute bacterial rhinosinusitis, and at the 7 days, those are
> patients that are usually getting worse.
>
> Now, as we moved through the study, it is very labor-intensive,
> needless to say, and what we did was we actually did endoscopic
> cultures on some patients, and if it came back as positive, then, we
> would go ahead and put them in the study the following day, so we
> waited one day.
>
> I think this is the way to enrich the group of patients. We do find
> that there is about an 80 percent concordance. As a matter of fact, we
> did endoscopic cultures on all of our patients, and in our small
> study, we had 100 percent concordance with endoscopic versus tap.
>
> So, I am not saying it\'s the gold standard, but it was something we
> were able to do.
>
> DR. LEGGETT: Dr. Cross.
>
> DR. CROSS: Normally, if we have an indwelling catheter with an
> abdominal infection, we are very leery of putting any stock in the
> cultures that we get out of the catheter. I was just wondering whether
> or not you evaluated the issue of possible contamination when you
> leave the catheter in the nose over four or five days.
>
> DR. ANON: Contamination of what aspect?
>
> DR. CROSS: Of having other organisms. I mean were you looking only at
> the loss of your isolate on the initial culture, or had you been doing
> complete cultures at each of those time points, in fact, looking for
> other organisms, as well?
>
> DR. ANON: What I will do is Ron Jones, if I may defer, he did all of
> our micro work, so I will allow him to comment.
>
> DR. LEGGETT: Tell us about your potential conflicts of interest.
>
> DR. JONES: Currently, well, let\'s go back about three years. I am
> funded by approximately 29 different pharmaceutical companies for
> various aspects of in-vitro test development, as well as evaluations
> of new drugs as far as laboratory levels and surveillance studies. Do
> you need the whole list?
>
> DR. LEGGETT: Go ahead.
>
> DR. JONES: Thank you.
>
> What we did in the studies, as you saw from the outline on one of the
> slides, is there was daily samples taken over the time period. The
> paired sample in the beginning was at the ostia of the sinus, as well
> as the puncture, the paired sample, and the pathogen, and in every
> instance, was found as part of normal flora of the nose, as well, and
> was found as a single pathogen in the sample that was taken from the
> sinus.
>
> Over the subsequent 4 days of sampling, no contaminant emerged at all
> in the 14 drug-bug pairs that we did in the 12-patient population of
> the pilot. So, as far as an evaluation specifically for contamination,
> all we can talk about is just the 12 patients, and it did not occur at
> all in that population.
>
> This is the results at each time. Getting back to an issue that was
> brought up by Barth Reller about the correlation of semiquantitative
> use, bacteriology in these types of situations and the correlation
> with counts, I would go and just say what Barth just said is
> absolutely correct, about the semiquantitative streaking on plates of
> the specimens, as well as the correlation with the actual Gram stain
> smears, was essentially at a 100 percent level, so we can use
> semiquantitative or move on to using more dilutions and quantitation
> if needed.
>
> DR. LEGGETT: Thank you.
>
> Ciro.
>
> DR. SUMAYA: With obtaining the sinus aspirate via the SinoJect, how
> many times has this been done, not only in your experience, but in
> others, the procedure, and has it been included in children,
> particularly young children, and have there been any adverse side
> effects?
>
> DR. ANON: Number one, the SinoJect has been used by a number of sites
> for clinical studies. As a matter of fact, Jack Gwaltney\'s group uses
> it, I believe still?
>
> DR. GWALTNEY: No, we have never used it.
>
> DR. ANON: I apologize. I know there are some other groups that use it,
> I don\'t know how many, I couldn\'t tell you. No one has ever done an
> indwelling study before, it has never been done like that. In
> children, anytime you do an inferior meatal antrostomy, you need to
> make sure that the maxillary sinus has expanded below or is at the
> level of the floor of the nose.
>
> While I do a lot of pediatric otolaryngology, all of our studies have
> been in adults, and I have not done children as have Dr. Wald.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: In looking at the mechanism of repeated sampling from
> your system, and knowing that the consistency of the fluid in the
> sinus can be anywhere from thin to extremely thick, having seen Dr.
> Gwaltney\'s slides this morning and having some experience with otitis
> media in kids, once you get your initial tap, in some of these cases,
> I would imagine that the mucus and pus is so thick that you may have
> to irrigate.
>
> Once you irrigate, you sort of set up a change in pathophysiology of
> the sinus disease itself, and when you go in each day subsequently, I
> am wondering whether you have to add saline to lavage or whether you
> can just have someone tip their head back, or whether you put a little
> catheter through this catheter to fish around this sinus, but then if
> you have a tiny little catheter, you may not get the big hunk of thick
> pus.
>
> Can you tell me mechanically how reliable daily sampling is?
>
> DR. ANON: First of all, we do not lavage the sinus. When we have
> really thick mucus, we just put in about maybe 1 cc of
> non-preservative sterile saline. If you consider that the sinus volume
> is about 30 cc, I don\'t think that really affects it.
>
> Number two, yes, we actually did the teapot approach. I don\'t have
> photos, but I have had patients, we tried to figure out every
> mechanism that there is to put the head, and, yes, there were times
> when we just couldn\'t get anything. The catheter is very small
> because that is the way it was designed. Actually, we are looking at
> doing some research, actually, we have done some research on
> developing a larger catheter that won\'t clog, and also we have a
> stopcock, we are looking at trying to put at the end, so there will be
> no questions about contamination, aeration, or anything else, and we
> have got actually designs on the drawing board for that.
>
> The other thing I would like to do, the sinus, if you saw in the
> photos even from the company, the catheter sits fairly high, and we
> are also conceptualizing a small curve that we can actually go in a
> little bit more, so we get into the depth of the sinus, and then just
> pull it back out.
>
> DR. LEGGETT: Don.
>
> DR. PORETZ: You said your patients were on steroids. Were all your
> patients \--
>
> DR. ANON: No, sir, not in the study. My patients that I treat in my
> office, that are non-study patients, I put them all on
> corticosteroids.
>
> DR. PORETZ: Are those systemic steroids?
>
> DR. ANON: Yes.
>
> DR. PORETZ: Or inhaled steroids?
>
> DR. ANON: No, as does Jack Gwaltney, I believe, that nasal inhaled
> steroids do not play a role in the disease, and I believe that it\'s a
> rhinosinusitis is the proper term, which is inflammation of the upper
> airway, and that oral prednisone in our hands is what we use to treat
> the inflammatory component.
>
> DR. PORETZ: And you treat all your acute sinusitis patients with
> steroids?
>
> DR. ANON: Yes, all my adults.
>
> DR. PORETZ: In conjunction with antimicrobics?
>
> DR. ANON: Yes.
>
> DR. LEGGETT: Thank you.

**Charge to the Committee**

> DR. COX: I just wanted to start out first by thanking the presenters
> today for a series of very insightful and excellent presentations on
> acute bacterial sinusitis. I think today\'s discussions and the
> committee\'s advice that we receive will be very helpful to us as we
> revisit and further refine the guidance that we provide with regards
> to clinical studies in acute bacterial sinusitis.
>
> We have three questions today to guide us through our discussions on
> several key issues in clinical trial design.
>
> \[Slide.\]
>
> The first question is: How does one ensure that patients in clinical
> trials of acute bacterial sinusitis have bacterial disease? Please
> discuss the methods of obtaining microbiologic data including sinus
> punctures and nasal endoscopy.
>
> Some of the elements that the committee might want to consider in
> their discussions, based on what we have heard today, might be the
> role of diagnostic methods, such as sinus puncture for microbiologic
> evaluation, methods for obtaining these samples, and then also how a
> more highly characterized patient population might influence the
> efficiency of the studies that would be performed in acute bacterial
> sinusitis.
>
> In addition, we also heard information discussed with regards to
> clinical and radiographic criteria. We also heard discussions about
> the duration of symptoms that patients might have who might be
> eligible for study and also that there may be different populations of
> patients, those with more urgent disease and those with more
> persistent disease.
>
> I think this also dovetails some with the method for microbiologic
> sampling and the timing at which any diagnostic procedure to obtain a
> microbiologic diagnosis might occur.
>
> \[Slide.\]
>
> The second question. The second question deals with a couple of issues
> in clinical trial design.
>
> Please discuss the issues of trial design in the study of acute
> bacterial sinusitis. Please include in your discussion:
>
> The strengths and limitations of placebo-controlled trials and
> non-inferiority trial. Please discuss how one determines a
> non-inferiority margin in non-inferiority trials for this indication.
>
> Also, please discuss the strengths and limitations of comparative
> microbiologic data.
>
> We have heard discussions today on the challenges of determining a
> non-inferiority margin based upon the available data from studies in
> acute bacterial sinusitis, and we have also heard some discussion on
> the issue of placebo-controlled studies and some of the safety
> provisions that might be included within the trial design, such as
> certain exclusion criteria or provisions for referral off protocol if
> safety dictates, for example, in the setting of disease progression.
>
> I think it also deserves comment that many of the clinical trials that
> we review these days are multinational studies. In looking at these
> data, the factors that we consider include the relevance of the
> disease in the population under study to that in the U.S. population,
> the use of adjunctive therapy, the use of the comparators that might
> be used in these multinational studies.
>
> It goes without saying for trials, both U.S. and/or studies abroad, it
> is essential to assure that there are adequate provisions to protect
> patient safety and also that adequate patient informed consent occurs
> in the study, whether it be in the U.S. or internationally.
>
> As we move on to the second part of the question, the second part of
> the question intends to address the issue of the micro-only study,
> which is often a non-comparative study.
>
> I think really what we are asking the committee to comment on here is
> the potential value of adding microbiologic data in a comparative
> trial.
>
> \[Slide.\]
>
> Moving on to Question 3. Question 3 asks for advice with regards to
> the endpoints in trials of acute bacterial sinusitis.
>
> Please discuss the issues of measuring outcomes in patients in trials
> of acute bacterial sinusitis. Please include in your discussion
> measuring time-to-resolution of symptoms as an endpoint compared to
> fixed endpoints.
>
> I think this question speaks to the issue of the research question
> that we are trying to address in acute bacterial sinusitis. We have
> heard comments today both talking about fixed endpoints and
> time-to-resolution endpoints.
>
> I guess just one additional comment I will make here is that one of
> the other potential considerations here is the effect that using one
> of these types of endpoints might have on the sample size and the
> efficiency with which studies of acute bacterial sinusitis could be
> conducted as it may be influenced by the endpoints that are used to
> determine the primary efficacy outcome.
>
> With that, I will turn it back to Dr. Leggett.
>
> DR. LEGGETT: Thank you.
>
> I would like to remind everybody that there is not going to be a vote
> at the end of this session. It is just for our discussion purposes.
> Also, several members of the committee have planes to catch, so if we
> could keep our comments pithy, it would be very helpful.

**Committee Discussion**

> DR. LEGGETT: Regarding the first question, how does one ensure that
> patients in clinical trials of acute bacterial sinusitis have
> bacterial disease, would anybody like to start? Janet.
>
> DR. ELASHOFF: I certainly don\'t have any specific notions about this
> from a medical point of view. I just want us to keep in mind that
> however we do the trial, we want to be able to tell physicians who use
> the antibiotic later, who they should be using it on in a way that
> they will actually be able to use that information, so that in
> designing the trial, we need to keep that in mind in terms of how we
> specify who goes in and who has profited.
>
> DR. LEGGETT: Anyone else? Dr. Bradley, can you start us off?
>
> DR. BRADLEY: I was going to wait until Dr. Wald made a few comments.
>
> DR. WALD: All right. I think, one, we talked a lot today about what
> the gold standard is, and I think if we subject the patient who we
> suspect\--and we can talk about why we suspect it in a moment\--if we
> suspect the diagnosis of acute bacterial sinusitis, if we do a sinus
> aspiration and we recover organisms in high density or a positive Gram
> stain that we regard as likely etiologies, then, we know we have acute
> bacterial sinusitis. I think that is the gold standard and the proof
> of disease.
>
> I think that I would try to select a population that I thought was
> highly likely to have bacterial disease, and I would do that on the
> basis of clinical primarily symptoms because patients don\'t have
> that.
>
> The physician examination unfortunately of most patients with acute
> bacterial sinusitis does not distinguish them from patients with acute
> rhinitis, so you can\'t look at a patient and know that they have
> sinusitis, you can only know that they have respiratory symptoms, so I
> think we rely very heavily on historical items.
>
> I would again say that there are probably two presentations that we
> may want to at least stratify for, and the classification that Dr.
> Gwaltney suggested as urgent, or what I have called in the past
> \"severe\" disease, and a second presentation of more persistent
> symptoms.
>
> The more stringently we describe those two categories, I think the
> higher likelihood of getting a positive bacterial aspirate or feeling
> secure that we are dealing with a population that has acute bacterial
> disease.
>
> In my studies of children, I have used a 10-day rule, 10 days of
> respiratory symptoms, either nasal discharge or cough, or both, that
> were not improving, and again with an emphasis on the \"not
> improving\" part because there are many patients with respiratory
> symptoms that are resolving, but are present at 10 days.
>
> So, I think the more tightly we can describe that population, the more
> likely we will have identified a group of patients that are different
> from patients who have simple, uncomplicated viral URI.
>
> DR. LEGGETT: Could you or Dr. Gwaltney give us some specifics about
> which symptoms, how many symptoms? Should we try to make the symptoms
> be the same for all the drugs, that sort of thing?
>
> DR. GWALTNEY: I am not quite sure what you mean when you say the
> symptoms be the same for all the drugs.
>
> DR. LEGGETT: When we looked at the published trials, one trial had
> just facial pain and the fever, and the other trial had postnasal drip
> or cough or purulent discharge, what should be the bottom line number
> of things that need to be there for us to clinically think that this
> person was more likely to have acute bacterial sinusitis.
>
> DR. GWALTNEY: One of the good things, if a placebo-controlled trial
> were to be done in which sinus aspirate cultures were taken before
> onset of treatment, and either a post-therapy culture or the method we
> saw described by Dr. Anon, if that kind of trial was done, one of the
> great benefits would be that we, for the first time ever, would have a
> correlation between symptoms and symptom patterns, and the presence of
> infection.
>
> So, we would learn a lot, which then would help us in the future
> maybe, or maybe not, maybe it wouldn\'t. I would think the thing to do
> about the symptoms, we have done a number of studies on the common
> cold, and there are about seven symptoms - sneezing, runny nose, nasal
> obstruction, cough, sore throat, headache, et cetera, and there are
> systems that have been designed and pretty well validated based on
> severity of the symptoms.
>
> The type of data are, of course\--what is the word I want\--they are
> non-parametric data, but they still I think are important because the
> illness is what bothers the patient. So, this system collects these
> symptoms on a daily basis and the patient quantifies the severity of
> the data, and this kept up during the course of the illness.
>
> So, not only can you determine the length of the illness, but you can
> also determine the severity of the individual symptoms, and it would
> seem to me that that would be the kind of a symptom record that would
> be good to keep in this type of study.
>
> Now, as to what you would require to put the patients in the study, I
> think Dr. Wald has done a nice job in terms of what she just said. I
> believe it probably would be of value to enroll patients after a
> certain duration of illness, because I think the chances of getting a
> positive bacterial culture would go up if you waited for a week or\--a
> week, to me, would sound like a reasonable period of time\--and not
> being improved. I think we have to keep emphasizing that because it
> kind of gets lost in the discussion, but it is not just the symptoms
> are there, they are not improved.
>
> I think with that kind of collection of clinical data and correlating
> it with results of Gram stain and culture, we could learn a tremendous
> amount about the clinical picture of the disease in addition to
> learning whether antibiotics had any benefit in the treatment of the
> disease.
>
> DR. LEGGETT: What about the use of x-rays and\--did you have something
> to say, Don?
>
> DR. PORETZ: I just wanted to ask, do you really believe that patients
> would volunteer to be in a study if there was placebo-controlled arm
> especially if they go through a sinus puncture?
>
> You have done this for several years, patients would be willing to be
> on a placebo arm?
>
> DR. GWALTNEY: I think in the current environment in which I think the
> public is pretty much aware of the fact that antibiotics are not what
> you should get all the time when you have an illness, and in talking
> with physicians, I think there are patients that come in and when they
> really need antibiotics, will turn them down if, say, they have a
> strep throat or something, so I don\'t think there would be any
> trouble enrolling enough patients to do that, particularly if they
> were told they were being followed carefully.
>
> I guess there is an advantage of having an indwelling catheter in that
> you really have a handle on what is going on. You could do a Gram
> stain every day, do a culture every day, although I am not sure it is
> necessary to do it daily, so, in addition to monitoring the severity
> of the patient\'s illness and determining what is happening, whether
> they are getting worse or getting better, you have bacteriologic data
> to guide your treatment, and if somebody seems to be getting in
> trouble, you can always take them out of the study and treat them.
>
> It would seem to be it would be a pretty safe kind of a study that
> would be ethically justified on the basis of safety.
>
> I think you could argue do we have enough information now. Medicine is
> an art obviously and I think there is a fair amount of compelling data
> that convinces me that antibiotics do work.
>
> I would be honest in doing a trial\--although I am not going to be the
> one to do it\--but I do think they work based on what has been
> published, but I still think it might be worth going on and doing the
> placebo-controlled trial and settle this issue which has been banging
> around now for three decades and doesn\'t seem to be getting resolved.
>
> DR. LEGGETT: Dr. Powers.
>
> DR. POWERS: I think this issue of patients and antibiotics has two
> sides to it that never gets brought out. One of the placebo-controlled
> trials that I presented, that was done in Europe, there were
> approximately 200 or so patients who refused to be in the trial.
>
> A hundred or so refused because they absolutely wanted antibiotics, 72
> refused because they absolutely did not want antibiotics, and I think
> that is the side of the story that we keep forgetting. There are
> patients who are very willing not to get an antimicrobial in this
> disease.
>
> DR. LEGGETT: Any other comments?
>
> DR. GWALTNEY: I think it goes without saying the patients who were not
> treated would be offered treatment at the end of the study if they
> wanted it, so it would not be that they would never receive treatment.
>
> DR. WALD: I think that is important, in fact, the fail-safe might be a
> whole lot less than 10 days. This is why I think somehow a score is
> going to be important because I think you would need to have some
> semi-objective ways to say that a patient was getting worse, or if
> they were even not improved at 72 hours, you could call that a
> failure. I mean expect antibiotics to kick in by 72 hours, so if
> someone was no better according to some score or some schema, then,
> you could say that they popped out of the study and that they deserved
> antibiotic therapy. Certainly, if they worsened, that would be a call
> to drop them out.
>
> So, I think you would need that kind of very close attention to
> detail, so that patients would be assured that they are not going to
> be left out there dangling.
>
> Just to go back to I think the question that you asked, which was what
> are some minimum specific criteria that we are going to use to define
> the patient groups. I don\'t know if people felt satisfied.
>
> If we talk about the urgent group, would we want patients to all have
> fever, do we want them all to have facial pain, do we want them all to
> have purulent discharge, I mean are there some minimal criteria that
> make physicians want to treat patients urgently, and if there are,
> what are they.
>
> The second presentation, I think is easy. I really think you really
> can use duration, and you can use very simple things, because you
> can\'t probably ask someone who has got intense headache and a fever
> to wait 7 days, clearly, you are not going to do that.
>
> So, the patients that you can ask to wait 7 or 8 or 9 days are those
> patients who have no fever, but have instead these persistent
> respiratory symptoms which are spoiling their quality of life. It is
> not killing them, it is just making them uncomfortable.
>
> So, those are the patients I think that we could simply look at
> duration of simple things like nasal discharge, or cough, or both.
>
> DR. LEGGETT: Would fever, purulent discharge, and facial pain be
> enough to adequately filter out viral rhinosinusitis in an urgent
> situation?
>
> DR. WALD: I think you are going to get some influenza in there, there
> is no question about it. I think it is a much harder group to figure
> out really who has bacterial disease, and it actually I think
> heightens the importance of the aspirate.
>
> I mean at 10 days, when someone is still symptomatic and not
> improving, I feel pretty confident that they have a bacterial
> component to their disease. At 3 days, you know, you can be pretty
> miserable with a lot of viral upper respiratory infections, so I think
> it is harder to sort out, but I think that would be a good beginning,
> fever, purulent nasal discharge, probably with headache in the older
> patients maybe with facial pain.
>
> DR. LEGGETT: Would you lump them all in the same group, or would you
> make sure they are somehow stratified into two separate analyses?
>
> DR. WALD: I think you absolutely have to stratify them.
>
> DR. LEGGETT: What is your opinion about the relative frequency, would
> we get an \"n\" big enough to make any sense with that urgent group?
>
> DR. WALD: I have to defer to the adult, the people who care for
> adults.
>
> DR. GWALTNEY: Maybe Dr. Sydnor can answer this better than I can. It
> is my impression that the number of people that present in the urgent
> category is relatively small. I think if you were only to do a study
> of that group, it would take quite a bit of work and quite a number of
> sites to do that.
>
> I really don\'t know the proportion, but I would say it is probably 1
> to 10, or even 1 to more than 10, the ratio between those two groups.
>
> DR. SYDNOR: I would agree with you heartily.
>
> DR. LEGGETT: So, it sounds a lot more feasible in trial design, even
> though we would like to capture that urgent group, that we sort of
> limit it to 7 or 10 days of symptoms, and then just allow people to
> treat the early ones, and not put them in the study.
>
> John.
>
> DR. BRADLEY: I think again that the microbiology is going to be an
> essential part of the studies and however you design the entry
> criteria, the stricter you make it, with the more symptoms including
> fever and pain, duration of disease, that you will enrich for the
> bacterial components.
>
> But if you ease up on the entry criteria, you will still get some
> bacterial patients, but they will be fewer as they go into your study,
> but as you evaluate the two arms of the study, whether it is placebo
> controlled or comparator controlled, you will be able to track symptom
> response in both groups.
>
> In terms of the microbiology, which we were discussing this morning, I
> think either this catheter, which looks like it would work for adults,
> I have some trepidation in sending a kid home with a little nasal
> thing in his antrum or her antrum, but the repeated sinus punctures,
> which Dr. Sydnor seemed to think were relatively benign, might be
> another way that we could reproduce the double tap otitis media types
> of studies.
>
> We now know that probably you would want to get that second tap at
> around 5 days plus or minus a day or two, so that you could get some
> nice comparative microbiology between the two arms.
>
> The other point that Dr. Powers keeps bringing up is that although
> microbiology is very important, the symptomatic relief of disease is
> also important, and although they are certainly correlated, there is
> not a one-to-one correlation, and with otitis, with certain
> antibiotics, you seem to have persisting positive cultures, yet, you
> have got a clinical response, which is what the parents and the
> children perceive, and you can have children with negative cultures
> who have horrible disease, who would be considered clinical failures,
> but it is probably a small proportion that just have intense
> inflammation that could be address with anti-inflammatories, and not
> antibiotics, we will get wonderful information on the natural history
> of sinus disease as the studies go forward.
>
> DR. LEGGETT: Dr. Powers, you talked about the correlation between
> success or the lack of optimal or suboptimal, however, you said,
> between the cultures in the otitis.
>
> How about the flip side, how about the correlation between failures
> and persistent bacteria?
>
> DR. POWERS: There is no data to do this obviously in acute bacterial
> sinusitis. Looking through the NDAs, we had one\--
>
> DR. LEGGETT: No, I mean in terms of the otitis.
>
> DR. POWERS: Right, I am just sort of taking that reference. When we
> looked at this in otitis, it is, and the correlation between clinical
> failures and people that had a persistent positive culture was very
> good.
>
> This is something I think back on that we probably should have
> mentioned back last July when we were going through that otitis media
> discussion. When we are talking about validating an endpoint, it has
> got to work in both ways.
>
> It has got to be that microbiological failure predicts clinical
> failure, but also it has got to go the other way, too, that clinical
> success has got to be micro success, as well, and what we saw was that
> is where it fell down, that people who were clinical successes, at
> least in these otitis media studies, 63 percent of those children
> still had their organism present.
>
> So, that correlation means it has got to go in both ways.
>
> DR. LEGGETT: Don\'t you think that was a matter of where you chose to
> draw the line as we saw from the 5-day data, for instance?
>
> DR. POWERS: I think it is. I think that what we are seeing is that it
> is on-therapy evaluations that become problematic and, sort of
> referable to our early yesterday discussion during the closed session,
> when one takes a microbiologic specimen at the time that the
> antimicrobial is on-board, you also don\'t really know what that means
> at that time.
>
> As Dr. Bradley is saying, perhaps what we would need to do is also do
> the clinical and microbiologic evaluations at the same time, so that
> we can correlate those two together, and also perhaps do it later on
> when the antimicrobial is not on-board.
>
> As far as the double tap studies in otitis, that is not the way they
> are done. It is done earlier in the disease when the drug is still
> around.
>
> DR. LEGGETT: Ciro.
>
> DR. SUMAYA: Although I realize that the urgent, acutely severe form,
> in contrast to the long-term persistent 7 to 10 days of
> non-improvement in a number of signs and symptoms, the severe form or
> urgent form, I would hate to just displace it, realizing that the
> numbers may be small, because I think it may provide some nice
> information clinical to microbiologic associations of correlates as
> opposed to the more persistent group, and it is one where I think we
> can obviously learn significantly about the microbial status in that
> type of patient.
>
> I think it will pay off although the numbers I have to admit would be
> small, and perhaps this could be a second stage study after we do one
> that is more with the persistent group.
>
> DR. LEGGETT: Jan.
>
> DR. PATTERSON: As far as the criteria, I agree with what has already
> been said. I think it would be useful to the clinical symptoms to
> differentiate between urgent and elective, and, like Ciro, I think we
> probably shouldn\'t exclude those urgent just because they are small
> numbers, because even if they may be less numbers, we may be more
> likely to see an effect of antibiotics with those.
>
> I want to clarify I am not against international studies and I think
> they are actually very helpful especially in terms of generalizability
> and in enrolling large numbers of patients and finding patients that
> haven\'t been pre-treated.
>
> I think actually for this particular infection, that there are U.S.
> IRBs these days even that would accept a placebo-controlled trial and
> actually have accepted that.
>
> I mean I think that a placebo-controlled trial for elective, people
> that fit in an elective category, not the urgent category, would not
> be an unreasonable thing, but I was just concerned about the
> appearance of saying that if all of our U.S. IRBs think it is
> unethical, then, why should we ask other countries to do that, so I
> was just concerned about the appearance of that.
>
> Anyway, we have kind of touched on some other things. I think that the
> idea of a study with a puncture versus antibiotics, or a puncture
> versus antibiotics plus puncture is actually very interesting, because
> if indeed the puncture is quite helpful in relieving the symptoms and
> maybe ultimately the disease, that would be I think very helpful to
> know.
>
> Another point that John made earlier, that we also discussed
> previously at these meetings, is the idea of streamlined drug
> development, and if a drug has studies that show it is effective for
> community-acquired pneumonia, that it might strengthen the case for
> other bacterial respiratory infections like this, but that we do need
> to have some specific studies looking at sinusitis because there are
> some other organisms, like staph and strep, that aren\'t involved in
> community-acquired pneumonia.
>
> DR. LEGGETT: Would several of you care to address the radiologic
> thing? Will the use of radiologic criteria likely enhance the
> bacterial yield?
>
> DR. WALD: I think imaging gives you very general information, and as
> the study that Dr. Gwaltney presented, abnormalities on images are the
> rule rather than the exception in anybody who has upper respiratory
> symptoms.
>
> So, the way I think that they are useful is twofold. One, there
> aren\'t too many otolaryngologists who would do even a sinus
> aspiration without a road map, because just as Jack Anon was saying
> before, you want to know if the floor of the nose is above or below
> the floor of the sinus, so most people are not going to want to engage
> in even a relatively simple invasive procedure without know what the
> anatomy and the landmarks are.
>
> Secondly, I think if you happened on the extraordinary patient who had
> a normal image, of course, you would exclude them from the study. So,
> I think normal images tell you the patient doesn\'t have sinusitis,
> abnormal images don\'t tell you that the patient does have acute
> bacterial sinusitis. They tell you that the patient has sinus
> inflammation, but for our purposes, especially if we are thinking
> about aspiration, I think some image is necessary.
>
> DR. LEGGETT: Would a regular x-ray be enough, looking at the things
> that Dr. Gwaltney or whoever pointed out with the air fluid levels?
>
> DR. WALD: It would be for me. I still like plain radiographs. I think
> that CTs are certainly a much more sensitive test. They tell you a lot
> more because you are looking at really many images of the paranasal
> sinuses, not just one cumulative image, but I think for this purpose,
> a plain x-ray would suffice.
>
> DR. LEGGETT: The issue of nasal endoscopy for culturing, anyone\'s
> feelings? The little data that I saw didn\'t make me very excited
> despite the fact that in the small pilot trial of Dr. Anon, it seemed
> to correlate, but we have other trials that didn\'t.
>
> Is anyone in gross disagreement? Barth, what about your take on nasal
> endoscopy cultures?
>
> DR. RELLER: I don\'t think you can make a diagnosis of bacterial
> sinusitis without a culture, and I think the cultures are of value in
> relation to the quality of the specimen. I think only the aspirates
> can be unequivocally interpreted at this point.
>
> DR. LEGGETT: What are people\'s takes on a trial design, such as was
> shown with Dr. Anon, where we do the sinus tap, wait a day to see if
> we have bacteria, and then begin treatment in this group, not the
> urgent group, but in the group that\'s 7 days? Janet.
>
> DR. ELASHOFF: While everybody else is thinking, it means an extra, a
> definitely two-visit start-up to the trial, so logistically, it is
> more complicated and it is more expensive. I think you would have to
> know that you really wanted to do it that way.
>
> I guess you could always have a rule that they are not counted in the
> trial if they didn\'t have it, or they are analyzed separately or
> whatever.
>
> DR. LEGGETT: Dr. Gwaltney.
>
> DR. GWALTNEY: We also have the advantage of the Gram stain, and there
> is a pretty good correlation, so if the Gram stain was positive, of
> course, you have got to have, as someone said, 10^5^ organisms roughly
> to have a positive Gram stain, but if that were positive, I think that
> would be good enough evidence to go on.
>
> The limited amount of information we had from Dr. Anon, which is
> wonderful information, in that case, with the Pneumococcus, there was
> a perfect correlation in those four cases.
>
> DR. LEGGETT: But we may not be with Hemophilus or Moraxella.
>
> DR. GWALTNEY: Well, I showed you the Gram stain with the H. flu, and I
> think there is no reason to think you probably wouldn\'t see the same
> with those other organisms.
>
> DR. LEGGETT: Jan.
>
> DR. PATTERSON: Another thing that came up in the otitis media
> discussion was the effect of the pneumococcal conjugate vaccine, since
> with otitis, that is where we see the really severe distinct disease,
> and if it is being used more widely, how will that affect this
> disease? I mean will it change the character of this disease, will we
> see even less urgent or severe than we used to.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: I think on balance, the impact of the pneumococcal conjugate
> vaccine on otitis has been very small. People calculate overall cases,
> it is about 6 percent. For the type-specific pneumococcus, it is
> higher than that, but we are seeing replacement serotypes already, so
> I wouldn\'t count on it making a very big difference in the
> epidemiology especially in adults, although certainly some adults may
> harbor the same organisms as their kids.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: In looking at the original lecture earlier today by
> Renata Albrecht saying that in the draft guidance from 1999, they were
> looking for 25 pneumococcal isolates, and we have got 4 right here,
> the potential to use techniques like this, to use pretty stringent
> enrollment criteria to enrich for bacterial isolates, has the
> potential to incredibly fast-track the data analysis and potential
> approval of a drug.
>
> I mean 4 out of 25, as a pediatrician, I don\'t know if gatifloxacin
> has an approval for sinusitis in adults, but if they didn\'t, they
> would be well on their way.
>
> In terms of the numbers that Dr. Powers presented earlier, looking at
> possible drug effect with the numbers, and knowing that there is
> probably a whole set of pharmaceutical companies waiting to tap into
> Dr. Anon\'s system, John or Ed, how many patients do you think would
> be required, or Dr. Albrecht, if the microbiology were there and you
> had a system with clinical, as well as microbiologic endpoints?
>
> DR. POWERS: I think that is the data I actually showed. Remember, the
> reason why we were using only 25 organisms was because we had a
> separate microbiological trial and a separate clinical trial, so we
> weren\'t linking the two together.
>
> We were making an assumption there that if the drug came out
> non-inferior in the clinical-only trial, we just wanted to see that
> there was microbiologic efficacy in the micro trial. Well, what we
> presented today is those two things don\'t link together.
>
> What we would like to see is obviously a higher number because we
> would hope that if you use sinus aspirates to get people into the
> study, everybody is going to have a positive culture. That number 25
> wouldn\'t even be an issue anymore because we would hope that there
> would be plenty of people.
>
> What I showed is that using a time-to-resolution endpoint, that would
> be about 250 people in the trial, so this way we would get more
> microbiological data and have stronger conclusions at the end of the
> day.
>
> DR. COX: The hope is here that with the more highly characterized
> patient population, I mean you have seen the numbers that we have been
> seeing. The question is, is could it be done more efficiently with a
> more highly characterized population. What that exact number would be
> is still another issue that would be determined by statistical
> considerations, et cetera, but I think a more highly characterized
> population might reduce the number some.
>
> DR. LEGGETT: A point was made about the potential placebo-controlled
> trial of probably trying to enrich it, of missing out on the thinking
> we saw in urgent, but it was actually an emergent, frontal sinus,
> something like that.
>
> Those still represent cases of sinusitis. Should a trial for a new
> drug be limited to maxillary sinusitis given the fact that it\'s the
> most common form, or what do we do about those exclusions that were
> suggested of micro aerophilic strep in the frontal sinusitis? Alan.
>
> DR. CROSS: It seems that we really wouldn\'t have a sufficient number
> of cases of the frontal and sphenoid to actually decide whether or not
> they behave differently than the maxillary. So, it seems that you
> would have to probably substratify for that upfront and then the issue
> is will we actually be able to get any microbiologic data.
>
> I think from what we have heard, the real importance is to hook up the
> microbiologic data with the therapy, and I think that by including
> those other sinuses, it would fall outside the goals of the study.
>
> DR. LEGGETT: Ellen
>
> DR. WALD: I agree with that, and it has sort of been a sad observation
> on my part that at least 50 percent of the patients who present with
> complications, present with complications that is their presenting
> illness. It isn\'t as if they had a prodrome that we could have
> identified rightly and treated them and prevented it. They come in
> with that complication whether it is an orbital abscess or a brain
> abscess.
>
> So, although I like to think that we treat sinusitis and prevent
> complications, I think that isn\'t something we can look at in this
> context.
>
> DR. LEGGETT: Joan.
>
> DR. HILTON: For me, the clinical endpoint still isn\'t very well
> defined. I wonder if we are looking for a resolution of symptoms, and
> if that comes from patient diaries.
>
> DR. LEGGETT: Can we address that as we get to the clinical endpoints?
>
> DR. HILTON: Okay.
>
> DR. LEGGETT: I am just trying to beat this Question No. 1 to death.
>
> DR. HILTON: Sure.
>
> DR. LEGGETT: In that regard, Ed, when you talk to us, is there
> something that I didn\'t jot down to have us address?
>
> DR. COX: I think we are all set with Question 1, if you want to move
> on. Thanks.
>
> DR. LEGGETT: Tom.
>
> DR. FLEMING: Before we leave it, there are a couple of issues that I
> wanted to pursue, but I wanted to make sure because I have been very
> interested in my clinical colleagues\' insights here as to how we
> would ideally define the eligibility for this population.
>
> The motivation is clear that we want to enrich this population for
> those with bacterial infections, and yet we want to have a population
> that is representative as best possible of what we could apply in the
> real world.
>
> Having heard all of this discussion, I am trying to summarize in my
> own mind where we have come. I have heard from Dr. Wald that we might
> be looking at a combination of urgent cases, as well as for those that
> aren\'t, those that would have persistent symptoms for at least 7 days
> without improvement was clarified, so that we are more likely to be
> looking at a bacterial population.
>
> Is that essentially where we are from the consensus of what I am
> hearing, which would mean that sinus punctures wouldn\'t be considered
> to be an integral part of defining the eligibility criteria, or am I
> missing\--is somebody willing to summarize the essence of what we
> would, by consensus, define to be the patient capture population?
>
> DR. LEGGETT: My understanding may be flawed, but it was my
> understanding that everyone was going to get a sinus puncture and then
> we would follow them with clinical endpoints, so that we could link
> the microbiology with the clinical endpoint.
>
> DR. FLEMING: So, basically, it would be defining the population as I
> had summarized from Dr. Wald, but all of them would have had a sinus
> puncture to have truly done the best we could to maximize the
> percentage that had bacterial infection.
>
> DR. LEGGETT: Right, so that if you are beyond 7 days, you get that
> symptom list, and the only way you are going to get into this study is
> if you have got a fever and signs of severe illness if you are less
> than 7 days.
>
> DR. LEGGETT: Dr. Gwaltney.
>
> DR. GWALTNEY: The other thing to remember is that although these
> people may be getting sinusitis, they still have a cold, so they have
> got the cold illness and then on top of that, the sinusitis illness,
> and I think that is important to consider in answering your question.
>
> There are two methods that have been used for common cold diagnosis.
> One is the method of George Jackson, which is based on the
> quantification of the symptoms, and a minimum symptom score of 6, and
> that has been used for quite a long time.
>
> Another system is just the idea that a person has to have one or more
> respiratory symptom on a single day or one respiratory symptom for two
> or more days, a very liberal criteria, but that has worked pretty
> good, too.
>
> So, I think that without getting to the specifics, you would want a
> group of people who meet some kind of criteria like that and have gone
> the duration of illness, and then you do the aspiration, and then
> those would be the ones that get enrolled in the clinical trial.
>
> DR. LEGGETT: Go ahead, Tom.
>
> DR. FLEMING: Maybe just a comment and then a question. The comment is
> I think there is here a lot that I see very attractive because it
> makes a lot of sense to do the best we can to try to define a
> population that is maximally bacterial rather than viral.
>
> I think, getting back to Dr. Bradley\'s question, if we made the
> assumptions in Dr. Powers\' presentation, for example, that if we had
> entirely a bacterial population, we could increase the cure rate from
> 65 to 80 percent at 15 percent delta, we could then do that with a
> trial of about 350 patients, something to keep in mind is as you then
> have the fraction of people that would, in fact, be bacterial, you
> then 4-fold increase the sample size.
>
> So, if that was the case for 100 percent bacterial population, if our
> eligibility were yielding only 50 percent, then, in the spirit of what
> Dr. Powers\' calculation showed, the same size would go up 4-fold. It
> would take us, then, about 1,200 people to be able to see an
> antimicrobial effect in a population that would only have 50 percent
> bacterial.
>
> So, the motivation for capturing a population that is much more
> targeted toward bacterial is really strong. The only uncertainty that
> I have comes back to a point that I think is related to Dr.
> Elashoff\'s very first comment, and that is it is very important for
> clinical trials to be able to establish efficacy as Dr. Powers\'
> presentation had indicated.
>
> My sense, though, is I always want research to be as applicable and as
> generalizable as possible to a definable real world population, so
> once we finish the trial, if we establish that we have efficacy, have
> we established it in a definable real world population, that we can
> then go out and be able to apply.
>
> So, if sinus puncture is part of this, my question is would this then
> be an achievable definable population. Surely, it is well defined, but
> would the performance of a sinus puncture be something that could be
> presumed to be fairly widely then implemented after the trial?
>
> DR. LEGGETT: I don\'t think so, but I think the inference is that
> particular subgroup, a physician could be educated that they would not
> offer antibiotics to people that were not in that subgroup, and, in
> fact, there is an ongoing CDC and Emerging Infection Network program
> called Judicious Use of Antibiotics in Upper Respiratory Symptoms
> plastering doctors\' offices, nursing homes, daycare centers, et
> cetera, of which many states also have a copy, including Oregon, that
> we post everywhere, no antibiotics unless\... and that list.
>
> DR. FLEMING: Would that \"unless\" basically be if you weren\'t in the
> eligibility criteria, so would that \"unless\" basically mean if you
> didn\'t do a sinus puncture, then, it wouldn\'t be advised that you
> proceed?
>
> DR. LEGGETT: No, it would be that you have those symptoms, but you
> don\'t have a sinus puncture, so, in other words, you mimic that
> group, but you don\'t need a sinus puncture.
>
> DR. FLEMING: What I am not sure about, though, is with the sinus
> puncture, our intention, of course, is to achieve a much more targeted
> population with bacterial infection. If we use just the symptoms
> alone, what we could conceivably have is in the group with the
> symptoms, but where the physician and patient never went through the
> sinus puncture, we may have a much lower overall rate of bacterial
> infection, because we are not filtering out those people who, if they
> had gotten the sinus puncture, wouldn\'t have been found to have had a
> bacterial infection?
>
> DR. LEGGETT: My thought is we do not exclude those people after the
> sinus puncture if they don\'t have bacteria, they are in that group.
>
> DR. FLEMING: Are they still in the trial?
>
> DR. LEGGETT: They are still in the trial.
>
> DR. FLEMING: Then, I am perfectly comfortable, and essentially in the
> trial, I assume you would be doing some assessments within the
> subgroup that had the sinus puncture and those that did not.
>
> I am not sure whether you would plan to power the trial accordingly.
>
> DR. LEGGETT: If they had bacteria.
>
> DR. FLEMING: Well, both, because I am interested in both.
>
> DR. WALD: Well, everybody will have had a puncture. That is going to
> be an entry criteria, it sounds like.
>
> DR. FLEMING: That\'s true. So, it is going to have to be whether they
> had bacteria.
>
> DR. WALD: I guess the hope would be that, you know, we are going to
> collect a lot of information, and that maybe we could then be more
> predictive after we look at which symptoms and signs are correlated
> with positive bacteriology, and therefore do a better job even when we
> are not doing sinus punctures in the future, you know, after the study
> is completed.
>
> DR. FLEMING: So, basically, in this study, as now I am more clearly
> understanding the way you are proposing this, the sinus puncture will
> be done routinely, but the results of that will not be used to
> determine whether someone is eligible.
>
> So, is the sinus puncture doesn\'t show bacterial infection, that
> person is still on the trial. That is what you are proposing, so that
> essentially then it does provide us the ability to have something that
> is very generalizable. The only limitation from the design that you
> are saying is if it turns out the sinus puncture shows half the
> people, in fact, have viral infection, then, we are in the
> circumstance of needing to do a 1,200 person study rather than a 350
> person study.
>
> DR. LEGGETT: John
>
> DR. POWERS: Let me ask a more specific question about something Dr.
> Gwaltney said, because that is the way I was thinking about it, but
> then Dr. Gwaltney brought up perhaps an intermediate way to do this,
> and that is if you are going to do the sinus puncture on everybody at
> baseline, could you then use the Gram stain as a screening test. If
> you have a negative Gram stain, they are not enrolled in the trial, if
> they are positive, they go into the trial.
>
> Then, you have got another even more narrowed-down subset. If the
> person has a positive Gram stain, but still is culture-negative, they
> could stay in the trial, but we would analyze them separately versus
> people that Gram stain positive, culture positive.
>
> DR. LEGGETT: Right, so my thought about that was that they go in the
> trial in the sense that we follow their symptoms and signs throughout,
> but they don\'t get drug. If they do have bugs, they get drug.
>
> Could you then compare\--
>
> DR. POWERS: We would randomize them. The important point is at what
> point do they get randomized, that is the important point.
>
> I think what you could do is if somebody comes in, they have signs and
> symptoms\--I mean what I have got written down here is so you have a
> person that comes in and they have to have a specific duration of
> illness, a constellation of signs and symptoms, and a positive
> radiograph, with the radiograph again not being specific, but as Dr.
> Wald pointed out, probably most people aren\'t going to stick anything
> in somebody\'s sinus until they actually even have that anyway.
>
> When you have those three things, then, you tap the person. You can do
> a Gram stein right then and there. If your Gram stain is negative, you
> are out, you are not enrolled in the trial at all. If your Gram stain
> is positive, you get randomized to placebo or to drug, and then if you
> are positive culture or not, hopefully, that will even out in both
> arms.
>
> DR. LEGGETT: Then, we are back to his question of they may not be
> comparable populations.
>
> DR. FLEMING: But let me see if I follow. So, it\'s a positive Gram
> stain, a positive radiograph, and symptoms. That would define your
> eligible population for the trial. So, the sinus puncture, if it were
> done or not isn\'t integral to defining the population.
>
> DR. POWERS: You won\'t have that positive Gram stain until after you
> have done the puncture.
>
> DR. FLEMING: So, we are using it.
>
> DR. LEGGETT: Barth, then John.
>
> DR. RELLER: I am wondering if we are not letting perfection getting in
> the way of good here. To me, it would be totally applicable to
> clinical practice, and yet achieve the rigor that we have not had
> heretofore to define those patients as best as we can from what we
> know, duration, everything that has been said, that have a high
> probability, and the odds favor, done well, that it would be in the
> order of 60, 70, 80 percent positive cultures.
>
> Then, after this were done, just so that no one would be enrolled
> unless they had\--because that is the only way you can tell whether
> they really have bacterial disease or not, and this is operating on
> the premise that the only hope for an antimicrobial effect is in
> patients with bacterial sinusitis. I mean that is what all the
> placards and CDC and everybody else has seen, these drugs aren\'t for
> people with viral illness, which is the commonplace.
>
> Then, you would for education and clinical practice, I mean nobody is
> going to ever expect, based on any clinical criteria, that you are
> going to able to assess 100 percent accuracy who has bacterial
> sinusitis. If you could, we wouldn\'t be here.
>
> Consequently, if you can get 75, 80 percent and say, okay, in audits,
> Quality Assurance, all of that stuff, you are only treating those
> people who meet the entry criteria for this trial. They happen to be,
> in order to be evaluable by FDA, have to have a sinus puncture.
>
> Then, you would be miles ahead of where we are, and it should be that
> if there are enough patients in that non-bacterial, that you might
> even be lucky with a placebo in there to show that if they didn\'t
> have bacteria, it didn\'t make any difference relative to placebo.
>
> Maybe as a segue into Question 2, I was sort of deciding whether to
> say this with Question 1 or Question 2, but if the pitfalls that we
> have all been trying to avoid, in the marvelous presentations earlier,
> I mean this issue of should we have clinical trials or micro-only
> trials, you know, the clinical, we have thousands of patients
> enrolled, and at the end of the day, everything that we have seen, we
> are not even very confident particularly with this\--I was very
> impressed with Dr. Fleming\'s presentation yesterday and today\--we
> are not even sure that it\'s better than placebo, and I have grave
> questions whether we will ever find out with the clinical-only trial.
>
> On the other hand, we also have good information that however
> important microbiology is, to establish an etiologic diagnosis and to
> objectively say that there is bacterial infection, it is not a
> surrogate for what the patients want and what physicians want for
> their patients, I mean that they get better, and we help them get
> better if they have got something that we have got a good possibility
> of helping them with antibiotics if they have the bacterial infection.
>
> So, why not skip all this clinical-only or microbiology and only
> having one kind of trial, and that is just what we have been talking
> about, and then the placebo issue, the creep and non-inferiority
> business.
>
> If you did drug A versus placebo, could you avoid the Pollyanna, the
> creep, the possibility of lowering standards over time is to say that
> you are only going to accept all the things that we said, only taps,
> and that you would not be able to have drug A versus the comparator,
> or A versus B, unless you had documented objective good evidence of
> the kind of quality that we are talking about from my previous study
> with placebo.
>
> Now, I think from what I have heard, that would automatically mean
> going forward, that you would have a placebo arm, so that then you
> could have A versus B and a placebo in there. It would increase the
> numbers a little, but on the other hand, if you had two effective
> treatments, you would have 2 to 1, treatment versus placebo, and given
> the numbers of the people who don\'t want an antibiotic with
> education, who do, you would be balancing the numbers off that I think
> people would go for, and then with the microbiology and the numbers
> that we had earlier, it wouldn\'t take a lot of patients and then we
> would have what we really want, that would satisfy all of these things
> that have been discussed at length.
>
> So, what I would do if I were king, is that there would be tap only, A
> versus placebo or A versus B with a placebo arm, and the only ones
> that would be evaluable would be those who had bacterial disease, and
> then we would really know exactly where we stood, and then the future
> trials could be based on what we got out of something like that.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: Well put. I think we were all moving towards one clinical
> trial rather than two separate especially since we have all agreed on
> the need for better micro.
>
> In doing clinical trials, the way that I envision this is that it is
> going to be double blind, so that neither the patient nor the doctor
> will know, and when you have the symptoms that we have laid out as
> inclusion criteria to get into the trial, I think that you are really
> getting a highly enriched population for sinus disease that you want
> to treat.
>
> If you make this a multicenter study, then, the quality of Gram
> stains, especially given how heterogeneous this fluid is that you get
> out, I think it is going to make it fairly difficult to use that as an
> enrollment criteria, as a practical enrollment criteria.
>
> So, to me, a patient comes in, they have got all the symptoms, they
> meet the criteria, they get their puncture, they get randomized, and
> neither the doctor nor the patient knows what they are getting, and
> whether it\'s placebo versus the experimental drug, which would
> probably be better, or a comparator, to me, that is less relevant than
> this prospective, double blind assessment.
>
> The other thing is if the Gram stain will be positive if you have got
> 10^5^ or more, there may be people with 10^3^ or 10^4^ organisms which
> represent sinus disease that needs to be treated out there that we are
> going to be missing and excluding from the trial if we exclude people
> by Gram stain.
>
> So, from what I have learned today, it seems as though we need to
> define the spectrum of densities of organisms in the sinus which can
> produce clinical disease, and, of course, we can look at the response
> in each group depending on their density of organisms.
>
> The other point that has to do with the statistics is the improvement
> that has been projected with treatment versus no treatment is based on
> some of these earlier studies which were enriched for viral
> rhinosinusitis, and as Dr. Wald published in something earlier this
> year, maybe some of the studies that showed no effect in otitis media
> is because the enrollment criteria for otitis were so lax, if I am
> paraphrasing you correctly.
>
> So, we may actually have a bigger effect with antibiotics, which would
> mean we would need fewer patients in order to show a benefit.
>
> DR. POWERS: John, I think one of the issues that I would like Dr.
> Fleming to comment on, because I think you were going in this
> direction before we got there, and that is that one of the reasons to
> try to select the patients who are most likely to have bacterial
> disease before you randomize is because if you randomize them and you
> are wrong about the percentage of people that you thought had
> bacterial disease, if we are only going to look at the people that
> have bacterial disease as part of the endpoint, you need to power the
> study for those people.
>
> Suppose you thought my criteria predicts 80 percent of people with
> bacterial disease and you are wrong, and it comes out that 60 percent
> of the people had bacterial disease, and you powered the study based
> on 80, unless you had a bigger treatment effect than you thought, like
> you were saying, now you have got trouble because your study is going
> to end up not being able to show a difference because of a numerical
> phenomenon.
>
> So, I think the reason why I was saying perhaps Dr. Gwaltney\'s
> suggested step as an intermediary is if you have a positive Gram
> stain, you are right, there is people that have a negative Gram stain
> that end up having a positive culture down the line, but it is going
> to be a power phenomenon, and I thought Dr. Fleming was going in that
> direction before we go off that.
>
> DR. FLEMING: I am hearing a couple of things or at least I am a little
> bit confused and I am still struggling to try to make sure I
> understand what the consensus is. Clearly, what we would like to do is
> identify a population as enriched as possible for bacterial infection,
> and in my words, I would like to do it with as noninvasive a procedure
> as possible because if I could it in what way, I can capture the
> broadest population and I know this is something that can then be
> broadly implemented in the real world.
>
> However, if I have to use a sinus puncture to much more reliably
> capture that, then, I am persuaded that we should do so. My
> understanding is what I am hearing are that the conditions should be
> persistent symptom and a positive radiograph, and I think I am hearing
> the positive Gram stain that would come as a result of part of what we
> would learn from the sinus puncture, am I hearing that?
>
> DR. LEGGETT: No, not from any of us.
>
> DR. FLEMING: Okay. I would love to understand what it is, the
> committee consensus is for what the exact eligibility would be.
>
> DR. LEGGETT: That is what we are wrestling with.
>
> Jan.
>
> DR. PATTERSON: Well, I think it is what we talked about before we got
> off on this Gram stain stuff, which is the clinical symptoms and
> duration of 7 days, and then the radiography and then the tap. You are
> going to have the tap information at least at 2 days, you are not
> going to have it instantly.
>
> I think there is a lot of problems with excluding and including people
> based on the Gram stain. As John said, the quality can vary immensely
> between institutions and the people who read those things. They may
> not be sensitive, you might have 10^4^ organisms, and not 10^5^, yet
> you have bacterial sinusitis with 10^4^.
>
> As far as doing them right on the spot, most offices now, are not set
> up to do gram stains because of clear regulations, you can\'t do it in
> your office. You could, I guess, investigational purposes you could
> use it that way and have another IRB approval for doing the Gram stain
> for research, but I think that it is not practical and I think that we
> would, in terms I think maybe one of the points you are making about
> it being generalizable, I don\'t think the Gram stain would be used in
> routine practice even if you did a puncture.
>
> DR. COX: Just one thing that has been hinted at, and I just wanted to
> sort of bring it up, and that is the issue of the number of clinical
> studies that we would expect, and we are talking now about having a
> clinical study that would have well characterized clinical entry
> criteria and also microbiologic criteria in acute bacterial sinusitis.
>
> I think we have talked some about the number of studies here, and this
> actually was an issue that we did talk about previously in the March
> 2003 advisory committee, and in that setting where there is a broader
> development program and there is multiple indications within the
> respiratory tract, that may be a setting where, in fact, it would be
> appropriate to have a single well-done acute bacterial sinusitis
> thing, but that would be in the context of an overall drug development
> program that included other indications in the respiratory tract, so I
> just wanted to follow up on that point.
>
> DR. CROSS: I simply wanted to echo what Jan said, that a Gram stain
> won\'t work. Aside from the CLIA regulations, that means we have had a
> whole generation now of physicians who are very unfamiliar with
> reading a Gram stain, which means it would have to get done in the
> main micro lab, and part of accuracy of the Gram stain, at least in
> terms of finding organisms is how much time you actually spend on it.
>
> I think that it is just fraught with lots of problems and oftentimes
> in our hospital now, when you ask for even a STAT Gram stain, it is
> done at the end of the day, so you might as well just wait for your
> culture. So, it really doesn\'t add very much and also adds the
> component of missing people who do have infection, but at a lower
> concentration of organisms.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: I always learn a tremendous amount at these meetings. The
> Gram stains are very valuable, but they are only valuable when they
> are positive, neutrophils and organisms. They are not sensitive. It is
> the numbers that we went over.
>
> So, to exclude people with a negative Gram stain is going to exclude
> those people who have 10^3^, 10^3.5^, 10^4^, 10^4.5^, when you get up
> to 10^5^, or whatever, then, they are more likely to be positive.
>
> Just an aside, I think that what CLIA said, not that I agree with it,
> but one can\'t charge for a Gram stain as a provider unless you go
> through all the validations, et cetera. I don\'t think there is
> anything that says that one can\'t do a Gram stain and put that in
> your repertoire along with clinical things and other things to
> interpret how you give initial therapy on a patient, but that is just
> an aside.
>
> DR. LEGGETT: In our residency treatment group of some 50 physicians,
> we don\'t even have a microscope.
>
> Ken.
>
> DR. BROWN: I would like to confirm that the committee has taken what
> was presented to us as science by Dr. Gwaltney and Dr. Powers, that we
> do not know that antibiotics are better than puncture and lavage and
> have acted upon that, and we have already decided that antibiotics are
> better or there is some other reason why we haven\'t heard about
> including puncture and lavage in the design of this trial.
>
> DR. LEGGETT: Barth.
>
> DR. RELLER: With what we have discussed, can you have that in your
> placebo arm?
>
> DR. BROWN: I would love to see it there.
>
> DR. RELLER: If everybody gets a puncture, then, the relief of pus
> under pressure is going to be in the placebo, and this is another
> reason to do it.
>
> DR. LEGGETT: May I interject? It\'s quarter of 3:00 and we still have
> two more things to go. Let\'s try to keep it really focused to this
> and answer this first question. If we don\'t have a consensus, we will
> just say we don\'t have a consensus.
>
> DR. SYDNOR: I think one important point, I think this is very
> important. I have the feeling people envision this study being done in
> some doctor\'s office, and his patients come in, and he enrolls them
> in the study. That is not the way to do it.
>
> There should be several sites, and there shouldn\'t be too many, and
> this should be done by investigators who know what they are doing and
> they advertise in the newspapers. You will never get enough patients
> unless you very aggressive recruit outside of a private practice.
>
> We did these studies for years and years, and that is the only way you
> are going to get the patients. So, you establish the site and then you
> get the people and the expertise to do whatever you want. You hire
> somebody who knows how to do Gram stains.
>
> I see no problem in using a Gram stain to start treatment if you have
> a positive Gram stain done by a competent person. That is not very
> hard to do. But I certainly would also enroll everybody whose cultures
> become positive on the next day or the day afterward, so that your
> patient population that\'s enrolled in the antibiotic trial is
> everybody who had a sinus aspirate culture that is positive, and there
> might be a few that would have a positive Gram stain, and not a
> positive culture, and you could argue about that, but essentially,
> everybody that has a positive culture would be the ones that should be
> enrolled.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: I would just like to make two comments. One is that a sinus
> puncture is not therapeutic. Maybe sinus lavage starts to approach
> therapy, but a sinus puncture is not therapeutic, it is generally
> designed to get the smallest amount of fluid that you can get to make
> a diagnosis. We are using it for diagnosis, not for therapy.
>
> It quickly seals even if it doesn\'t heal, so it doesn\'t remain a
> portal of drainage. So, I don\'t think people should think that that
> is a therapeutic arm.
>
> I would just say, too, that the Gram stain is much too stringent a
> criteria. It is more stringent than quantitative cultures, that we
> should not use it. While you can train people to do it, it is really
> more difficult to interpret a gram stain than to do a lot of other
> things, and that I think all of the patients who have fit the criteria
> and have undergone sinus puncture should be randomized to get
> treatment, you know, active drug or placebo. I don\'t think we should
> eliminate patients at that juncture.
>
> Then, we can do an analysis on those who have a positive culture, on
> those who have a negative culture.
>
> DR. LEGGETT: Tom.
>
> DR. FLEMING: Briefly, if I am following the consensus for the
> eligibility. If we were, in using a sinus puncture, able to enrich the
> population, the fraction that have bacterial infections from 40
> percent to, let\'s say, 80 percent. I had mentioned earlier that would
> lead us to getting a 4-fold reduction in sample size, which would be
> pretty profound.
>
> But if we are putting forward criteria, which I think I am hearing,
> which are based on persistent symptoms and positive radiograph, but
> not on the sinus puncture or Gram stains, and if that, let\'s say,
> gets us to 70 percent, and hence the sinus puncture would simply get
> us incrementally from 70 to 80, then, that increment would only have a
> factor of about 1.3-fold on sample size, which is not trivial, but it
> is not profound.
>
> So, I want to endorse my colleagues if they are saying we think we can
> get a lot of the enrichment using persistence symptoms and positive
> radiograph or rather procedures that I would call more noninvasive,
> then that has the attraction from my perspective that it is very
> generalizable and well defined and we may not be giving up that much
> in efficiency.
>
> DR. GWALTNEY: I rarely disagree with my good colleague, Dr. Wald, but
> I don\'t see how you can justify treating patients who you know, based
> on the best test you have don\'t have an infection with antibiotics
> which are dangerous.
>
> DR. WALD: I think you are not going to know that for 24 to 48 hours,
> and I think that you can then analyze those patients. Those patients
> would surely be treated today. While I agree with you as a general
> rule, I would not endorse treating patients with antibiotics who
> don\'t have bacterial infections, I think for the purpose of this
> study, it would not make sense or endear those patients to you to oust
> them from the trial at that juncture.
>
> DR. GWALTNEY: I don\'t think a two-day delay either has any real
> clinical relevance or real scientific relevance. I think it would be
> perfect acceptable to wait until you know your culture results.
>
> DR. LEGGETT: Can we move on to Question 2. We have already sort of
> danced around this.
>
> The strengths and limitations of placebo-controlled and
> non-inferiority trials. I think we are all in agreement that
> non-inferiority is not going to help us, it hasn\'t so far. I would
> like to hear some more specifics about the placebo-controlled versus
> adjunctive, therapy controlled, those sorts of statements at this
> point.
>
> DR. PORETZ: As far as the placebo-controlled, if you do a study with
> the first company that presents a drug, and it shows that
> antimicrobials are of benefit in acute sinusitis, then, future studies
> I don\'t believe can have a placebo-controlled arm. Is that true?
>
> DR. POWERS: It depends. It depends what the magnitude of that effect
> is. If the magnitude of that effect is very small, say, it\'s 4
> percent, what it turns out to be on here, we could say that that drug
> could be approved for sinusitis and put in the label that look, you
> need to realize that the benefit of this drug is only 4 percent and
> make your choices.
>
> On the other hand, if you then wanted to use that 4 percent to do a
> future non-inferiority trial, you are talking 1 1/2, 2 percent margin
> and 3- 4,000 patients in that trial. It wouldn\'t be feasible to do a
> non-inferiority trial with those numbers of patients.
>
> So, what that placebo-controlled trial actually shows will determine
> the future. If it comes out to be 35, 50 percent benefit, then, maybe
> you can select a margin for the future.
>
> DR. LEGGETT: Janet.
>
> DR. ELASHOFF: I just wanted to say that a study with one specific
> antimicrobial that comes out looking very effective can\'t necessarily
> be applied to others, and that each one has to have their own trial
> and the issue of whether to use a placebo or whether that one can be
> compared to something else, then goes on for that.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: Can I ask the FDA a question. Can you insist now that some
> drug company take this on?
>
> DR. POWERS: I think what we can do is we can say that there are, and
> what we have said, and that is why we got to this meeting, is we have
> said there are five ways you can do it, five potential controls in a
> trial, one of which is no treatment, one of which is placebo,
> historical control, an inactive control, or a dose-response trial.
>
> If you want to do a non-inferiority trial, you have to justify to us
> what the non-inferiority margin you would pick would be. Several
> companies have done that and come up with the number of 12 percent.
> Now, from the data we presented, that number doesn\'t really seem
> scientifically justifiable.
>
> So, that is what we are left with, and that is why we ended up here.
> One of things we can say is if you folks recommend it, that the
> Advisory Committee has recommended that perhaps doing a
> placebo-controlled trial\--which we almost want to get away from
> calling it that in that it is a superiority trial versus other
> symptomatic therapies.
>
> We don\'t want to make it sound like we are sending these patients out
> onto the street with absolutely nothing and we haven\'t done anything
> for them at all, so we are going to highly recommend that as one of
> the things if that is what the committee thinks.
>
> DR. LEGGETT: Tom.
>
> DR. FLEMING: I would like to follow up on a couple of the comments. I
> think a very good question surfaced a couple minutes ago, and that is,
> if we did a superiority trial of some type, and that superiority trial
> showed positive benefit, then, would we now have a foundation upon
> which we could in the future then do non-inferiority trials? In
> principle, yes, and I think Dr. Powers\' answer was on target in
> responding to that.
>
> Of course, in principle, it is yes depending on the nature of the
> effect. The criteria in the ICH guidelines have been formulated as
> guiding when you can do an non-inferiority trial. It is when you have
> an active comparator that has substantial efficacy, that is precisely
> estimated in a context that can be generalized to the setting in which
> you are going to do your non-inferiority trial.
>
> So, if we show in placebo controlled or some other superiority trial a
> 30 percent improvement with precision in that estimate, absolutely, we
> now have a basis in the future for doing a non-inferiority comparison
> plus clinically, that is exactly when you would want to do it. You
> wouldn\'t want to then continue to use placebo if you have a profound
> effect.
>
> On the other hand, if it\'s positive, but it is really a trivial
> effect, then, as Dr. Powers points out, you have violated the
> principle of having substantial efficacy, but I wouldn\'t even want to
> do a non-inferiority trial in that setting. It is just a trivial
> difference.
>
> Yes, it would take an infinite sample size to rule out a trivial
> inferiority, but it wouldn\'t be a setting where we would be compelled
> to anyway, so the exact setting in which clinically and ethically you
> would want to follow up with a non-inferiority trial is exactly when
> we could.
>
> The reason that it is difficult to do so now is that we don\'t have
> the past history of these types of studies. We have got to start at
> some point. If we start at this point, we will have the foundation for
> doing so in the future.
>
> Now, what does that mean we have to do now, do we gave to do placebo?
> I would say what we have to do is a superiority trial. Now, a placebo
> is one obvious way to do that. There are other options. You could look
> at comparison of experimental to standard, and just hope you are
> superior.
>
> Well, if you were, that would be enough as long as you could believe
> the standard wasn\'t harmful. You could do a dose-response and that
> would be also sufficient although there is a risk for a false negative
> there, and that is if the lower dose carries a lot of the benefit, you
> may not be able to see the benefit.
>
> You could do a standard plus experimental against standard, and if
> that is superior, that also is the evidence you would need, although
> that would only make sense if it was clinically sensible to add on
> your experimental to the standard.
>
> So, for all of these reasons, there are a lot of settings where I
> think the obvious superiority would be a placebo, and I completely
> agree with Dr. Powers in that setting. I think the term \"placebo\" is
> often misunderstood. It gives the sense that the control arm isn\'t
> getting anything, and that\'s not true.
>
> We should be delivering to the control arm, standard state-of-the-art
> implementation of standard of care, so symptomatic therapy at whatever
> it would be at state-of-the-art against which we would be adding this
> experimental intervention for which there hasn\'t as yet been proven
> efficacy.
>
> In so many areas in clinical trials, patients on both arms are
> benefitted because you are achieving a higher level of standard of
> care and a higher level of attention and management in a clinical
> trial. So, those patients, even if they are on the standard of care
> symptomatic management, with the additional care they are getting,
> tend to do better than not being part of the trial.
>
> So, the concept of being randomized to a placebo, I think is often
> misleading as to what the control arm is really getting.
>
> DR. LEGGETT: Could I take the liberty of asking if there is general
> consensus from this committee that we do not believe a 4 percent
> imprecise improvement is significant? Does anyone disagree with that?
> Ellen.
>
> DR. WALD: Could we just discuss adjunctive therapy for a moment,
> because I don\'t think there is a standard adjunctive therapy, and I
> wouldn\'t specifically endorse its use as an alternative arm.
>
> I think there is very little evidence, less and worse evidence than we
> have for antibiotics, and I think giving patients multiple medications
> sometimes makes their adherence less good, so I have, as a rule, not
> used them when I think that my antibiotic is my potent treatment
> piece. I would be interested in other opinions.
>
> DR. LEGGETT: I think I would be happy either with decongestants or
> without.
>
> DR. POWERS: Could I ask Peter Starke from the Pulmonary Division to
> address some of this because our Division met with the Pulmonary
> Division to address this question just a whole back.
>
> DR. STARKE: Good afternoon. First of all, I should say I am a
> pediatrician, so that is my background.
>
> To my knowledge, there are no adjunctive therapies that are approved
> for sinusitis at this time, however, I would say that you can\'t very
> well get away with not treating patients for pain. So, if they have
> pain, headache, sinus pressure, and I use that in the general term of
> pain, not in terms of sinus disease, but pain somewhere in the facial
> area, you can\'t help but treat that pain.
>
> I think that is the basic therapy that one would give as you start to
> get into other therapies, for example, any intranasal therapies, first
> of all, I am not sure that it gets into the sinus, as has been pointed
> out, but it may be treating other disease that is comorbid disease,
> and one of the things that you haven\'t talked about that I would be
> interested in hearing about is allergic disease.
>
> I think that you have been good in terms of the way you have been
> separating out the terminology here, acute bacterial sinusitis from
> rhinosinusitis, because the allergists that we hear from would like to
> combine the terminology and call acute rhinosinusitis, the problem
> there being that it dilutes what is actually bacterial disease and
> what we want to think of as bacterial disease, acute bacterial disease
> with other etiologies.
>
> As you all know, acute rhinosinusitis is usually viral in nature, but
> we have a large proportion of patients with sinus disease who also
> have allergies, so that is the second condition that may require
> co-administration of medications.
>
> I would suggest the way we think of it is that once you have gotten
> through this first level of enrollment, that one actually has to think
> about whether any patients who are on other medications for allergies,
> they have to be balanced within the groups and you have to look at
> outcomes based on that, as well.
>
> So, certainly patients who have allergies, you wouldn\'t stop their
> medication, but you are going to have to balance it out.
>
> DR. POWERS: I think what matters to us is not which adjunctive
> treatments they receive, but that it is standardized across the arms
> of the trial. When you look back at some of placebo-controlled trials,
> it is at the investigator\'s discretion of who gets what, and I think
> that is what becomes problematic because if that is imbalanced between
> the arms, then, if there are treatment effects that we don\'t know
> about for these adjunctive therapies, then, we can\'t figure out what
> it means.
>
> DR. STARKE: Presumably, the randomization process helps to balance out
> those things, but you would need to look at efficacy for each
> subgroup, particularly for allergic versus non-allergic disease.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: For purposes of a trial, and our upper bound of symptoms
> being 28 days, is we are trying to avoid including in this study
> group, patients with allergic disease, and if people were on that kind
> of medication, I would say that would be an exclusion characteristic,
> because it is going to be hard enough as is.
>
> DR. LEGGETT: Would you accept the use of non-inflammatory agent and
> hope you had balance?
>
> DR. WALD: You mean for pain?
>
> DR. LEGGETT: Yes.
>
> DR. WALD: I agree with John, I think whatever you do, you do across
> both sides, and you could make it PRN and then use that as an outcome,
> as well, you know, who stops needing pain medication faster in the
> antibiotic versus placebo or comparator.
>
> DR. LEGGETT: Good point.
>
> Tom.
>
> DR. FLEMING: Just on that point, we have to remember what
> randomization does and doesn\'t do for us. Randomization gives us
> comparability at baseline, at least it eliminates systematically
> occurring imbalances. Randomly occurring imbalances can exist in
> smaller sample sizes.
>
> But it doesn\'t influence, of course, what might be differential needs
> for ancillary care post-baseline if the intervention that we are
> randomizing to actually is influencing outcome.
>
> So, if the antibiotic is effective in reducing symptoms including
> pain, then, it could be systematically emerging over the course of
> time that the control arm needs more pain medication, which is, in
> fact, one of the results of the intervention. The intervention is
> reducing the need for as much pain medication.
>
> DR. LEGGETT: Ed, how do you feel about this discussion so far about
> placebo and non-inferiority, and can we move on?
>
> DR. COX: I think we have covered the issues for the first bullet.
>
> DR. LEGGETT: What is the thing about comparative microbiologic data?
>
> DR. COX: I think we touched on that some in the discussion of the
> first question, and that deals with the current guidance document
> which recommends a clinical trial followed by a microbiologic-driven
> study.
>
> I think we have touched on that some in discussing how a clinical
> study highly characterizes the patients clinically, and that also
> includes rigorous microbiologic evaluation, may be able to serve that
> role.
>
> In the setting of broader development program, that study, if well
> done, is sufficiently large and there is a broad range of indications,
> that may be a study that could support acute bacterial sinusitis. I
> think we have covered that issue of the comparative microbiologic
> study.
>
> DR. LEGGETT: So, after Tom\'s question, we will move on to point 3?
>
> DR. COX: I think that sounds good.
>
> DR. FLEMING: I promise to keep this comment brief.
>
> There was just one issue raised in the implementation of
> placebo-controlled trial that I would like to comment on, and that is
> might we have cross-ins occurring at some point. Let me just say if
> they are very infrequent in occurrence, I am not so worried, but if we
> wrote into the protocol, for example, that after a given number of
> days, there isn\'t resolution, then, we would cross-in, and we would
> define those people to be failures at that point.
>
> I think it is important to realize that a very non-trivial bias could
> emerge. So, for example, suppose that in a true placebo, there would
> be 50 percent resolution at day 3 and 70 percent resolution at day 10,
> so it goes from 50 to 70.
>
> Let\'s say the antimicrobial intervention is a placebo, it doesn\'t
> provide any benefit. We would see 50 at day 3 and 70 at day 10. Now,
> in the control arm, if we randomized in the patients to the control
> arm, if the 50 percent, there will be 50 percent resolved at day 3, if
> the other 50 are crossed-in, because they haven\'t resolved at day 3,
> and we call them failures, then, we are imputing failure for all time,
> so you would have 50 percent resolution at day 3 and still only 50
> percent resolution at day 10, so we would see a 50 versus 70
> difference in a truly indurate agent purely because of the bias that
> we induced by calling somebody failure when they crossed over.
>
> DR. WALD: Wouldn\'t the same thing happen in both groups?
>
> DR. FLEMING: It would, but only if you would call, then, those on the
> microbic side when you are crossing them over, so you are going to
> cross over the microbic sides to microbic side as well?
>
> DR. WALD: I wouldn\'t call them crossovers, you just have patients who
> failed therapy for whatever reason, in whichever group. You are
> blinded, you don\'t know, and what you probably would have is an
> alternative antimicrobial as your fail-safe, so patients who were
> getting an antibiotic and failing it, now are getting another one,
> patients who were getting placebo are now getting an antibiotic, and
> you don\'t have to know who they are.
>
> DR. FLEMING: But even if you do this, what you are presuming is that
> what will occur beyond that point, in fact, would not have been
> influenced by the microbicide, so let\'s suppose that, just to change
> the example, then, let\'s suppose that the microbicide is effective in
> leading to an enhanced resolution, but it is particularly evident when
> you look at it over a longer period of time than just over the first
> few days.
>
> Then, by imputing failure, then, you would not be underestimating or
> not fully capturing the benefit. The fact of the matter is some of
> these people will resolve if you continue to follow them even if they
> haven\'t resolved early, and so imputing failure, whether you are
> doing so equally at day 3, in the microbicide and the control arm,
> still could be giving bias.
>
> My own sense the outcome should be assessed as it actually occurs in
> all patients, at day 3 up to day 10. Let\'s say you have defined day
> 10 to be the final day of your follow-up, then, I don\'t mind if you
> crossed them over after that because you are not influencing the
> assessment of the outcome.
>
> But the bottom line is you should be assessing the outcome on all
> patients until the date at which you have defined the final period of
> follow-up to avoid any biases, and if the cross-ins are fairly
> minimal, you are going to have only a minimal diluting.
>
> DR. POWERS: I think what Dr. Fleming is getting at, I think from the
> clinical point of view, is it depends upon what the natural history of
> the disease is and how you would expect that to occur in the placebo
> arm.
>
> Unfortunately, that is one of the pieces of the pie that is missing in
> this disease, is we don\'t know what that is. Dr. Wald, you had said
> earlier that we expect antimicrobials to work in 48 to 72 hours, but
> that is what we are trying to measure in this trial, would be how long
> does that take.
>
> We know the antibacterial effects probably occur at that point because
> Dr. Anon\'s data there showed that we can track over time. What we
> don\'t know is how does the clinical symptoms impact, and if you look
> at just those four patients that Dr. Anon showed, it looked like there
> was a lag time of maybe two days beyond when the organism was gone and
> the symptoms resolved. So, we need to know.
>
> I think the danger here is putting that early escape thing too early
> in the course of this illness.
>
> DR. WALD: I would just say that in clinical practice, 72 hours, if
> your patient is not improved, you do something as a clinician. That is
> the time point whether you have otitis media, acute sinusitis, or
> acute pneumonia. If you are not somewhat better by 72 hours, you check
> your diagnosis, if it\'s correct, you change your drug.
>
> DR. LEGGETT: That is how a clinical trial is different from clinical
> practice.
>
> DR. WALD: But if you are using placebo here, a non-active comparator,
> that you have to promise patients something, at least that would be
> important to me as someone to sign up for this.
>
> DR. POWERS: Let\'s take another disease where know antimicrobials have
> very little effect, like secondary acute infections of acute
> bronchitis.
>
> We know that at 2 weeks, about 40 percent of those people at still
> coughing, and at 4 weeks, about 20 percent of those people are still
> coughing. If you considered at 2 weeks that those people were failures
> and you switched them all over to antimicrobials, it could look like
> antimicrobials had a big effect, when, in fact, they don\'t.
>
> So I think that is why we need to know what the natural history of the
> illness is to pick that time point. I understand, as Dr. Leggett said,
> the issue for us is that is fine what clinicians want to do in
> clinical practice, and we are not trying to tell them not to, but in
> the terms of this kind of a clinical trial, we have to be careful
> about placing that time point too early for the escape.
>
> DR. COX: Dr. Leggett, before we completely leave Question 2, just
> hearing some of the additional comments, I am wondering if we can just
> get a little more clarity on placebo-controlled studies and comfort
> level because we have talked about two different groups here with the
> persistent group the urgent group.
>
> I am just wondering if we can get a little more feel from the
> committee members with regards to the setting of placebo-controlled
> studies and people\'s comfort level there.
>
> DR. LEGGETT: Listening to Ellen and Jack, I get the feeling that
> people would not be quite so comfortable in the urgent setting in less
> than 7 days, but may be comfortable with 7 days or longer.
>
> DR. COX: Thank you.
>
> DR. GWALTNEY: Well, I would just like to say that if you have a
> treatment\--this is a general statement and it is very obvious, but I
> think we tend to forget it particularly in current times\--if you have
> a treatment and you don\'t know if it works, one thing you can be sure
> is it is going to have side effects, because I don\'t know any
> medicine that doesn\'t have side effects, and so if you have a
> disease, and you take a treatment which doesn\'t work, then, the odds
> are that something bad is going to happen to you rather than something
> good, and antimicrobial agents do cause toxic epidermal necrosis and
> anaphylaxis.
>
> When you have seen one or two of those patients, it is very
> impressive. It is rare, but it is impressive, so if you are in a
> trial, I think the investigators and the subjects need to realize that
> it is not always that it does good, you know, it is very obvious, but
> we tend to forget that.
>
> DR. LEGGETT: Mark.
>
> DR. GOLDBERGER: Just to follow up on the last couple of comments,
> then, I take it you have seen the patient population that was defined
> a moment ago, perhaps less rapidly progressive, more than 7 days of
> illness. Most people here feel a protocol could be developed that
> would get, for instance, through their IRBs, because realistically,
> you know, when we deal with pharmaceutical company, and if we are
> pushing fairly strongly in a certain design, we have to realistically
> be comfortable that what we are telling them we think they should do,
> they will be able to go out and reasonably implement them.
>
> It is helpful sometimes to get some feedback from people who are
> closer to those issues than, for instance, we are.
>
> DR. LEGGETT: Keith.
>
> DR. RODVOLD: Being a past member on IRBs, as well as doing a lot of
> trials, I think that you are going to run into the problem of that.
> There is going to be about 50 percent of IRBs are going to be
> uncomfortable with placebo no matter what kind of study you put up,
> and that already goes on.
>
> The other aspect of it in the groups that will let you go through an
> IRB with a placebo trial, I think you are going to have to have a
> rescue for that arm, and I don\'t think, in the beginning, you are
> going to be able to double randomize, randomize them back again.
>
> I think you are going to come down to some critical point in time, and
> that is where Ellen\'s comment about clinical practice is 72 hours is
> when you would make another call, IRBs are loaded with people that are
> practitioners, as well as academic people, and some IRBs are totally
> more practical people than academic people.
>
> I think they are going to demand, at least in the early trials if you
> launch these, that you are going to have to rescue them at day X, and
> that day X will probably be clinical practice experiences versus trial
> experiences.
>
> I agree with Jack\'s comment about limiting this to the really
> selective centers that have great experiences and good, highly-trained
> people, but their IRBs will still get in the way a little bit, so
> those are some practical issues as a past IRB members, as well as a
> trial person that I think come to play after all this academic
> conversation.
>
> DR. LEGGETT: Jan.
>
> DR. PATTERSON: I think I might frame it a little bit differently and
> say sinus aspirate and adjunctive therapy compared to sinus aspirate,
> adjunctive therapy and antibiotics instead of saying the term placebo.
>
> Ellen says it is not that the aspirate itself is not therapeutic, but
> the adjunctive therapy may help and taking some of the pressure off
> may help at least symptomatically acutely.
>
> I think you could frame it, is it really truly placebo if you are
> doing those other things? I think you could frame it a little bit
> differently.
>
> DR. POWERS: I think that is one of the points I wanted to raise.
> Before I came to the FDA, having been an IRB member myself and being a
> clinical investigator, one of the things I thought is when you go an
> IRB, you are presenting your case of why you think this trial is
> worthwhile to the IRB, not presuming the IRB knows everything about
> this disease.
>
> One of the things that we really discovered looking through these 14
> placebo-controlled trials, I mean when I started this out I said,
> okay, we will find out what the number is, we will pick the number,
> and we will go forward with an non-inferiority trial.
>
> It is surprising to me of what we found, and I don\'t think most IRBs
> would know that that is the case. So, I think part of it is picking
> investigators who would present that case in a cogent way to their
> IRB.
>
> DR. LEGGETT: Moving on to Question 3. Discuss the issues of measuring
> outcomes in patients in trials of acute bacterial sinusitis.
>
> I assume the outcomes we are going to be measuring are, in part, the
> symptoms and signs that got us into the trial, and then return to
> daily activity.
>
> Ellen, what other things can you think of off the top of your head
> that we would want to measure as an outcome?
>
> DR. WALD: I think those are the things. You just try to say when nasal
> congestion has resolved, nasal discharge has resolved, cough has
> resolved, sleep has returned, appetite has returned, activity has
> returned, so it is a composite of those real-life issues.
>
> I would again say, though, that there are certainly at least some
> parents, I don\'t know about adult patients, who won\'t say they are
> completely well, so you may not get to baseline, you know, they just
> have some minor residual symptom that will keep them from saying they
> are entirely well, and I don\'t like to hold that against my study
> drug. So, you need a way out of that, I think.
>
> DR. LEGGETT: Jack, anything to add?
>
> DR. GWALTNEY: Well, I think it really is an advantage to do
> quantitative bacterial cultures, because there you are dealing with
> interval data, they are in increments of log to the base 10, so you
> don\'t need very large sample sizes in order to look for differences
> in bacterial titers in your different groups.
>
> So, I think that is a great advantage to doing, not just
> semiquantitative, but quantitative cultures, which aren\'t a big deal,
> you just do the dilutions and plate those things out.
>
> Certainly, your sample size is a much smaller for dealing with those
> kind of data than with the clinical data, which are just ordinal and
> which have much larger variance.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: In the clinical trial design, with some other diseases,
> we have discussed the difference between primary, co-primary, and
> secondary endpoints and having microbiologic endpoints versus clinical
> endpoints and actually having a different delta if it\'s a
> non-inferiority trial with a microbiologic endpoint as opposed to a
> clinical endpoint, so it gets very complicated very quickly.
>
> I will go back to the FDA and sort of throw it to you. How would you
> see endpoint evaluations because we have talked about clinical scores,
> Kaplan-Meier plots of time-to-resolution of symptoms have been
> presented, and then now we will have some microbiology hopefully that
> will allow us a micro endpoint, which could be more precisely defined.
>
> DR. POWERS: What we don\'t want to do is we don\'t want to separate
> out analyzing microbiologic outcomes and analyzing clinical outcomes
> without linking them to the individual patient especially in a
> disease\--one might think that is more appropriate in a disease like
> meningitis where we are more certain of that association.
>
> Here, what we have presented today is we are completely uncertain of
> that association. What we have been trying to look for other diseases
> like exacerbations of chronic bronchitis falls exactly into this idea
> of symptoms, and there, the microbiology, who knows what it actually
> means. So, we have been working towards things like patient diaries
> and coming up with some kind of scale very similar to what was done in
> the influenza trials.
>
> That takes a lot of work, but we are actually trying to do that or get
> it started and then maybe get somebody at the IDSA interested in this
> to take if forwards, because we want that kind of scale to be
> available to everybody if we can get that moving.
>
> DR. LEGGETT: Very good idea.
>
> Janet.
>
> DR. ELASHOFF: With respect to time of resolution of symptoms as a way
> to talk about an endpoint, so that then you are doing a Kaplan-Meier
> analysis, like any outcome that you might talk about, it has its pros
> and its cons.
>
> I just wanted to mention a couple of specific issues. One is that in
> the past, it seems that the clinical cure has been defined at a
> physician visit, essentially by the physician interviewing the
> patient.
>
> To talk about time to resolution of symptoms, you would have to have
> it done every day with some kind of patient diary, hopefully,
> something electronic, or maybe even people calling up on the telephone
> and punching 1, 2, 3, 4, or 5 for each symptom or something like that
> because paper diaries are notoriously problematic.
>
> I wanted to mention, though, something that one has to think about in
> looking forward. For placebo-controlled trial, there is no real
> problem with time to resolution as an outcome, but if you saw a really
> high effectiveness of some antibiotic and now, in the future you want
> to use a non-inferiority trial with this same outcome, defining
> non-inferiority margins for time to resolution can be extremely
> problematic especially if the hazard ratios over time are not
> constant. It may not at all be clear how to define such a
> non-inferiority margin.
>
> So, if one is going that way and thinks that you would ever do
> non-inferiority trials in the future, you need to be proactively
> thinking about how to deal with that.
>
> DR. LEGGETT: Would it be statistically valid to come up with a fixed
> endpoint once you knew where it was supposed to be from this first
> trial, so in the future, none of your early trials, you have a fixed
> endpoint?
>
> DR. ELASHOFF: It might be reasonable although I would guess that that
> sort of thing would shift around with your populations, just
> everything else seems to shift around.
>
> DR. LEGGETT: Joan.
>
> DR. HILTON: My comments were on a related topic. I was concerned about
> how frequently the endpoint was going to be measured because if you do
> want to do time to resolution, you have to have frequent measurements,
> over time, and I wondered what the total duration of the follow-up
> time is meant to be.
>
> Finally, it seems to me that if we do a time to event type analysis,
> then, when a subject fails on one arm, we stop following them, so
> whether they have a rescue or escape therapy afterwards, that
> information wouldn\'t enter into the analysis. So, that would be one
> complication removed if we went with that type of an outcome an
> analysis.
>
> DR. LEGGETT: So, you are saying we could have a rescue if we did the
> time to resolution?
>
> DR. HILTON: But that requires you to be able to assess the outcome
> repeatedly and accurately, so I wondered if Janet\'s idea was one of
> the feasible options or if you have figured out how you would do that.
>
> DR. POWERS: I think what we are using as a model here is something Dr.
> Cross pointed out a couple of hours ago, and that is the influenza
> trials. The symptoms of that disease are very similar to acute
> sinusitis. The way those trials were done showed a difference for
> influenza drugs, so it would seem like a good model, and the way that
> was done was twice daily, patient diaries.
>
> DR. LEGGETT: Alan.
>
> DR. CROSS: It seems that one of the things we addressed earlier is
> trying to tie in the microbiologic resolution with the symptoms, and
> so far we have talked about getting a puncture at study entry.
>
> I guess short of doing what Dr. Anon has done, which I think might be
> heard to do on the whole population in the study, how can we actually
> expect to tie in the microbiologic resolution with the clinical
> outcome?
>
> DR. LEGGETT: And another practical complication other than the second
> sinus tap, if it\'s resolved at the time that you do that second tap,
> you are not going to get anything.
>
> Barth.
>
> DR. RELLER: The taps are, to me, crucial for enrollment. I am not sure
> they are at all important as a second tap down the line with the
> emphasis\--I mean we already have discussed that there is, from what
> we know, not a clear relationship between cessation particularly if
> the second tap is done anywhere near to where the antibiotic is or
> certainly not on antibiotic that it is going to yield any information,
> so if there is not a clear\--Dr. Fleming went over it, it can\'t be
> used as a surrogate because it doesn\'t correlate well with resolution
> of symptoms.
>
> What we want is do they have the disease or not, for which we
> absolutely need microbiology. What we need for resolution of symptoms
> is what has been discussed, like in the influenza trial. So, I would
> put the emphasis on the first tap and scrap the second tap unless, in
> contrast to the reality currently, where people have failed and the
> persist in being symptomatic, then, I think, well, would like to see a
> tap, is to require a tap if somebody is registered, they still have a
> positive radiograph, and they are the same or getting worse after
> therapy.
>
> What do you think about that, Dr. Wald, of a second tap if they are
> going to be a failure and they are worse?
>
> DR. LEGGETT: Wouldn\'t that be a different trial? Wouldn\'t, in that
> trial, we are trying to figure out that we could use a surrogate
> marker? I don\'t think that is the purpose of this trial, but go
> ahead, Ellen.
>
> DR. WALD: I guess you could draw the analogy to acute otitis media. I
> think that is where you are trying to learn, you know, why did the
> patient fail, was it a bug-drug problem, or, you know, once in a while
> patients do fail clinically just because they need that sinus
> ventilated. It doesn\'t happen very often, but it can be the results.
>
> I think you are just trying to learn stuff from that second tap. If
> the patient agreed, I think it would be fabulous.
>
> DR. WALD: John.
>
> DR. POWERS: We have noticed\--there is one NDA we didn\'t present
> because we wanted to look at this before\--but one NDA did do sinus
> punctures before and after, and we noticed a pretty poor correlation
> actually between the clinical outcomes and the microbiological, and
> one thing struck us, and that is that what may also impact on this is
> the quantity of organisms at baseline, which we don\'t know, so if you
> only tap the failures, and those people have a particular organism
> present, is it because that drug isn\'t effective for that particular
> organism, or because those people started up at here, at a higher
> level, and everybody else started down here?
>
> Without the quantitation to assess that, it is very hard to make any
> comments about drug efficacy versus some baseline parameter that you
> didn\'t know, like the quantitation of the organisms.
>
> HIV trials have it down. You have got viral load, and if you drop 2
> logs, even if though you are not suppressed, that is considered a
> success, and we don\'t do that in bacterial trials, so it is hard to
> know.
>
> DR. LEGGETT: I would like to echo something that Barth said. We are
> not going to create the perfect trial here.
>
> DR. POWERS: I think our concern is that what we see, I can see someone
> taking Dr. Anon\'s data and telling us, look, our drug makes the bug
> go away faster, therefore, we want to get labeled as better than that
> guy\'s drug, and that is what concerns us about that because we don\'t
> know whether making the organism go away faster, what it means
> clinically.
>
> We also don\'t know even in the setting of a clinical trial whether
> that means that those people had more bugs than the other guys did at
> baseline.
>
> DR. RELLER: I am more interested in the second tap, if it were done to
> see if the organism is resistant to the drug used, because I think one
> thing that has actually not been discussed in the context at all is
> what is resistance in terms of these major pathogens, the putative
> pathogens, the recognized pathogens for the treatment of sinusitis.
>
> There has been a lot of discussion of drugs, penicillin-resistant
> pneumococci, drugs that would, by some criteria, be called inactive,
> but they work anyway, and I think we don\'t know that information for
> bacterial sinusitis.
>
> That is my interest in the second tap, for those people who don\'t get
> better. If they get better, we will know what susceptibility is on the
> first one.
>
> DR. LEGGETT: We are going to let the FDA determine when to do that.
>
> DR. POWERS: That is the problem with interpreting this. If you only
> tapped the failures, you still can\'t tell what it means as far as
> interpreting antimicrobial resistance. I don\'t want to get into this
> one NDA, but the one we looked at, 21 people had a second positive
> culture.
>
> Everybody got tapped, it was 100 and some patients, everybody got a
> baseline and a follow-up tap. The follow-up tap was done at day 10 or
> so, not on therapy at the end.
>
> Of the 21 people that still had a positive culture, all 21 were
> clinically cured. So, to be able to evaluate what resistance means,
> you need to tap the successes, as well as the failures, because the
> presence or absence of the organism here, it is how it correlates
> clinically that means something.
>
> So, in other words, clinical guidelines suggest amoxicillin for this
> disease. If we know that you are going to get better no matter what
> drug you get on day 7, so, it may be that your amoxicillin-resistant
> Strep pneumo is still in your sinus, but you are better, so
> correlating those things requires looking at the people who are
> successes, as well as failures, to be able to make that distinction.
>
> DR. LEGGETT: John.
>
> DR. BRADLEY: Earlier, I mentioned about the difficulties in doing
> these double tap studies for otitis, you tap them on entry because
> they have symptoms and then you tap them three to five days into their
> treatment, and some of those centers are now trying to do quantitative
> cultures on those ear taps, which I think plays perfectly with what
> you said.
>
> I was unable to get any parent talked into a double tap study despite
> the fact that we offered conscious sedation for them, however, that is
> not to say that other studies didn\'t collect the data, and that I
> don\'t use those data in figuring out whether an antibiotic works or
> not.
>
> So, the concept that a world wide study could potentially be set up
> with sites where multiple taps would be reasonable seems to be a
> logical way to collect all of this valuable microbiologic data that
> you both are asking for.
>
> I would ask Dr. Gwaltney and Dr. Sydnor if they have done a multiple
> tap study, if it would be feasible to do this with the current feeling
> of how people view antibiotic therapy, the public.
>
> DR. LEGGETT: Dr. Gwaltney.
>
> DR. GWALTNEY: I showed you a slide that went from 1979 to 1997. Those
> were all double tap studies. We have not done one double tap study, we
> have done a dozen double tap studies. I can\'t remember the total
> number of patients, but it is in the hundreds, so they can be done.
>
> But I personally like the idea of leaving the indwelling catheter in
> there, the way Dr. Anon described, because you don\'t have to do the
> second tap, not that it can\'t be done, we did it for years and years,
> and I think we could do it tomorrow, although we are not doing it
> anymore, so I am not looking for business, we are through, but I think
> it could be done in the United States.
>
> There is I think a very nice aspect of leaving the catheter in because
> then you are seeing the cultures over time, and it doesn\'t appear to
> be a very long time before the infection is eradicated and you have
> got the quantitative cultures and the clinical material, the x-ray,
> everything to quantitate with the evidence of infection.
>
> And this is an infectious disease and we really need to know if we are
> doing something about the infection.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: You wouldn\'t need to have that many of those kinds of
> patients in whom serial data were available to learn when we should do
> a second tap if we wanted to only approach it that way.
>
> DR. POWERS: I think that would be a useful approach. It is kind of
> like getting two taps with actually only one tap, but getting multiple
> time points along the way. One of the things I think we would want to
> see though is that same material after the drug is gone from the body
> to see if there any kind of relapse, because that gets to this
> question of are we just measuring suppression or is that organism
> truly gone.
>
> DR. LEGGETT: Ed, are we just about finished or what things have we not
> touched on?
>
> DR. COX: I just had a question I thought maybe Dr. Gwaltney might
> address. I am just thinking about the catheter going in and the issue
> of, say, for instance, a drain or a catheter, and the initial culture
> might be sort of the cleanest sample, if you will, but after the
> device has been in place for a while, the issues of will that culture
> represent, in part, what is in the catheter.
>
> Would that be an issue, too, of potential concern here with the
> follow-up culture?
>
> DR. GWALTNEY: I think that is a good question. I think the answer is
> no. The reason is I am certain that material gets into the sinus all
> the time. We know when you blow your nose, you get it in there, and
> the sinus, for whatever reasons including the mucociliary escalator
> and probably nitric oxide and other things fights that continuous
> contamination that gets in there.
>
> I think if you have catheter in situ, in the artificial situation. The
> sinus is still doing its thing, so theoretically, I think there is
> good reason to think the sinus is still going to do all right in spite
> of the fact the catheter is there, but more importantly, at least we
> have a little bit of information on 4 patients, and the sinus became
> sterile. They were just culturing for pneumococci, they were culturing
> for bacteria, and it became sterile.
>
> So, I can\'t say with assurance that would happen with more patients,
> but it is so easy to find out. This is such a doable experiment from
> which we would learn so much new important information. That is why I
> find it very desirable or very attractive.
>
> DR. LEGGETT: Barth, Tom.
>
> DR. RELLER: I want to come back to John\'s comment. It seems to me
> that the greatest information we are going to get for resolution of
> organisms related to their susceptibility is the detailed clinical
> follow-up relative to the organism that was present and having that
> bacteriology on everybody in the first place.
>
> I don\'t think a second tap is\--I understand what you are saying, but
> I mean we are going to get that information, which brings to a
> question that in relation to this second tap, which I am not
> advocating routinely because I think it makes it far more complex that
> the good that we would lose by emphasizing getting people the first
> time.
>
> But, Dr. Gwaltney, in the studies where you did do a second tap, and
> given these dramatic pressure and what happens, is there a phenomenon
> in those persons, for whatever reason don\'t resolve, who get a
> superinfection after initial antibiotic, or does that just not occur
> clinically?
>
> DR. GWALTNEY: We don\'t have a lot of information on that, but people
> who don\'t respond to initial therapy and end up getting a sinus
> aspirate culture\--and my wife was one of these, she went through this
> whole thing\--when they get the sinus aspirate culture, most often you
> don\'t grow anything, and that is quite puzzling, but that is not
> always true, but as far as what has been published and what I am aware
> of, you don\'t find some resistant pneumococci or some unusual bug or
> something like that.
>
> I mean you would think that would be the case. That is not so. So,
> some people now think, and certainly is a reasonable hypothesis, that
> chronic sinus disease in these patients that don\'t recover from the
> acute infection is something else. Maybe there is something wrong in
> the immune system of those people, but despite what I originally
> thought would happen, retap these failures, you don\'t find anything
> that really explains what is going on.
>
> DR. RELLER: That is useful information in terms of our understanding.
>
> DR. GWALTNEY: Yes.
>
> DR. LEGGETT: Tom.
>
> DR. FLEMING: I have an overall comment relative to Question 3, so I am
> happy to defer and wait for other discussions on retap, is there more
> discussion of this?
>
> DR. LEGGETT: I hope not.
>
> DR. COX: I have heard a couple of folks talking about retapping in the
> setting of failure, and we have discussed 2 in part, but I was
> wondering if we could just get a little more feel from the committee
> about just retapping in the absence of failure. I am not hearing much
> in favor of that.
>
> DR. LEGGETT: I don\'t sense a consensus opinion about why we would do
> it, what it would show. I think everybody, maybe it\'s because there
> is not a lot of data in addition to some theoretical issues, leave it
> open to folks.
>
> DR. BRADLEY: I think there is valuable information on the natural
> history of the disease to retap all of those who are culture positive
> at the first tap, all of them, whether they respond clinically or not,
> just as we learned in otitis media. So, that is my vote, and I know
> that there are probably people who disagree with that.
>
> DR. LEGGETT: Whoever would like to speak up is fine.
>
> DR. SUMAYA: I would think that a retap would be very useful again more
> from the natural history of the disease. Nonetheless, I think I would
> try to limit it in this particular study to those that relate to
> failures.
>
> DR. LEGGETT: Jan.
>
> DR. PATTERSON: I don\'t really think I would favor a retap except in
> the case of failure although if you had a center that really could do
> double tap studies, it might be useful to have it done in that one
> center for the natural history of disease.
>
> DR. CROSS: I agree, I think it would be nice to have, but it would be
> a very hard sell.
>
> DR. LEGGETT: Ellen.
>
> DR. WALD: I would like to learn as much as we could from those
> indwelling catheter studies, and not insist on a second tape unless
> there was a clinical failure, and then if it was possible, do it.
>
> DR. LEGGETT: That is essentially my feeling.
>
> DR. RELLER: I agree with the two of you.
>
> DR. PORETZ: I would tend to agree. Dr. Gwaltney has done it for years.
> Although that new catheter is fascinating and I think if you could
> make use of that, that would be a major plus.
>
> DR. LEGGETT: John.
>
> DR. POWERS: I did a poor job of explaining what I was trying to say to
> Dr. Reller earlier. I think if you want to look at the letter we wrote
> in the Peds ID journal, in this month\'s journal, what we did for
> otitis media was we made a 2 by 2 table, and we took clinical success
> yes/no, positive culture on the second tape yes/no, so you need to
> have the yes part of clinical success to fill out that cell of the 2
> by 2 table to evaluate this correlation.
>
> If you only tap failures, you only got 2 of those 4 cells. It is
> therefore very difficult to evaluate the impact if
> antimicrobial-resistant organisms if you can\'t fill out the other two
> cells of that 2 by 2 table.
>
> That is where I think the utility of doing follow-up sinus punctures
> on all people comes from. It would probably be impossible if you had
> to do two taps, but that is where I think the idea of this kind of
> leaving the catheter in becomes very attractive because the patient
> goes home, comes back, and really don\'t need a second procedure, just
> has to get the sampling done.
>
> DR. LEGGETT: As long as we could get everybody to guy the SinoJect.
>
> DR. CROSS: I had a question for either Ed or John. Earlier, in other
> meetings we have talked about the need for either one study or two
> studies.
>
> I guess the import of what we have been discussing here is that if we
> get one rigorous, high-quality study in which we have both
> microbiology and good clinical design, that that would be adequate for
> going forward for an NDA?
>
> DR. LEGGETT: I though that was in the setting of we are also looking
> at community-acquired pneumonia, looking at otitis, and looking at a
> bunch of other stuff, so there would be an aggregate of data. If they
> only were going for acute bacterial sinusitis, my vote would be no,
> two trials.
>
> DR. COX: That is consistent with what we talked about in the March
> 2003 Advisory Committee. In the setting of a well done, adequate and
> well-controlled study of acute bacterial sinusitis, good clinical and
> microbiologic characterization in the setting of an overall program
> with other indications that do provide evidence that the drug works
> well in the treatment of respiratory tract infections, other
> indications, some of which may by more serious infections, then, in
> that setting, it may be appropriate to consider one well-done acute
> bacterial sinusitis study, but in the instance of where those other
> indications aren\'t there to provide support to the acute bacterial
> sinusitis indication, then I think we would be looking at more
> conventional 2-study approach.
>
> In that setting, certainly, well-done studies would provide more
> compelling evidence of the drug\'s efficacy.
>
> In addition to, you know, in this setting where a more narrow program
> is being pursued, a more limited number of indications, we need to
> also get sufficient number of patient exposures in order to gather the
> safety data that we need also.
>
> DR. LEGGETT: Keith.
>
> DR. RODVOLD: In regards to the double tap, one of the things I would
> say about his studies that he is doing I think is also important, it
> has been discussed and we made a lot of decisions, is that I think you
> need to characterize from drug family to drug family, cidal versus
> static drugs, drugs that penetrate well, don\'t penetrate, and by
> doing his studies in small pilots with different groups, I think that
> would sort out for you maybe when to do a double tap with which type
> of compound that is in study at this point.
>
> Without doing more work and going across drug families with protein
> binding issues and all kinds of other pharmacological characteristics,
> and just stamp this thing at this point.
>
> I think there is a little bit of concern about that from my
> perspective, too, in all these trials, that if you do one placebo
> study with the fluoroquinolones, that is applicable across the
> boardwalk, too, I think that is a little concerning to me, so I think
> you are going to have to go through a few iterations of this, both of
> his trials, but also a placebo trial with different families to make
> sure it holds up across.
>
> Pharmacologically, there are lots of different drugs here.
>
> DR. LEGGETT: If we did need a good superiority trial, though, it would
> put us not in a position of the azithromycin in otitis situation.
>
> DR. FLEMING: Let me give an overall comment relative to Question 3 and
> try to tie in some of the other issues that were raised.
>
> I would surely endorse what I think many have said, in fact, I think
> all have said, and that is the endpoints that we would need to assess
> would be both clinical endpoints and microbiological endpoints.
>
> In the absence of having a truly validated surrogate for the clinical
> endpoints, I would argue that the clinical endpoint of resolution
> should be the primary endpoint, microbiologic endpoints would be very
> important secondary measures.
>
> As it relates to the formulation of this primary clinical endpoint, in
> principle, given that we are looking for measures that are sensitive
> and clinically relevant, I could see either a fixed time assessment or
> a time-to-event analysis as being appropriate.
>
> My concern with the fixed time is I wouldn\'t want it to be too early
> because fixed time early ignores all of the information after that,
> and in a self-resolving disease setting, I wouldn\'t want it to be too
> late, because a lot of the signal could be earlier, and that is the
> reason that I would be very interested in pursuing the time to event.
>
> I think what Dr. Powers has indicated as a possible model is something
> important to think about. Whether it\'s fixed time or time to event, I
> think it is going to be important to have validated measures that we
> are going to be using, so I think the concept of following on what\'s
> spent on influenza and traveler\'s diarrhea, looking at twice daily,
> patient diaries validated is I think a very interesting concept.
>
> As has been pointed out, time to event does give you a big more
> efficiency and power, but you get what you pay for. It does require
> more information, so it is going to require something like this that
> has more frequent assessments.
>
> My final comment is clearly, when this study is done, it will not only
> serve the purpose of giving us insights about benefit-to-risk of this
> antimicrobial, but hopefully it works toward setting the stage for
> design of future trials and potentially allowing us to do comparative
> studies and potentially non-inferiority trials.
>
> It is going to be tempting and in fact relevant to explore the data
> and find out whether time to event was most sensitive or would it have
> been more sensitive to look at fixed time at day 3 or day 7 or day 14.
>
> That is certainly relevant to do, but I would just caution against a
> strategy that would say post hoc, we will take whichever one of those
> was the most significant, fix that as the established effect for a
> future non-inferiority because we have something called regression to
> the mean, and that is, if you look at multiple point in time, one time
> may show up as more striking, but that may be more randomness that it
> looked better at day 5 than it did at day 7, so fixing in the future a
> non-inferiority margin based on what appear to be the most striking
> difference is at risk of a regression to the mean.
>
> You are overestimating the true effect at that one particular time
> point. So, yes, we can explore, but we have to be very cautious not be
> overinterpreting noise in the data as well.
>
> DR. LEGGETT: Any final comment by anybody except Ed or John or one of
> you guys?
>
> DR. POWERS: I had one comment, it had nothing to do with the
> scientific discussion. I think from looking at all these discussions
> today, you can see how much work all the FDA staff put into
> accumulating all of this data, and I wanted to thank all the medical
> officers that actually did a lot of this work in pulling all of this
> information together, because I learned a ton doing this.
>
> I also wanted to thank the statistical staff, Dr. Erika Brittain, who
> did such a good job that she is going to leave the FDA next week, I
> wanted to thank her for helping us out with all this stuff.
>
> Finally, I wanted to thank Leo Chan for putting together all the AV
> stuff and showing all the movies and everything that came out so well.
>
> \[Applause.\]
>
> DR. LEGGETT: Have we begun to answer your questions?
>
> DR. COX: I think we got a lot of very helpful advice today and I join
> John in thanking folks and also thanking the committee for all their
> discussions and helpful advice today.
>
> DR. LEGGETT: Thank you. I think we will adjourn.
>
> \[Whereupon, at 3:50 p.m., the proceedings were adjourned.\]

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