U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

	PUBLIC HEALTH SERVICE

	FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

	ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

	67TH MEETING

	THURSDAY,

	OCTOBER 21, 1999

		The meeting took place in the Kennedy Ballroom, Holiday Inn, 8777 Georgia Avenue, Silver Spring, MD, at 8:00 a.m., L. Barth Reller, M.D., Acting Chairman, presiding.

Present:

L. Barth Reller, M.D., Acting Chairman
Rhonda Stover, R.Ph., Executive Secretary 

Gordon L. Archer, M.D., Member
Celia D.C. Christie-Samuels, M.D., M.P.H., 
   F.A.A.P., Member
Robert L. Danner, M.D., Member
Barbara E. Murray, M.D., Member
Carl W. Norden, M.D., Member
Judith R. O'Fallon, Ph.D., Member
Julie Parsonnet, M.D., Member
David E. Soper, M.D., Member

Keith A. Rodvold, Pharm.D., Consumer Rep.

David Battinelli, M.D., Guest Expert
J. Thomas Bigger, M.D., Guest Expert
Richard Platt, M.D., Guest Expert
Jeremy Ruskin, M.D., Guest Expert

Allen Brinker, M.D., M.S., FDA Representative
Mark Goldberger, M.D., FDA Representative
Robert Hopkins, M.D., FDA Representative
Sandra Kweder, M.D., FDA Representative

Andrea Meyerhoff, M.D., M.Sc., DTMH, 
   FDA Representative
Leonard Sacks, M.D., FDA Representative
Robert Temple, M.D., FDA Representative

Carl E. Calcagni, R.Ph., Sponsor Representative
Deborah Church, M.D., Sponsor Representative
Alan Hollister, M.D., Ph.D., Sponsor Representative
Joel Morganroth, M.D., Sponsor Representative
Stephen Zinner, M.D., Sponsor Representative

Also Present:

Eckhard van Keutz, D.V.M., Ph.D.
John Lettieri, Ph.D.
Dr. Dagmar Kubice
John DiMarco, M.D., Ph.D.

	A-G-E-N-D-A

	OPEN SESSION

Issue:  Avelox(TM) (moxifloxacin), Bayer Corporation Pharmaceutical Division, for the treatment of community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, skin and skin structure infections, and acute sinusitis.
		
Call to Order 
	L. Barth Reller, 
	M.D., Acting Chairman	5

Conflict of Interest Statement	
	Rhonda Stover, R.Ph., Executive Secretary	5

Open Public Hearing	10

FDA Introduction 
	Mark Goldberger, M.D., M.P.H.
	Director, Division of Special
	Pathogen and Immunologic Drug
	Products, ODE IV, FDA	10

Sponsor Presentation

	Introduction
		Carl Calcagni, R.Ph., Vice President,
		Regulatory Affairs, Bayer	13

	Efficacy/Safety 
		Deborah Church, M.D.,
		Director, Anti-Infectives, Medical
		Affairs, Bayer	16

	QT Background
		Joel Morganroth, M.D.
		Clinical Professor of Medicine,
		University of Pennsylvania	47

	QT Data
		Alan Hollister, M.D., Ph.D.,
		Deputy Director, Clinical Pharmacology,
		Bayer	64

	Risk/Benefit
		Stephen Zinner, M.D.
		Charles S. Davidson, Professor of 		Medicine,		Harvard Medical School
		Chair, Department of Medicine, Mount
		Auburn Hospital	89

Discussion and Questions	96

FDA Presentation

		Robert Temple, M.D.
		Associate Director for Medical Policy
		Director, Office of Drug Evaluation I, 		FDA	131

	Efficacy
		Andrea Meyerhoff, M.D.,M.Sc., DTMH
		Medical Officer, Division of Special
		Pathogen and Immunologic Drug Products, 		ODE IV, FDA	142

	Safety
		Leonard Sacks, M.D.
		Senior Staff Fellow, Division of
		Special Pathogen
		and Immunologic Drug Products, ODE IV, 		FDA	161

	Post Marketing Adverse Event
		Allen Brinker, M.D.
		Medical Officer, Division of Drug Risk
		Evaluation I, FDA	178

Discussion and Questions	188

Adjourn	268

	

	P-R-O-C-E-E-D-I-N-G-S 
	8:03 a.m.
		DR. RELLER:  Good morning.  I'm Barth Reller in the Division of Infectious Diseases and Director of Clinical Microbiology at Duke University Medical Center, Acting Chairman for today's meeting of the Anti-Infective Advisory Committee.
		I would like to call the meeting to order.  At the outset I would like to ask all speakers to talk directly into the microphone.  One doesn't have to get real close.  They are very sensitive but direct the voice toward it, not immediately into it so that we can have an accurate transcription of all of the deliberations today and that all can hear your cogent comments.
		Next we'll have the Conflict of Interest Statement read by our Executive Secretary, Rhonda Stover.
		MS. STOVER:  The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
		Based on submitted agenda for the meeting and all financial interest reported by the committee participants, it has been determined that all interest in firms regulated by the Center for Drug Evaluation and Research which have been reported by the participants present no potential for the appearance of a conflict of interest at this meeting with the following exceptions:
		Dr. William Craig is excluded from participating in today's discussion and vote concerning Avelox.  In addition, in accordance with 18 U.S.C. 208(b) full waivers have been granted to Drs. Robert Danner, Carl Norden, Julie Parsonnet, and Keith Rodvold.
		A copy of these waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A30 of the Parklawn Building.  In addition, we would like to note that in 1996 Dr. Rodvold consulted with Johnson and Johnson regarding levofloxacin.
		Further, he has had interest in Eli Lilly, Rhône-Poulenc Rorer, Bayer Corporation, and Bristol-Meyers Squibb unrelated to their competing products.
		We would also like to note that Dr. Gordon Archer's employer, Virginia Commonwealth University, has an interest in Bristol-Meyers Squibb which is unrelated to the firm's competing product.
		Although the interest of Dr. Rodvold and Dr. Archer do not constitute a financial interest in the particular matter within the meaning of 18 U.S.C. 208, it could create the appearance of a conflict.  However, it has been determined notwithstanding these interests that it's in the agency's best interest to have Drs. Rodvold and Archer participate in the committee discussions concerning Avelox.
		Further, one of our committee members has had an interest relating to Avelox that we believe should be disclosed.  FDA believes that it is important to acknowledge the participants' involvement so their participation can be objectively evaluated.
		Dr. Barbara Murray previously participated in an in vitro activity study of moxifloxacin sponsored by Bayer.  With respect to FDA's invited guest speakers, Dr. Jeremy Ruskin and Dr. Richard Platt have reported interests which we believe should be made public to allow the participants to objectively evaluate their comments.
		Dr. Ruskin would like to disclose that his wife owns stock in Johnson and Johnson.  Dr. Platt would like to disclose that he has led or participated in studies funded by Merck and SmithKline Beecham.  He has also participated in discussions about potential studies funded by Parke Davis and Bristol-Meyers Squibb.  Further, he has had fees paid to his department for Merck consulting.
		In the event that the discussions involve any other products or firms not already on the agenda which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such 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.
		DR. RELLER:  Thank you, Rhonda.  
		I should next like to have each member of the committee, as well as our invited experts and consultants who will contribute so much to the discussions.  I'll begin on the right with Dr. Battinelli.
		DR. BATTINELLI:  David Battinelli, Vice Chairman for Education, Boston University School of Medicine.
  		DR. RUSKIN:  Jeremy Ruskin.  I'm Director of the Cardiac Arrhythmia Service at Massachusetts General Hospital, Boston.
		DR. PLATT:  I'm Richard Platt.  I'm a professor of ambulatory care and prevention at Harvard Medical School.
		DR. O'FALLON:  Judith O'Fallon, Biostatistics, Mayo Clinic.
		DR. RODVOLD:  Keith Rodvold, Colleges of Pharmacy and Medicine, the University of Illinois, Chicago.
		DR. CHRISTIE:  Celia Christie, Department of Child Health, University Hospital of the West Indies, Jamaica.
		DR. SOPER:  David Soper, Medical University of South Carolina in Charleston.
		DR. DANNER:  Bob Danner, Critical Care Medicine, NIH.
		MS. STOVER:  Rhonda Stover, FDA.
		DR. PARSONNET:  Julie Parsonnet, Stanford University, Division of Infectious Diseases.
		DR. ARCHER:  Gordon Archer, Medical College of Virginia Campus, Virginia Commonwealth University, Division of Infectious Diseases.
		DR. MURRAY:  Barbara Murray, Division of Infectious Diseases, University of Texas Medical School.
		DR. NORDEN:  Carl Norden, Division of Infectious Diseases, Cooper Hospital, University of New Jersey Medical School.
		DR. MEYERHOFF:  Andrea Meyerhoff, Medical Officer, Division of Special Pathogens, FDA.
		DR. HOPKINS:  Bob Hopkins, Medical Team Leader, FDA.
		DR. SACKS:  Leonard Sacks, Medical Officer, Division of Special Pathogens, FDA.
		DR. GOLDBERGER:  I'm Mark Goldberger, Director of the Division of Special Pathogens.
		DR. KWEDER:  I'm Sandra Kweder.  I'm the Acting Office Director, Office of Drug Evaluation IV.
		DR. RELLER:  Thanks.  It's now time for the open public hearing.  Are there any remarks to be made?  Since there is none, we'll move to the sponsor presentation.
  		DR. GOLDBERGER:  Barth, can I just make a couple of remarks?
		DR. RELLER:  Yes.
		DR. GOLDBERGER:  Thank you.  I would like to just join in the welcome of everyone, Dr. Reller, advisory committee members, invited consultants, members of Bayer Pharmaceuticals.  Today we are here to discuss Bayer Pharmaceuticals marketing application for the quinolone antimicrobial moxifloxacin.
		Individuals who have worked in infectious disease are certainly aware over the years of how modifications, for instance, in the beta lactam antibiotics have led to significant changes in the activity spectrum.
		More recently we have become aware of the potential for doing the same thing with fluoroquinolone antimicrobials and in response to growing problems with infections, particularly resistant infections due to gram positive organisms, an effort has been made to modify many of the newer fluoroquinolone antimicrobials to enhance their gram positive activity.  We'll be talking about such an antimicrobial today.
		Not surprisingly when one does structural modifications, one changes not only activity but sometimes one changes the toxicity profile as well.  We have become increasingly aware over the last few years of the broad range of toxicities associated with the fluoroquinolone antimicrobials.  We will, of course, be discussing the safety profile of this drug as well.
		As part of that discussion we will be having some commentary about the issue of QT prolongation associated with this antimicrobial.  It is important to note that QT prolongation occurs with a wide range of noncardiac drugs and including a range of antimicrobials beyond simply the fluoroquinolones.  Assessing the significance of such prolongation is not an easy issue.  
		We are extremely fortunate that in addition to our invited guests the company also has Dr. Joel Morganroth, an extremely well-known expert who as part of the company's presentation will be giving an overview of this issue to hopefully provide those of us who are infectious disease specialists with some reasonable understanding of the issue.
		We are looking forward to an interesting discussion today.  We thank you for your attention.  Thank you.
		DR. RELLER:  Thank you, Mark, for helping me read the agenda in the right order and for that broad overview.
		Dr. Kweder, do you have anything you want to say at this time?
		So having had the stage set by the FDA, we will now move to the sponsor presentation.  This will be led by Carl Calcagni who is the Vice President for Regulatory Affairs at Bayer Corporation Pharmaceutical Division.  
		It has been requested and worked well yesterday that we have the entire sponsor's presentation.  Then there will be an open discussion on all issues raised by this presentation with assistance from Carl in directing the questions to the appropriate members of his presenting team, as well as consultants to Bayer.
		Carl, please.
		MR. CALCAGNI:  Thank you, Dr. Reller.  Thank you, Dr. Goldberger.  I think you set the stage.  I will probably repeat some of the things you said and you will probably hear about the agenda once again.  I apologize for the repetition but I think it's important to set the stage for today.
		My name is Carl Calcagni as you see before you.  I'm the Vice President for Regulatory Affairs at Bayer Pharmaceutical Corporation in West Haven, Connecticut.  I wish to thank the members of the advisory committee, the FDA, and the other participants for this opportunity today to present Bayer's new drug, moxifloxacin hydrochloride to be known commercially as Avelox.
		Bayer submitted its NDA 21-085 application approximately 10 months ago.  Bayer corporation is a global leader in the development of quinolones and anti-infectives.  Cipro, or ciprofloxacin hydrochloride known by most of you, was approved in 1987, quite a long time ago.  It has over 12 years of marketed clinical experience in the USA.
		Over 200 million patients have been treated worldwide.  Today Bayer presents this advanced generation of quinolone that was synthesized at our Bayer AG Leverkusen, Germany facility.
		Moxifloxacin was synthesized with a purpose and developed with a purpose; to cover respiratory tract pathogens for enhancing gram positive and atypical activity; to provide longer half life to ensure once daily dosing; to improve compliance by shorter course of therapy and good tolerability; to potentially minimize antibiotic resistance; and to provide a new alternative for community respiratory tract infection treatment.
		Moxifloxacin has current approval status in the listed countries.  It has been recently marketed in Germany and is currently in process for the mutual recognition procedure in Europe.
		Bayer's objectives today are to demonstrate that moxifloxacin is safe and effective for acute bacterial exacerbation of chronic bronchitis, acute sinusitis, community acquired pneumonia, uncomplicated skin and skin structure infections, and to review the observation of the QTc prolongation with moxifloxacin, assess its relative risk factors, and present submitted labeling that is appropriate and responsible.
		Moxifloxacin dosage administration is once-a-day for the following indications and duration of therapy.  Acute bacterial exacerbation of chronic bronchitis, five days; uncomplicated skin and skin structure infections, seven days; acute sinusitis, 10 days; and community acquired pneumonia, 10 days.
		The agenda today will reflect our review of the efficacy and safety by Dr. Deborah Church who is the director at Bayer for the anti-infective group, followed by a backgrounder on the QTc by Dr. Joel Morganroth, clinical professor of medicine, University of Pennsylvania, presenting the background.
		Then for purposes of our data presentation, Dr. Alan Hollister, who is the deputy director of our clinical pharmacology group.  Following that, and providing the risk benefit and conclusion, will be Dr. Zinner who is the Charles S. Davidson Professor of Medicine, Harvard Medical School, Chair of the Department of Medicine at Mount Auburn Hospital.
		In addition, Bayer has in attendance today the listed experts for consultation by the advisory committee, the FDA, and Bayer if needed.
		I would like to present Dr. Deborah Church to present the efficacy and safety section.
		DR. CHURCH:  Good morning.  My name is Deborah Church and I'm here today to speak to you about the efficacy and the safety of moxifloxacin, a new 8 methoxy quinolone developed by Bayer.
		What I would like to do is start off by just setting the stage and going through the items that I'll be discussing during my presentation.  I'll discuss with you the rationale for development, the microbiology, the pharmacokinetics and pharmacodynamics of the compound.  
		We'll talk about the findings of moxifloxacin and drug resistance.  I'll share with you the clinical and bacteriological results submitted in the NDA for the four indications we are seeking approval for; acute sinusitis, acute exacerbation of chronic bronchitis, community acquired pneumonia, and skin infections.  
		I'll also share with you outcome analyses that we did, particularly with the morbidity parameter.  When speaking about safety, I'll discuss with you drug interactions, excretion, and metabolism.  When discussing exposures of patients we'll talk about adverse events, serious adverse events, premature discontinuations, deaths.  I'll compare moxifloxacin with the controlled drugs when talking about selected quinolone related events.
		For the particular topic of QTc prolongation and the observations with moxifloxacin, Dr. Morganroth and Dr. Hollister will go on to talk about that later in the presentation.
		Despite the predictions that infectious diseases were on the decline, we have actually seen today that respiratory tract infections still account for significant mortality and morbidity.  Drug resistance has increased over time.  We know that is the case with the organisms which you'll hear today; haemophilus influenzae, moraxella catarrhalis, and in particular with streptococcus pneumoniae or know as strep. pneumo.
		It thus makes sense that new antibiotics and a change in selection and use may be needed to alter these trends of resistance.  Potent new fluoroquinolones such as moxifloxacin should have an important place in the management of infectious diseases.
		I have put this slide here that you have seen yesterday also just to show the impact of decreasing penicillin macrolide susceptibility of strep. pneumo in the United States.
		This diagram goes through the last two decades.  Looking at the left-hand side of the slide, you'll see that the number of macrolides suspectable to penicillin in 1979 approached about 97 percent.  A year ago that percent went down to about 64 percent.  With respect to resistance in 1979 was about a 0.2 percent.  As of a year ago that increased to 14 percent.
		That's not only the case with penicillin but also the case with the macrolides.  An example being on the slide, erythromycin.  In 1979 100 percent susceptibility.  Looking at 1998, down to about 77 percent.
		So why did Bayer set out to design moxifloxacin?  We had an increased knowledge of quinolone structure activity relationships which facilitated the following.  We had excellent gram negative coverage but we wanted to look for enhanced gram positive, atypical, and anaerobic activity. 
		We'll share with you an innovative approach to resistance in terms of efflux as well as other mechanisms of action.  We wanted to look for the optimal pharmacokinetics and pharmacodynamics.  
		We wanted to select the appropriate dose not only for therapeutic efficacy, but we also wanted to look for a compound that had a low propensity for resistance and, of course, a favorable safety profile.
		This is the structure of moxifloxacin.  This is the apparent ring of the quinolones.  We now know by changing some of those side chains on quinolones we can actually do a number of things.  The first thing is we can enhance the antibacterial profile.  The second part of it, we could try to look for mechanisms to minimize resistance.  How do we do that?
		This part of the chain is the C-7 which is the bicyclic amine which actually enhances gram positive activity as well as minimizes efflux, particularly for strep. pneumo and staph. aureus.  This is the C-8 position which is the methoxy position which actually enhances anaerobic activity, as well as minimizes development of resistance through DNA gyrase as well as topoisomerase 4.  
		We have done a number of in vitro experiments with moxifloxacin.  I would like to share with you some of those highlights.  This is the in vitro activity of moxifloxacin against the key respiratory tract pathogens, strep. pneumo.  Unlike the beta lactams regardless of whether the strain is penicillin susceptible or penicillin resistant, the MICs for moxifloxacin are identical at 0.25.
		A very similar case with haemophilus influenzae, moraxella catarrhalis.  Regardless of whether there is production of beta lactams or not, those MICs are identical at 0.06.  We certainly know that atypicals are on the rise.  They are important pathogens in community acquired pneumonia, once again with very favorable MICs for moxifloxacin.
		How about with regards to other respiratory tract pathogens?  Well, with haemophilus parainfluenza and strep. pyogenes the MICs are 0.25.  With regards to staph. aureus methicillin susceptible at 0.125 and for MRSA and MIC at 4.
		We also know that moxifloxacin is active against a wide variety of clinically important anaerobic species.  For the sake of brevity I've just placed two examples here, bacteroides with an MIC of 2 and peptostreptococcus with an MIC of 0.25.  
		It is important to note in general that the MIC value is less than 2 for the minority of the anaerobes.  Moxifloxacin in contrast to other quinolones is very active against M. tuberculosis with an MIC of 0.5.
		I've placed this slide here to reinforce that the MICs for moxifloxacin and for strep. pneumo is unaffected by resistance by penicillin.  I'll tell you about a second item I would like to bring in also.  We have a list of three quinolones here; moxifloxacin, levofloxacin, and ciprofloxacin.  Macrolides, examples are clarithromycin and azithromycin and the beta lactams with amoxicillin, clavulante acid and cefuroxime axotal.
		You can see as I go down the macrolides that if the organism is a pen. susceptible strep. pneumo to a pen. resistant strep. pneumo that the MICs do increase.  The same thing happens with the beta lactams.  Certainly not the case with the quinolones.  The second important feature is when looking at the three quinolones here the most active of the three quinolones is moxifloxacin with an MIC of 0.25.
		Now, I would like to tell you a little bit about the findings with moxifloxacin and drug resistance.  What I'll do is give you two findings and actually give you an example of an in vitro experiment and some in vivo examples.
		With regards to the mechanisms of resistance mutations in nor A gene that up regulate the membrane associated drug efflux pump despite increased antibody efflux from nor A containing strep. pneumo and staph. aureus, moxifloxacin MICs remain identical to the wild type.  That is, identical wild type MICs to mutant MICs.
		Mutations in topoisomerase 4 and DNA gyrase, simultaneous independent mutations in both grl A and gyr A are required to increase the moxifloxacin MICs.  Even when this occurs, though, the MICs are still near the clinically observed minimum concentration of the drug.
		This is just an example to give you differential emergence of resistance between levofloxacin and moxifloxacin with one particular strain of strep. pneumo 4241.  If you look at the X axis we have the number we have the number of passages from serial exposures at 0.5 times the MIC which is also the same as the number of days.
		If you look at the Y axis you actually have the MICs.  If we look at zero we'll see that the MIC for moxifloxacin, which is designated by the yellowish green line here, you'll see that the MIC is about 0.25.  Levoquine or levofloxacin the MIC is 1.  		If you look at a particular day such as day four, you'll see that the MIC for moxifloxacin is less than or equal to 1.  If you go to levofloxacin you'll see there's an increase of about 10 fold.  If I go out to day six, what I'll see is there's a plateau for moxifloxacin.  If I look at levofloxacin, there's about an MIC of about 100.  What I've tried to show you here is there's slow development of resistance to moxifloxacin and to a lesser extent for levofloxacin. 
		How about with staph. aureus?  Same type of diagram here, the isolate being strain 133.  Once again the MIC for moxifloxacin about 0.125.  Higher for levofloxacin.  If I look at, for example, day four, I see that it's less than 1 for moxifloxacin, higher than that, close to 10 for levofloxacin.  Moxifloxacin plateaus here and about a 64 when going out to day six to eight for levofloxacin.  Once again, showing you the slow development of resistance to moxifloxacin and to a lesser extent than levofloxacin.
		This is an example of an in vivo model.  This actually is a rat granuloma pouch model looking once again at the two pathogens that I've just shown you, staph. aureus 133 and strep. pneumo 4241.  The items here are the type of mutants created whether it's the first step or multi-step for both the pathogens.  The MIC for moxifloxacin from day zero to day eight are identical across the board.  Therefore, there's no development of moxifloxacin resistance in the rat granuloma pouch model.
		I would like to summarize what we've said so far.  We've targeted both the DNA gyrase as well as topoisomerase 4.  There's been minimization of resistance that has been demonstrated in vivo by the example that I've given you with levofloxacin.  The animal studies have shown no emergence of resistance in the rat granuloma pouch model.  These important results are achieved via the methoxy group at C-8 which significantly delays the selection of resistance in the bicyclic amine at C-7 which minimizes drug efflux.
		Let's talk a little bit about the pharmacokinetics and the pharmacodynamics of moxifloxacin.  They are pretty straightforward.  The half life at steady state is 12 hours which actually supports once daily oral dosing of 400 milligrams.  The Cmax is 4.52. 
		Another important item if you look at the concentration over a 24-hour period, you'll see the concentrations above the MICs of the relevant pathogens I've just spoken to you about, strep. pneumo, staph. aureus, haemophilus and moraxella.
		I would like to talk to you not only about the pharmacokinetics and pharmacodynamics and also tissue penetration.  Here basically is respiratory as well as sinus tissue.  Looking at the plasma concentrations once again from 3.3 to 3.7, way above the MICs of the relevant pathogens that I've shown you.  Tissue are fluid concentrations.  
		Particularly I would like you to note the macrophages which have a 61.8, as well as the epithelial lining fluid at 24.4.  I would like to show you that ratio.  Looking at the ratio between tissue and plasma at 21.2 for macrophages and 8.7 for the epithelial lining fluid.  
		Just in the form of a comparison, I would like to show you levofloxacin.  This is at 2 and 4 hours.  If I look at the 2 hours 21.2 for moxifloxacin versus 7.3 and 8.7 versus 0.8.
		Those are two other parameters that are well known to look at correlations with quinolone efficacy.  There are the Cmax or maximum concentration to the MIC 90 which should be at least eight to 10.  Looking at the area under the curve divided by the MIC 90 of greater than 100.  I would like to show you how moxifloxacin compares to other quinolones with this.
		Just on top just to go over this, moxifloxacin, levofloxacin, ciprofloxacin, sparfloxacin, and grepafloxacin.  This is particularly looking at the Cmax over the MIC 90.  We know for optimal antibiotic effect and to minimize development of resistance that the Cmax to MIC 90 ratio should be at least eight to 10.  
		For haemophilus influenzae, moraxella catarrhalis if you look across the board those are pretty much above eight to 10.  Let's look at strep. pneumo, a very important pathogen.  You can see that looking at levofloxacin, ciprofloxacin, sparfloxacin, and grepafloxacin, these numbers are less than the eight to 10.  Moxifloxacin is above that with an optimal number of 18.
		Now, what if I wanted to look at AUC and MIC 90, once again looking at the same quinolones, haemophilus influenzae, moraxella catarrhalis, once again those numbers for optimal antimicrobial effect and to minimize resistance should be greater than 100.  Across the board those are over 100.  If I want to look at strep. pneumo, once again looking at the other quinolones less than 100, moxifloxacin at 192.  
		So far what I've shown you about pharmacokinetics and pharmacodynamics, moxifloxacin PK, certainly supports once-a-day dosing.  It provides plasma and tissue levels above the MIC for the relevant respiratory pathogens for the entire 24-hour period.  A 400 milligrams once-a-day dose of moxifloxacin provides optimal pharmacokinetics and pharmacodynamics.  Moxifloxacin pharmacokinetics results in the optimal overall pharmacodynamic characteristics that you just saw, Cmax over MIC area under the curve over MIC compared to the other four quinolones.
		Now, I would like to take you a little bit through the general aspects of the clinical development program that we did as well as go into the individual indications.
		We did Phase II and Phase III studies that were performed in the four indications you'll hear about; acute sinusitis, acute exacerbation of chronic bronchitis, community acquired pneumonia, and skin infections.  We used the FDA/IDSA guidelines as well as the primary efficacy variable with clinical outcome.  That was assessed at test of cure which we defined it some number greater than or equal to seven days after the last dose of drug.  We also looked at secondary variables which included the bacteriological responses as well as safety.
		As provided in the points to consider, the treatment groups were tested for equivalents and the intent to treat population and safety population included all patients who took at least one dose of study drug.
		Just to give you the idea of how many studies we did and how many patients were in these trials, we did 15 trials in respiratory tract infections plus three for skin for a total of 18 studies.  With regards to the number of patients, there were 8,306 patients in the NDA of which 3,109 received comparator, which I'll talk what comparators we used later on in the presentation, and 4,015 patients were on moxifloxacin at 400 mg.
		Now, what I would like to do -- these slides are pretty much set up the same way -- I'll talk to you about each indication individually.  I'll show you the clinical responses and the bacteriological responses.
		This is for acute sinusitis and we're looking at the clinical resolution at test of cure.  I just want to start out by telling you that D96-024 and D96-023 were the first sinusitis studies that we started off with.  024 was a double-blinded prospective multi-sentry trial performed in the United States.  We found the drug to be efficacious at 81 to 80 percent.  But when doing this trial against cefuroxime 250 milligrams BID for 10 days, the seven days of moxifloxacin did not show equivalence to cefuroxime.
		We did a very similar trial outside the United States in Europe and we found this study to be equivalent to cefuroxime.  We then proceeded to do a sinusitis study at 10 days which is 100, 107, a doubled blinded prospective multi-sentry trial done in the United States with a 90 percent cure rate.  
		I want to mention that these are not taking into consideration improvements.  These are true cure rates.  Ninety percent versus 89 percent for cefuroxime at 10 days.
		One hundred and sixteen is the study I mentioned which was actually the seven-day study in Europe which had a 90 percent cure rate for seven days of moxifloxacin versus 84 percent for cefuroxime did show equivalence.  116 is the 10-day study which is quite similar to the U.S. study with a 94 percent cure rate, 95 percent for cefuroxime.
		What about microbiology?  Three target pathogens here; strep. pneumo for moxifloxacin at seven days had a 98 percent eradication rate, 95 percent for cefuroxime.  With regard to haemophilus influenzae, 86 percent versus 85 percent.  For moraxella catarrhalis 88 percent versus 67 percent, although there were small isolates for that arm.
		So for acute sinusitis both in North America as well as outside North America the studies demonstrate equivalence between the 10 days of moxifloxacin and the 10 days of cefuroxime.  The microbiological efficacy of the seven days of moxifloxacin was demonstrated against the three targeted pathogens.  Moxifloxacin given for 10 days is clinically and bacteriologically effective for the treatment of acute maxillary sinusitis.
		Now, I would like to go on with acute exacerbation of chronic bronchitis.  We have two studies there I would like to talk to you about.  The first one is D96-027.  It's a double-blinded prospective multi-sentry trial done in the United States and the 124 which was done in Europe doubled blinded also.
		With respect to the 027 we actually looked at 10 days of moxifloxacin versus five days of moxifloxacin and saw almost identical rates of 91 percent versus 89 percent.
		When looking at the five days of moxifloxacin in the control which was clarithromycin given over 10 days.  It was 89 percent versus 89 percent, identical rates.
		For the ex-US study at five days moxifloxacin had identical numbers with the U.S. trial.  And with regards to clarithromycin given over seven days, that was 89 percent versus 88 percent.
		I know this is a busy slide but these are the organisms that we are looking for approval for; haemophilus influenzae, 90 percent for moxifloxacin versus 64 percent for clarithromycin; strep. pneumo 89 percent versus 95 percent; moraxella catarrhalis 86 percent for moxifloxacin versus 98 percent for clarithromycin; staph. aureus 94 percent versus 84 percent; kleb. pneumo 85 percent versus 91 percent; haemophilus parainfluenza 84 percent versus 100 percent.
		I've told you so far for acute exacerbation of chronic bronchitis that moxifloxacin is consistently demonstrating equivalence to the comparator.  It's effective against the major pathogens associated with this disease.  A five-day treatment arm is recommended based on the favorable clinical and bacteriological results.  The shorter duration may increase the compliance and facilitate patient convenience.
		There were also a number of studies that were done in community acquired pneumonia.  The first two studies, D96-026 and D96-025 were actually studies done in North America.  119 and 140 were done outside of North America.  
		Just to take you through them, 026, a doubled-blinded prospective multi-sentry trial with moxifloxacin over 10 days having 95 percent cure rate versus a 95 percent cure rate with clarithromycin over 10 days.
		The open study, 025, had a success rate of 93 percent with moxifloxacin over 10 days.  The 119, the European study, was 93 percent with moxifloxacin versus 92 percent with clarithromycin.  140, 89 percent for moxifloxacin versus 89 percent with the comparator which here was amoxicillin given one gram three times a day.
		Just to give you an idea about pathogen eradication rate for community acquired pneumonia, strep. pneumo 89 percent, almost identical to the control, 88 percent; haemophilus influenzae 90 percent, once again higher than the control at 74 percent; moraxella catarrhalis 86 percent versus the identical number for the control 86; kleb. pneumo 87 versus 80 percent; staph. aureus 94 percent versus 90 percent. 
		With mycoplasma as well as chlamydia we did also cultures as well as serological testing and those numbers are for mycoplasma 94 percent versus 95 percent for the control; for chlamydia 92 percent versus 96 percent.
		So moxifloxacin is clinically and microbiologically effective in community acquired pneumonia.  It shows favorable activity against typical as well as atypical target pathogens associated with the disease.
		Now, we talked about enhancement of gram positive activity and I want to show you some of the results of our skin trial.  Two trials, once again 97005, the U.S. trial, and 0131, both double-blinded prospective multi-sentry trials with clinical cure rates 89 percent for moxifloxacin given over seven days in the U.S. versus the control which was 90 percent with cephalexin.  Looking at 131 it was 95 percent for moxifloxacin given over five to 14 days versus 93 percent for cephalexin plus or minus metronidazole.
		Just to give you some of the eradication rates for the particular pathogen seen there, the predominate pathogen was staph. aureus at an 82 percent eradication rate in the U.S. study versus 93 percent for the control.  For the ex-U.S. study 92 percent versus 88 percent for the control.
		Once again, moxifloxacin is clinically effective, microbiologically active for uncomplicated skin infections, 400 milligrams once a day for seven days as recommended for optimal patient compliance and convenience.
		So I just want to show you the indications and durations in doses and the different indications we just talked about.  I've shown you evidence for the efficacy of acute sinusitis over 10 days for the targeted pathogens seen here; acute exacerbation of chronic bronchitis for five days for the same pathogens plus haemophilus parainfluenza, kleb. pneumo, as well as staph. aureus, and for community acquired pneumonia for a 10-day duration, same organisms with the atypical, and skin infections for seven days with gram positive coverage.
		I want to show you two additional analyses that we did.  The first one is looking at penicillin intermediate and resistant isolates to strep. pneumo from our pivotal trials using 400 milligrams of moxifloxacin in control.  Overall there were 146 of 207 isolates.  71 percent of the strep. pneumo were actually penicillin susceptible.  
		This chart goes through penicillin intermediate as well as penicillin resistant strains.  Those were defined as intermediate, an MIC of greater than 0.1 to less than 2 and resistance was an MIC of greater than or equal to 2.  
		I've done this by the particular indications; sinusitis, community acquired pneumonia, acute exacerbation of chronic bronchitis.  I'll ask you to look at all studies which is the combination of all these results.  
		For intermediate isolates we had 31 isolates for an eradication and cure rate of 87 percent.  There were 11 isolates in the control arms and those controls once again were clarithromycin and amoxicillin at 1 gram TID for an eradication and cure rate of 82 percent.
		For those isolates that were resistant we had 15 isolates for an eradication rate and a cure rate of 87 percent.  With regards to the control arm, there were five isolates and 80 percent eradication and cure rate.
		So 46 or 37 percent of the strep. pneumo isolates were recovered from patients treated with moxifloxacin, had MICs in the penicillin intermediate or resistant range.  The high clinical success rate that was observed in patients with penicillin intermediate and resistant strep. pneumo suggest that these infections respond to moxifloxacin at 400 milligrams.  These clinical and eradication success rates were either comparable or higher than those observed for comparators.
		Now, I want to show you one additional outcome analysis which basically has to do with morbidity.  We wanted to examine additional benefits of moxifloxacin.  We did a retrospective analysis of the data from acute exacerbation of chronic bronchitis patients and community acquired pneumonia patients with the intention that these patients being, of course, outpatients.
		The data was analyzed for overall hospitalization rates and we pulled the studies across the U.S. as well as internationally and we compared those data with our control drugs.
		Now, this is looking at worsening of respiratory conditions which resulted in hospitalization.  Remember that these are outpatients with acute exacerbation of chronic bronchitis and community acquired pneumonia patients.
		We selected adverse events based on COSTART terms of worsening of bronchitis, worsening of pneumonia, or lung disorder.  Lung disorder, for example, was exacerbation of COPD would be a good example and any of the above.
		Just to let you look at this one particular line of any of the above, there were 18 patients that worsened their condition and resulted in a hospitalization of the moxifloxacin arm.  That was versus 30 patients in the control arm.  So hospitalization rates were lower and the acute exacerbation of chronic bronchitis patients as well as the pneumonia patients treated with moxifloxacin when compared to the control.  The P value of that was 0.02.
		So I just want to conclude with efficacy saying that moxifloxacin is microbiologically and clinically effective in the treatment of acute sinusitis, acute exacerbation of chronic bronchitis, community acquired pneumonia, and skin infections.
		The clinical and eradication success rates that you've seen for penicillin intermediate as well as resistant strep. pneumo were either comparable or higher than those observed for the comparators.  The data from the additional morbidity analysis demonstrated favorable results from moxifloxacin versus the comparators.  With respect to the hospitalization rates in patients that had acute exacerbation chronic bronchitis and community acquired pneumonia.
		I'd like to give you a short review of moxifloxacin safety profile just in the form of a summary.  
		Moxifloxacin dosage adjustment is not necessary to the elderly, particularly speaking here about age, gender, race, either mild, moderately, or severe renally impaired patients, or mild to moderate hepatically impaired patients.  
		An important feature which you'll hear Dr. Hollister speak about in his presentation is moxifloxacin is not metabolized by cytochrome P450 enzyme system.  It also has no apparent clinical effects on the cytochrome P450 enzyme system.  Unlike other quinolones, for example, levofloxacin which is primarily exceeded from the kidneys and trobofloxacin from the liver, moxifloxacin exhibits a balanced excretion by both renal and biliary routes.
		There are no clinically significant drug/drug interactions and I've placed here a number of them; theophylline, warfarin, digoxin, probenecid, ranitidine, and glyburide.  As with other quinolones, although this is not an issue of safety, reduce moxifloxacin bioavailability with antacids and iron if given concomitantly.
		Just to give you an idea of what safety profile we have, worldwide 5,233 patients were enrolled in either the 200 or 400 milligram arm of moxifloxacin.  99.2 percent of these patients were evaluated for safety and 89 percent of these patients were treated with the 400 milligram dose.  Of the 400 milligram moxifloxacin treated patients valid for safety, 4,008 patients, 87 percent were enrolled in the control trials.  You'll see that number when I show you some of the safety tables.
		To give you an idea of what safety procedures we did, we monitored clinical evaluations, laboratories including chemistries, hematology, electrolytes, urinalysis, PT/PTT, additional studies such as theophylline, 12-lead ECGs which you'll hear those results with Dr. Hollister.  We monitored adverse events.  We did this during baseline and during end of therapy and the follow-up was usually four weeks after the last dose of drug.
		Just to give you an idea of the number of patient exposures, we had a total of 21 studies.  With regards to the 400 milligram controlled studies, there were 4,008 patients; all moxifloxacin treated patients, 5,189; and with comparators 3,689.
		What I would like to do is go through the incidents of adverse events by individual events.  What I've done here is placed any adverse effect which has been greater than or equal to 2 percent.  This also does not take into account whether the investigator thought it was drug related or not so we have all the adverse events here.
		I've also placed them in the frequency of highest frequency to lowest frequency.  I'll show you the comparison of moxifloxacin with the controlled drugs.  Overall any event, 46 percent for moxifloxacin versus 45 percent for controlled drug.  The most frequent events were nausea, diarrhea, headache, and dizziness, quite similar with the controlled drugs.  All the events past dizziness were 3 percent or less.
		Now, if you were wondering what that adverse event profile looks with any individual comparator, I've placed that also.  Quite busy but just to point out a number of items.  When looking at something, for example, as GGTP, the highest values were in the amoxicillin 1 gram TID as well as the cefuroxime 500 milligram BID arms.
		When looking at something, for example, as liver functions, 11 percent with amoxicillin, 1 gram TID.  If I was to look at this particular study with moxifloxacin the comparison would be 6 percent there.
		How about premature discontinuations.  Once again, the rates are quite low and similar to the comparators.  Moxifloxacin had a 5 percent premature discontinuation rate to adverse events.  That was versus 4 percent for the control.  When looking at any individual event, as you can see they are quite low, less than 1 percent for moxifloxacin.
		With regard to serious adverse events, once again quite similar.  Four percent for moxifloxacin and 5 percent for the control.  Looking at any individual event, once again those were less than 1 percent.
		So, in summary, just the part of the adverse event profile, the incidents of adverse events were quite similar; 46 percent for moxifloxacin at 400 milligrams versus 45 percent for the control.  We're looking at serious adverse events, 4 percent versus 5 percent.  Premature discontinuations due to adverse event, 5 percent versus 4 percent.
		So moxifloxacin was comparable to the FDA well established control drugs.  Most adverse events reported were mild to moderate in severity and required no therapy. 
		Now, what I would like to do is show you some mortality rates.  What I'll do is consider deaths that we recorded through 30 days post study drug administration.  I'm going to show you three subsets.  The first subset will be those patients that were enrolled in the indications we are seeking approval for; respiratory tract infections and skin infections.
		If you look at the moxifloxacin arm, there were seven deaths versus 15 deaths in the control arm for a P value of 0.056.  Now, if I wanted to look at those patients that had acute exacerbation of chronic bronchitis as well as having community acquired pneumonia, those deaths were five in the moxifloxacin arm versus 15 in the control for a P value of 0.009.
		What if I just wanted to look at those pneumonia patients?  You would see there are four deaths from moxifloxacin versus 12 from the control.  The P value is 0.045.
		The mortality rates were lower in the community acquired pneumonia patients and the combination of those patients with acute exacerbation of chronic bronchitis.  Rates were lower with moxifloxacin than those that we're seeing with the control drugs.
		Now, there are a number of selected events that have been associated with some of the quinolones and I have selected some of those to show you the rates we have with moxifloxacin versus control drugs, the first one being CNS.  I selected seizure.  One patient on moxifloxacin 400 milligrams versus 2 for the control.  This particular patient actually had a preexisting condition of seizures.  
		With respect to pain in the achilles tendon, there were two versus zero for the control.  Neither of these patients had any action taken for the pain in the achilles tendon and there were no tendon ruptures.
		With regard to phototoxicity, two with moxifloxacin versus three for the comparator.  I must mention that these two patients actually had more of a sensitivity to bright light than actually phototoxicity.
		Being such an important issue with quinolones we did in vitro and in vivo studies that did not show any evidence of phototoxicity.  We actually did a double-blinded placebo controlled clinical phototoxicity study and we looked at moxifloxacin at seven days and saw it was comparable to the placebo.
		Certainly with the recent events with trobofloxacin and elevated liver functions, we looked at that.  1.6 percent adverse events associated with liver functions abnormalities with moxifloxacin versus 1.9 percent with the comparators.  I just want to give you a little bit more information on the next slide.
		Preclinical in Phase I hepatic safety that we looked at, the morphologic liver alterations were seen in monkeys only at lethal doses and they were not seen in the dogs which are considered the species sensitive to this situation of hepatic safety.
		Elevation of liver enzymes were slight and transient in nature.  As we stated previously, liver impairment did not influence the pharmacology of moxifloxacin in our Phase I studies.
		Once again, as we mentioned previously, moxifloxacin is excreted via multiple routes.  20 percent renal, 51 percent hepatic, and 25 percent transintestinal.
		I would like to show you the liver functions that we collected during our Phase III program.  I have divided this into three parameters and three functions.  SGBT, SGOT, and bilirubin.  The three parameters were greater than upper limit of normal.  It actually means that anything that is up with the limit is normal.  Greater than 1.8 times the upper limit of normal or greater than three times the upper limit of normal for each of the parameters.
		If you look across the board with moxifloxacin in control, you will see that the rates are identical and very similar, I should say, between moxifloxacin and the control.
		There was the other important issue that there's no difference noted when comparing this by gender, race, or age group, and that the premature discontinuations, that were due to the elevations of LFTs that were greater than three times the upper limit of normal, were equal numbers both in the moxifloxacin treated patients and with the controlled treated patients.    
		So summary of safety.  So far we've heard that only adverse effects occurring in greater than 5 percent of the patients were nausea and diarrhea.  Premature discontinuations were less than 1 percent for any single adverse event.  
		The mortality rates in community acquired pneumonia and the combination of those patients with acute exacerbation of chronic bronchitis for the moxifloxacin treated patients were lower than those observed with the comparators.  
		When looking at those selected events associated with quinolones such as phototoxicity, liver function abnormality and seizures were rare with rates comparable to the control drugs.
		Before I end I just want to give you a summary of all the attributes I have spoken about.  Excellent pneumococcal activity.  Activity against haemophilus influenzae, moraxella catarrhalis including beta lactams positive.  Activity against atypicals.  We even talked about activity in vitro with MTB.  
		Optimal PK/PD for the major respiratory tract organisms.  The important issue here, once daily dosing for short duration of therapy of five to 10.  Minimization of resistance.  No dose adjustments in special populations including the elderly and hepatically and renally impaired patients.  
		No interaction with the cytochrome P450 system.  No significant clinical drug/drug interactions.  Favorable morbidity and mortality trends.  And a favorable safety profile including hepatic safety as well as phototoxicity.
		In conclusion, moxifloxacin is safe and effective in respiratory tract infections as well as skin infections.  The favorable pharmacokinetics and dynamics of moxifloxacin enhances efficacy as well as safety.  The once daily short five to 10 duration offers a patient compliance, convenience, and safety advantages.  Thank you.
		I would like to leave the podium and give this to Dr. Joe Morganroth who will talk to you about the background of QT prolongation.
		DR. MORGANROTH:  Thank you very much, Dr. Church.  Mr. Chairman, ladies and gentlemen, it's my pleasure today to provide you some information about the QT interval on the electrocardiogram, a topic which actually, I think, is quite timely in light of the increased regulatory interest that this particular ECG wave form change has engendered over the last few years and is now the subject of points to consider in Europe and draft guidelines at the FDA.
		The QT interval is an important electrocardiographic safety measure in drug development.  It's important as you look at drug development data to ask some very critical questions about the methodology and the form of interpretation of the QT interval.  I think it's no longer necessary to assume that with a couple of hundred ECGs randomly selected in clinical trials, hopefully on the drug and not before and after, that you can, in fact, be able not to make a lot of proper judgments about the QT unless you have a form of development that I'll describe to some degree and is present in some of the new guidelines.
		The first thing that I wanted to show you is an electrocardiogram.  I show you this principally to remind you that we're not going to be talking about the kinds of ECG information that relate to morphology and PR interval QRS interval, heart rates, etcetera, which are all valuable pieces of information.  We are going to concentrate only on one of the wave forms which is the QT.  I remind you that the EKG has a background of a grid in order to measure the interval durations.  The waveform itself can be subjected to a lot of different measurements.  Again, we are going to concentrate only on the QT interval which I remind you is made up of both depolarization, the QRS, and repolarization, the junction of the QRS and the ST segment, the J point to the end of the T, the so-called JT interval.  Historically and conventionally we measure the entire depolarization, repolarization sequence rather than just repolarization which is the part of the ECG complex we are most interested in today.
		The grid itself is important because the tiniest of the little boxes that you can see on an electrocardiogram when obtained at 25 millimeters a second standard speed that the paper runs through the EKG machine.  That smallest little box has a duration of milliseconds of 40, a number I had asked you to remember as we get into what this particular duration of various drugs do to the QT interval.
		It's obvious from just what I've shown you that one should think about how the QT is measured in a drug development set of electrocardiograms.  This is not an interval that is simple and easy to measure such as heart rate.  That's because one is looking at a T wave which may have low amplitude.  There may be noisiness to the baseline.  There can be low amplitude signals.  
		In fact, the T wave can be distorted by the presence of a U wave which is when abnormal and bizarre, in some cases, may in fact indicate the early after depolarization that is the hallmark of the beginning potential for repetitiveness of ventricular beats that can form a ventricular tachycardia, and if associated with a polymorphic form and a long QT has gone under the name of torsade de points which we'll talk a bit more in a moment.
		In terms of the difficulty of measurement, it's important to remember that you still need a human being for this process, I believe.  The use of computers that think that they can find the end of the T wave and differentiate it from the U wave, we're still not there.  Taking the measurements off of a routine computer reading of an electrocardiogram is generally potentially faulty and it requires some experience to differentiate U waves from T waves and some degree of art to that rather than pure science by any means. 
		In terms of the quantitation of QT durations, the normal value accepted in the United States is approximately 440 milliseconds.  The variability of the QTc duration in man over the day is really quite marked.  It can range from 15 to 70 milliseconds with trivial changes in time or position or food or what have you.  
		Actually, if we look at multiple measures that have been made in a group of normal volunteers, the average was 75 milliseconds over a day when ECGs were taken on an hourly basis and 5 percent of those electrocardiograms had levels of 500 milliseconds or greater, a level that there is some concern in terms of the clinician's feeling about significance in terms of drug discontinuation.
		Cardiac patients tend to start with longer QTc.  They tend to be a bit more variable.  As you recall, the QT interval duration is very dependent on the heart rate.  As you heart rate slows, the QT gets longer.  As your heart rate speeds, the QT gets shorter.  So if you're dealing with an infectious disease patient who may have fever and tachycardia in the initial electrocardiogram may show a short QT.  
		As the treatment breaks in and the patient's depheresces and the heart rate slows, the QT can lengthen.  It's very important to do a correction of the QT.  The classic correction is the Bazett formula from the 1920's which is a square root function of the heart rate.  This breaks down very frequently when you get to tachycardiac rates so the Fredericia Q group function generally tends to do a better job.  
		There are linear regression formulas.  Often in the research mode of QT, if you will, we are beginning to look at QT dynamicity, looking at the RR as it relates to every QT and perhaps defining a specific square root function.  
		Remember Bazett is .5 and Fredericia is .33.  Something between .33 and .5 may, in fact, be the best number to correct for an individual study in an individual patient.  Again, I mention that it's a research mode.  The importance is that we're not sure exactly yet how to correct in all settings.
		Let me spend a moment because I know one of the questions this committee is going to address, which I think is No. 4, at the end of the day is to provide some guidance on drug development and QT issues.  I'll just spend a moment to emphasize what the committee on proprietary medicinal products in Europe have issued as points to consider in terms of the QT interval.  This came out essentially about a year ago -- a year and a half ago.  Excuse me.  Some of the points that were emphasized in terms of drug development and QT issues are, No. 1, that a centralization of the electrocardiograms is greatly encouraged because of the site to site variability.  This is such a difficult measure if you put in the variation of how individuals read electrocardiograms  at various sites.  That produces so much noise that you can find a great deal of false/positive and false/negative.  Centralization is important and that the ECGs, in fact, should be read by experienced cardiologists that have looked at and thought about U wave issues versus T waves.
		The committee has recommended that the standard 12-lead electrocardiographic intervals be done in a manual mode avoiding automatic QT measures meaning as the computer prints it at the top of the ECG.  Or to try to obtain QT data from Holter monitoring and that the manual reading is needed in order to provide a precise mechanism.  
		Digitizing a pad with point to point computer digitized human readings with five millisecond resolutions are possible.  I remind you that if you use an eyeball cardiologist and calipers, that the point of the caliper can be as wide as maybe half of those little tiny boxes or about 20 milliseconds.  
		We're going to be talking in a few minutes about drug changes in the zero to 10 millisecond range.  It's important to use digitizing methods and not eyeball calipers and automatic readings.
		Obviously the fifth point that the committee is making is that you should probably try to measure your EKG while you have as much of the drug on board as possible rather than getting an EKG before and after.  That really tells you whether the drug has caused permanent damage to the heart rather than actually looking at effects.  Still we see many data sets that have not adequately sampled their ECGs.
		I must point out that the Bayer presentation on moxifloxacin despite the fact that their program began before the CPMP guidelines has adhered to these policies in terms of using centralization to their ECG reading set and using the single cardiologist in applying a good number of these principles and, therefore, their data set as well as their timing of the ECGs were appropriate to understand their QT effect.
		Now, the QTc change that's important in many people's minds from a regulatory point of view is any QTc change like one millisecond, you know, or anything that's real is sufficient to be of concern because it's an effect.  The question is at what level of QTc duration do you have something to worry about in terms of clinical relevance and importance.
		A second issue is how do you tell whether if you have a very small mean change in the QTc like one, two, three, four, five, six milliseconds which is, you know, half of a little box or less than half a little box.  It's like quarter of a box.  To determine whether that mean change is, in fact likely to be of significance.  
		Well, you look for outliers like in many phases of drug development safety issues.  You try to find how many patients go beyond a certain limit that are important like going above 3x on your liver function test.  
		Well, the committee decided to pick numbers that are derived from our terfenadine variability data that actually suggest that if a drug causes a QTc change, it is more likely that it's the drug doing it rather than spontaneous variability if, in fact, you reach 60 milliseconds or more.  
		It's a clear concern that the drug is causing that effect.  Less than 30 milliseconds is more likely than not due to spontaneous variability.  Obviously between 30 and 60 would be the borderline zone.
		At the FDA in many divisions a 15 percent criteria is used.  One usually cuts the data at 10, 15, and 20 percent.  If you ask clinical cardiologists, their concern tends to be at 500 milliseconds because it's at that level when a cardiologist sees a QTc duration increase that consideration for a drug reduction or discontinuation is often made.  Again, there's great variability among cardiologists.
		The QTc dispersion which is really simply taking the longest QT in any one of the 12 leads and subtracting the shortest QT.  There's a great deal of controversy right now as to whether it really reflects repolarization of the heart of maybe just a quantitative means of determining T wave changes on the electrocardiogram.  
		Nevertheless, it's an interesting measurement in which if the committee felt that if your dispersion increases by 100 milliseconds on drug from baseline or changes by 100 percent, that would be considered a significant effect.
		I must remind you that the QT interval prolongation doesn't cause the individual patient at the time that that occurs any notice.  It doesn't cause any symptoms of any kind whatsoever.  It does not effect the cardiac function in any way.  Until it as a risk factor adds with some other factors; hypokalemia, ischemia, heart failure, changes in sympathetic tone, something has to develop in addition to QT in order to produce an important clinical event, the worst of which, of course, is Torsade de Pointes, a polymorphic ventricular tachycardia which can be short enough to just cause no symptoms, occasionally; dizziness, potentially severe enough to cause fainting with self-remission or can go on to degenerate to ventricular fibrillation and death.  There is a wide spectrum of potential effects of the QT prolongation with other cofactors.
		I have already mentioned to you that the clinician believes that the QTc often has to hit a 500 or greater before this becomes an important risk factor.  However, we need good epidemiological data to try to link the degree of QTc prolongation with torsade and the degree of risk.  
		At the present time from a public health point of view, any effect on the cardiac repolarization is considered something worth discussing, something worth putting into the risk benefit assessment of the drug to determine whether or not it should be approvable or not.
		There are many things that cause the QTc to prolong and they are listed on this board.  I'm not going to go through them other than to point out it's a wide cascade of events whether it's metabolic, congenital, potassium channel, genetically based deficiencies in the congenital long QT syndrome, CNS disorders, electrolytes, ischemia, etcetera.
		There are also, if you will, a whole host of types of drugs that have been well studied and well reported to effect the QT interval.  Antiarrhythmics, of course, historically being the most concern but we have now learned in the last decade and emphasized the fact that noncardiac drugs are very frequently potential actors in this realm from all kinds of various classes, as you'll see, and a whole host of miscellaneous classes.  
		I must point out that is why the CPMP guidelines are suggesting that every single new chemical entity and biologic should be studied for a QT effect preclinically with, for example, herb potassium channel model.  There's a great debate as to which is the best screening methods preclinically, but that one should consider what the preclinical risk of your drug is just like one would do other toxicological studies.  
		In man despite what you find preclinically, because there may not be good correlation between preclinical models and humans, that in man one should include electrocardiographic study for QT interval in all drugs, particularly in Phase I and in an intense way if there is a positive or equivocal preclinical study.
		I thought you would find this interesting, and this is in your handouts, to look at what the Food and Drug Administration in the United States has done with the labeling of QT prolongation or a drug that has had Torsade de Pointes which implies QT prolongation and has mentioned it or pointed it out in the label.
		You'll see that erythromycin, clarithromycin, and you can read these, etcetera, are drugs that have QT notice in the label.  The azoles, ketoconazole and itraconazole specifically not only have it in the label but there are black box warnings.  That's probably because and I suspect more appropriate because of the 3A4 P450 system interaction which is profound, although, of course, erythromycin has that interaction.  
		In fact, an intravenous study with erythromycin has shown as many as half the patients that receive that drug may have QT prolongation of important note.  Dr. Hollister will give you more information about that.
		There is a whole host of -- I'm going to ignore the antiarrhythmics for a moment, of course, but there's a whole host of CNS drugs, more than it seems to me any other class seems to be the ones that are popping up all over the place.  But there are many, many drugs that have QT prolongation.  They are noted in the label.  Some are emphasized, as I mentioned.  Most are not.  
		This is the interesting slide.  This is a slide of over 60 drugs that have in the literature, have in other drug labels or with other regulatory agents -- we could focus that a bit but you have it in your handouts so that's fine -- have QT prolongation known or torsade association with it.  Mostly QT prolongation.  
		Drugs like, for example, imipramine which no one questions has a QT interval prolongation and is an important drug.  Most of these drugs -- excuse me, all of these drugs have no mention in their label of a QT effect whatsoever which is interesting.  		There's a great deal of heterogeneity about how one warns physicians in the label as to the QT interval.  A lot of it has to do with historical relevance of once drugs are on the market to come back and change the label with less data is not easy.
		Let me point out that drugs that prolong the QTc, of course, are the antiarrhythmics.  We have the most information about them.  This may be not relevant in terms of the discussion today or more noncardiac drugs but I give it to you as a bench mark that when you are dealing with drugs that prolong the QT from the antiarrhythmic point of view, and this is giving it to cardiac patients, often with arrhythmias, like ibutilide being given to patients with serious supraventricular arrhythmias for acute conversion.  
	The rate of Torsade de Pointes per year; how often that problem occurs is extraordinarily high for this type of class in this setting.  It can be in the one to 10 percent.  That's one out of 10, one out of 100 people.  I'll ask you to remember that huge number because from a public health epidemiologic point of view that's huge.  
		Compare it to terfenadine because terfenadine was the noncardiac drug that I think got all of us interested in this issue of QT prolongation.  The first thing that was clear is that terfenadine in the early '80s was released around the world as the first antihistamine that had no sedating activity and had a good antihistaminophinic profile.  It was very popular and very successful.  Two hundred million patients approximately were on the drug by the first 10 years.  
		In the 1989 to 1991 range there were 83, and maybe now more than 150 in that early period, instances of cardiac issues, fainting.  In fact, some cases of Torsade de Pointes and some reports of prolonged QT despite the fact that no one had noticed on any of the electrocardiograms any QT effect done in the usual way, not as the CPMP recommends.
		If one looks at the reported incidents, which of course is always underreported, and obviously this is probably the best case for the drug, it's about one in 200,000 patient months.  I've heard other estimates as much as high as one in 10,000.  The number is probably, in my opinion, somewhere around one in 100,000.  That's a lot different than one in 100 or one in 10 that you may get with an antiarrhymic.  
		That rate needs to be compared to the benefit and the risk.  The amount of QTc prolongation that terfenadine produced after one looked at this very carefully with a digitizing manual method at its clinical dose of 60 milligrams BID was six milliseconds.  By the way, the same number you're going to be seeing today from moxifloxacin.
		Of course, what was interesting about terfenadine and what is very different about terfenadine and moxifloxacin is that this drug, terfenadine, has a major interaction at P450 3A4.  In fact, the parent compound terfenadine is where all the QT effect occurs.  
		If you block its metabolism by co-administering ketoconazole or erythromycin in blocking 3A4, you don't convert terfenadine until it's acid metabolite fexofenadine, now on the market as an antihistamine called Allegra.  What happens is that with blockade by the drugs that you see on the bottom, or an overdose or other problems with the liver, you can get a QTc that goes up nice and linearally with drug dose or with this metabolism.  
		In fact, you can induce a rate of Torsade de Pointes that is in the one to 10,000, one in 100,000 rate.  If you're giving it for sniffles as an antihistamine, that was considered largely unacceptable from a risk benefit.
		Today you will be discussing the risk benefit of moxifloxacin and the QT effect.  I think that you will, and I'll summarize very briefly and quickly, that the effect on the QT at therapeutic doses, 400 milligrams per day of moxifloxacin, is this six millisecond number.  You'll see that it's similar or less than most of the other antibiotics, particularly of the macrolide class, and, of course, of the conazole class, and frankly of sparfloxacin and many other of the fluoroquinolone class.
		What's important in my mind personally as you distinguish this drug in a risk benefit, is it's not used for months or years but it's used for five to 10 days.  This short duration is the most salutatory anti-concern that I would have about the QT prolongation.  The other thing is it is being used for not sniffles but for potentially life threatening bacterial infections.  
		Another, and probably the second most important reason that I'm not as concerned about this issue, is that there are no drug interactions at 3A4 which, therefore, make the likelihood of the QT going longer on this drug less obviously than on most of the metabolic issues save, of course, by giving another drug that prolongs the QTc with it.
		I think these issues can be easily worked out in appropriate cautionary labeling as you'll hear.  This issue of QT prolongation will become something that won't be as difficult to deal with as the day progresses.  Thank you very much for your attention.
		Let me ask Dr. Hollister to come up and give you the data in detail about the QT effects of moxifloxacin.
		DR. HOLLISTER:  Thank you, Dr. Morganroth.  This morning I would like to talk to you about moxifloxacin and our evaluation of its effect on the QT interval.
		During the early development of moxifloxacin in our preclinical and Phase I we found a mean six millisecond prolongation of the corrected QT interval.  We decided to initiate a series of prospective studies and retrospective analyses of the data to try to identify what the level of risk was and what cofactors in terms of the risk might be present.
		As Dr. Morganroth has pointed out, why is QT prolongation an issue?  Experientially it is a risk factor for ventriculary arrhythmias including Torsade de Pointes.  The magnitude of the risk, particularly in these short intervals, the magnitude of prolongation does not predict risk.  Obviously there are limits.  If you have something that prolongs 100 milliseconds, that's likely to be a much greater risk than something that prolongs a very short time.
		I think the issue here is that these small prolongations are neither necessary nor sufficient for determining risk, and it's the other things that go along with the prolongation that help you evaluate clinical risk.
		The risk is greater with drug accumulation.  Dr. Morganroth talked about the terfenadine story.  In many other situations with noncardiac drugs the issue is the drug that causes the QT prolongation accumulating.
		There are specific subpopulations that are more sensitive to the QT prolongation effect of drugs.  It is appropriate for us to evaluate the subpopulations that have received moxifloxacin to see if there is any signal for risk in those subpopulations.
		So what I'll go over, Dr. Morganroth has done a lot of QT background.  There is some that leads into my preclinical studies that I will cover just briefly in terms of evaluation of the moxifloxacin effect on the QT interval and the mechanism that's involved here.
		Then I will show you our analyses of the electrocardiogram and clinical subpopulation risk factors or risk predictors that are taken from the literature as being associated with QT prolongation and/or the onset of ventriculary arrhythmias.  In addition, I will give you an evaluation of those that our outliers; that is, those that have greater QT prolongations, adverse events, and deaths.
		So we are all on the same page, we are talking about the QT interval, as Dr. Morganroth has explained from the beginning of the Q wave to the end of the T wave.
		This QT interval represents the depolarization/repolarization time of the myocardium and the normal range is 300 to 450 milliseconds.  Females tend to have a little bit wider range at 470 milliseconds as "normal."  There is a lot of spontaneous variation as you've seen from Dr. Morganroth's studies.
		The issue of correcting for heart rate is quite important because in this setting we re treating ill patients who have an elevated heart rate often times at the onset of therapy and with successful therapy their heart rate will shorten.  As Dr. Morganroth told you, as you slow the heart rate, the QT interval will prolong.
		The corrections that are used in the majority of the data that I will show you are this Bazett's correction, the square root of the RR interval divided into the QT measurement.
		Now, in terms of an individual myocardial cell, this is a tracing of the action potential in the myocardial cell and in time link fashion the potassium channels are currents that are involved in some of the phases of the depolarization/repolarization.  This is the familiar Phase 0, Phase I, plateau Phase II, and repolarization Phase III of the myocardium.  
		During this period of time repolarization of the cell is dependent on the outward movement of potassium, the so-called potassium rectifier channels, the Ikr and the IKs channels you'll hear them termed.  Sometimes I believe Dr. Morganroth used the genetic term for the channels as well.  
		These outward going channels are responsible for repolarizing the cells to their resting potential.  Interruption, a blockade of these channels will prolong the action potential duration perhaps in a fashion like this.  With sufficient prolongation, what may happen is you have summation of the heterogeneity of repolarization in the myocardium that gives you these so-called early-after depolarizations.  
		These early-after depolarizations are time related to the appearance of U waves so when a lot of early-after depolarizations are occurring and summating, you see changes or appearance of a U wave and sometimes giant U waves.  This can lead to a progressive, a repetitive depolarization of the cells and a ventriculary arrhythmia.
		Now, in our preclinical studies we looked at these repolarizing or rectifying potassium channels, Ikr and IKs.  These do vary by tissue preparation and our results varied by tissue preparation.  The bottom line we feel is that moxifloxacin is a weak blocker of the Ikr channel relative to sparfloxacin, for instance.  It's one-third the potency of sparfloxacin.  We have other data currently underway that has not yet been reviewed by the FDA.
		In the classic guinea pig myocardium model IV action potential duration, there is a concentration dependent prolongation of the action potential with an apparent threshold for moxifloxacin in the order of 50 micromolar as opposed to sparfloxacin, around three micromolar.
		During the course of these studies there was no appearance of early-after depolarizations with moxifloxacin which indicates there is no presence of that risk factor from an electrophysiological point of view.
		Moving on to the animal arrhythmia studies, we have the classic animal arrhythmia study is an anesthetized methoxamine infused rabbit.  Methoxamine, the alpha agonist, is infused to induce reflex bradycardia because that potentiates the onset of arrhythmias, particularly arrhythmias of the long QT form and Torsade de Pointes.
		Moxifloxacin and sparfloxacin in this model were infused at two milligrams per kilogram per minute for an hour.  I'll show you a slide of the actual data in a moment.  With moxifloxacin one of six animals showed PVCs after a total cumulative dose of moxifloxacin of 96 milligrams per kilogram.  No ventricular tachycardia arrhythmias occurred with moxifloxacin.
		In contrast, sparfloxacin showed premature ventricular contractions in half of the animals at earlier time points.  Three animals showed ventricular tachycardias including one that had classic Torsade de Pointes during the course of the infusion with sparfloxacin.
		In another even higher dose preparation in an anesthetized dog, we were able to obtain ventriculary arrhythmias but only at extreme concentrations of the drug, greater than 200 milligrams per liter or approximately 50 fold the Cmax that we're talking about in humans.  This is not possible in the conscious dog because CNS toxicity occurs at lower concentration than these concentrations and these concentrations cannot be reached orally.
		This is a slide of the data of the rabbit arrhythmia model with plotting the QT interval in milliseconds against the time of infusion of the test drug here at two milligrams per kilogram per minute of either moxifloxacin or sparfloxacin.  Methoxamine infusion was actually begun 10 minutes before the zero time point.
		Here in the sort of yellowish is sparfloxacin, the actual data and a regression line with indications of the time points at which ventricular tachycardia and Torsade de Pointes occurred during the sparfloxacin infusion.  Moxifloxacin, in contrast had no events of ventricular arrhythmias with the infusion.  Somewhat less of a slope in terms of the effect on the QT interval.
		Now, the literature tells us that clinical studies of patients with QT prolongation and arrhythmias associated with QT prolongation show a number of ECG risk factors that can be monitored.  Amongst them are the magnitude of QT prolongation which is about the only thing that we have looked at clinically in the past.  
		Now we know the dose dependency or concentration dependency of QT prolongation is another way to help assess risks.  Using this committee for proprietary medicinal products criteria, if you have a high frequency of patients exceeding limits in that criteria, that may be a signal for a risk issue, the increased dispersion of the QT interval.  
		I'll give you my definition of that when we get to the slide and Dr. Morganroth as alluded to it.  In addition, reverse rate dependency is another characteristic that has been described with drugs that prolong QT interval and cause arrhythmias.  I'll define that when we get to the slide.  There are several others that I will give you as well.
		This is our worldwide and North American experience in terms of moxifloxacin and the effect of moxifloxacin on the QT interval.  This is the change in the QT plus or minus the standard deviation here in our data set of all paired valid ECGs.  In order to meet those criteria, we had to have a base line and on-drug ECG.  The on-drug ECG had to be obtained during a window of time during which we were confident drug concentrations would be high.
		This shows the all comparators with the average changes here.  Then for your interest the comparator drugs are broken out.  This is not all the comparator drugs but many of them to show you the size of change here.
		Now, to put this in perspective in terms of antibiotics, the next slide shows some literature values that we found for erythromycin, clarithromycin, grepafloxacin, and sparfloxacin.  The erythromycin orally, a mean prolongation in a study with approximately 160 patients in it of 13.8 milliseconds.  The IV study that Dr. Morganroth mentioned showed very large prolongations in the QT interval and a high frequency of patients exceeded 500 milliseconds.
		With clarithromycin the various references in the literature range from three to 11 milliseconds of QT prolongation.  Grepafloxacin in its registration data, 10 milliseconds.  Sparfloxacin has in its label 11 milliseconds.  Other references will give you a range of that data.
		Very pertinent to these drugs is the fact that there are important drug interactions because of metabolic issues.  I will show you some of the data with respect to moxifloxacin.  
		There is the potential for drug accumulation because of the drug's route of elimination sometimes interacting with the drugs that may be co-administered with the drug as well.  For perspective, I'll show you where the moxifloxacin mean six millisecond falls with respect to these other commonly employed antibiotics.
		I took the data from our Phase I trial base to try to determine whether or not there might be a concentration effect relationship.  Plotted here are the QTc for our 211 patients -- 211 subjects, mostly Phase I normal subjects, plotted against the moxifloxacin concentration that was drawn at the time the EKG was obtained.  As you see, there is an upward slope as we regress this data.  There is a lot of scatter around the data.  These are the 95 percent limits.  This is the limit of normal for males.
		This regression is significant.  The ability of this regression line to account for the variability, though, is poor.  The R squared is only about three percent of the variability is accounted for by a regression.
		Now, another way to look at these kinds of data are the outlier frequency.  This committee for proprietary medicinal products provided a guidance document about two years ago giving these definitions for normal, borderline prolongation, prolongation, and risk of arrhythmia here in terms of the corrected QT interval.
		In terms of the change in the QT, as Dr. Morganroth showed you, those that changed less than 30 milliseconds implies no concern with respect to a drug.  Thirty-one to 60 possible drug effect and greater than 60 is concern for arrhythmias.  In addition, this parameter QT dispersion, should that exceed 100 milliseconds or increase more than 100 percent, are also criteria for concern.
		So using these data, or these criteria, and some of the ones that have been employed by the FDA, we have made a table here of the frequency of outliers.  Here with greater than 500 milliseconds.  Here a change in the QT interval of more than 60 milliseconds.  Here a change more than 30 milliseconds to an abnormal value be it male or female.  Then a simple change in the QT of greater than 15 percent.  		This is the moxifloxacin database, the all comparators in our all paired valid database.  You see there are minor differences here and here in terms of the frequency.  If you take any of those outliers overall, there is very little difference between moxifloxacin and all comparators.  For your interest, the other drugs that are underneath this all-comparator category are shown there as well.
		The QT dispersion is defined as the greatest difference in the QT interval between any two leads in the 12-lead EKG.  Again, it's considered a risk if the QT dispersion exceeds 100 milliseconds.  
		In a Phase I study that was cross-over administering placebo, 400 milligrams moxifloxacin, 800 milligrams moxifloxacin orally, and EKGs obtained repeatedly after administration of these drugs, the QT dispersion, whether it's the absolute QT or the Bazett's correction of the QT, were measured.  This is the mean and standard deviation for values of placebo, on moxifloxacin 400, moxifloxacin 800.  
		As you see, there is no difference in QT dispersion on what we think are therapeutic doses and super therapeutic doses of moxifloxacin.  We have no evidence that moxifloxacin increases QT dispersion.
		Another characteristic of drugs that are associated with QT prolongation and caused Torsade de Pointes is this co-called reverse rate dependency.  Basically this is a prolongation of the QT interval that does not shorten proportionately as the heart rate increases leading to the possibility that you can have the R on T phenomenon and arrhythmias.
		In such a drug you would expect plotted on this sort of a graph an upward going curve.  Our data with moxifloxacin determined over multiple heart rates at 400 milligrams and at 800 milligrams show the opposite direction of the slope of the curve.  Our expert interprets this as no evidence for reversed rate dependency with moxifloxacin.
		Another potential risk group are those that start with long QT intervals.  We tried to address this issue by taking the top quartile of people in terms of the duration of their QT interval prior to drug therapy.  Then we ask the question what happens to the QT in these people when they are treated with moxifloxacin or the comparator drugs.  
		These are the data from our largest database and it shows that if you start with a longer QT, in fact you have a shortening of the QT interval on average, the so-called regression to the mean.  Patients with longer baseline QT intervals are not at greater risk for QT prolongation.  This is in contrast to data that has been generated with erythromycin, for instance.
		So to summarize these electrocardiographic risk factors for QT prolongation that we took from the literature and applied to our data set, we have a magnitude that is a mean of approximately six milliseconds prolongation.  There is a concentration dependence to that prolongation.  It's a shallow sloped curve and does not account for the vast majority of the variation in QT interval.  
		In terms of the QT outliers using the CPMP and other criteria, there's no overall difference in the frequency of outliers with moxifloxacin versus comparators.  We found no effect on QT dispersion, no reverse rate dependency of QT prolongation.  Those patients that started with long baseline QTs actually decreased the duration of their QT interval.
		Now, other factors have been published in the literature that are pertinent to risk evaluation of drugs that may prolong QT are QS widening, T wave abnormalities, appearance of new U waves.  There is no QRS widening with moxifloxacin.  T wave abnormalities are not different between the moxifloxacin and comparative groups.  There were no differences in the appearance of U waves pre and on therapy with moxifloxacin.
		Now, there are a number of clinical subpopulations that are recognized as being at higher risk for QT prolongation and arrhythmias with drug administration.  The ones that are published in the literature include cardiovascular disease, age - older age, gender.  Females are more susceptible than males to this effect.  
		Electrolyte abnormalities, particularly low potassium, bradycardia, particularly profound bradycardia associated with increased frequency of arrhythmias and Torsade, and as you are well aware, drug interactions that increase the concentration of the relevant drug.  
		In addition, reduced organ function that can increase the concentration of the relevant drug also are issues in terms of evaluating risks.  The co-administration of drugs that themselves prolong the QT interval.  Is there a synergistic action.  Clearly with some drugs there may be.  
		Then finally the accumulation of metabolites that may be associated with an increased risk of arrhythmia that may accumulate in organ dysfunction.  A good example is the hydroxy metabolite of quinidine.
		So in a series of slides here I'll show you these clinical risk factors, their presence or absence or the parameter and the effect on the QTc, corrected QT interval, here plus or minus the standard deviation.  Here for cardiovascular disease, the presence of cardiovascular disease, we had about 122 subjects in our population.  They did not show more QT prolongation than subjects without cardiovascular disease.  This, again, is in contrast to a drug such as erythromycin.  
		Here with age, age greater than 65 years is associated in the literature with excessive QT prolongation and increased risk of arrhythmias.  We did not find an increased QT prolongation in elderly patients treated with moxifloxacin.
		Similarly in terms of gender the females in the literature are more susceptible to QT prolongation and arrhythmias.  There is no difference in those patients treated with moxifloxacin in the change in QT interval.
		Electrolyte imbalance, hypokalemia.  Here very small numbers of patients if we take the cut at 3.5 milligrams per liter.  The mean, plus or minus standard deviation, here is small and there is no interaction effect in terms of the prolongation of the QT interval with moxifloxacin.
		With heart rate bradycardia is recognized as being -- profound bradycardia -- a risk factor for QT prolongation and for the onset of arrhythmias.  These show the mean change in the QT interval in 80 of our subjects that had bradycardia at entry into the study.
We find no effects of the hypokalemia or bradycardia.
		Now, moxifloxacin does not inhibit the cytochrome P450 enzymes as Dr. Church related to you earlier.  This means that it's very unlikely that there would be Phase I drug/drug interactions.  Our data with a variety of drugs that I'll show you on the next slide indicate there are no significant drug/drug interactions with cytochrome P450 metabolized drugs.
		In addition, moxifloxacin itself is not metabolized by the cytochrome P450 system including the specific 3A4 isoenzyme that is the most problematic to us clinical pharmacologists.  Because it's not metabolized by this system, there's no risk for accumulation of moxifloxacin during co-administration of other inhibitors which are so common.
		This slide shows an abbreviated list of the drug interaction studies that we performed with the enzyme system within the cytochrome P450 system, the specific isozymes that are responsible for the primary metabolism of these drugs and just a brief comment on the results.
		Theophylline is metabolized by the 182 isozyme.  Co-administration of moxifloxacin with theophylline does not result in increases or changes in theophylline levels nor changes in moxifloxacin levels.  Co-administration of moxifloxacin with glyburide does cause a slight decrease in glyburide concentrations, nonsignificant in terms of glucose control, and no change in moxifloxacin levels.
		Warfarin, which is stereoisomerically metabolized predominately by the 2C9 isozyme of cytochrome P450 has neither of its metabolites.  The stereoisomers or the metabolites are changed by co-administration with moxifloxacin and moxifloxacin levels are not changed during co-administration.
		Ranitidine is recognized as a weak inhibitor of the cytochrome P450 system and co-administration of moxifloxacin with ranitidine does not alter moxifloxacin concentrations.
		We have additional data that are not yet reviewed by the FDA, and our in vitro data that all support the concept that there's no interaction at the cytochrome P450 system with moxifloxacin.
		Looking at additional clinical risks factors, co-administration of moxifloxacin with drugs that are known to prolong the QT interval in a small number of subjects in our largest data set had co-administration of these drugs.  They did not show excessive QT prolongation with the addition of moxifloxacin.  
		Also, renal dysfunction and hepatic dysfunction.  I'm showing you here the extremes of our renal dysfunction data in Phase I studies less than 30 milliliter per minute creatinine clearance does not influence the effect of moxifloxacin on the QT interval.  With hepatic dysfunction, again with reduced hepatic function we studied child pew class A and B patients.  There is no increase in the QT effect of moxifloxacin.
		Now, with renal dysfunction there is some accumulation of the M2 metabolite of moxifloxacin, the glucuronide metabolite.  Despite that accumulation, there is not excessive QT prolongation.  With hepatic dysfunction there is some accumulation of the sulfate metabolite moxifloxacin.  Again, there is no apparent effect of that metabolite on the QT change with moxifloxacin.
		So to review these data in terms of clinical subpopulations that might conceivably be at risk during co-administration of moxifloxacin, with cardiovascular disease, age, gender, concomitant administration of QT drugs, organ dysfunction, electrolyte imbalances, specifically potassium imbalances, and bradycardia, there was no change in the effect of moxifloxacin on the QT interval.
		Importantly there are no metabolic interactions that are likely to increase the concentration of moxifloxacin.  There were none.  Nor are there any interactions that moxifloxacin is likely to cause any accumulation of another drug that might conceivably effect the QT interval.
		Finally, organ dysfunction is not a risk for drug accumulation with moxifloxacin.  That also is an important factor in terms of risk assessment of this drug.
		Another way to approach the whole issue is from the other direction.  You say let's take those people that really did show the QT prolongations and ask whether or not they had adverse events.  What I've done here is with our largest safety database is looked at the people that met any criteria as being a QT outlier by the CPMP criteria and the others for which in our largest database we have 38 with moxifloxacin and 28 with all the comparators.
		Then we ask the question did they have cardiovascular events.  One of 38 subjects exhibited sinus tachycardia rate 130 about three days into therapy of her community acquired pneumonia.  That's the only cardiovascular event associated with these QT prolongations with moxifloxacin.
		In contrast with our comparators, four subjects had cardiovascular adverse events.  Two were sinus tachs.  One was an atrial flutter.  One was a ventricular arrhythmia resulting in death.  We found no evidence of a signal here.  In those patients that have QT prolongation with moxifloxacin we found no clinical risk for cardiovascular adverse events that exceeded those of comparator drugs. 
		If we look at the broader database, too, we also ask the question are there other cardiovascular events going on that might conceivably be a signal for arrhythmia or other problems with moxifloxacin.  We called these surrogates for QTc prolongation.  
		We searched the database with moxifloxacin and all comparators and these were terms that had the most frequent.  Your briefing document has a larger table of all of these terms and shows that the frequency of tachycardia, evidence of myocardial ischemia, palpitations, heart failure, episodes of syncope, or arrhythmias were no different between moxifloxacin treated subjects and the all-comparator treated subjects.
		I would remark that amongst these arrhythmias with moxifloxacin the three arrhythmias that we had were -- in fact, if you look closer the data were atrial fibrillation.  One was a sinus arrhythmia which is a normal heart rate.  One was the appearance of a solitary PCV on an EKG.  In contrast with our comparators, two of those were ventricular arrhythmias that resulted in death.
		If we take our data and look at it in terms of deaths whether it's any death in the treatment program, deaths within 30 days, deaths within seven days, or deaths on therapy, comparators here in red, moxifloxacin in blue, in each cut of the data for deaths there is a favorable trend for moxifloxacin.
		So to conclude our evaluation or risk factors here, we do know that moxifloxacin produces a mean six millisecond QT prolongation.  In our evaluation of the database, we could find no electrocardiographic or clinical subpopulations that were predictors for excessive QT prolongation by moxifloxacin.
		Those patients who had the greatest changes in QT interval with moxifloxacin did not experience more cardiovascular events.  Finally, deaths were less common in moxifloxacin treated patients than in the comparator treated subjects.
		So to try to give you a benefit risk evaluation here, Dr. Church has given you information regarding broader spectrum of coverage for moxifloxacin compared to many of the other quinolones.  In fact, other antibiotics to some extent.  We think there are in vitro improved efficacy ratios for moxifloxacin with some indication in vitro superior resistance characteristics.
		The pharmacokinetics are straightforward and reliable in that they are not affected by organ dysfunction or interaction with other drugs.  Elimination is by multiple systems so that drug does not accumulate.
		The short duration of therapy has been mentioned before.  It's once daily therapy.  There's one peak per day for five days or maybe 10 days, depending on the indication.  Also, factors into low risk compared to other drugs.  No dose adjustments are necessary because we didn't find things that cause drug accumulation.  There are no interactions with the cytochrome P450 system which is central to so many of the noncardiac drugs that cause Torsade de Pointes.  
		We found no liver, CNS, or phytotoxicity in comparison to the background rate in comparator drugs and we have favorable morbidity and mortality trends in data that Dr. Church showed you.
		Against this benefit here, we do have some risk that is difficult, if not impossible, to quantify in terms of QT prolongation.  As we look very closely at the population, we could find no electrocardiographic or subpopulations that were at particular risk and that's in contrast to many other drugs.  Overall our database shows no clinical evidence of risk with moxifloxacin in terms of this QT prolongation.
		With this benefit risk ratio in mind, we propose the following label for moxifloxacin.  Moxifloxacin as with some other quinolones and macrolides has been shown to prolong the QT interval of the electrocardiogram.  The degree mean plus or minus standard deviation of QT prolongation with moxifloxacin in our clinical trials was six plus or minus 26 milliseconds, compared, for example, to two plus or minus 23 in patients treated with clarithromycin.
		Consequently, moxifloxacin should be used with caution in patients with congenital or acquired syndromes of QT prolongation, or in patients taking concomitant medications known to prolong the QT interval, examples are Class IA and Class III, even though our database found no evidence of risk in those populations.  Thank you.		
  		Now, it's my pleasure to introduce to you Dr. Stephen Zinner, the Charles Davidson Professor of Medicine at Harvard Medical School and Chair of the Department of Medicine. 
		DR. ZINNER:  Thank you very much.  In addition to my new job, I'm a rapidly aging infectious disease doctor.  
		It's my task to very rapidly and briefly summarize for you some of the principles that have been seen with moxifloxacin.  I just want to start with my disclosure list of companies for whom I'm a consultant and those companies that have supported some of my research studies over the years.
		I believe you've heard today that moxifloxacin is safe and effective for the treatment of acute exacerbations of chronic bronchitis, community acquired pneumonia, acute sinusitis, and skin structure infections.
		In addition, I believe that the moxifloxacin does have excellent in vitro activity against all of the common respiratory tract infective organisms.  I believe it has pharmacokinetics and pharmacodynamics that promote rapid killing.  It has some novel properties that might minimize the development of antibiotic or antimicrobial resistance.
		I think also there has been demonstrated a possible positive impact on mortality and hospitalization in patients with lower respiratory tract infections.
		I think we still need new antibiotics today in our current clinical environment.  We certainly heard yesterday, and are well aware, that resistance among the respiratory tract to infective organisms is certainly increasing.  In some cases in some parts of the world and in some parts of this country a high-level penicillin resistance among pneumococci may be seen in up to 10 or 15 percent of strains.  We continue to see penicillin and beta lactam resistance among strains of moraxella catarrhalis with roughly 30 percent of strains being beta lactamase producing.  
		And we have also seen some increase in resistance to the microlides in vitro.  In some studies among strains of penicillin resistant strep. pneumoniae as many as 40 and in some cases 50 percent may also be resistant to the microlides.
		The respiratory tract continues to be a site of infections that are associated with significant morbidity and mortality.  We have been bombarded with new pathogens including Legionella and some other atypical pathogens.
		Unfortunately for those of us in infectious diseases who like to think we can make the diagnosis in most of these cases, therapy is usually empiric and directed against the broad range of common causative organisms.
		Moxifloxacin has an excellent in vitro activity against these common respiratory tract infections with low MICs well within the drug concentration range for this drug.
		In addition, if you look at these organisms, pneumococcus, haemophilus, and moraxella, the common bacteria causing these infections, with respect to whether or not they are resistant to beta lactams, here are two quinolones, moxifloxacin and levofloxacin.  You can see that their MICs do not change with or without penicillin or beta lactam resistance.
		However, with respect to clarithromycin, amoxicillin, clavulante, and cefuroxime you can see that certainly penicillin resistant strains have a much higher MICs for those antibiotics.
		Now, with respect to antimicrobial resistance, I think common properties for the fluoroquinolones is that they are in general not affected by beta lactamase or other mechanisms including those that affect microlides or aminoglycosides for example.
		However, there are some differences that do exist among the fluoroquinolones with respect to resistance mechanisms.  You've heard about the nor A mutations and the efflux pump, as well as topoisomerase mutations.  Really that should be DNA gyrase and topoisomerase 4.
		With respect to moxifloxacin's resistance perspective, the efflux pump mechanism virtually do not affect moxifloxacin, at least with strep. pneumo and staph. aureus.  In fact, one needs more than two mutations to show resistance in in vitro situations.
		In vitro passage studies have shown a low propensity for resistance and in the rat granuloma model did not show in vivo resistance development during exposure to moxifloxacin.
		I think one of the particular properties of this drug that is particularly of interest to me and particularly useful are its excellent pharmacokinetics and pharmacodynamics if the drug is greater than 90 percent bioavailable when administered orally and achieves a Cmax at steady state of 4.5 milligrams, well above the MICs for the pathogens under consideration.
		In addition, it has a long half life, elimination half life of 12 hours.  It achieves high levels in serum tissue and the levels of which are greater than the MIC, 90 for most of the respiratory tract organisms over the entire dosing interval.  
		Of these pharmacodynamic parameters of Cmax to MIC, which has a bench mark of eight to 10 in some circumstances, and the AUC/MIC 90, which has a bench mark that seems to change over time, at least whether you use a low one of 20, a high one of 125, or anything in between, certainly both of these parameters are far exceeded by moxifloxacin.  And the drug is rapidly bactericidal against the bacterial pathogens that have been studied.
		The clinical profile has been well presented to you.  As you know, the development was focused on acute sinusitis, acute exacerbations of chronic bronchitis, community acquired pneumonia, skin and skin structure infections.  The studies were designed to show equivalence according to the FDA approved study designs.  A single dose of 400 milligrams once a day is useful for either five to 10 days depending on the indication.  I'm particularly attracted to the shorter course possibilities with this drug.
		And as you know and have seen, these studies showed equivalence with the comparators for acute exacerbations of chronic bronchitis with clarithromycin, community acquired pneumonia with clarithromycin and amoxicillin, sinusitis with cefuroxime and skin structure with cefuroxime.
		The safety profile, as you have heard, over 5,000 patients have received 400 milligrams once a day, roughly 39,000 exposure days.  The adverse effects, there were no surprises with respect to the quinolone class of drugs.  Most events were present in less than five percent except for nausea at nine percent and diarrhea at seven percent.  This continuation and serious adverse effects on moxifloxacin were similar to that of comparators.
		In addition, there was no hepatotoxicity, no nephrotoxicity, no phytotoxicity seen with this drug.  The QTc prolongation, about which we have heard a great deal, is comparable to commonly used antimicrobials.  No cardiac events were seen at increased rates related to QTc with the drug.
		I think that the moxifloxacin's clinical pharmacology really does support the entire safety profile in that it has a balanced metabolism in elimination.  It is not metabolized as we've heard by the P450, which I think may be important with respect to minimizing any risk associated with the slight prolongation of the QTc.  No drug/drug interactions have been seen other than iron and antacids similar to the other members of the class.
		No dosage adjustments are needed in either renal or hepatic insufficiencies and there appears to be no risk of serious adverse effects due to interactions with other agents because of the metabolism.
		Some unanticipated positive outcomes that turned out -- although the studies were clearly not designed to show this, there was a slight lowering in overall mortality rate in patients with respiratory tract infections treated with moxifloxacin compared with comparators and some lower rates of hospitalization or rehospitalization than the comparators in this patient group.
		So, in summary, I think moxifloxacin demonstrates safety and efficacy for its proposed indications, acute sinusitis, acute exacerbations of chronic bronchitis, community acquired pneumonia, and uncomplicated skin structure infections.
		I believe that the benefits of this new drug balance any theoretical risks attributed to the small prolongation of the QTc interval especially given its metabolism, excretion, and its short course of therapy.
		Any potential risk attributed to this QTc prolongation I think is appropriate addressed in the proposed labeling that you've just seen.
		Despite limited clinical data, moxifloxacin is effective in infections caused by penicillin resistant streptococcus pneumoniae.  I believe this drug is a useful addition to the antimicrobial armamentarium in addition to its clinical success.  
		It might also provide beneficial effect on hospitalization rates and mortality rates in respiratory tract infections and may have a different effect, at least, on antimicrobial resistance.  Thank you.  Carl.
		MR. CALCAGNI:  Dr. Reller and the advisory committee, this now concludes our official presentation.  If there are any questions, we can triage those questions to the participants or the experts that are available that we have in the room.
		DR. RELLER:  We're now ready for discussion questions for the sponsor presentation.  Dr. Ruskin.
		DR. RUSKIN:  I don't know what sequence you'd like to deal with this.  Perhaps if there are efficacy questions, they should come first.  My questions obviously relate to the cardiovascular issues.  I'm happy to ask them at this point or wait until later.
		DR. RELLER:  I don't think that we need a particular sequence of taking.  We'll take them as they come up to be focused on the data presented by the sponsor and issues raised by it.  Of course, after the FDA presentation there will be a combining and we'll get to voting on the questions.  Please go ahead.
		DR. RUSKIN:  I have a couple of questions for Dr. Hollister.  The con med data is of particular importance.  The concomitant medication data is particularly interesting and important.  I only have the briefing document so I was unable to tell precisely what medications you were talking about when you referred to other agents that prolong the QT interval.  The numbers are small but obviously it's an area of great interest.  Can you educate me as to which agents were used and in how many patients?
		DR. HOLLISTER:  Sure.  There were 61, I believe, in patients on that slide with concomitant medications that are generally accepted to cause QT prolongation; that is, with moxifloxacin.  Amongst those there were two with amiodarone and one with sotalol.  We have a list of the other medications that correspond, in fact, to a number of the medications that were shown on Dr. Morganroth's list as ones commonly recognized as causing QT prolongation.
		DR. RUSKIN:  Is that available in slide form?  Is it possible to look at that?
		DR. HOLLISTER:  Yes, it is.  Carousel five, slide 32, please.
		DR. RUSKIN:  Oh, I'm sorry.  This is Dr. Morganroth's slide.  I was asking if you have specific numbers of patients.
		DR. HOLLISTER:  These are the drugs.
		DR. RUSKIN:  Okay.
		DR. HOLLISTER:  Our patients were co-administered during the course of the study with moxifloxacin.
		DR. RUSKIN:  So there were three patients in the entire database who were receiving a Class III anti-arrhythmic agent.  Is that correct?
		DR. HOLLISTER:  That's right.  When we first identified a QT prolongation, we modified the entry criteria for the protocols, the Phase III protocols, to not allow those patients in who were taking the Class IA and Class III antiarrhythmics.
		DR. RUSKIN:  When did that exclusion begin?  How many patients had been entered into your trials before that exclusion came into effect?
		DR. HOLLISTER:  I think about one-third of our Phase III patient database could have had these drugs on board when they entered into our trials of moxifloxacin so 2/3.  It was an exclusion criteria.
		DR. RUSKIN:  And the exclusion criteria applied only to antiarrhythmic agents?
		DR. HOLLISTER:  Yes, that's right.  To these Class IA and Class III antiarrhythmic agents.
		DR. RUSKIN:  And can you tell me how many patients were exposed to cisapride or any of the major psychotropics?
		DR. HOLLISTER:  Not off the top of my head but we would be happy to provide that data to you.
		DR. RUSKIN:  I think it would be important to look at. 
		Two other questions and then a comment.  I guess one other question and two comments.  The other question is how did you define cardiovascular disease?
		DR. HOLLISTER:  We used the ICD 9 codes for cardiovascular disease.  I have a slide of those specific codes if you would like to see them.
		DR. RUSKIN:  What I'm getting at -- I don't want to waste your time or the committee's time.  What I'm getting at is that the definition of cardiovascular disease can be very broad or very narrow.  A broad definition in this situation is not terribly helpful because what you're interested in are the highest risk subsets.  
		Those are patients with left ventricular dysfunction and congestive heart failure primarily.  If there is any way that you could help me understand what percentage or what numbers of patients, in fact, had those two diagnoses, it would be helpful.  Do you have any LV function data for example?  I wouldn't expect that you would here but I have to ask the question.
		DR. HOLLISTER:  We don't -- none of our protocols involved determination of LV function but certainly a number of the patients that entered our protocols had histories of diagnoses, of heart failure, left ventricular dysfunction and the like.  We can look at the historical data that was recorded as patients entered into the study and provide that to you.
		DR. RUSKIN:  It would be helpful to look at the QT effects in the subset with congestive heart failure in particular.  This may have some importance in treating some of the pneumonias because clearly with the exacerbation of chronic bronchitis, there will be a subset of those patients who have congestive heart failure.  It would be interesting to know what the effects are.
		The last two points are comments.  One is that although there was no mean change in QTc effect in the setting of hypokalemia and hypocalcemia five percent, one in 20 of your patients who were hypocalcemic, had developed QTc prolongation of greater than 60 milliseconds which is, I think, important to emphasize and what you would expect with an Ikr blocker and not trivial.
		The last comment relates to the proposed labeling which you read which surprised me a little bit.  I would just like to read it back to you and get your comments.  
		The last sentence says, "Consequently moxi. should be used with caution in patients with congenital or acquired syndromes of QTc prolongation..." and I underscore congenital or acquired "...or in patients taking concomitant medications known to prolong the QTc interval Class IA and Class III antiarrhythmics."  
		And you followed it with a statement that, "We found no evidence of risk in these patient populations."  I would suggest that you haven't studied those patient populations.  That, I think, is the core of this issue, and that is that the highest risk patients are patients about whom we have no data here.  You have no information.  
		I didn't see one patient in this database who had congenital long QT syndrome.  You've got three in the entire database who were exposed to Class III antiarrhythmic agents.  That's just a fact of life.  That's the nature of the patient population in conjunction with the constraints that you set on the protocol.  
		We need to, I think, restrain our comments, or at least confine our comments to the database that exists and you don't have the data to make that statement.
		DR. HOLLISTER:  I meant to be sure to say that with the limits of our database we found no effect in those admittedly small numbers of patients.  Again, they are small numbers.
		DR. RUSKIN:  You have no database there.  You have no database.  You don't have a single patient with long QT syndrome.  You have three patients on antiarrhythmic agents.  There is no database on that subset.  This is a beautifully worked up drug.  You deserve to be congratulated.  I think you've done a wonderful job of evaluating it.  The comments, I think, that you make should be confined to the data that you have, not data that you don't have.
		DR. HOLLISTER:  I agree.
		DR. RELLER:  Dr. Battinelli.
		DR. BATTINELLI:  I just wanted to as a practicing clinician in some ways amplify what Dr. Ruskin said and point out another piece of -- another problem with that data on the 61 patients.  I would be concerned about patients on a variety of medications as most of my patients are.  I would agree with some of the others that we're not going to measure the QTc on every single person who comes in for an upper or lower respiratory tract infection.
		Dr. Ruskin was concerned that there were only three patients on Class III agents.  If you look at the drugs that you listed, you listed over 33 drugs and only had an N of 61.  There was no patient there on more than one or two at best.  I would be concerned with other drugs that are commonly used for long periods of time such as cisapride and some of the others.
		DR. HOLLISTER:  I agree.  The numbers often times were one or maybe two in an individual patient.  The number of individuals with those drugs was small.
		DR. RELLER:  Dr. Rodvold.
		DR. RODVOLD:  To follow-up with their comments, did you change your protocols to exclude people with cardiovascular diseases or any type of diseases associated with arrhythmias after you found this in your Phase I work?
		DR. HOLLISTER:  No, we did not.  The exclusions were for the antiarrhythmic drugs.
		DR. RODVOLD:  But any cardiovascular disease anyone had, they could enroll?
		DR. HOLLISTER:  That's correct.
		DR. RELLER:  Dr. Christie.
		DR. CHRISTIE:  I have a question in Dr. Church's detail.  She indicated that six patients who were treated with moxifloxacin had atrial fibrillation versus none of the controls.  I just wondered what happened to those patients?  What were the clinical outcomes?  If she could tell us more about those six patients, please.
		DR. HOLLISTER:  Okay.  I have information on those patients.  In the largest database we had a total of 13 patients experienced atrial fibrillation either during therapy or within 30 days after therapy with moxifloxacin.  That is in contrast to two patients that we identified in the comparator drugs.
		Of those eight patients that experienced atrial fibrillation during therapy, and we define that as up to 24 hours after termination of the last dose of moxifloxacin, six of them had histories of atrial fibrillation.  Four of them were on antiarrhythmic drugs that are commonly used for atrial fibrillation.  There were no adverse events associated with those.
		DR. RELLER:  Dr. Platt.
		DR. PLATT:  I'd like to ask you two questions about the concentration effects on QTc.  Also about the outliers.  First you said that on average the QTc prolongation was six milliseconds plus or minus 26.  That's a standard deviation.  Would it also be fair to say that something on the order or two or two and a half percent of people exposed to the drug have QTc prolongations greater than 60 milliseconds?  Am I understanding that data correctly?
		DR. HOLLISTER:  The number for our all-paired data set were 10 subjects had QT prolongations more than 60 milliseconds on moxifloxacin 400.
		DR. PLATT:  Well, there's another slide you showed that it was something like 1.7 percent, I think, had --
		DR. HOLLISTER:  Yeah, 10 divided by 787 is about 1.3 or 1.2.
		DR. PLATT:  Which is consonant with that standard deviation you showed; that is, among all comers a couple of percent might have those prolongations that are above the 60 millisecond cutoff for whatever 60 milliseconds is worth.  I just want to make sure I'm understanding properly what you're saying.
		DR. HOLLISTER:  Yes, that's true.  It might be useful to ask what's the comparable percentage for those comparator drugs because in that same slide it looked as though it was a four to one excess with prolongations of 60 milliseconds or more.  		DR. PLATT:  That takes me into my question about concentration effects.  That regression line you put up, if I squint at it properly, it looks as thought at the upper end there was maybe a 20 millisecond increase in the fitted line.  Was I reading that properly?
		DR. HOLLISTER:  No.  Perhaps better than just looking at the QT would be the delta QT so that you've got in-patient comparisons because that's what the delta of six milliseconds is.
		DR. PLATT:  Right.  Well, in the briefing documents we were sent, there was actually a graph that showed delta QTc and it looked not unlike that regression line you showed but it did have -- it looked as though it was pointing to 20 milliseconds at concentrations of 4,000 to 5,000 micrograms.  
		I'm going toward this same question.  If 4,000 to 5,000 micrograms per mil. is the steady state concentration expected by the end of a treatment regimen, is that --
		DR. HOLLISTER:  The Cmax.
		DR. PLATT:  Right.  What proportion of individuals -- putting that data together, what proportion of individuals who have concentrations of 4,000 to 5,000 micrograms would be expected to have a delta QTc of 60 milliseconds or more?  Can you predict that from the data that you have?
		DR. HOLLISTER:  Only in a way, I think.  You know, we tried to obtain the EKGs at or near the Cmax concentration.  That range was broad in the database so I can't say that every one was obtained there.  In the database in which we were attempting to obtain a Cmax EKG, the mean change was six milliseconds.  In the more tightly controlled Phase I studies, you see the regression line there.  Maybe I should show the delta QT because there may be some very interesting biology on that.  
		Jim, maybe you can help me find the delta QTc change.
		Because it's interesting that at very low concentrations of drug it's negative so that when you're at or around the therapeutic --
		Okay. Renée, that's slide No. 45 on carousel five.
		At around the what we think are the Cmax concentrations that are going to be achieved with steady state, the slope actually is for delta right in the range that we found it with the Phase III database.
		Here I showed you earlier the QTc.  This is the delta QTc.  Here's the zero time point and out this direction here with milligrams per liter of the drug concentration.  Again, a lot of scatter in the data.  Most of our Cmaxes are going to be falling in this range of the data.  You know, as well as this regression line can predict what the change is with all the variability that you see in the scatter there, our finding with the large database was it was around six.
		DR. PLATT:  Just one more comment and then I'll relinquish the microphone.  It seems to me that these data are quite consistent with the clinical data you showed but show the tyranny of small numbers.  That is, if you plotted the 95 percent confidence intervals around the upper range of doses, what proportion of people would have delta QTc that are in the range that could be worrisome?  
		It's likely that if you treat a lot of people, you'll have a small fraction which is a substantial number in that four to five range.  For those who are more than one or two standard deviations above, that still may be a lot of people.  It would be useful to know how many that is and what kind of QTc prolongations you could expect for them.
		DR. HOLLISTER:  The numbers that we have from the all-paired valid EKG database are 10 of 787 met that criteria of being greater than 60 milliseconds prolonged.  That might give you the proportion of people that might be above this number at therapeutic concentrations of the drug.  
		We have our largest database with consequent problems in terms of the EKG interpretation.  That number is about 23 out of the 1,200 patients meet that criteria, but the noise is much larger in the comparator group, too, so they come up a great deal also. 
		I think your earlier point about these are variable measures and it's hard to ascribe huge effects to measure that has a variability that's four to five times the measure.
		DR. RELLER:  Dr. Murray.
		DR. MURRAY:  Just one.  You made a comment that this had not been studied for prolonged periods of time.  Do you have any reason to suspect that prolonged administration would lead somehow cumulatively to an effect on the QT? 
		The reason I ask is because there is a tendency once the drug is out there on the market to use it for a number of nonapproved indications.  One I can think of immediately is osteomyelitis with a staphylococcus where fluoroquinolone might be used for prolonged therapy.  One would theoretically think of using the most active in vitro one on the market since few have been studied for osteo.  
		Do you have any sort of information on prolonged therapy or would this need to be addressed in the labeling?
		DR. HOLLISTER:  Obviously we're not going for that kind of labeling or those indications.  We do have very limited numbers of patients that have been studied for more than 12 days, I believe, in our database.  In terms of the effect on QT, we don't have data.  All I can say as a clinical pharmacologist is we don't have those issues of drug accumulation going on here.  If there is a relationship between drug concentration and the effect on QT, then the maximum effect that we get is unlikely to be any worse.
		Another way of approach that would be some of our Phase I trials where we did acute administration and then chronic administration of the drug.  On average the change in QT reduced slightly with chronic administration but those were not the length of time that you're talking about for some of these very chronic illnesses.
		DR. MURRAY:  Thank you.  And I have not as a question to answer now but perhaps to just let the sponsor know I would be asking it later, or would like it hear it addressed later in the context of -- and some of this may come up in the FDA's presentation -- in the context of assessing the strength of efficacy in general for pneumococcus which might allow us to have a sense of the strength of efficacy against resistant organisms.  
		I would be interested in a review, perhaps in the afternoon or in the question/answer session then, the total number of pneumococci in the CAP studies and how many of those were bacteremic.  And an assessment of the severity of the illness of people that were treated with moxifloxacin broken out, in fact, in terms of penicillin resistance and intermediate much as we heard yesterday.  
		I don't expect you to throw that out now but it would be something that -- and some of it may come out in the FDA presentation.
		DR. HOLLISTER:  I believe Dr. Meyerhoff will have some information on that.  We have additional information that we can provide you on that in the afternoon.
		DR. RELLER:  Dr. Christie.
		DR. CHRISTIE:  This drug was not tested in children but once it is approved, it will be used in children.  My concern was would you expect any cardiovascular problems or any problems in children once the drug is approved?
		DR. HOLLISTER:  Well, you are correct that the drug has not been studied in children.  We have toxicological data in young animals that indicate that it shares with many of the other fluoroquinolones, some of the effects on joints that are found with other fluoroquinolones and represent a relative contraindication.  With respect to the cardiovascular effects or EKG effects, QT effects, we have no information.
		DR. CHRISTIE:  What can we do about that?
		MR. CALCAGNI:  In accordance with the pediatric regulations, we'll have further discussions with the FDA.  There are requirements as of April of this year to certainly study any drug that potentially will be used in children.  It was not indicated for children and we're not requesting it, but consistent and in the spirit of evaluating drugs, we will be looking at it.  We can't put it in our labeling because we did not study it at this time.
		DR. RELLER:  Dr. Parsonnet.
		DR. PARSONNET:  I have a few questions very much related to what Dr. Platt had asked.  It relates to some of the outliers.  You had it looks to me a difference in the number of outliers, at least by the CPMP criteria that you talked about, the greater than 500 milliseconds and the greater than 60 millisecond change.  I was wondering in those two categories you had 10 in one and three in the other.  There were three who had longer than 500 milliseconds and 10 in the other group.  Whether they were the same people, the total was 13?  
		DR. HOLLISTER:  Yes.  Those categories are nonexclusive categories so, in fact, someone who met a criterion to be greater than 500 milliseconds often times met one of those other criteria, either greater than 60 or greater than 30 to an abnormal value.
		DR. PARSONNET:   Well, that's what I'm asking.  I'm asking was that the case.  How many of those three were also in that group of 10?
		DR. HOLLISTER:  I would have to look at the data.  I can't answer right off the top of my head.
		DR. PARSONNET:  And I guess that then comes to the question that I have which is it seems to me to some degree looking at your dose response, that regression curve that you did, that there is some degree of idiosyncracy to the prolongation of the QT.  		Some of your people in your very low categories had very prolonged QTs and that this may not be in this respect having a sort of -- and also it's not clear to me that this is a normally distributed variable. That there aren't some people that your means don't reflect, that most people don't change at all but some people change a lot.
		I was wondering whether -- and this is a question as well for my consultants -- whether, No. 1, the data of QT prolongation are normally distributed and, No. 2, what we are really interested in is the proportion of people who are those outliers as opposed to this mean difference which really to a clinician may be really have much meaning.
		DR. HOLLISTER:  We analyzed our data both in terms of the mean change in QT as well as frequency of outliers and all those data are available to you.  I believe Dr. Morganroth can comment about the distribution of QT prolongation and it's variable.
		DR. MORGANROTH:  The small change in a mean QTc duration is not terribly meaningful to clinicians, just as you say, particularly when you're dealing with numbers in the one to 10 millisecond range which are not clinically easy to measure and generally are not measured to that specificity.
		But when you see in a drug development program in several hundred to 1,000 plus patients a small three millisecond, six millisecond change in QTc, the real question, I think, is whether it's real or not or whether it is -- is it really an effect on cardiac repolarization.  That's where one goes back to look at some of the preclinical potassium channel information that might be useful.  
		Also to look at the outliers analysis because, in fact, if the drug is inducing a QT change and the QT change is not spontaneous variability, which is what accounts for most of that distribution you see on the concentration QTc graph in which we don't believe the data are normally distributed for that reason, then the outlier percentages are a guide, if you will, as to the likelihood that, in fact, the drug is causing a QT change versus that it's not when you are dealing with very small millisecond change.  		I look at the data somewhat differently than it's been presented by Dr. Hollister.  When I see a 60 millisecond category in which you have 1.3 percent of the drug under consideration meeting that criteria in .3 percent of the "control" group, in this case comparators rather than placebo, while that is statistically probably not different, to me it's meaningful in the sense that there is a difference numerically that is used as a supportive mechanism with IK channel data to suggest that a six millisecond effect is real meaning it's more likely real than not meaning it's more likely caused by the drug or not.
		As someone over here suggested, the other way that I look at it is what percentage of patients being treated by the drug are going to have a change in the QTc that's more likely due to the drug than spontaneous variability.  I think the answer for this drug, and for many drugs of this nature, is in the two to three percent range of patients, which is somewhat comforting because that suggests that 97 percent of the patients are not going to have it. 
		The other issue which is very important is concomitant drug medication that prolong the QT.  In the database of this nature, and frankly in almost all the databases, there isn't sufficient numbers of patients on cisapride or amiodarone or sotalol to really come to any data driven conclusion, it becomes an issue of wobbling in caution.
		Just like the pediatric issue.  We don't have data on pediatrics but we still have to do something or say something about it.  I think the same thing holds here.  Does that answer you question?
		DR. PARSONNET:  It answers my question somewhat but my concern still is that actually I think that 1.3 percent versus .3 percent may be statistically significantly different.  I also am concerned that the way this is being presented, especially in the way that you are proposing in the labeling, is not as informative to the physicians using it than actually providing that percentage of people who have a dangerously -- what is considered to be a potentially dangerous prolongation of QT.
		DR. MORGANROTH:  The only comment I would make is to say that having a 60 millisecond change shouldn't be looked at as necessarily a dangerous level.  It's a level picked by CPMP to suggest that it's due to the drug versus spontaneous variability.  Remember, normal healthy persons can have a 75 millisecond change over the day.  
		The really salutary effect is that this drug is only going to be used for five or 10 days.  You take an antihistamine and it might be used for weeks or months or other drugs that may be used for years.  Then a 60 millisecond change chronically which may be, of course, more or less depending on the time of day, would be much more important.  I think that's another factor you should consider.
		But I agree with you.  I think that it's important to know the percentage of patients that reach certain criteria and what the likelihood that the drug is, in fact, causing the QT rather than not at all affecting the QT because just a six millisecond change is something that most clinicians would think is ridiculously trivial.  In this case I think it's an effect that needs to be understood so that concomitant medication use can be appropriately guided.
		DR. RELLER:  Dr. Ruskin.
		DR. RUSKIN:  I would agree with those comments and perhaps state it a little differently.  That is, a small change in mean QT is very difficult to interpret.  The outliers are really the only subsets of interest.  What is critical about looking at an agent that you think may affect the QT is what its ion channel profile is.  What you know about this drug is that it's an Ikr blocker and that it is both dose and concentration dependent.  Those are very important properties.
		The effects appear to be relatively small but the fact is it's an Ikr blocker.  A weak Ikr blocker will not cause a problem in the vast majority of patients to whom it's given.  The only patients in whom we have concerns are high-risk subsets.  Those are patients who have what Dan Roden has called reduced repolarization reserve.  
		That is, people with ion channel genetically based ion channel abnormalities that predispose them to agents that block Ikr to predispose them to problems with ion channel blocking agents; (2) People at particularly high risk, elderly females with structural heart disease; and (3) people on concomitant Ikr blockers for other reasons.  Those are the subsets in whom we have no data here.
		I think that when you make a decision about whether or not you use a drug in large populations of patients, you have to be influenced by the benefits and the risks.  If you have a drug that clearly as a favorable profile as this one does, you may decide that the benefits outweigh what is probably a very small risk but you want to be intelligent about how you label it.  
		That was the reason for my comments to Dr. Hollister about the proposed labeling.  There is absolutely no data here to suggest that this drug should be used with caution in people with congenial long QT or concomitant QT prolongation.  It just shouldn't be used with them period.  I think to answer your question, the outliers are the critical subset and they are the subset about whom we have little to no data.  That's where the concern lies.
		You can do a guesstimate of the upper bound if you assume about 60,000 person weeks or -- no, 6,000 person weeks of exposure here.  The upper 95 percent boundary for potential events here is somewhere around five per 100 -- no, five for 10,000.  		The event rate here could be as high as one in 2,000.  It's probably a lot lower than that but you can't exclude the possibility of, say, two events in 
-- excuse me, one event in 2,000 uses of this drug based on this data in this relatively low-risk subset.  That's the problem that you're faces with in grappling with this issue.  You've got short duration exposures which is almost a favorable thing but a very limiting feature in terms of assessing risk.
		DR. RELLER:  Dr. Temple.
		DR. TEMPLE:  Can I just ask Jeremy something?  In these people who might be at greater risk, is what you would expect to see a larger effect on QT or a different consequence of a given QT effect?
		For example, we know that people on diuretics are more susceptible to getting torsade from a drug that is capable of causing it.  But is that because their QT effect is larger or because they are more susceptible to whatever is there already?
		DR. RUSKIN:  I think it can be both, Bob.  I think that clearly you do tend to see longer QTs in people who have other predisposing factors like hypokalemia or other drugs that block Ikr.  There are certainly cases of torsade that occur without dramatic QT prolongation so it's not the QT and I think Joel said this, or someone in one of their presentations.  		It may actually have been Dr. Hollister who said very clearly that the degree of QT prolongation is neither necessary nor sufficient to predict risk.  It's a factor but it's certainly not the only factor.  You can see torsade with even modest degrees of QT prolongation in some patients.  Most people who develop drug induced torsade have QTc in the range of 500 or greater but by no means all.
		DR. TEMPLE:  That goes a little to how one might study the interaction.  If you have to get an event to learn something, that makes it very difficult.  If you simply have to look at the high-risk people and see whether their QT was more prolonged than other people, you could actually study that.
		DR. RUSKIN:  I think it makes it very, very difficult to study.  That's why you're left with using some sort of guesstimate of a risk benefit ratio never really getting a tight grip on the risk.  You've seen this with the antiarrhythmics that work by prolonging the QT interval and even there we have trouble estimating what the real risks are.
		DR. RELLER:  Dr. Soper.
		DR. SOPER:  As a follow-up to Dr. Christie's question, is this drug safe to give reproductive age group women who may be pregnant but who don't know it?  Has there been any inadvertent administration to this drug to a pregnant woman and do you have any outcome data?
		DR. HOLLISTER:  I don't have anything.  Dr. Eckhard van Keutz is the toxicologist who is associated with the development of this drug and he can answer that question in terms of the animal.
		DR. VAN KEUTZ:  We have started moxifloxacin in the normal range of reproduction toxicity studies and we have performed studies in rats as well as in monkeys.  In none of these animal species we have seen any indication of teratogenicity but we have seen signs of embryo toxicity.  This occurred only at dosages which were already maternally toxic.  
		This is certainly not a direct affect of the drug but it's indirect or a secondary affect due to the maternal toxicity.  In addition, we have seen in the monkey study, again at a maternally toxic dose, an increased rate of abortions but, again, no teratogenicity.
		DR. SOPER:  You talked about the arthropathy in small children.  Can you explain on that a little bit?  Or in small animals, I guess.
		DR. VAN KEUTZ:  Okay.  We have performed this typical young beagle dog toxicity study and the outcome of this study was that moxifloxacin is a very typical quinolone which means that we have induced these very well known damages to the joints at a dose of 30 milligram per kilogram which caused problems to P concentration and the plasma of approximately eight milligrams per liter.  
		I think at this athrotoxic concentration we are in the range of the other quinolones.  There's nothing which has surprised us.  For us it would be a surprise to have a quinolone which was not inducing the typical athrotoxicity.
		DR. RELLER:  Dr. Norden.
		DR. NORDEN:  I think we've all -- at least I've learned much more about QT than I ever thought I would know or want to know.  I am concerned and Dr. Ruskin has been very helpful.  One of the questions I have for the FDA grepafloxacin and sparfloxacin, which are both approved, are listed in the slides as having prolonged QT intervals of the same or slightly longer duration if you just look at the mean.  
		Do we have data on them?  I mean, were they studied in the same way or examined?  Do we have any experience that would help us in terms of evaluating this quinolone?
		DR. NORDEN:  I think that the comment that was made by Dr. Ruskin with regards to the company's efforts here in terms of studying this phenomena are certainly accurately.  I think that, as far as I know, neither sparfloxacin nor grepafloxacin was studied at nearly the same degree of intensity.  I think that is obviously an issue that we need to assess once we hopefully, as part of this meeting, get a framework for.  
		You'll notice that one of our last questions to the committee this afternoon is about talking a little more -- and there has already been some discussion about the parameters that are appropriate for anti-infectives and, in truth, probably for noncardiac agents -- to look at and the question will come up about assessing some of these other drugs.
		There is some information about QT changes on sparfloxacin.  I know some was done.  We were not involved in that assessment.  When I say we meaning current division who is reviewing this product.  
		As far as grepafloxacin, there was some information.  You saw the QT prolongation.  On the other hand, if I recall correctly, grepafloxacin did not seem to have in the initial data the same exposure prolongation relationship that, for instance, has been seen with this product.  That may, in fact, be a little different.
		I think it's fair to say that what Bayer has done for moxifloxacin probably sets a new standard for the overall evaluation of products, certainly anti-infective products, with QT prolongation.  The question is how to sort of use some of this to apply to new products and perhaps at some level to products that are already approved.  As was also noted, this QT prolongation is not limited to the fluoroquinolones.  There are issues, in particular, with the macrolides that may well also have to be subsequently assessed a little more.
		DR. KWEDER:  I actually have a question for Dr. Hollister.  Some of the slides that you've showed looking at the pharmacokinetics of the 400 milligram dose, as well as some of the ratios that you've looked at, the Cmax MIC 90 really do show, you know, that fall well above the eight to 10 range for strep. pneumo indicate that you've got a pretty wide margin for expected efficacy.
		When you take that in combination with the suggestion of a concentration effect that dose matters for risk of QT prolongation, and the fact that you also -- it's interesting that you also have some older studies of the 200 milligram dose that showed some degree of efficacy.  
		When you presented your QT data, it was for all moxi. studies.  Do you have any data on QT at the -- even the mean QT which we think may not be the ticket here, but do you have anything that teases out a distinction between that the 200 milligram dose and 400 milligram dose?
		DR. HOLLISTER:  I can let Dr. Church comment because the studies that you are referring to or the parameters that you are referring to were part of her presentation.  We do have some data at the 200 milligram dose level but that dose level was abandoned because in our Phase II trials we didn't think we had adequate efficacy at that concentration.
		DR. KWEDER:  Right.  I guess I'm thinking more about the linear pharmacokinetics here.  There appears to be a linear effect of the QT prolongation as well.  I'm just wondering if you have any data at any other dose of moxi. other than the 400 milligrams on the QT issue.
		DR. HOLLISTER:  The progression slide that I showed you was our Phase I database where doses ranged from 50 milligrams to 800 milligrams.  We've also included in the NDA and the special safety section on QT the IV data plotted in the same fashion indicating that it does look like it's a similar relationship throughout.
		DR. KWEDER:  Right.  And I'm just asking about in the other clinical studies, the non Phase I did you have any data?  Your mean QT changes come from the clinical trials.  Did you have any of that data from the 200 milligrams or were those studies -- I gather that they were already completed by the time you began to look at this issue in the clinical trials beyond the Phase I PK data.
		DR. HOLLISTER:  We do have limited information on the QT effect.  In our clinical pharmacology studies we did have a dose group with 200 milligrams orally during which we obtained Cmax EKGs and determined the QT interval there.  
		The 37 subjects that were in that trial had a mean change of 4 plus or minus 18 so it was less.  I think it's probably better yet, though, to sort of use the regression because that more directly relates the drug concentration with the effect on QT.
		DR. RELLER:  Dr. Danner.
		DR. DANNER:  Do you have data on how this drug affects potassium and magnesium excretion from the kidney?  The second question, in terms of the accumulation of this drug in tissues, over what time period does that occur?  What is the half life in tissues?  Is it likely if people use the drug for longer periods of time that the drug would continue to accumulate and levels would continue to rise in tissues?
		DR. HOLLISTER:  We do have some tissue accumulation studies in Phase I and Phase II and in small numbers of patients multiple time points.  We also have a dialysis and skeletal muscle study.  Most of those studies, however, were done with a single dose administration of very short term.
		There is, as Dr. Church showed you, considerable accumulation in pulmonary tissues which is helpful in this sort of setting.  Our data for skeletal muscle is that the concentrations reached in skeletal muscle are about 80 percent of the plasma concentrations of the drug.
		We don't have data to address the possibility of long-term accumulation in tissues but for skeletal muscle the ratios are less than plasma concentrations.
		We do have from clinical pharmacology Dr. John Lettieri who can also comment on some of those data.
		DR. LETTIERI:  I'll just make the comment that, in fact, the half life from tissue is the same as the parent drug, about 12 hours, so there wouldn't be accumulation beyond what you see with the single dose.
		DR. RELLER:  We're running short on time.  We will big up some with a slightly reduced lunch hour.  I would like to close this portion of it before the break with one final query because it directly relates to the sponsor's presentation and proposals.
		Dr. Hollister, given the limits of interpretation that have been expressed of the clinical importance of the mean QTc prolongation in a general population as opposed to a subset, could you share the sponsor's rationale for proposing the comparison and the proposed QT labeling, the comparison with a single comparator agent, clarithromycin.  What was the thinking there?
		DR. HOLLISTER:  The inclusion of clarithromycin was because that was used in the larger scale studies as the comparator drug.
		DR. RELLER:  Thank you.  We will break for 15 minutes and then reconvene.
		(Whereupon, at 11:00 a.m. off the record until 11:16 a.m.)
		DR. RELLER:  I'd like to ask everybody to take their seats so that we can begin the next portion of our -- the last portion of our morning session.  As always happens on the second day of a two-day meeting, there are those who must meet flights before the final hour and we want to have ample time for fair discussion and to address the specific questions asked of the advisory committee by the FDA.
		I would like now to ask Dr. Robert Temple to initiate the FDA presentation.
		DR. TEMPLE:  Thank you and good morning.  It's still morning.  How's that?  Okay.  That's okay.  I'll just use this.  I don't have any slides today and I would be surprised if I can tell you anything that Dr. Ruskin and others cannot but let me talk a little bit about QT prolongation and what it means to us.
		QT prolongation and the ability of drugs to do that, to cause torsade and sudden death, is clearly one of the most important adverse consequences of drugs.  It has lead to withdrawal of some therapies and severe limitations of use.
		It's a relatively new bad effect of drugs.  Wasn't really recognized, to my best knowledge, until about 1982 when we encountered a calcium channel blocker called lidoflazine.  We were very close to approving it when I ran into an English antiarrhythmic specialist named Dennis Krickler at a meeting and mentioned the drug and he said, "Oh, kills people, doesn't it?"  
		Whereupon, we looked and found in the literature plentiful evidence that at least in people who had recently been converted from atrial fibrillation it caused plenty of nasty arrhythmias.
Actually, the arrhythmias were published in the journal article and were obviously torsade, although, as far as I know, it wasn't named yet.  There they were.  Even an amateur could recognize them.
		It's clearly a growth industry.  Since the early day of lidoflazine and sotalol and things like that we've discovered dozens and dozens of drugs that have at least some property of this kind which has made everybody extremely nervous because it isn't clear what to do about this phenomena.
		Drugs with the capacity to block appropriate channels and cause QT prolongation show up in every drug class.  Terfenadine and astemazole are
 antihistamines with major effects depending on the dose and depending on whether you interfere with their metabolism.  
		Thioridazine, sertindol, pimozide, other antipsychotics seem to have some effects of this kind.  Type III antiarrhythmics do, of course, by definition because that's what they do.  Some of those effects are very large.  Nonetheless, some of those drugs are used usually to treat bad arrhythmias.  
		Calcium channel blockers sometimes have this property.  Lidoflazine did.  Bepridil does.  As a consequence, it's reserved for people whose angina doesn't respond to anything else.  There was once a drug in Europe called prenylamine which was one of the first drugs every discovered with this property, sort of a landmark drug.
		Drugs that alter GI motility like cisapride and domperidone have QT activities.  Ketanserin is an anti-hypertensive serotonin antagonist.  The list goes on and on.  I'm not sure everything on the list that Joel found is real but there are candidates in every category.
		From a regulator's point of view, it's very difficult to know what to do with these.  The poles of view, I would say, are that once you discover this property, you are really in trouble.  That's one because it's hard to know how to quantify the risk.  The other pole would be dose matters, concentration matters, size of the effect matters.  It's hard to know where to come out in these because the experience isn't good enough on the cases that are difficult.
What is also obvious is that what the drug is for always matters and how good it is always matters.
		I should say it's not clear to me, maybe people here can say, whether we should be looking at corrected QT or QT.  All the bad actors I know affect both.  I have never understood the logic of thinking that corrected QT is the better measure.  The reason for correcting QTs are historical and arose long before anybody began thinking about blocking potassium currents.
		The clearly bad actors, I think it's fair to say, all prolong both QT and QTc and have pretty good sized effects when you look at mean effects, in the neighborhood of 20 milliseconds or so.  Now, that may be what they do by themselves or it may be what they do when you inhibit their metabolism so that the concentration goes up.
		The drugs of that kind are drugs like sotalol and bepridil and other Type III antiarrhythmics.  The effects are so prominent with those drugs that you actually see cases of torsade in the NDA database.  It's not hard to detect these.
If metabolism blockage is required, you won't see those in the NDA database because that probably won't happen.
		There is concern that factors other than the absolute size of the QT prolongation matter that susceptibility can be enhanced and that there may be an interaction.  How well worked up this is not so clear to me.  But we do have several examples.  A drug called ketanserin, a serotonin antagonist, was put into a very large study, an outcome mortability study of patients with peripheral vascular disease.
		What was discovered was a profound increase in mortality in the patients who happened to be on a diuretic.  I don't think, but I'm not sure, that was because their QT was affected more.  I believe it's because the consequence of the QT prolongation effect of the ketanserin was more severe.  There are other examples in which hypokalemia has triggered events that perhaps were not present without that.
		It's also possible that some underlying conditions, as Jeremy said, like congestive heart failure may exaggerate the response to a given increase.  There may be an interaction of patient substrate and the size of the effect and it's very hard to say that's true.
		As I said, there's a point of view that says that any evidence of QT prolonging effect means that we are going to have major trouble.  The reasons for thinking that are several.  One is that every drug known to cause torsade which, by definition requires QT prolongation, is also associated with cases of polymorphic ventricular tachycardia which is without QT prolongation.  That makes you wonder what the precise mechanism is.
		Another reason is the general philosophical view that those responses for most events are continuous and they don't drop off to nothing usually, although there must be some things with thresholds.
		It also seems likely, but how well studied this is is not clear to me, that when the drug with a small effect is used with another drug that also has the same effect or is used in people who are unusually susceptible, there will be an interaction so that even a drug with a small effect might cause trouble.  I'm not sure how well studied that is but it doesn't seem unlikely.
		Probably most important is as a number of people discussed and Dr. Platt suggested, it isn't the mean that matters.  It's how you affect the distribution.  It may be that we should start representing QT effects not as means but as either cumulative distributions to see what fraction of people have a change or more than a certain size, or the bell shaped distribution, and then look at what the tails are.  
		It seems likely if the mean is very small, one millisecond or so, you may not be able to see much effect on the tail but that does seem where people should look.  By definition, if you change the meaning, you will probably change it in the distribution.  It seems likely that more people will get into a danger range and that's probably what everybody should focus on.
		Anyway, those are all reasons for thinking that any effect might be something to worry about.  I wouldn't dismiss that but I think there is another point of view that is also supported by some data.  It's fairly clearly that there's a dose response relationship in most cases between QT prolongation and dose, or concentration.  That would be better.  There is some relationship at least between the effect on the QT and how much trouble you get into.
		The reason can even address that question -- sorry.  The problem here is that while QT effects are frequent and easily detected in clinical trials, causing torsade is rare and it's not easy to detect that NDA databases.  But there is one advantage we have here.  That is that torsade is virtually pathomnemonic of an effect on one or another of the ion channels.  It's readily detected as a problem.  		It's, therefore, rather much as aplastic anemia, agranulocytosis, and things like that are.  It's fairly readily attributed to drugs.  People notice this and they immediately worry about what drug people are on and then report it to us.  
		So it seems at least likely that you can learn about whether drugs have the ability to cause torsade by looking for torsade in the post-marketing period.  It's a relatively favorable one.  Sudden death, on the other hand, is extremely difficult because many things cause sudden death but not that many things cause torsade.                           
		So the marketing experience with some of these drugs it seems to me matters.  Now, we know, for example, for terfenadine, that it's extremely easy to discover.  Not that we discovered this rapidly.  We should have but now we know more.  It's extremely easy to discover that terfenadine taken in combination with a cytochrome P450 3A4 inhibitor causes Torsade de Pointes.  There are many, many cases.  Hundreds.  It's very easy to detect that.  
		We looked also to see whether there were any cases in which there was no 3A4 inhibitor.  There may be a debate about whether there are any but there are very few.  Perhaps none.  That is a drug that has a small QT effect even in the absence of an inhibitor.
		Our experience with astemazole, another QT prolonger, was similar.  It was fairly easy to discover clear cut cases when people took more than the 10 milligram recommended dose, but few, if any, cases at the 10 milligram dose.  It doesn't really matter whether there was one or two.  There were many fewer, even though many more people were exposed to the larger dose again suggesting a dose response.
		For dofedilide, a drug recently approved to maintain sinus rhythm in people who have been having atrial fibrillation, the frequency of torsade went down when dosage was suggested for renal function.  It didn't go to zero but that's a drug whose mechanism is to prolong the QT.  The rate went down when the dose was appropriately modified.
		I've been talking with Jeremy about this but there are a few cases to my knowledge of cisapride induced torsade in the absence of an interfering drug.  He thinks he knows of some and he's going to report them from now on.  But most of the cases anyway occur when you interfere with its metabolism and send the blood level way up.
		Domperidone is another motility modifying drug which given intravenously causes torsade while the infusion is still going on.  It's really easy to detect but it's been difficult, not necessarily impossible.  There's probably some internal debate about it.  It's been difficult to conclude that it causes it when you give it orally when the blood level is much lower.
		This leads me to think that dose and size of response matter to how much of a risk a particular drug is.  What isn't clear is where the cutoff point is or if there is one.  I would feel happy to say that something with one millisecond mean increase probably is no problem and that something with a 20 millisecond increase probably is a problem.  I don't think any of us can tell you where the problem gets very small or disappears.
		Now, having said that, one wants to be sure one isn't giving more of a drug than one needs to.  You are the infectious disease people and need to think about this, but one important question is whether the dose at 400 really is needed in all cases or whether a lower dose would do just as well, at least for some infections, and keep people further away from whatever risk there is.  Dose becomes very important.
		I should tell you where we are as an agency.  We don't have a formal policy.  We don't even have a policy that we put out and then withdrew like the CPMP does.  They are ahead of us but we are thinking actively about this.  A joint FDA task force is forming to review all available data -- you learn a lot from history here -- and try to think about what an appropriate clinical and preclinical workup is of these cases and try to define risk as best we can.  
		So far, unfortunately for both us and you, it's kind of case by case and the only way to go is to try to make everybody pay attention and pull together the best expertise we can find.  
		Thank you.  Any questions?
		DR. RELLER:  Since we will be returning to this issue after the safety presentation, which I would like to do immediately after lunch so that we can have continuity fusing questions for Dr. Temple after and in concordance with the safety presentation, I've asked Dr. Meyerhoff if she would move her presentation forward before lunch.  
		Then we'll have her presentation and then our lunch break from approximately 12:00 till 1:00 starting promptly at 1:00 with the safety presentation by the FDA and then moving as swiftly but judiciously as we can to addressing the questions given the constraints of having sufficient voting members to have a real sense of the entire committee presented for FDA's further consideration.  		
		Dr. Meyerhoff.  Thank you, Dr. Temple.  We'll be back to you in the afternoon.
		DR. MEYERHOFF:  Good morning.  Can people hear me?  Can people hear me now?  Not projecting?  Can people hear me now?  Okay.  Thanks.  Thank you.
		Good morning.  I'm going to be presenting the FDA's perspective on clinical efficacy for moxifloxacin.
		As you've already heard this morning, Bayer is seeking a claim for four different indications on the draft label.  Those are acute bacterial exacerbation of chronic bronchitis, skin and skin structure infections, acute sinusitis, and community acquired pneumonia.
		These last two indications are particularly noteworthy because for both of them among the organisms that are sought in the label is penicillin resistant streptococcus pneumoniae.  This is a claim that has not previously been granted to any antimicrobial.  For those of you who were here yesterday, it is also under discussion for another drug in this class.
		I'm going to give an overview of the efficacy data initially by saying a number of pivotal trials have been reviewed for each of these four indications.  In general, the FDA's analysis by both intent to treat and for protocol populations generally agrees with that of the sponsor, and that is that clinical efficacy has been demonstrated in the four indications.
		I would like to focus my discussion on the claim for clinical efficacy and the treatment of infections caused by pen. resistant pneumococcus.  For this purpose I'll focus on the pneumonia and the sinusitis indications.
		Let me just make a couple of statements about language and usage because these terms get long and I think interfere with the flow.  In any case, when I'm using the term efficacy simply for the purposes of my talk, I'm referring only to clinical efficacy.  Resistance again only refers to penicillin resistance.  I think we are all in agreement that the MIC cutoff for that is the current NCCLS criterion which is two micrograms per ml.  Similarly, any references to pneumonia refer specifically to community acquired pneumonia.
		I would like to start by looking at overall efficacy in the pneumonia by highlighting two representative studies.  The first of these is D96026. This was conducted entirely in the United States entirely in outpatients spread over 60 centers.
		The control agent in this study was clarithromycin.  I would point out that the dose used, 500 milligrams BID, is actually twice the FDA approved dose for pneumonia for clari.  
		The test of cure visit was undertaken at the late follow-up; that is, 21 to 28 days following completion of therapy.  I think you can see from the table I'm showing that both per protocol and intent to treat analyses demonstrate efficacy rates that are equivalent to those observed for the comparator agency.  These do meet the statistical criterion for equivalence in that the 95 percent confidence interval around the differences and efficacious rates in both analyses have a lower bound that's greater than minus 10.
		I want to look at a second pneumonia study and that's No. 140.  This study was conducted entirely outside the United States at over 80 centers.  The comparator agent was amoxicillin, 1,000 milligrams TID.  Again, it think it's important to point out that this is twice the FDA label dose for amoxicillin for this type of infection.
		This study's organization was centered in Europe and the genesis for the choice of this dose is that a number of European countries are now recommending this higher dose of amoxicillin for initial treatment of community acquired pneumonia because of decreasing penicillin susceptibility among clinical isolates of pneumococcus.
		This study is interesting for a couple of reasons.  One is it was actually enriched for patients with pneumococcal infection by requiring some additional entry criteria.  Besides patients needing to have evidence of pneumonia, they also needed to have any two of the following five findings; that is disease of rapid onset within 48 hours of presentation; temperature greater than or equal to 39 degrees; pleuritic chest pain; frankly lobar infiltrate on chest x-ray; or gram positive cocci on sputum gram stain.
		Thought this is a study of two oral agents, about 80 percent of the patients were hospitalized.  I think we need to realize that's probably a somewhat different situation than we would see in this country.  Again, these patients were deemed suitable for oral treatment but a very large proportion of them did go into the hospital.  All of them had blood cultures drawn.  
		If we look at the overall efficacy rates in both the per protocol and intent to treat analyses, again I think we can see that equivalence is demonstrated to high dose amoxicillin in both cases.
		I want to turn now to talk specifically about pneumococcal and resistant pneumococcal infections.  I think there are a number of questions we want to ask about moxifloxacin when we start to consider this issue.  Firstly, does it work in infections due to penicillin susceptible pneumococci.  The first bullet point will be an attempt to address that question.
		Secondly, what kind of data do we have to tell us something about activity against resistant strains or strains with intermediate susceptibility to penicillin.  Thirdly, what types of supporting data can supplement what we can learn from the clinical trials.  
		There was a detailed discussion of these types of data this morning and I'm going to focus mostly on the first three bullet points for the purposes of my discussion.
		Drs. Church and Zinner summarized a significant amount of data on in vitro microbiologic studies, animal models, and PKPD ratios that I think attest to the preclinical activity against pneumococcus that has been seen for moxifloxacin.
		The data submitted in this original NDA are really our first opportunity to assess the clinical efficacy of this drug in gram positive infections.  The pneumonia indication is our first opportunity to see how it does in pneumococcal pneumonia.
		For the purposes of this particular organism, I would like to turn again to study 0140.  Again, this is the study that was enriched for pneumococcal infection and provides us with a significant number of patients who were infected with this organism.
		Overall, efficacy, which is shown in the first row of this table, again for moxifloxacin and the control agent look to be comparable.  The control was high dose amoxicillin for this study.  If we look at clinical efficacy in pneumococcal pneumonia across all of the pneumonia studies, a similar point is made.  That is, moxifloxacin achieves comparable efficacy rates to the comparator agent.  Just to remind you, the comparator is either high dose amoxicillin or clarithromycin in all of these studies.
		This study, 0140, is an unusual opportunity to gather data on bacteremic patients with pneumococcal pneumonia.  It enrolled over 400 and I think gives us a chance to look at this particularly interesting subpopulation.  
		I've chosen to focus on them for two reasons.  One is that patients with an infiltrate on chest x-ray who grow pneumococcus from their blood represent the gold standard in diagnostic criteria for pneumococcal pneumonia.  Secondly, these are a particularly sick subpopulation of patients with this infection.
		If you look at the first row of this table, you can see that there are 21 patients who were bacteremic with pneumococcal pneumonia in study 0140.  The clinical efficacy rate achieved among those patients treated with moxifloxacin was 70 percent.  For those treated with amoxicillin 100 percent.  These are small numbers.  They are not amenable to a lot of statistical manipulation.  I offer them mostly for your inspection.
		If we look at the second row in this table which is those patients who only had a positive culture from the respiratory tract; that is, not a positive blood culture.  Efficacy rates between the two treatment groups appear to be more similar.
		I would like to point out to those of you who had seen the briefing document that these numbers are slightly different from the table that you have in the briefing package.  The reason for that is back before I put the tables in, I learned of a small number of additional patients who were bacteremic and also for the need to reclassify some of those who had positive respiratory cultures.  
		For those of you who haven't seen the briefing package, I don't think these numbers changed things significantly.  The breakdown between moxifloxacin and amoxicillin for the bacteremic patients is quite similar as is the comparability of those with positive respiratory tract cultures.
		Let me give you a little bit of information on the patients who were bacteremic.  After Dr. Murray asked the question a little earlier this morning, I have tried to separate this out.  Of the 21 patients who had pneumococcus grow from their blood in this study, we had MIC data on 18.  Eight of those patients received moxifloxacin and 10 received amoxicillin.  This is only my recollection and I believe it's correct but I'm not 100 percent sure.  I would ask anyone at Bayer if they can remember those line listings better than I can.
		I think the eight moxifloxacin bacteremic patients all had pneumococcal isolates that were susceptible to penicillin.  The 10 patients who received amoxicillin who were bacteremic had two patients infected with resistant isolates.
		I'll give you a little bit of clinical information on the three patients treated with moxifloxacin who were clinical failures.  These were all men.  Their ages were 55, 75, and 85.  The MICs of their isolates ranged between .016 and .032.  Two of the patients had underlying congestive heart failure.  One of them developed an empyema on day six of therapy.
		Let's stick with study 0140 to start our discussion of efficacy in resistant pneumococcal pneumonia.  There were a very small number of isolates for us to look at in this study.  There were nine total, six in the group treated with moxifloxacin, three in the amoxicillin group. 
		Again, I think we can see there is a divergence in efficacy rates in this small number of patients with the 67 percent cure rate being the key in the moxifloxacin group and 100 percent cure in the three patients who received amoxicillin.
		Of the six penicillin resistant isolates from the moxifloxacin treated patients, five of them had MIC values of 2.0.  One had an MIC of eight.  Of the three penicillin resistant isolates from the patients treated with amoxicillin, two were bacteremic.
		I'll give you a little bit of clinical background on the two moxifloxacin failures.  The first, a 67-year-old woman with a history of chronic bronchitis whose pneumococcal isolate had an MIC of two.  This woman took a full course of therapy but was observed to relapse eight days following completion.  She was considered a cure after treatment with augmentin.
		The second patient was a 38-year-old man, also with a history of chronic bronchitis.  His isolate had an MIC of eight.  He was discontinued from the study after six days for an insufficient therapeutic effect and was switched to treatment with IV cefataxime.	
		This is a limited amount of data but at this point it's not possible to conclude that moxifloxacin is the clinical equivalent of high doses of amoxicillin for the treatment of resistant pneumococcal pneumonia.
		I think the next thing we want to ask ourselves is there a way to learn more about the efficacy of moxifloxacin in this special subpopulation of patients.  We had very small numbers from study 0140.  For those of you who may have been following this issue over the past year, there have been a number of public and private discussions with industry about development of agents for resistant pathogens and the paucity of resistant clinical isolates when people actually go out and try to study them.
		In the course of these discussions, the possibility of pulling organisms has been raised as a means to accrue more patients.  Pulling a cross studies within an indication or pulling across indications.  If it's sound to pull organisms retrospectively, we may obtain a better powered assessment of moxifloxacin efficacy in resistant pneumococcal infection.
		First, I would like to look at what we can learn from the pneumonia studies as a whole.  0140 is our largest source of pneumococcal isolates that are resistant or of intermediate pen. susceptibility.  Another controlled study, D96026, and an uncontrolled study, D96025, also provide a handful of resistant or intermediately susceptible isolates.
		If we sum these up, you can see that a slightly higher efficacy rate is observed for the moxifloxacin treated patients who had frankly resistant isolates.  An efficacy rate that approaches that which was seen for pneumococcal infections over all for this drug is achieved with the patients from whom intermediately susceptible isolates are cultured.
		I've raised the question of pulling data and I would like to take a minute to make explicit some of the questions inherent in this.  Can we go back and retrospectively combine data from a number of studies that were not designed to have their data combined across studies of different design within the same indication.  
		From the previous slide you can see that some of these studies were controlled and some uncontrolled.  Some blinded, some open label.  Different studies had patients evaluated for test of cure at different points in time following completion of therapy.
		Is it reasonable to pull data across indications?  When we looked at this NDA and looked at the different indications included in it, the one other site of infection that we thought may be amenable to this kind of analysis was sinusitis.  The reasons for that are that the sinuses are another point along the respiratory tract and they are normally sterile space that is closed.
		So I'm going to take a minute and talk about the sinusitis indication.  This slide is mostly a discussion of efficacy in sinusitis overall.  I've picked a representative study, 100107, which compared moxifloxacin to cefuroxime in a 10-day regimen.  
		The per protocol and intent to treat analyses both demonstrated equivalence between the two treatment arms by the statistical criteria that were perspectively determined for this study.
		I would like to point out that the medical officer analysis for this study differs slightly from that of the sponsor in that the medical officer determined the test of cure visit that took place a little bit later at 27 to 31 days following completion of therapy.  Again, for those of you who may have seen other numbers on this, this is the medical officer analysis and it's a later follow-up visit.
		How can we use the sinusitis indication to learn something about efficacy of moxifloxacin in pneumococcal infections?  Probably the best study for looking at this is No. D96023 which used the only method that FDA is currently considering appropriate for obtaining sinus specimens for microbiologic efficacy analysis and that is antral tap studies.
		A number of pneumococcal isolates were cultured in D96023 which was an uncontrolled study.  All of the patients in this study were treated with moxifloxacin.  Thirty of them had a susceptible isolate, six a resistant isolate, and nine an isolate of intermediate penicillin susceptibility.
		I think you can see from looking at the cure rates on the bottom row that they were high and consistent between the three groups.  This is providing us a slightly different look at moxifloxacin efficacy in pneumococcal and resistant pneumococcal infections.
		I think we can say that clinical equivalence of moxifloxacin to approve comparators has been demonstrated in all four indications including sinusitis and community acquired pneumonia, data step pneumoniae.  However, the efficacy rate for moxifloxacin was less than that of high dose amoxicillin for the treatment of pneumonia in two subpopulations of interest.  Those are patients who had frankly penicillin resistant strains of pneumococcus and those patients who had pneumococcal bacteremia of any degree of susceptibility or resistance to penicillin.
		As you've heard, preclinical data, PKPD ratios, and efficacy against penicillin intermediate strains of pneumococcus are supportive of this clinical efficacy.  I think the question remains whether or not there are sufficient data to support a claim of efficacy in the treatment of pneumonia and/or sinusitis due to penicillin resistant pneumococcus.  Are there any questions?
		DR. RELLER:  Dr. Murray.
		DR. MURRAY:  Yes, just one.  The severity of pneumonia, do you have a sense of that?  We heard data yesterday about how many of the pneumonias were classified as severe.
		DR. MEYERHOFF:  I cannot give you that kind of breakdown.  All of these patients were amenable to oral therapy.  At the same time we can see that some proportion of them were bacteremic.  I can't give you a sense beyond that.
		DR. RELLER:  Gordon.
		DR. ARCHER:  You didn't mention it but I assume that the isolates that were penicillin resistant were all moxifloxacin susceptible at the same MICs that we heard this morning?  And do you have any of the relapse isolates from those two patients?  Were they more resistant to moxifloxacin?
		DR. MEYERHOFF:  In answer to your first question, I believe yes, that's true.  No, I don't have MIC data on those repeat isolates.
		DR. ARCHER: Does the sponsor have such data?
 		DR. CHURCH:  Dr. Meyerhoff is accurate when she is stating about the MICs to moxifloxacin in those patients.  They were all susceptible.  With regards to MICs done afterwards, I believe there are not and I'll have to look at any of my colleagues.  Barbara Painter?  That's correct.  There are no MICs after the initial ones.
		DR. RELLER:  So the organism was recovered after therapy but no testing was done for the agent to which the patient -- with which the patient failed?
		DR. CHURCH:  Probably because the patients -- are you talking about the initial patients that Dr. Meyerhoff showed that are failures or patients that were cured?
		DR. RELLER:  No, the failures.
		DR. CHURCH:  The failures.  I do not have that information it sounds like.
		DR. MEYERHOFF:  They didn't say they were microbiologic failures.  We're not sure of that actually.
		DR. RELLER:  I understand that.  That's why I'm asking the question.  I mean, actually Dr. Meyerhoff specifically said in her addressing efficacy, her numbers were based on clinical efficacy.  Is that correct?
		DR. MEYERHOFF:  That's correct.
		DR. RELLER:  I mean, we don't know.  If mean, if they were not microbiological failures, then, of course, we wouldn't have any post therapy MICs.
		DR. MEYERHOFF:  There were no cultures in the follow-ups.
		DR. RELLER:  Meaning they were not done in the clinical failures or they were done and no organism was recovered?
		DR. MEYERHOFF:  Not done.
		DR. RELLER:  Thank you.
		DR. MEYERHOFF:  You're welcome.
		DR. RELLER:  Dr. Christie.
		DR. CHRISTIE:  To look at the severity of this in another way because I think it's important.  You did say that 80 percent of the patients were hospitalized in 0140?  I guess I wonder in that population could you break out how many received moxi versus hydomcymox.  Could you break out as well to the resistance in the bacteremic cases.
		DR. MURRAY:  These weren't U.S. based studies thought,  Were they?
		DR. MEYERHOFF:  No, they weren't.  They were done in probably 30 or 40 foreign countries.
		DR. MURRAY:  So hospitalization should not be taken as a sign of severity necessarily?
		DR. MEYERHOFF:  The sponsor is saying that's correct.  I think that's a caveat we have to bear in mind when we look at these patients.  They are sort of mixed.  If you would compare them to an pneumonia patient we would see in this country, they could get oral therapy but 80 percent of them needed to be in the hospital by somebody's judgment.
		DR. RELLER:  Dr. Platt.
		DR. PLATT:  This is a question actually for Dr. Church left over from this morning but I think it fits here better than anywhere else.  Although the common treatment course is 10 days, you showed a serial passage for resistance lasting either six or eight days for what looked like a single strain of staph. aureus and strep. pneumoniae.  Do you have more data that takes a larger number of organisms out well beyond the usual treatment course?
		DR. CHURCH:  No, we do not.
		DR. RELLER:  I'd like to thank Dr. Meyerhoff for bringing us to this point before lunch.  Despite the written agenda, we will -- well, in accord with the written agenda despite the time that we stopped, we will reconvene promptly at 1:00, please.
		(Whereupon, at 12:02 p.m. off the record until 1:01 p.m.)

	A-F-T-E-R-N-O-O-N   S-E-S-S-I-O-N
	1:01 p.m.
		ACTING CHAIRMAN RELLER:  Were ready to begin the afternoon session.  First will be the FDA presentation about safety by Dr. Leonard Sacks.
		Dr. Sacks.
		DR. SACKS:  Good afternoon.  Im Leonard Sacks, Im the Medical Officer at the Division of Special Pathogens, and what Ill be doing over approximately the next 20 minutes is reviewing the FDAs perspective on the safety of moxifloxacin as demonstrated to us in NDA 21085.  
		My safety review will be divided into two broad sections.  Firstly, Ill be covering issues of general safety, and then I will move on specifically to issues of cardiac safety, and in the discussion of cardiac safety I will move across the various topics that have been addressed this morning, the in vitro information that we have, the animal studies, the Phase I and II study data, and finally the big clinical database of Phase III trials.
		In terms of general safety, this is the database that we are looking at.  We are looking at 4,370 patients treated with the recommended 400 milligram oral dose of moxifloxacin.  There were 557 patients treated with 200 milligrams a day, and we are looking at 3,415 patients on comparator agents.
		This slide demonstrates the most common adverse events occurring in at least three percent of patients treated with moxifloxacin or comparator agents. These are drug-related adverse events.  As you can see, the rates here are slightly different from those reported this morning, which referred to all adverse events, and they are pretty comparable between moxifloxacin and comparator.  All events, 32 percent in moxifloxacin treated patients, 30 percent in comparator treated patients, far and away the commonest adverse events reported were nausea and diarrhea, gastrointestinal occurring in respect to the agent, seven percent of the moxifloxacin treated patients, six and five percent of the comparator treated patients.  Headache was found in three percent of both.  Dizziness was slightly more common in the moxifloxacin treated patients, three percent as opposed to two percent.
		What I then did was summarize some of the known quinolone-related toxicities, just to see the effects of moxifloxacin in this regard, and the information here is similar to that that was presented earlier this morning.  Phototoxicity, as far as I could establish, was reported in four patients on the moxifloxacin arm, two of these were actually attributed to the drug, two were not.  Hemolytic uremic syndrome was not described in the database at all.  Tendon rupture was not reported in the database either, although there were two patients with Achilles tendon pain, and there were no cases in the comparator group.
		Looking at the question of hypoglycemia, this was seen in five percent of the moxifloxacin treated patients, four percent of comparator treated patients.
		Looking for the specific effects on the central nervous system, we noted previously that dizziness was slightly more frequent in the moxifloxacin treated patients.  In this example of all adverse events, we see a rate of four percent among moxifloxacin treated patients, two percent among comparator treated patients.  Convulsions were described in two patients on moxifloxacin and two patients on the comparator, no significant difference, and abnormal liver functions as a whole were reported in two percent of both moxifloxacin treated patients and comparator treated patients.
		Given the current concern about quinolone toxicity, hepatotoxicity, Im just going to go into the issue of liver functions in a little bit more detail.  This slide shows the treatment emergent abnormalities in AST, ALT, alkaline phosphatase and total bilirubin.  These abnormalities, I must point out, were categorically defined as either normal or abnormal depending on the cutoffs for each of the studies, and we see that the rates are very similar across the board.  They are seven percent for elevated AST on the moxifloxacin, and eight percent among controls.  ALT was equivalent among the two arms.  Alkaline phosphatase four and three, and bilirubin three percent of the moxifloxacin treated patients were elevated, two percent of the comparator treated patients.
		This was an attempt to climb the NDA iceberg and take a look from the very top at the most toxic possible liver events to try and capture any cases of drug-induced hepatitis.  And, what Ive done here is presented patients who had at least a two-fold increase in AST and ALT and bilirubin related to therapy, and these patients were to have at least one of these parameters significantly abnormal.  Using this analysis, you can see that there were seven patients identified on the database, four in the moxifloxacin treated group, three in the Cephalexin, three on comparator agents as listed there, and Ive listed the individual results pre and post treatment -- yes, pre and post treatment, the results for each of the parameters, and here are the outcomes where they were available.  These were resolved, this was reported as improved.  This patient who developed an on treatment bilirubin of 7.2 was reported to have a bilirubin of 2.2 milligrams per deciliter five days after stopping treatment, and we know that the patient was listed as a clinical cure after 30 days, although the final outcome of the adverse event Im sorry, I dont have the information on.  These are the three comparative patients, just to show comparative levels of treatment emergent abnormalities.
		Lets move on now to examine the deaths in the study.  This presentation, I must mention, is different from that that was shared with us this morning.  These are absolute numbers, these are not normalized for numbers of patients.  This just illustrates the 38 deaths on the patient database according to when they occurred, and these are the deaths that occurred while on treatment, three on moxifloxacin, one on comparator.  Remember again that these are not normalized for the patient denominators.  These are the deaths that occurred over a period of time, and these are deaths which occurred after 30 days following treatment.
		I think one of the purposes of this slide is to illustrate that there are differences in the death rate according to when these are analyzed.  Overall death rates, these were calculated for all patients on the database.  This includes both patients on the 200 milligram and the 400 milligram dose and patients over the entire period of the study.  This incorporates the latter data points, and you can see that these death rates are very similar for moxifloxacin and comparator treated patients, .45 percent and .47 percent, respectively.
		Im now going to change gears and move on to the cardiac safety, just to cover a couple of issues.  Lets move on to the next slide which addresses some of the data that youve already seen on the in vitro models, just to point out that the effect on the delayed inward rectifier current, the Ikr, we see that in one of three experiments on models moxifloxacin was able to block this particular ionic channel in mouse atrial cells at a concentration of 75 micromolar as compared to, that's probably .75 micromolar, as compared with .23 micromolar in sparfloxacin, so its about one third as potent as sparfloxacin.
		For completeness, I believe that the status of the IKs is less well established in terms of its effect on the QT interval, but moxifloxacin did show some blockage if the IKs, and, perhaps, more importantly the action potential duration was prolonged by moxifloxacin as a concentration of 50 micromolar and sparfloxacin at a much lower concentration, three micromolar.
		Lets turn to the animal studies.  This is a busy slide summarizing a number of animal studies.  Most have been performed, as you will see, in beagle dogs, looking at various doses, various infusion rates in combinations with other medications.  The point I want to highlight on this slide is basically the reasons for getting the most striking QT prolongations, and you will note that this is related predominantly to the rate of infusion and, obviously, to the dose of the drug, and here you can see a 69 millisecond prolongation in dogs who were given 30 milligrams per kilogram as a bolus.  Here you can see that high infusion rates produce the same sort of effect, and a 30 milligram per kilogram dose every 15 minutes gave a 64 millisecond prolongation.  Giving Sotalol concurrently does not seem like a good idea.  Theres 113. And, when you give extreme overdoses, such as was demonstrated in this study, you can obviously get very prolonged QT intervals and clinical episodes of ventricular -- the Torsade de Pointes and ventricular extrasystoles.
		Lets move on to the next slide.  We are now turning to a little bit of human data.  This may be slightly different from the slides youve seen earlier presented by the sponsor.  In this case, we are looking at the change in QTc interval related to treatment, and this is a population of patients who were given single doses of oral treatment, anything over and above 200 milligrams, 181 patients in the group. Again, the points here are that we have a regression line there which shows a positive slope, its a shallow slope, but it is, as you see -- its not showing anymore, I apologize -- its significantly different from zero with a p value of .001.  The superimposed mauve lines there indicate the anticipated serum concentrations after a single oral dose of 400 milligrams taken from a subpopulation and analyzed by members of our staff.  The dotted line shows the mean and the standard deviation on either side, so thats where the bulk of these concentrations seem to fit after the first dose of 400 milligrams.
		Lets move on to the next slide.  Just in terms of the Phase I and Phase II clinical participants, these were mean prolongations of the QTc that were found in that population group.  You can see there are 112 patients treated with a recommended 400 milligram oral dose, a mean prolongation of 6.9 milliseconds with quite a wide range. Those treated with intravenous infusions of 400 milligrams at varying periods of time developed more marked QTc prolongations, mean prolongations, 28 subjects, the mean prolongation of 12.1, and a mean prolongation was increased, at least the mean prolongation was detected in patients on placebo, 3.5, which does emphasize that there is some variability in placebo treated patients.
		Lets move on to the next slide.  Im not going to cover this in any detail, I think weve been through the definitions of outliers before.  Just to bear in mind that we were a little bit more lenient on females, because they start off with a longer QT interval to normally.
		Next slide, so in terms of the three categories, normal, borderline and prolonged, what we are looking at in this shift analysis is patients on a 400 milligram oral dose who changed from their baseline status, and of the 107 patients who had a normal baseline QT interval you can see that nine percent of them developed borderline prolongations and 2.8 percent of them developed prolonged QT prolongations, as compared with 2.4 and 2.4 in the comparator.  Note again, small numbers of patients, weve got a total of 41 in that group.  There were no patients of the 12 patients with borderline at baseline who developed marked prolongations, whereas here one of the five patients with borderline developed marked or significant prolongation on treatment.
		Lets move on to the next slide.  This is really just a summary of the Phase I and Phase II clinical data, trying to establish whether there were any events which looked like actual arrhythmias as a result of the drug.  The first one was described as an elderly woman, who was given a single 200 milligram oral dose of moxifloxacin, she developed a subjective complaint of irregular heartbeat 12 hours after the dose, and an ECG which was performed after the event was normal.  And, the relationship with this is remote.  The other patient was a young healthy male.  This male apparently tolerated a 33-minute infusion of 400 milligrams of moxifloxacin.  He remained on the IV and 11 minutes later he developed weakness, he developed nausea and a sinus bradycardia of 35 to 40 per minute.  He fainted and there was an episode of asystole described for several seconds.  Cardiac resuscitation was implemented, he developed a ventricular rhythm, junctional and sinus rhythm with no sequelae.  The events were analyzed by two cardiologists, and they were deemed a vasovagal syncope.
		Lets move on to the next slide.  At this point I think it became -- or, in fact, earlier on in the Phase I and Phase II studies, it was apparent that further investigations should be implemented to look at the broader clinical database in terms of the effects on the QT interval.  The protocols, all ongoing protocols were modified as of May, 97 to incorporate a baseline and a follow-up ECG two to six hours after the dose.  Also, there were exclusions included in this modification, in this addendum.  Patients with baseline prolongations of the ECG were excluded from QT analysis, and also patients on medications known to prolong the QT interval were prohibited, and this included many that we discussed this morning of the antiarrhythmic group primarily, except for terfenadine, so amiodarone, sotalol, disopyramide, quinidine, procainamide and terfenadine were not permitted.
		Lets move on to the next slide.  This is the size of the database.  We are looking at 8,341 patients valid for safety.  This was before the four month safety update, and that will account for some small differences between the companys figures and some of ours.  Two thousand, one hundred and thirteen of the patients had ECGs.  Youll notice that in large number, 1,002 patients, were excluded for technical reasons, and I will go into some of these in a little bit more detail, and we are left with 1,111 patients who had paired valid ECGs of reasonable quality, 559 of these were on 400 milligrams, the recommended dose of moxifloxacin, 37 on the low dose of 200 milligrams, and 515 patients on the comparator.
		So, lets look at some of the reasons for excluding patients, next slide please, and you can see that a lot of these are practical reasons.  In a large percentage of patients, the ECGs were not paired, the relative timing of the ECGs was not known, which was first, which was subsequent. They did not fall into the six-hour time window. The quality was not interpretable, scale may have been missing. There was a restriction on the number of PVCs that allowed interpretation of the QT interval, both in the pre and the post dosing ECG, and atrial fibrillation also made the calculation of the QT interval unreliable.
		Lets move on to the next slide.  This is similar to the slide that I showed you on the mean QTc prolongation of Phase I and II studies.  This is in the general clinical database, and we see that of the patients with valid paired ECGs, patients on the recommended 400 milligram dose, 611 patients in this particular calculation. The mean prolongation here was five milliseconds.  Ive mentioned that the company presented this information based on the four month safety update and they got a figure of six milliseconds.  Here is the 95 percent confidence interval around that mean.  In parentheses Ive just included the uncorrected QT intervals.
		Just to compare this with the 136 patients in the comparator group who were treated with clarithromycin, and you see that the mean prolongation here was two, with a confidence interval of minus 2 to 6, and overall this is all comparators, including the clarithromycin treated patients, there was really no change in the -- no mean change in the QTc interval on treatment.
		Next slide.  This is another attempt to look at outliers, in terms of the bigger clinical population, and what we see here is of the 424 patients who started off with normal QT intervals pre-treatment, there were 15 percent who developed borderline prolongations and 2.4 percent who developed significant prolongations after dosing. Compare this with ten percent and 2.6 percent in the comparator, and a similar sort of effect noticed for borderline.  Those who started off, 100 patients starting off with borderline prolongations, 26 percent developed prolongations, and on a comparator there were 90 patients starting off with borderline prolongations, 21 percent developed prolongations on treatment.
		Lets move on to the next slide.  This is, again, another look at the tip of the iceberg.  This was an attempt to characterize the most severe aberrations of QT abnormalities, and this was just looking at patients who developed a QT interval of greater than 500 milliseconds at any interval during the study.  This could have been pre or post.  And, what you see here is that there were three patients who developed QTc prolongations on moxifloxacin of greater than 500 milliseconds.  There were three patients in the comparator group who started off with 500 milliseconds or greater prolongations, and normalized on comparator treatment, there was one patient on a comparator arm who increased from 494 to over 500.  
		It has been pointed out to me, and, perhaps, the company will address this later on, that one of these patients was shown to have been misread and the speed of the ECG tracing was misinterpreted, but they will have to provide that information.
		So, based on our information, we had three out of 559 patients treated with moxifloxacin who developed treatment emergent QTcs of greater than 500 milliseconds, compared with one out of 515 among the comparator, again, very small numbers to make any statistical inferences.
		Can we move on to the next slide?  This was another attempt to look at predisposing conditions resulting in prolongations of the QTc, and I selected the one which certainly impressed me the most.  This is looking at the effects of hypokalemia, and you can see that this is looking at prolongations, treatment emergent prolongations of the QTc of between 30 to 60 milliseconds and greater than 60.  These intermediate prolongations among patients with normal potassiums before treatment, there were 12 percent of the moxifloxacin treated patients who developed prolongations of intermediate severity.  Once you looked at the populations who were hypokalemic, this figure went up to 18.9 percent.  Notice that in the comparator there was no increase.  When we look at those who developed more extreme prolongations of greater than 60 milliseconds, 1.7 percent of the patients who were normokalemic on moxifloxacin had extreme prolongations before with normal potassiums and when you looked at the population with low potassiums that went up to 8.1 percent, which was statistically significantly different.  Note again that the comparator didnt show the same increase.
		Can we move on to the next slide? This is another attempt to try and look at clinical events which may be telling us that either there were arrhythmias or surrogates for arrhythmia, and across the board you can see that these event rates are very similar between the 3,000 odd patients reported for the 400 milligram moxifloxacin dose and the control dose. 
		I do want to draw your attention to atrial fibrillation which was significantly more common, there were 12 cases in the moxifloxacin treated data group, as compared to two in the control group.
		Okay, I think we can move on to the next slide, so Im going to summarize by saying that we noted that moxifloxacin blocked the Ikr at a concentration approximately three times that of sparfloxacin. It prolonged the action potential duration by about -- at concentrations of 50 micromolar compared to three micromolar for sparfloxacin.  It showed a dose-related prolongation, both in animals and in humans.  The mean prolongation was five milliseconds in this database, it appears to be six when you look at the revised database, on the oral dose, 12 milliseconds on the intravenous.  Outlier analysis showed three or possibly two out of the 559 treated moxifloxacin patients with QTc emergent values of greater than 500, but otherwise the outliers looked pretty similar between the two groups.
		I wanted to draw your attention again to the effects of hypokalemia on moxifloxacin-induced QT changes.
		Now, I think weve revised the order of the program, so I will hold until we have the next presentation, before going on to the questions.
		Okay, so without further ado, let me introduce Allen Brinker, who will present some information on the post-marketing experience with QTc prolongations.
		DR. BRINKER:   Were ready for the first slide. Very good, thanks for the introduction, Leonard.  My name is Allen Brinker, and Im going to be presenting some data to you this afternoon from the post-marketing environment, specifically reporting rates for serious cardiac dysrhythmias among the marketed fluoroquinolones; azythromycin, clarithromycin and cefuroxime.
		My presentation will be divided into the following categories, an introduction to reporting rates, the strength and limitations of spontaneous adverse event reports, the methods that I utilized to calculate these reporting rates, a very important topic that I will come back to again and again is interpretation of these reporting rates, given some comments about the tyranny of small numbers and other such comments about making a lot out of very small numbers, and finally results of discussion.
		Next slide, please.  In general, a crude reporting rate can be calculated as the number of spontaneous domestic reported cases over some estimate of domestic use.  In this case, its domestic prescriptions, and this can be calculated for any specific interval of marketing or year on the market.  Im going to be using a two-year interval this afternoon, because some of these drugs, specifically, sparfloxacin, has only been on the market for two years.
		Next slide, please.  The numerator comes to us from our spontaneous case reports database or AERS database, which include the spontaneous reactions collected by the FDAs -- and I just mentioned the acronym, Adverse Event Reporting System, or AERS.
		Next slide, please.  The denominator is total prescriptions, which comes to us from the IMS HEALTH National Prescription Audit, or NPA.  The NPA is a proprietary product that we use internally within the FDA, and the numbers that Im going to be presenting to you this afternoon are used with permission from IMS HEALTH.
		Next slide, please.  Just a little bit of background on the spontaneous adverse events collection process.  In our country we utilize a passive surveillance system to collect spontaneous reports from clinicians, nurses, pharmacists and individuals.  This is sometimes referred to by the division that collects these reports, the MedWatch Division.  This is a cost-effective process for the evaluation of safety in the post-marketing environment, and it is most applicable for qualitative signal generation.  Currently, we receive approximately 250,000 such adverse case reports per year.
		Next slide, please.  There are some substantial limitations with regard to a spontaneous adverse reporting system, the biggest of which is probably reporting, or as we refer to it, under-reporting, in that we receive next to none or maybe 15 percent of incident cases within the population, and these statistics for how many cases are actually reported to us vary for the specific adverse event.  There are studies that suggest that we receive a higher proportion of such reports for serious adverse events, such as liver failure, and probably practically none for trivial or clinically mild processes.  We know that spontaneous reports are influenced by publicity, and there are more reports early in a market life of a drug, and this has been termed the Weber phenomenon.
		Next slide, please.  As far as case ascertainment used in this analysis, because of the difficulty in collection, in classification and detection of Torsade de Pointes, I utilized the coding term ventricular arrhythmias in cardiac arrest to collect cases for this reporting rate.  I included all  unduplicated domestic cases, and as I said earlier this was calculated, or these calculations were performed after the second market year.
		Next slide, please.  I will be presenting rates to you this afternoon that have been adjusted -- Ill be presenting both, actually, but I will be specifically highlighting those that have been adjusted for secular trend.  Secular trend is based on the observation that the reporting of adverse events has increased since the early 1980s.  Next slide, please.  That phenomenon is highlighted on this particular slide.
		Next slide, please.  Adjustment for secular trend increases the weight of cases that were reported in the past.  Its applicable in a comparison of drugs, drug products first marketed in different years, and I will highlight in this analysis we had drugs spanning ten years, and so it was very important to consider secular trend, and I will be presenting both crude and adjusted rates.
		Next slide, please.  General limitations that I want to touch base with again include that reporting rates do not equal incidence rates.  The relationship between reporting rates and incidence is unknown, and comparisons of reporting rates do not include the unique benefits of each agent.  This is sometimes referred to as a risk benefit ratio or risk benefit analysis.
		Next slide, please.  Further limitations include the biases for comparisons between drug products, given differences in indications and off-label use, the patient population where the drugs are used, the prescriber specialty, and the particular drug sponsor.
		Next slide, please.  I also want to highlight whether or not these data are most applicable for a qualitative or quantitative evaluation, and I will be presenting both.  For the subjective interpretation of the data, one must have a signal threshold, which you might refer to as a rate ratio, and conjecture and literature reports cite a rate ratio, a relative risk of two or three below which epidemiologic or observational data probably cant distinguish noise from association, and that would probably be an underestimate for these data.
		Another way to do that would be objective, and that would be application of 95 percent confidence intervals.  However, because the distribution of these data are uncertain I do this with trepidation.  Fortunately, in my conclusions that I draw from these analyses you come out with the same impression.
		Next slide, please.  Given all that, let's press on with the results.  This table lists domestic case reports in the first two years that were returned under the term ventricular arrhythmias and cardiac arrest and usage data for the first two years of marketing for the agents specified in my introduction. These agents are listed by year of introduction over here.  The prescriptions over here, I want to note, are given to you in terms of thousands, so for the first agent here, norfloxacin, thats 2.7 million prescriptions.  As we go down the list I want to make one important point, and that is that for both cefuroxime and for sparfloxacin they both had only one case, and given the qualitative nature of these data that raises substantially our uncertainty with regard to any point estimate calculated for these particular agents, and thats magnified even further when we consider that sparfloxacin introduced in 1997 only had 49,000 prescriptions in its first two years of use, first two years on the market.  So, in comparison to 3.8 million for cefuroxime, so as you will see, I will come back to sparfloxacin.  The jury is out with regard to this agent.
		Next slide, please.  So, this slide presents the crude and adjusted two year reporting rates for these specific individuals, or these specific agents, and they are ranked on adjusted reporting rate right over here.  The first thing I want to point out is the reporting rates that I have listed here are per 10 million prescriptions.  So, for cefuroxime the first -- that one case represents an adjusted reporting rate of three per 10 million prescriptions, so in absolute magnitude these are very infrequent events, or at least these are reported very infrequently.
		The second thing I want to point out to you from this list is that sparfloxacin comes in with an adjusted reporting rate of 145, which sticks out like a sore thumb in comparison to the others.  I cant -- I dont know what to make of that number, other than its based on so much uncertainty given the limited use and the one case that it really cant be isolated.
		Now then, with regard to interpretation of this data, I said that I will be performing, or I would subject them to both a qualitative and quantitative analysis.  One way to look at these data would be to normalize to the lowest individual here, the one with the lowest rate, cefuroxime, in which case your first agent, cipro, comes in with a rate ratio of nine, and then all the rest of these agents, including really clarithromycin because the difference between nine and 30 is only three-fold, would really follow -- there would be a gap between examination of this agent and the rest of the agents, which arent even necessarily a comparison -- which include a comparison between classes, given that this is cephalosporin and the issue we are talking about today is for a fluoroquinolone.  So, I dont necessarily think that would be the most valid comparison to normalize to cefuroxime.  It is one way to look at the data.  I would probably prefer to normalize to ciprofloxacin and group all of these agents probably in the same  qualitatively as having basically the same reporting rate with a difference of three-fold between them.
		Next slide.  I highlight those points right here.  Qualitative assessment is going to vary with your threshold that you choose.  Its also going to vary with your reference agent, whether or not you choose a drug with similar agents, and choose cefuroxime, or whether you normalize to ciprofloxacin and do it by class.
		Next slide, please.  However, I find no qualitative difference seen in the reporting of this adverse event among these antibiotics with the possible exception of sparfloxacin.
		Next slide, please.  In this interpretation of the data Ive given you 95 percent confidence intervals for the adjusted reporting rates, and I want to point out that the confidence bands overlap basically with the exception of clarithromycin seems to stand out a little bit in comparison to cefuroxime, but given the nature of these data I would not call attention to this difference. I also want to  call attention to sparfloxacin, yet again you really see the effect of one case and a low denominator with a confidence interval of 3.7 to 807, thats so far out there as to make it uninterpretable.
		Next slide, please.  So, these data suggest no or very limited quantitative differences seen in the reporting of this adverse event among these antibiotics.  I note the possible exception of sparfloxacin.
		Next slide, please.  With regard to sparfloxacin, given its limited use in the one case these data cannot be used to isolate it.  It is interesting to note that among these antibiotics it stands out and its the one whose label actually includes the incidence of QT prolongation in comparison to erythromycin and cefaclor in the label.
		Next slide, please.  As far as a supplemental sensitivity analysis, I was unable to differentiate between these agents in this analysis, and so I went back and using the same coding term I performed this exercise in a comparison of cisapride versus omeprazol, and this product was chosen because it actually leads the list of adverse drug reports for QT prolongation and Torsade.
		Next slide, please.  And, this table summarizes those findings.  Okay. There are four cases for omeprazol in the first two years versus 27 for cisapride, gives you an adjusted reporting rate of 13 versus 63, which is almost a five-fold difference, and its interesting to note that the 95 percent confidence intervals are divergent for these two point estimates.
		So, next slide, please, I believe that this actually suggests that we can use these agents to possibly detect a difference with regard to certain agents in a comparison of agents with similar use.
		Next slide, please.  So, I want to finalize with what I believe is the take home message, and that is that I chose to examine a rather general term of cardiac arrhythmias and it doesnt really address the issue of QT prolongation with specific -- specifically for moxifloxacin.
		Leonard, if youll join me now well see if there are any questions.
		ACTING CHAIRMAN RELLER:  Questions for Dr.s Sacks and Brinker.
		Yes, Dr. Ruskin.
		DR. RUSKIN:  I have a question for Dr. Sacks.  You showed a mortality slide that confused me, and Im probably just being dense about this, but I was impressed with the data that Bayer showed, and you described what you said were raw mortality rates, yet at the bottom you showed percentages.  I dont know how you get a percentage without using a denominator, yet you said you hadnt used a denominator.  So, can you unconfuse me?
		DR. SACKS:  Sure, or Ill try.  The graphic just represented the numbers of patients dying, but the calculated value was based on the denominator of all patients in the safety database.
		Now, the fact that you may be confused between the companys data and mine is based on the fact that Ive included six deaths on 200 milligram doses which were not included by the company, and theyve included the denominator for those patients on the 200 milligrams, or at least theyve excluded the denominator for those 200 milligram patients, whereas weve included them.  The other difference between our data analyses was that they excluded the patients who died after 30 days, where you would have seen that there were a couple of disparities in the number of deaths after day 30.  And, in fact, we went through this at some length.  
		There are many different ways in which you can look at that data, in terms of indications, in terms of dosages, in terms of duration of follow up, that give substantially different results.
		DR. RUSKIN:  Is it fair to say then that if you include all patients exposed to moxifloxacin at any dose and compare those with the comparators that there was no difference in mortality?
		MR. SACKS:  Across all time frames, that was our impression, yes.
		DR. RUSKIN:  What about leaving out the late deaths?  If you leave out the greater than --
		MR. SACKS:  Perhaps, we could get back to the slide.  I havent done the calculation specifically for that interval.  Im not sure if anyone in the audience can help me with that.  I think we do have some calculations.  The one with the bar graph, perhaps, it will just give you --
		DR. KWEDER:  Slide eight, John.
		DR. SACKS:  Yes.  I think what you see are the number of deaths after 30 days, there were one, two, three -- there were six in the moxifloxacin treated arm and two in the other. So, I guess the calculation is a little bit complicated to perform, but it may just give you some sort of relative idea.
		DR. RUSKIN:  And, I had one other question that related to exclusion criteria. We heard about the fact that patients exposed to Class 1A and Class 3 anti-arrhythmic drugs were excluded from the protocols, at least part way through, but I wasnt aware earlier that patients with baseline QT prolongations were excluded.  Can you tell us what the cutoff was and when that was implemented?
		DR. SACKS:  That was implemented at the inception of the ECG studies, that was in, I think it was, May, 97 did I say?  Im not sure what the actual baseline was, and we could ask Bayer to supply us with that information.
		DR. HOLLISTER:  Alan Hollister from Bayer.  This exclusion was subjects with known congenital QT prolongation. That was the term that was used for exclusion, not baseline prolongation.
		DR. RUSKIN:  So, was it based on an interval or a clinical diagnosis?
		DR. HOLLISTER:  It was based on a history of known QT prolongation.
		DR. RUSKIN:  Can you tell us how many patients were excluded on that basis?
		DR. HOLLISTER:  Any idea?  No.
		ACTING CHAIRMAN RELLER:  Dr. Parsonnet.
		DR. PARSONNET:  The sponsor showed us a number of different ways of looking at QT prolongation, including greater than 60, a change in greater than 60, and 500, greater than 500 absolute QTc, and I was wondering, you presented -- your data looked quite different because you presented, it looks like, just the greater than 500, whereas, the sponsors data look most pronounced for the greater than 60 change.  And, I was wondering whether you looked at that as well, and why you chose to present us just with the absolute greater than 500.
		This is not in my area, obviously, so Im not really sure what numbers we should be paying most attention to.
		DR. SACKS:  I can answer that in part.  We did look at prolongations.  For practical reasons, I was given the prolongations by the Cardiorenal Division, at levels greater than 80 milliseconds, and we thought that that was, perhaps, not the standard comparison as referred to in the CPMP document.
		But, based on that comparison, we got very similar results to those presented by Bayer.  There were nine patients who developed a greater than 80 millisecond prolongation on moxifloxacin out of about 559, versus one patient on comparator.
		DR. PARSONNET:  I just have maybe a question for the consultants about, are there certain numbers that we should be paying more attention to than others?  What are the significant values for us to really consider?
		DR. MORGANROTH:  Joel Morganroth.  As I said before, I think that the real issue is not that the numbers you are striving for tell you that thats a danger level versus a safe level.  Its really a cut point, an outlier cut point, that suggests that the drug is more likely causing that QTc increase than spontaneous variability.  And, when you look at normal variability data to make that judgment, 60 milliseconds turns out to be very good atr that, 15 percent change from baseline tends to be very good for that.  Obviously, anything higher than that, which is implied by 500 or greater, would, of course, be almost always, but not always, drug effect versus spontaneous variability, and I think thats the purpose.
		The issue as to which amount of QTc is sort of dangerous versus not, as weve heard today, I think is not clear because there is no good relationship thats ever been established between degree of QT prolongation and incidence of Torsade.  As Dr. Ruskin appropriately pointed out, weve seen cases of Torsade with very minimal QTc prolongation, but most clinicians have seen most of the Torsade with 400, 500, 550, 600 milliseconds.
		And, I think as Dr. Temple pointed out, 20 milliseconds or greater as a mean effect would be sort of a number that Id be very nervous about, where anything in this one to ten range, or one to, I guess, less than 20 range, is unknown in terms of where that risk is in terms of quantitative risk compared to the benefit that you have to judge.
		DR. RUSKIN:  I would agree with that, but I would add one point, and that is that, while it is true that its important to distinguish spontaneous variability from drug effect, we have the benefit in many of these studies now of a control population.  So, its important to ask what the drug does in relation to the control agents, and if you see a change in distribution in relation to a control population then you are talking about more than just spontaneous variability, you are talking about a difference between two sets of agents, and there appears to be some difference here.
		What the clinical significance of that is, and how much it actually predicts events, is something that we cant answer, but there does appear to be some difference.
		ACTING CHAIRMAN RELLER:  Dr. Norden.
		DR. NORDEN:  Yes, can I ask Dr. Ruskin a question based on Dr. Sacks presentation?  Do you have any concerns about the difference in the rate of atrial fibrillation in the two populations, which was striking?
		DR. RUSKIN:  I was intrigued by that.  I have no idea what the significance of that is.  I can tell you, and this is getting very hypothetical, that there are some people who believe in the concept of atrial Torsade and that Class 3 agents, typical Ikr blockers, may have effects on atrial muscle that may predispose them to arrhythmias, perhaps, AF.  I am not aware of any clinical data to support that, its purely hypothesis at this point.  But, I was equally intrigued by the observation, I dont know how to explain it.
		DR. RODVOLD:  If I understood all the presentations, most of the data thats on the QT against serum concentrations from Phase I, Phase II, mainly human volunteer type studies, dose ranging studies, was there a population analysis done on PK of serum levels in patients in these studies, and are those serum levels in those patients different than those volunteer data?
		DR. SACKS:  Yes, Im not aware of any such data on the clinical database and the clinical trials.  I dont know if Bayer has any other to offer or not.
		ACTING CHAIRMAN RELLER:  Dr. Platt?
		DR. PLATT:  Both Dr. Morganroth and Dr. Temple have said 20 milliseconds is a number to keep in mind.  And, with that thought I wonder if we could see Dr. Sacks slide No. 12.
		I appreciate that these data come from normal volunteers, but it seems the data are very consistent with the clinical trial data, and what I understood from the briefing papers is that the steady state concentration is about 4,500.  If thats correct, that suggests that even though there isnt much data, Dr. Ruskins comment that most of the data were looking at dont speak about the likely clinical population who would be treated comes to bear because it suggests that at 4,500 the best guess is that the prolongation would be about 20 milliseconds. And, of course, theres only one person who is out at that concentration on this table, but it would also suggest that there might be a substantial fraction who are up above 60 milligrams as prolongation.
		So, is that a -- my question is, is that a correct interpretation of these data, that most of the data dont speak to the clinical use, but that theres a suggestion that 20 milliseconds might be in range?
		DR. RODVOLD:  Can I add to that just one moment before you answer that?  Is that slide correct on the bottom statement, that mean serum concentrations for the 400 milligram is 2,165?  The briefing document from the FDA says its 4,500 for steady state, but even single dose in the sponsors packet says 3.3 or 3.36, and I was wondering how you got 21 up there?
		DR. SACKS:  This was a subpopulation that we analyzed.  This was based on a single oral dose, 400 milligrams, and it was taken at presumed Cmax, which could have been any time from two to six hours afterwards.  I noticed that in the sponsors briefing package the numbers of patients referred to, they were small, but I cant really make a claim for exactly why those differences occurred.
		This is definitely not steady state, I must point that out, this is Cmax.  I dont know if the company has any responses.
		DR. HOLLISTER:  I think theres always concern when we are trying to do regressions, and, in fact, the FDA took us to task for having multiple points down here at a very low level, or zero level, and rightfully so, because if you are trying to do a regression to identify a drug effect, then a zero concentration should not be included in your regression line.
		So, there may be some of that influence here.  These are, as the slide indicates, just single dose, and with multiple dose administrations the concentration is higher.  The dearth of points out here doesnt help us very much in terms of identifying the relationship.  I think the bottom line, though, is that in the several thousand patients who did receive steady state concentrations, who got the EKGs at presumed Cmax, our mean effect was six milliseconds.
		DR. MORGANROTH:  This is Joel Morganroth.
		In reference to Dr. Platts prior question about the 20 milliseconds, those comments, and I assume what Dr. Temple meant, hes here and he could speak for himself, but what I meant was, if you look at large Phase III databases in drugs on clinical development, and if you look at electrocardiograms taken and measured properly, if you see a mean change of 20 milliseconds and you look to see what happened to those drugs that reached that level or greater when used clinically, and you find that a lot of them have a lot of incidence of Torsade.  I showed you a slide earlier with anti-arrhythmic drugs that had 20 to 60 milliseconds in which the prevalence of Torsade was, what, anywhere from one in ten to one in 100, and I think Dr. Temple mentioned a drug that had a 20 millisecond, I dont think it was approved in the United States, Im pretty sure it was not, it was approved in Europe, and it had a lot of Torsade that occurred afterwards in a non-cardiac drug.  And so, thats where the number 20 comes from, if you reach a mean of 20 or greater in a big population, you know, thats a long enough number that  clinical experience suggests that that might be important in terms of actual real Torsade incidence in the treated population.
		And, with moxifloxacin, that database turned out to be six, and Im not sure -- I dont think its fair to take normal volunteers and find that at a certain level that some of them had 20 milliseconds, because remember the normal variability could be much higher than that, and to make any suggestions that, therefore, that would be a more dangerous drug than if you dont see that, you see a flatter dose response curve.
		In my experience, the dose -- or let me put it a different way, the concentration in plasma to the QTc effect relationship looks almost like that slide you saw for every drug that Ive seen.  I mean, theres very poor correlations between plasma concentrations and QTc duration in milliseconds.  With dose and QTc, theres some drugs that have a good relationship, like terfenadine.  You have .128 milliseconds per milligram of dose, and its at linear.  But, most other drugs its too scattered to really make even an oral dose to QTc relationship.
		ACTING CHAIRMAN RELLER:  Dr. Murray.
		DR. MURRAY:  Yes.  I apologize, because this has probably been asked and answered, but the levels that we have heard about, the blood levels, drug concentrations that we have heard about, are all from early phase trials, or are some of these from actual patients, and what are -- particularly, I ask in respect to data we heard yesterday where blood levels in sick patients, or in patients at least, were actually higher than in the Phase I and II studies, or Phase I studies?  So, when we see 3.6 or 4.52 on day ten of multi-dose as a Cmax, what is that -- is that from patients, and, if not, do you have data from patients?
		DR. SACKS:  The results that Ive presented, as far as Im aware, are from Phase I and II studies, they are not from clinical trials.  Thats being concurred with.
		DR. MURRAY:  So, they are not data from lots of real live patients?
		DR. SACKS:  No.
		ACTING CHAIRMAN RELLER:  Dr. Soper.
		DR. SOPER:  Well, I cant say that Im impressed with QTc intervals or whatever they are, which is a questionable hint of a possible significant measurement, but I am impressed about this 33-year old male who, an interesting use of words, tolerated the 400 milligram infusion to arrest 11 minutes later, and this was felt to be a vasovagal reaction.  Does this imply that this isnt related to the drug, and can you expand on this adverse cardiac output?  Its on, I think its your No. 16.
		DR. KUBICE:  Im Dagmar Kubice, Im a Clinical Pharmacologist from Bayer.
		I happened to be on the ward when this happened, actually I was the treating physician, so what I can tell you is that this episode happened right after blood was withdrawn from an IV cannula, and thats something like a drop in heart rate that well see quite often afterwards as a vagal episode.  But, this was very extreme.
		DR. SOPER:  So, this individual has a line in his arm, you are putting a needle into something which doesnt stick his skin and drawing out 10 ccs of blood, and you think that that is a vasovagal reaction in this case?
		DR. KUBICE:  Well, you see that, and I mean if you talk to other Phase I units, I mean, this, thank God its not very often, but it happens, and its when you are manipulating an IV cannula.  Thats a very strong vagal episode.
		DR. DiMARCO:  John DiMarco from Virginia.  Im an electrophysiologist, and Id just like to comment on this, that since we started doing tilt tables in people with neurocardiac or vasovagal syncope, or whatever you want to term it, its really remarkable what you can see.  I think the record at our lab is 57 seconds of asystole in somebody with recurrent syncope.  And, in its in somebody with a normal heart, Im sure Jeremy or Joel have, you know, similar heart harrowing experiences, and yet these people recover.
		The fact that they do get -- because they are in that situation they do get some CPR often, they do come back with an idioventricular rhythm, then a junctional rhythm, and thats just what we call neurocardiac syncope.
		DR. RUSKIN:  I would agree.  I listened to this without the slightest bit of concern.  Its a classic vasovagal reaction, and we see it in the cath lab and electrophysiology lab every day, just manipulating catheters with indwelling lines.  So, I would have no concern about it being a drug-related proarrhythmic effect of any kind.
		ACTING CHAIRMAN RELLER:  Dr. Parsonnet.
		DR. PARSONNET:  I was just curious about whether you had any more information about the dizziness that seemed to be more apparent in the sponsors product than in the comparator, and whether that was vertigo or whether it was lightheadedness.
		DR. SACKS:  I, myself, cant give a whole lot of clarity on that.  It wasnt listed as vertigo, it was listed as dizziness, and I think thats probably the limit of my knowledge of the data.  Perhaps, Bayer may have some additional comments on that.
		DR. HOLLISTER:  Alan Hollister.  You know, one of the protocols that we conducted was the sinusitis, where we were doing antral taps, and I dont know about you, but I faint when somebody sticks a needle through my bone into my nasal sinus, too, and most of the episodes of dizziness were due -- occurred around those times or with blood drawing, but not all.
		ACTING CHAIRMAN RELLER:  Barbara.
		DR. MURRAY:  So, you dont think this is that frequently seen with other fluoroquinolones, CNS sort of symptomatology?  I mean, you think this was episodic due to a particular intervention, the dizziness, or did you think that there was -- not that its a significant drawback, but it certainly, with other fluoroquinolones there is that --
		DR. SACKS:  Correct.  I think the answer in part is the fact that even the sinusitis studies were controlled, so, in fact, my sense is that there was an increased signal and it probably does relate to the drugs.  It did not come across from viewing the data that this was directly an arrhythmic effect, but certainly it did seem to be drug attributed.
		DR. HOLLISTER:  In the all adverse drug reaction group, there were uncontrolled sinusitis studies, that is, ones that the subjects only received the moxifloxacin.  So, we dont have the comparative frequency there.
		But, I agree with you that there are multiple causes of dizziness, and we certainly cannot rule out that this may be a fluoroquinolone effect.
		ACTING CHAIRMAN RELLER:  Dr. Temple.
		DR. TEMPLE:  Just to come back to the QT, I was left slightly confused by one of the discussions.  Dr. Platt, I think, was asking whether the dose had been pushed enough to find out what the QT effect would be at relevant concentrations, because in the data relating QT prolongation to concentration relatively few people were up where you thought they ought to be.
		Did I understand Dr. Morganroth and the company to be saying that their conclusion about what the true QT prolongation effect is comes from patients who were studied, several hundred of them anyway, at whatever their concentration -- at whatever their -- at approximately their Cmax, so whatever that was was what they reach, and that that was the nature of, that was the source of the six millisecond average response?  I mean, is there a contradiction between those two, and is it resolved?
		DR. PLATT:  It sounds like a contradiction to me.  I dont understand how people on therapy can have levels that are substantially lower than the Phase I normal volunteers.
		DR. MORGANROTH:  This is Joel Morganroth.  I think there isnt a controversy.  I think that Bob is right in the sense if you take single doses in healthy volunteers in a Phase I unit, what I dont think Bayer did is they pushed single doses high enough to reach steady state 400 milligram a day plasma concentrations steady state.  Okay, so, well, Ill let them comment on the plasma levels, Ill just address the QT issue.
		What I said before was, if you take whatever the relevant concentration is in patients at 400 milligrams a day in Phase III large clinical trials, in which they didnt measure any concentrations so we dont know what those concentrations are, but at that dose you get a mean of six milliseconds.  And, when you compare big Phase III trials with other drugs that have, lets say, 20 milliseconds in their clinical dose, the 20 milliseconds acts seemingly badly in marketing experience, if you will, where the smaller durations we dont have any data to suggest that they do or dont, frankly.  There doesnt appear to be, from what we heard at the last presentation, that they do.  
		But, Im not addressing plasma concentrations, so the real question, or an additional question, or another question is, how much can you rely on plasma concentrations to reflect QTc changes and what they did with single doses versus multiple doses.  And, did they give enough of a multiple dose accelerated, you know, dosing schedule to see what the QT could do at 3x dose, 5x dose, et cetera, I dont think they have that data.
		But, I cant answer the concentration issues, maybe Dr. Hollister can.
		DR. HOLLISTER:  We were very interested in just this problem, and do you have the slide number, carousel five, slide 61.  In partial answer to your question, I took data from our crossover studies, where patients were treated with a single dose of moxifloxacin anywhere from one week to six weeks apart, in terms of wash out, and measured the change in QT interval that they had with their first exposure and with their second exposure.
		And, this is a plot that we know Dr. Temple likes.  Okay, change in QT after the first and second exposure to moxifloxacin, the first exposure is plotted on the X axis, the second exposure on the Y axis, and although this slide is kind of small and doesnt project very well these are the axes here.
		So, for instance, this person out here, first exposure to moxifloxacin had an increase in the corrected QT interval of 89 milliseconds.  The second time, either one to six weeks later, had a decrease of 11 milliseconds.  So, this, you know, kind of supports the whole concept that there is a great deal of intrinsic variability in the measurement, and what we are doing is, we are seeing a little bit of effect on top of that intrinsic variability.
		If you look at the clustering of the dots, you know, ideally if there were no relationship between the first and the second exposure, in terms of the change in QT, you would have a scattergram that would be essentially a circle, but, in fact, that circle is displaced up this way about six milliseconds, I think.
		DR. PLATT:  That all sounds fine.  It seems to me, though, that the clinical data is giving a prolongation that is exactly what you saw with the single dose of 200 milligrams on Dr. Sacks slide, and so either dose doesnt make -- serum concentration doesnt make a difference, or the mean concentration in your clinical trial group who had paired ECGs was on the order of what your volunteer population achieved with a single dose of 200 milligrams.
		And so, that just sort of takes me back to Dr. Ruskins question, do you have enough data on the clinically relevant concentrations that will be achieved when you leave the clinical trial environment?
		DR. HOLLISTER:  Well, I think the key is, the clinical trials were clinically successful, okay, at whatever concentration we achieved in those clinical trials.  That concentration resulted in a QT change of about six milliseconds.
		DR. PLATT:  Fair enough.  Hard to know where that will go, and if you believe Phase I data, it makes it just hard to understand.
		I guess the other thing to keep in mind is, if theres that upward tilt, and some people achieve those higher concentrations, a very much larger fraction of those people will have more than 60 millisecond prolongations than two and a half percent.  It might be 20 percent or 30 percent who have 60 millisecond prolongations if, in fact, the average is on the order of ten or 20.
		DR. HOLLISTER:  Well, I agree, and I think thats sort of the essence of the issue, is, you know, if someone achieves a very high blood concentration of a drug, and thats why we tried to emphasize that, you know, heres a drug that doesnt have any interactions that result in drug accumulation, heres a drug that doesnt have any elimination issues that result in drug accumulation.  That, I think, is how we factor the pharmacokinetics of this drug into the risk equation.
		DR. RUSKIN:  Just a point of clarification in reference to Dr. Platts comment. I didnt -- if I implied that I didnt think the data from the clinical trials was relevant, I certainly didnt mean to do so.  I think that that is the only relevant data, and its what we have to base our assessment on.
		What I did say was that in the higher risk subsets, which are very hard to study, people with congenital long QT syndrome, people with phenotypically normal EKGs, and genetic abnormalities of K channel metabolism, people on concomitant Class 3 anti-arrhythmic agents, those are the ones that we worry about, and thats the small subset in whom we have no data, and that was really the only point I was trying to make.
		I think the clinical data that you have is very important, and it probably applies to 99 percent of the patients who are going to be treated with the drug.
		DR. SACKS:  I was just asked to project this back-up slide, which shows very small numbers of patients, its the information that we have available, looking at much higher serum concentrations based a small study of intravenous infusions at different infusion rates.  And, perhaps, that will give you some idea of the very small amount of data that we do have to show what happens when you give higher doses to the change in the QTc interval on the Y axis.
		ACTING CHAIRMAN RELLER:  Dr. Temple.
		DR. TEMPLE:  Actually, in a carefully --
very, very carefully controlled environment, you, perhaps, could study the interaction of drugs that prolong the QT interval that are known to in your drug.  You know, people have -- even people who work for the FDA have carried out studies of interfering with terfenadine metabolism and noting what happened, which was impressive.  That might be a piece of information that would be useful.
		To my knowledge, Jeremy, I dont know that there is anything quite like that.  People assume that if you add this drug sotalol it will be a problem, but it may be they are working the same --
		UNIDENTIFIED SPEAKER:  It was in dogs.
		DR. TEMPLE:  Is it?  Well, and maybe thats a clue, but you can form hypotheses in which if youve already blocked the system you dont do much by adding a rather poor blocker to a big blocker.  So, you dont really know until you look, but maybe the dog models have told the answer to that, I dont know.
		DR. RUSKIN:  Unfortunately, your hypothesis has not been borne out by clinical experience, and that is that the effects of most of these agents appear to be additive.
		But, you are right, its something that could be tested on an in-patient basis if someone wanted to do the trial. Theres certainly a lot of people getting sotalol initiated on an in-patient basis.  So, its conceivable that one could do that, but absent those data I think one would have to be very cautious about labeling.
		DR. PLATT:  One last question, Dr. Sacks, how do you interpret the hypokalemia data?
		DR. SACKS:  I think the best I can do is just share it with you.  I think theres definitely a difference in the incidence of significant prolongations in patients who are hypokalemic compared to normokalemic, and its a concern that I raise, a genuine concern that I do raise.
		ACTING CHAIRMAN RELLER:  Dr. Battinelli.
		DR. BATTINELLI:  I just wanted to ask Dr. Ruskin a question, and then maybe make one observation, and that is that the majority of the people that are going to be prescribing this antibiotic do not have Dr. Ruskin and some of the others' background.  And, I dont think Dr. Ruskin is going to be prescribing this a lot in his office, maybe he will based on what he learned here.
		And so, as a clinician who is not going to look at the QTc each time the prescription is going to be written, and whose patients will be some of Dr. Ruskins and some of others on some of these other agents, Im also very concerned at least about how the label is currently being asked to be arranged.
		The other part is that Dr. Ruskin has been referring to the 1A and 3 anti-arrhythmics, but I seem just to infer from his comments about cisapride that theres just as much concern with that drug as with the anti-arrhythmics.
		DR. RUSKIN:  Well, the second question is either than the first, and I would agree that I would have concern about any drug concomitant use of this agent or any other Ikr blocker with any other drug that belongs in QT interval, absent convincing data that it was safe.
		The first question is much harder to ask, and it comes up in reference to anti-arrhythmics and all sorts of other agents that have far more profound effects than this drug, and that is how does one factor in the way in which drugs will ultimately be used by the medical community, and I certainly dont have an answer to that.  I think thats the $64.00 question.
		The data on this drug would appear to be reasonably comforting with regard to the fact that there are no signals, and most importantly that there are no interactions with the cyp 450 system, so that its unlikely that there will be a lot of catastrophes from metabolic interactions with drugs that interfere with the metabolism and excretion of the drug.
		If that were present, I think the concern would be much, much higher, but my major concerns relate to precisely what you described, and that is use with other drugs that prolong the QT, and then that very rare undetected individual, who either has the long QT syndrome at baseline, or what we now know to be a phenotypically normal EKG, but a genetic abnormality of K channels that make them particularly susceptible.  And, that ends up being some sort of a risk benefit assessment, and how you do that is not easy in this situation.  The drug appears to be effective.  I initially thought that it looked pretty good again pen resistant Strep. pneumoniae.  I thought that that would be, perhaps, a major factor in its favor, and I was impressed with the mortality data, although I must admit Im a bit confused about that now that Ive seen Dr. Sacks analysis.
		So, I think its very hard to know exactly how you balance these things, but I can tell you that if we were to eliminate all drugs that affect the QT interval we would have a profound impact on our pharmacologic armamentarium in cardiology, psychiatry, infectious disease and most other areas.  The more we look, the more drugs we find have these effects, and each drug that comes up gets held to a higher and higher standard.  It gets more and more difficult to evaluate and to make these assessments.
		So, the bottom line is, I dont have a simple answer for you, and you cant control practice, you just have to label things as intelligently as possible, and I think do very careful post marking surveillance.  I should add that at least I know Dr. Morganroth, and Im aware of quite a few cases of Torsade with sparfloxacin that have been reported in Europe.  So, I know youve got one case here, but there are a lot more than that that are now reported outside this country, and I think very, very careful post marking surveillance would be critical here.
		ACTING CHAIRMAN RELLER:  Dr. Ruskin, relative to the possible additive component with cisapride, the class 1A3 anti-arrhythmic agents, compared with those added compounds and the rare congenital hereditary aberrations where does hypokalemia figure in, which would be encountered much more commonly than at least some of the others, in terms of --
		DR. RUSKIN:  Well, its probably a very important factor, along with bradycardia.  Certainly, we know that Ikr blockers, for example, Ikr is really most active at slow heart rates, and bradycardia is a very important predisposing factor to Torsade.
		One of the ways of preventing Torsade, even with a very potent Ikr blocker, is just to drive the heart rate up.
		Potassium is in a similar category, and that is significant hypokalemia is a very powerful stimulus to Torsade in the setting of a drug which blocks Ikr.  So, I think it is a major issue. 
		How to quantify it, how to put it into the equation, is something I cant even begin to figure out how to do.  It certainly ought to be in labeling, but how that translates into clinical practice is a very difficult issue.
		ACTING CHAIRMAN RELLER:  To follow up on that, and this would be addressed to you, Dr. Hollister and Dr. Morganroth, any or all, in listening to the discussions I have the impression that its very difficult, it, perhaps, may be easier to delineate whats real, that is related to the drug versus what is risk, but you, I believe, suggested that though the risk may be difficult to quantitate that the comparator gives possibly important information also.
		So, in that light, is there an important difference in the QTc measurements with this agent and one of the commonly used comparators, the six milliseconds and the two milliseconds for clarithromycin, and fuse that question with the experience here on the QTc changes with this agent versus the comparator in the presence of normal kalemia and hypokalemia, given what you said about hypokalemia?
		DR. RUSKIN:  Thats a long question.
		ACTING CHAIRMAN RELLER:  But, you see where Im going, or asking, is there a difference between these agents, and does hypokalemia bring it out, and does it bring it up to where its something thats important?
		DR. RUSKIN:  I think the simplest answer I can give you is that the numbers are too small to answer that question.  I just dont think you know.  I think you know -- all you know is that there is some theoretical risk here that you cant get your arms around.  You know that clearly there under some circumstances in some small subsets of patients, there will be some risk for trouble with this agent.  Nobody can tell you what that incidence will be, except that it will be low.  And, one has to balance what is likely a very low risk against the potential benefits of the agent.
		With regard to comparators, it would appear that this looks better than sparfloxacin and probably not quite as good as most of the comparators, although certainly the differences are rather small, and I think thats about as far as you can take it.  I think that those numbers are interesting, but the numbers are so small that I cant make any useful conclusions from them.
		ACTING CHAIRMAN RELLER:  The reason Im asking these specific questions is, in terms of fairness what constraints, restrictions, warnings, things that are pointed out of having them relative to the possible or probably relative risk, that we dont know what it is.
		DR. RUSKIN:  Well, some of your responses I think, or some of what you do is based on data and some of it is based on what you know about a drug being an Ikr blocker, and you have to do the best with both of those.  And, in this situation, from my perspective, it would involve contraindicating the drug with concomitant agents that prolong the QT interval, contraindicating its use in people with known QT prolongation, and making very clear statements about the additive risks of hypokalemia and bradycardia and other factors which predispose to Torsade in the setting of an Ikr blocker, which this is.  I think thats all you know.
		There is no way to take it a lot further than that, that Im aware of.  And, one could argue that that should be applied to several of the drugs that are already out there.
		ACTING CHAIRMAN RELLER:  Thank you, thats very helpful.
		Dr. Temple.
		DR. TEMPLE:  I thought you were also posing the question of whether its fair to discover something and label a recent drug with harsh labeling restrictions when there are some old drugs around that look like they might be just as much of a problem and they are not labeled yet.  This comes up all the time.  Its a concomitant of learning things, and as a general matter we have taken the position that we need to label the new drug the way it is properly labeled, and well get back to the others and try to change them, too. 
		But, people observe to us that quinidine, a probably more dangerous anti-arrhythmic than many of the newer ones, had relatively light weight labeling compared to some of the newer drugs, and we eventually went back and heavied it up.  But, that comes up all the time, you sort of have to do what you have to do, and then go back and get them, perhaps, with a greater urgency than weve always done it.
		ACTING CHAIRMAN RELLER:  Its the intention of question four, I believe, to make sure that we get a sense from the voting members of the committee to be transmitted for your final consideration.
		At this point, I would like to turn to Dr. Mark Goldberger, to focus things for us so that we can address expeditiously the questions, while we have a full quorum.
		DR. GOLDBERGER:  Thank you, and we have posed four questions for the panel.
		The first, has moxifloxacin been shown to be safe and effective for the treatment of uncomplicated skin and skin structure infections, community acquired pneumonia, acute exacerbation of chronic bronchitis, and acute maxillary cellulitis.  Weve listed the indications separately, first of all, because one needs to obviously look at the efficacy for each indication separately, and also because it is reasonable at times to consider looking at safety in the light of the amount of efficacy achieved and the indication in question.
		If the answer is no for one or more indications, what additional information would be required?  If the answer is yes for any or all of the indications, are there any caveats regarding its use that you would recommend be included in the product labeling?
		As part of your discussion of the community acquired pneumonia indication, and I would also add to this the sinusitis indication, please address the applicants request that the indications and usage include PRSP.  Should you recommend inclusion of PRSP, should any mention also be made of PISP in this section?  Obviously, this is an issue that was addressed in part yesterday with a different product as well.
		If the answer to question one is yes for one or more indications, do you believe that the labeling proposed by the firm regarding the prolongation of the QT interval produced by moxifloxacin is adequate?   If not, what modifications would you suggest?  And, again, weve heard a lot of comments about this already, a variety of concerns.  Its important to do the best you can to be as specific as you can with this regard for our further discussions with the company.  Obviously, this is the type of information that could ultimately affect other products as well, but as Dr. Temple said a moment ago, a journey of a 1,000 miles basically begins with the first step, and this is, you know, probably the first place where we have sufficient data and the opportunity to get expert opinion about this issue.
		If moxifloxacin is approved, do you have any recommendations regarding Phase IV studies or data collection that the applicant should be requested to perform?  And, this can include any variety of issues, including looking at alternative doses in some of the indications if you believe that might be reasonable, additional types of surveillance data in terms of resistance, other issues in terms of looking at the QT prolongation, or other, for instance, safety issues.
		And finally, the last question, and I guess we are focusing more on this last question for Dr. Ruskin and Dr. Morganroth, although obviously anyone who likes can participate, do you have any recommendations regarding the parameters, both qualitative and quantitative, that may be most useful in assessing the significance of QT prolongation caused by anti-infective products?
		Now, what particularly obviously is a starting point, trying to distinguish basically cardiac and non-cardiac, and, obviously, anti-infective or non-cardiac drugs.  This could obviously have just been listed that way, but we dont feel its appropriate to step over into other peoples territory, we have enough problems with the anti-infective products. But, we would appreciate, we have gotten some advice, we would appreciate, for instance, whether there are certain screening tests early in development that might be very helpful in determining how much other data ought to be collected during the Phase III studies, or whether, regardless of early screening tests, a certain amount of EKG data should be collected on all drugs, on certain classes, et cetera.  Whatever advice, and, again, you know, as specific as you are able to make it, would be very helpful.  This would obviously apply both to new products and potentially to getting additional information on products that are already in the marketplace.
		Thank you.
		ACTING CHAIRMAN RELLER:  In considering these questions, since the safety presentations and the discussion across all indications, I think it may be most efficient to address the efficacy components by indication and then to address the safety issues, because they are concentrated on questions two, three and four.
		We are going to vote.  We can discuss, if necessary, the members should not feel compelled to comment when something has already been stated, so what I would like to ask in sequence for the four requested indications, and we recognize that this is a perspective of the advisory committee presented to FDA for consideration.  
		The first question is, has moxifloxacin been shown to be effective for the treatment of uncomplicated skin and skin structure infections?
		Dr. OFallon.
		DR. OFALLON:  Yes, I thought, for all four.
		ACTING CHAIRMAN RELLER:  And, actually, youve made a further refinement.  Lets have you vote on all the components all at one time, not as a package, but individually, and if there be -- Keith?
		DR. RODVOLD:  If I understand you, Im voting on all four, but one by one?
		ACTING CHAIRMAN RELLER:  If you think that its been shown to be effective for all four, say so. If theres something for which you think it has not been sufficiently -- there are sufficient data, point that out, so that Rhonda Stover, our Executive Secretary, can take a composite vote and break it down into the individual indications.
		DR. RODVOLD:  For all four indications, I think the data proves that its safe and effective.
		ACTING CHAIRMAN RELLER:  Efficacy.
		Yes, Dr. Christie, your vote on efficacy for these four indications.
		DR. CHRISTIE-SAMUELS:  For efficacy, for uncomplicated skin and skin structure infections, the answer is yes.  For community acquired pneumonia the answer is yes.  However, I am not convinced that the data shows that there is efficacy for bacteremic pneumonia, nor am I convinced that the data is efficacious for patients who have drug resistant Strep. pneumo.  I think the numbers were very small, and I think six to seven percent is probably not convincing for me.
		For acute exacerbation of chronic bronchitis, the answer is yes for efficacy.  For acute maxillary sinusitis the answer is yes for efficacy. However, again, back to drug resistant strains, the data presented by the drug manufacturers, I think that might not be very convincing also for drug resistant Strep. pneumo.
		Thank you.
		ACTING CHAIRMAN RELLER:  Help refine, we will come back to Dr. Christie, because we are going to address this in 1B, the issue of resistant and intermediate strains, in terms of susceptibility to penicillin, so that we will take your comments, keep them separate and go on for the general indication without regard to the subcomponents.
		DR. CHRISTIE-SAMUELS:  In general, the answer would be yes for all four.
		ACTING CHAIRMAN RELLER:  The specific indications, but without regard to the subcomponents of a particular organism.
		DR. CHRISTIE-SAMUELS:  Without regard to bacteremic pneumonia or drug resistant isolates.
		ACTING CHAIRMAN RELLER:  Dr. Soper.
		DR. SOPER:  Yes, for all four.
		ACTING CHAIRMAN RELLER:  Bob?
		DR. DANNER:  Yes, for all four.
		ACTING CHAIRMAN RELLER:  Yes, all four.
		DR. PARSONNET:  Yes, for all four.
		DR. ARCHER:  Yes, for all four.
		DR. MORGANROTH:  Yes, for all four.
		DR. NORDEN:  Yes, for all four.
		ACTING CHAIRMAN RELLER:  Thank you.
		Now, we will tackle head on, and also in relation to the extensive discussions undertaken yesterday of what our recommendations are to the agency regarding penicillin-resistant Streptococcus pneumoniae and penicillin intermediate Streptococcus pneumoniae.
		Dr. Goldberger, would you like for us to handle those individually or together?
		DR. GOLDBERGER:  The penicillin resistant Strep. Pneumoniae?
		ACTING CHAIRMAN RELLER:  Those strains that have MICs above -- .125 or above to penicillin.
		DR. GOLDBERGER:  I suppose depending on what the committee thinks, you may want to just include them all together.  I will leave that to your discretion, and to what the comments sound like.
		ACTING CHAIRMAN RELLER:  All right, we understand.
		Dr. OFallon.  Do you want me to start on the left side this time?  Thats all right, thats what well do.
		Dr. Norden, did you vote on the last one?
		DR. NORDEN:  Oh, yeah.
		ACTING CHAIRMAN RELLER:  I thought so.  Okay.
		DR. NORDEN:  I always vote.
		I guess Im with Dr. Christie on this, but it bothers me because I think Im not sure were being consistent from yesterday.    If you total it up there, the sinusitis and pneumonia cases based on Dr. Meyerhoffs review, there are 14 isolates, as I see it, which are resistant.  I mean, my answer is very simple about intermediate, it shouldnt be included in any label, just as we did yesterday, but for the resistant there are 14 in the sinusitis and pneumonia, and there were 12 successes.  And, my recollection is that yesterday we didnt have that many more resistant isolates either, although they were all in pneumonia.  I am not convinced by this, and Im going to vote no, but I do think Im not sure Im being very consistent.
		DR. GOLDBERGER:  There was a question we actually asked yesterday that no one commented on, probably because it was by that point 5:30, and that was about in future studies whether organisms from different body sites could be combined for information.  No one touched upon that.  One of the differences between yesterday and today, as you pointed out, all the isolates were from community acquired pneumonia.  Here they are from community acquired pneumonia and sinusitis, leaving aside the one from bronchitis.  The question is, is can they be reasonably combined?
		There may also be differences in the total body of pneumococcal experience with the product, which we havent spent a huge amount of time talking about, which I think are probably different.
		ACTING CHAIRMAN RELLER:  Carl, just to recap the numbers, for those community acquired pneumococcal pneumonias, for which we are absolutely  certain of the etiology, in the database that we are talking about today there are eight such patients in the highly resistant, 17 in the moderately resistant, versus the comparative numbers for yesterdays discussion of 14 and 44, so, roughly, the database is about a third as big for bacteremic pneumococcal pneumonia.
		DR. NORDEN:  Not bacteremic, just pneumococcal pneumonia.
		ACTING CHAIRMAN RELLER:  Im talking about bacteremic.
		DR. MURRAY:  But, the bacteremias, none of them were penicillin resistant.  There were about ten bacteremias, from what -- ten or 11, but she presented data on the seven, on the efficacy in bacteremia from seven of ten.  But, if you are penicillin resistant, none of those were thought to be bacteremic.
		So, I agree, we didnt have the body of pneumococcal experience, in my opinion, we didnt have the 218 cases, we didnt have the number of penicillin resistant or intermediate, we didnt have the number of bacteremias within the penicillin resistant intermediate, and we didnt have data on the severity.  We were told of 14 severe in the intermediate, four severe in the penicillin resistant group yesterday.  We didnt see an animal model looking, although I assume it would be the same, of penicillin resistant versus penicillin susceptible pneumococcus showing equal efficacy with moxifloxacin.
		So, whereas, based on pharmacodynamics I would think it should work, I didnt think we had the same body of literature, which is just what you said.
		DR. NORDEN:  Im very comfortable with that, and Barbara has helped me, but I think that if we are not going to combine the studies, we are only going to talk about pneumonia, I think then my vote is much easier.  I think eight isolates is not a lot, and we dont have the other information that we did have yesterday in terms of severity of bacteremia and so on, so Im comfortable voting no.
		I think that Dr. Goldbergers question is a legitimate one, though, about pooling for future and for, you know, other products or this product.
		ACTING CHAIRMAN RELLER:  The question we are addressing now is the database for strains that are less than fully susceptible to penicillin for community acquired pneumonia.
		DR. NORDEN:  Ill stay with the no vote.
		ACTING CHAIRMAN RELLER:  And, this is for intermediate and fully resistant strains.
		DR. MURRAY:  Right, and I would agree with that also, and as far as pooling, I certainly would never pool efficacy from acute exacerbation of  chronic bronchitis, and I would be somewhat reluctant to pool sinusitis efficacy with community acquired pneumococcal also.
		DR. GOLDBERGER:  Yes, we werent really thinking in terms, frankly, of acute exacerbation of chronic bronchitis.
		ACTING CHAIRMAN RELLER:  Dr. Archer, we are combining --
		DR. ARCHER:  Let me just say, since I was recused from yesterday afternoons discussion, I abstain on this vote.
		ACTING CHAIRMAN RELLER:  Okay.
		Dr. Parsonnet.
		DR. PARSONNET:  I agree with everything Dr. Murray has said.  I dont think that there is evidence, enough evidence, but I think from a physiologic perspective its likely that it will work, so I would encourage the sponsor to collect more information.
		I also think we cant really add the sinusitis in, since most sinusitis would clear up whatever you gave them.  So, I think we really have to go with the pneumonia and have enough isolates of that particular category.
		ACTING CHAIRMAN RELLER:  I think the numbers are far too small to be comfortable with these strains, particularly, relative to the numbers shown yesterday, and even then I did not -- I favored having the data presented for what they were, and not a specific labeling after Streptococcus pneumoniae regarding the susceptibility or lack thereof to another agent, which, in fact, in what was presented, and especially in the very small numbers of bacteremic patients at least is efficacious, so that we dont have a label that says, you know, amoxicillin, including penicillin intermediate and penicillin resistant strains, for which there is certainly just as much data.  And, consequently, I do not think this should be included.
		DR. DANNER:  I agree, I also vote no on this issue.  We are going to cover the issue of cases of bacteremia and severity as a separate issue?
		ACTING CHAIRMAN RELLER:  We can address that, but if we say there isnt sufficient information then, I mean, it may be -- you know, may come up again later.
		But, I mean, we can, if you want to comment on that, please do so -- I mean, its appropriate to do so now.
		DR. DANNER:  In addition to thinking theres not enough information on penicillin resistant isolates, I also think theres not enough information on patients with bacteremia, or looking at data showing us that in a category of severe pneumonia that the drug is effective.
		ACTING CHAIRMAN RELLER:  Dr. Soper.
		DR. SOPER:  No for the penicillin resistant issue.
		ACTING CHAIRMAN RELLER:  Dr. Christie.
		DR. CHRISTIE-SAMUELS:  No.  I cannot recommend including PRSP, nor should we mention PISP.  I think the numbers are too small for that.
		In addition, I go back, and I still say that seven out of ten patients who got better with 70 percent, it was bacteremic Strep. pneumo., although that was sensitive, but I still think we need much more information than that, because here you are dealing with a patient who is likely to be hospitalized and a patient thats likely to be more sick.
		The other caveat would be, again, I think this drug, when its approved, will be utilized in children, and I think we really need to collect a lot more data, and I outlined yesterday my concerns with Strep. pneumo., necrotizing pneumonias, and pleural empyemas among abscesses in children, I really think we need to study that more.  We need to be very cautious if we utilize this drug in the pediatric population for pneumonias.
		ACTING CHAIRMAN RELLER:  Thank you.
		Dr. Rodvold.
		MR. RODVOLD:  I agree with Dr. Murray and vote no on both indications.  I think that some supporting information on the pharmacokinetics, both in models, it would have been helpful to add a little bit here to kind of reassure people.  And, I think also that theres no concentrations, from what I understand, in patients.
		And, yesterday Ortho McNeils presentation had pharmacokinetic data in patients to kind of reassure you, and you kind of wonder with this bacteremia number being different here, so I think in post marketing they may need to do a population analysis and get some numbers to see if the PK is the same, and that may be helpful also in the safety issues, and see what the concentrations in those patients are.  
		So, no, on the penicillin.
		ACTING CHAIRMAN RELLER:  Thanks.
		Dr. OFallon.
		DR. OFALLON:  No, on the penicillin, and bacteremia, no.
		Can I say, Id like to make one more, Id like to match the screw up a little.  One of the things that bothered me yesterday about the discussion was the fact that there were so few patients, and thats bad from a statisticians point of view, but the representativeness of those patients bothered me a lot.
		I kept listening to the pediatricians, and I happened to be sitting between two of them, they were very concerned about the fact that these things are applying to children, without very much information at all, because there are -- the studies arent being done in the kids.  And so, when you have them -- they also said that a very large percentage of the people that would be resistant, penicillin resistant, would be kids.  
		And, it just bothers me, I think that weve got to worry, not only about the total numbers of cases in considering the indication for penicillin resistance, but also the issue of who -- are those cases representative in any way, shape or form of the population that will actually be treated with it once the approval is given?
		ACTING CHAIRMAN RELLER:  Thank you for your comments.
		What has come across very clearly is, and its interesting because clearly there have been many discussions at these advisory committee meetings having to do with the questions about safety in children, but yet, the dilemma faced, you know, if someone has concerns about safety because of one issue then there arent going to be the studies, but, yet, we hear over and over again that these compounds are used off label.  And, thats something that, you know, will have to be somehow dealt with, because there are no indications for using these drugs for some of the very things that we keep hearing they are being used for, and thats why we need data, but they arent approved for using, and, therefore, I mean, its a dilemma.
		I dont want to get bogged down in this, but, Mark, whatever you want to say.
		DR. GOLDBERGER:  No, Ill just make a quick comment, as many of you know, Congress passed, not that long ago, a provision adding six months of exclusivity to either patent, orphan exclusivity or other types of exclusivity for companies in return, for instance, for performing pediatric studies.
		You are all aware of the concerns that have existed in using the fluoroquinolones in children.  Nonetheless, as more information has become available, we have been working with a number of the manufacturers about getting studies designed that would, (a) provide the kind of information everyone would like about both efficacy, short and longer term safety in children, and would hopefully help some of these manufacturers gain such exclusivity.
		So, over the next months to a year or so, you will be seeing more information about a variety of studies that will become available with some of the fluoroquinolones to assess different diseases in the pediatric population.
		ACTING CHAIRMAN RELLER:  I think were now ready to move to question two.
		We do have yes for all of the above indications, excluding the penicillin intermediate and resistant strains of Streptococcus pneumoniae in community acquired pneumonia.  What labeling regarding QT interval produced by moxifloxacin is adequate?  Is what has been suggested acceptable, or been proposed, and, if not, how would you change it?
		Dr. Norden.
		DR. NORDEN:  Its not adequate, and I would suggest as a very simple and practical way of doing this, that we ask Dr. Ruskin, who stated, I thought, very nicely several points that should be included in the label, and I think this is really something where an experienced cardiologist could do far better than a committee of ID docs.
		ACTING CHAIRMAN RELLER:  Could we possibly get the gist of it, realizing that this will be word smithed and refined by the agency as an alternative -- potential alternative labeling, that then we could make it more efficient to go around and see whether we like one or the other?
		DR. GOLDBERGER:  One just -- perhaps, as part of this, you had, you know, separated out the efficacy and safety vote, and the question came up as to how you wanted to handle the issue of safety in terms of any voting, and I dont know whether you want to roll that over into discussion with question two as well.  You know, we obviously defer to your discretion as to how to do that.
		ACTING CHAIRMAN RELLER:  I, perhaps, wasnt clear enough.  I thought I already rolled it over into number two.
		DR. CHRISTIE-SAMUELS:  Excuse me, are we going to vote on safety or are we going to discuss it?  Im not clear.
		ACTING CHAIRMAN RELLER:  Okay.  I think the most efficient way to do this is, are the data sufficient to have an unfettered, unadorned endorsement of safety for all of the above indications with this compound, yes or no?  And, basically, what that implies to me is that, you know, theres no specific addressing of any changes or warnings with regard to QTc or any other specific safety issue.
		Or, put another way - well, is this drug safe for all those indications or not?
		Carl.
		DR. NORDEN:  No, I think its safe, but I think it needs a warning label, and I think -- I mean, I would vote for its approval, if I were voting on that specifically, but I would still like the label to be rewritten and I reiterate my original suggestion.
		ACTING CHAIRMAN RELLER:  Dr. Murray.
		DR. MURRAY:  I agree with what Carl said.
		DR. ARCHER:  Me, too.
		DR. PARSONNET:  Yeah, I agree with that as well.
		ACTING CHAIRMAN RELLER:  Aye.
		DR. DANNER:  Im going to say no, and Im going to say no because of the following reasons.  I think when the drug is marketed, no matter what kind of warning you put in it, its going to be used in substantially different ways than its been used in the trials.  And, I think that this is exactly the kind of place that you get into trouble with, when a drug is approved, its carefully studied in a trial, people are carefully excluded who have prolonged QT intervals, are carefully excluded who are on drugs that can be additive with it in terms of the effect, and its used for a very short interval of time, and so its not clear -- I am absolutely convinced that the drug will be used differently once its marketed frequently.
		And, I think there are enough things that really havent been answered.  I dont know if the drug effects potassium and magnesium excretion, and whether it somehow is additive with other drugs that produces increased loss of electrolytes through the kidneys, because that has not been looked at.  It seems to possibly cause or increase the incidence of atrial fibrillation, and we dont have real drug levels from real patients correlated with QT times.
		So, I dont know, Im just somewhat concerned.
		The other issue with safety, obviously, is the risk benefit ratio, and Im not sure I see what this drug adds to drugs that we already have thats so unique that we need this drug, that we absolutely need it, and we need it now for some indication. There are other drugs that you can use.  They may have the same problem, but given that they havent been studied in this way, I dont know thats the case.
		ACTING CHAIRMAN RELLER:  Thank you, Dr. Danner.
		Dr. Soper.
		DR. SOPER:  I believe the drug is safe, and with the following comments.  And, that is, Ive had the benefit of a crash course in QT intervals, and my take home on this subject is that theres normal variability throughout the population, that this delta of greater than 20 does not really reliably predict any adverse cardiac events, and that its not quantifiable, so that the real risk with any of this data, literally, is unknown, that there are other drugs that have a similar, if not a more profound effect, that have already been approved and are in widespread use in this country, and that given the lack of information that we have, and the state of the art, where we are today, I think I would recommend we approve the drug as safe and effective, and then, as has already been alluded to, use Dr. Ruskins recommendations with respect to safety issues until we get better data.
		Thank you.
		ACTING CHAIRMAN RELLER:  Thanks.
		Dr. Christie.
		DR. CHRISTIE-SAMUELS:  Well, I guess Id have to say no, the data on safety are not convincing.  It seems to me, based on the discussion, that the QT  facts are clinically relevant, steady state concentrations needs to be studied further.  In addition, the concern about people using the drug for longer than 12 days, I dont think we have enough information on that, and I believe that that may occur, even though that probably would not necessarily be what we would recommend.
		The other concerns about other drugs that might prolong the QT interval, the problems with hypokalemia, the problems with death after the drug was discontinued, and, again, the age-old problem, the use of this drug in children, I think we need to study the drug and the pharmacokinetics, and we also need to study the safety in the pediatric population.  We need data on that, because although it was not studied, and although it wont be approved for children, Im afraid it will be used in this population and Im concerned about that.
		ACTING CHAIRMAN RELLER:  Keith.
		DR. RODVOLD:  Id approve it for safety with the word smithing that its going to be needed for the QT.  The other thing, although we also need to be considering the label on that, prescribers realize that they probably shouldnt exceed this dose currently, because we just dont know what it is, and theyve got to stay in the box of the dosing that they are recommending, and we may need to remind them that they can do whatever they want post marketing, but I think its important to emphasize that to them as well.
		ACTING CHAIRMAN RELLER:  Dr. OFallon.
		DR. OFALLON:  I was prepared to vote for safety with an appropriate change in the label, but the two that have talked about all the things that we dont know about, you know, the behavior of this drug have swayed me.  I think I shall have to vote against, I dont believe we know enough yet about the safety because of the cardiac problems.
		ACTING CHAIRMAN RELLER:  Thank you.
		Now, a greater exposition of question two, I think, Dr. Ruskin, that many of the members are looking to you for guidance for an alternative warning label to be considered contrasted to what has been proposed by the sponsor.
		Yes.
		DR. KWEDER:  Dr. Reller, while it certainly isnt a part of an official vote, could we hear on the safety issue from the three consultants as well?
		ACTING CHAIRMAN RELLER:  Oh, please, sure, with your request, yes.
		Dr. Bartinelli.
		DR. BATTINELLI:  Yes, I would say that the information provided, the drug is safe, and certainly as safe as a number of other drugs approved, with the exception that it needs a more careful labeling with respect to the QTc.
		And, I agree with some comments that this drug, as well as all drugs that are on the market, will be used differently than they are actually labeled for.  However, I believe that the only piece of information that the average clinician has to go on is, in fact, the warning label, which is very important and I think does bear more weight than some have given credit for.
		ACTING CHAIRMAN RELLER:  Dr. Ruskin.
		DR. RUSKIN:  I would vote yes on safety, with the caveat that labeling be very cautious, and that the sponsor buy in to participating in very careful post-marketing surveillance.
		ACTING CHAIRMAN RELLER:  Dr. Platt.
		DR. PLATT:  I was -- I thought Dr. Danners summary captured a lot of my concerns, and I think that on balance we dont know enough now to conclude that its safe.
		I think the other thing that gives me pause is the fact that this is a drug that may be very widely used, so even if the estimates of one to two percent, which I think are very conservative, of meaningful QT prolongations are correct, that might be tens or hundreds of thousands of people who would experience those.  So, it seems to me that knowing more would be necessary for me to say yes, so I think if I had a vote I would probably say no for now.
		ACTING CHAIRMAN RELLER:  And finally, Id like to make sure that there are no other comments that the voting members of the committee would like to make.
		Dr. Parsonnet.
		DR. PARSONNET:  I just have one comment, which also echoes a little bit what Dr. Danner said, which is that although I think this drug is safe, I think we also have to consider the other drugs, other antibiotics that are out there, and whether the risk benefit ratio is as good as other comparators or similar drugs that are there.  And, I think in balance this probably doesnt add a terrible -- it doesnt add very much to the antibiotic armamentarium that we currently have.
		ACTING CHAIRMAN RELLER:  A part of -- if necessary, we could vote on the proposed QT labeling, but its my sense, from hearing all the discussion, and I certainly would agree with it, that Im not keen at all about the proposed QT labeling as proposed by the sponsor, partly because there is wording about patients that we have little or no information whatsoever, and other comments that have come out.  And, consequently, for expediency I would like to hear the kinds of language that would go into, and if it would be in the form at your recommendation, and then we will have the voting members consider it.
		Dr. Ruskin, would you put this in a warning label, and, if so, I mean of that degree of emphasis, and what would be the things that you would think important to include if you thought or if you would recommend a warning label?
		DR. RUSKIN:  Well, I was hoping not to get put in that position, but since youve asked the question directly Ill answer.  I would include a warning label, and in saying that I guess I would also probably be inclined to urge that that be considered for other agents with similar effects, as we live through with the anti-arrhythmics, and that obviously the FDA will do a better job than I can with this, but to take a first pass at it, I guess it would say something to the effect that this drug is an Ikr blocker, or a weak Ikr blocker with a mild to moderate effect on the QT interval, that in the patient populations studied in the clinical trials no adverse effect on cardiovascular morbidity or total mortality was observed.
		However, there are no data on safety in patients with preexisting QT prolongation or those currently taking other agents which prolong the QT interval and, therefore, the drug should be avoided in those subsets.
		Furthermore, factors such as bradycardia or hypokalemia, which are known to exacerbate the QT prolonging effects of Ikr blockers, should be considered or approached with caution when using this drug in patients susceptible to those conditions.
		Something along those lines.
		ACTING CHAIRMAN RELLER:  Well go from my left around.  
		Dr. Kweder.
		DR. KWEDER:  As a follow on to that and, perhaps, something else the committee could consider in thinking about language, one of the tools that we have employed with increasing frequency is the requirement for a patient package insert with a drug, particularly, for those that are going to be administered in an out-patient setting.  I wonder how Dr. Ruskin would comment on the appropriateness of that in the case of this drug.
		DR. RUSKIN:  I think its a great idea.
		ACTING CHAIRMAN RELLER:  So that we have something to work with and people can disagree and we can come back and make substantive revisions, do you want to include that as part of the warning package?
		DR. RUSKIN:  Yes.
		ACTING CHAIRMAN RELLER:  Now, well come to the committee members, and is what is described, both the general wording, as well as the patient information component, does that satisfy your concerns about safety of this drug for the moment?
		DR. NORDEN:  Yes.
		ACTING CHAIRMAN RELLER:  Dr. Murray.
		DR. MURRAY:  Yes.
		DR. ARCHER:  Yes.
		DR. PARSONNET:  Yes.  I have, actually, an FDA question, which is, when we put this warning label on this particular drug, what happens to the drugs that it interacts with?  Do you then add it to the list of drugs on those warning labels, so that when somebody is on this medication and three days later their doctor says, well, you now have atrial fibrillation, we are going to put you on an anti-arrhythmic, is it going to be in that anti-arrhythmics description label that says being on -- previously being placed on this antibiotic is a contraindication?
		DR. KWEDER:  Thats a challenge, and we try to deal with that as best we can.  I mean, it gets to the point where some of these drugs have exhaustive lists of potential drug interactions, and as we go along we do try to update them as best we can.
		It certainly does offer a particular challenge when you are dealing with drugs that are for totally different indications, like an anti-arrhythmic and an antibiotic, but we will attempt to do that.
		DR. PARSONNET:  Because it is quite conceivable that somebody will be on this drug first and have something else added on.
		DR. KWEDER:  Absolutely.
		DR. PARSONNET:  And then, if its not in the label for that particular medication it may be missed.
		DR. KWEDER:  Right.
		ACTING CHAIRMAN RELLER:  Thank you both.
		Bob.
		DR. DANNER:  Im a little confused by what we are voting on. I mean, my answer is still no from before.  I agree that if the drug is approved that it has to have a warning label similar to whats been described.  I also wonder whether it shouldnt include something about the possibility that it may induce atrial fibrillation in patients, particularly, patients at high risk for that arrhythmia.  And, you know, whether it should contain information about the drug effect on QT may be aggravated by hypokalemia and, therefore, potassium levels, particularly, on patients who are on drugs that cause hypokalemia should be monitored, or at least baseline checked.
		I mean, I think there may be other things that need to go into the warning label to caution people.  
		I would also suggest that it say something about the fact that in the trials prolonged use of the drug, in terms of its cardiovascular safety, were not assessed, you know, by giving it longer than stated.
		You know, in terms of the other drugs that have been approved, I guess one of the problems that the pharmaceutical company has here is that, you know, they were, perhaps, the first to come along, take a drug with this issue and evaluate it so thoroughly, so its probably, you know, raised as many questions as it has answered.
		In the other drugs that have gotten approval, where a number of thousands of people have been studied, I guess Im not sure in all of those that people on Class 1A and Class 3 antiarrhythmics were excluded. So, in fact, if they studied those types of patients and didnt have an increase in problems, that would suggest that, perhaps, those drugs may, in fact, be relatively safer than we know this drug is, just because it hasnt been looked at in those populations.  I dont know the answer to that.
		ACTING CHAIRMAN RELLER:  Dr. Danner, thank you for your comments, all of which are recorded here for consideration, and well come back to some of these issues on the last question, I think, as well.
		Dr. Soper.
		DR. SOPER:  Yes, with the warning label as discussed.
		ACTING CHAIRMAN RELLER:  Dr. Christie.
		DR. CHRISTIE-SAMUELS:  Yes, with the warning label as discussed, and I guess we would also say that it has not been approved for use in children.
		ACTING CHAIRMAN RELLER:  Thank you.
		Keith.
		DR. RODVOLD:  Yes.  As I mentioned before, and in view of what Bob just said, Id put a dose duration, reemphasize that this data is around only this information at this time, and we dont know what it is outside of that, so just a friendly reminder of this dose and duration thats been studied.
		ACTING CHAIRMAN RELLER:  Dr. OFallon.
		DR. OFALLON:  Yes, with the various -- I would vote for all the amendments that have been suggested.
		ACTING CHAIRMAN RELLER:  And, I also, for the record.
		Question three, if moxilactam is approved, what -- I thought we needed some comic relief at this time of the day -- hows that for a recovery -- okay, now question three, if moxilactam -- could you read the question, Julie?  No.  If moxifloxacin is approved, do you have any recommendations regarding Phase IV studies for data collection that the applicant should be requested to perform?
		Carl, what studies data to you want to see?
		DR. NORDEN:  Well, I think the one I would most like to see is the one that Keith mentioned, and I think all of us were asking about, and that is PK data, concentrations in patients, not just in healthy volunteers, because Id really like to know whether this is the same, or as I suspect it will be different for sick patients, as opposed to healthy volunteers.  I think that would be very useful.
		ACTING CHAIRMAN RELLER:  Barbara.
		DR. MURRAY:  Studies such as we heard yesterday focusing on pneumococcal pneumonia, penicillin resistant susceptible strains, if the desire is to get that as an adjunct or a supplement to the labeling.
		DR. ARCHER:  I think prospective studies looking at -- continue looking at QT prolongation with this and similar compounds, but this one, since so much data has already been collected, to look at data in patients where applicable, and interactions with other drugs that might be pro-arrhythmics.
		DR. PARSONNET:  I agree with all those studies.  I would be interested in knowing whether people actually follow the warning labels and whether they actually adhere to what is recommended, and whether theres a way to access that data.  And, Im also just very curious about this AF phenomenon, and although I wouldnt -- I dont think its necessary to include that in the warning label, I would be interested in seeing whether theres any animal information that could be obtained about that, and I would certainly want that to be included as one of the things they followed up to see whether it occurred with greater frequency in follow-up studies.
		ACTING CHAIRMAN RELLER:  Dr. Danner.
		DR. DANNER:  Well, I agree with all of that, in terms of the further studies and monitoring, and I would like to see more data in bacteremia in patients with very severe illness due to pneumonia, such as patients requiring intensive care units, and Id like to see information on whether the drug has an effect on potassium or magnesium excretion, whether those -- and whether those effects are added are synergistic with other drugs that have that effect.
		ACTING CHAIRMAN RELLER:  Dr. Soper.
		DR. SOPER:  I have nothing to add.
		ACTING CHAIRMAN RELLER:  Dr. Christie?
		DR. CHRISTIE-SAMUELS:  Id be interested to learn more about the QT factor at relevant steady state concentrations, as discussed previously.  Id love to hear more about how the drug performs in patients with bacteremic pneumonia, not only penicillin susceptible strains, but penicillin resistant strains as well.  Id also like to learn more about the drug performance in patients who have community acquired pneumonia with pneumococcal isolates.  Id love to learn more about the drug in children, the pharmacokinetics, efficacy studies, especially in patients who have pneumonia, again, stressing what I said yesterday.
		ACTING CHAIRMAN RELLER:   
		DR. RODVOLD:  Ill go ahead, Barth, and I agree with what has been said.  In regards, Id urge sponsors to pursue the penicillin resistant indication  if they wish, but Id also encourage them to use studies that would be a little bit more helpful, maybe more domestic studies, controlled studies, blinded randomized, so that we are not kind of sitting on the edge of knowing whats going on, and so that when they present the data that it comes across more convincing, and the numbers would be up in -- and I think they can do that all post marketing, in addition to the safety hopefully, and they might be able to get by with a couple of good controlled studies and be back on the table within a year or two, or whatever its going to take, and try to combine as much of that as possible for us to get it all clinically relevant.
		ACTING CHAIRMAN RELLER:   Judith?
		DR. OFALLON:  I agree.
		ACTING CHAIRMAN RELLER:  I think it was mentioned earlier that it would be difficult and would need some courage in requiring close observation, but I think Dr. Ruskin pointed out earlier that if  Dr. Temple -- that if studies were undertaken in what people had the greatest concerns about of interactions, and a controlled situation to delineate that, to see whether these are competing for the same receptor mechanism or, in fact, are additive and get up to a magnitude that poses a risk would be helpful in the long run.
		Question four.
		DR. GOLDBERGER:  Dr. Reller, can I just ask Dr. Ruskin whether there are any other specific studies he might want to suggest that might better elucidate some of the issues as far as the risk of the QT prolongation, either clinical or preclinical.
		DR. RUSKIN:  No, I think theyve been pretty well covered.  I guess the one drug that would interest me, just because of its extraordinarily widespread use, would be an interaction study with cisapride, but other than that I think all of them have been covered.
		ACTING CHAIRMAN RELLER:  Dr.s Battinelli and Platt, do you have anything you want to add here?
		DR. PLATT:  One additional thing that I think would be worth knowing is the impact of moxifloxacin therapy on acquisition of resistance by pneumococci, and that might be learned by doing nasal swab surveillance for pneumococci after therapy, even though its not the organism being treated, understanding whether this change in MIC would be fairly helpful.
		DR. BATTINELLI:  I would just add that in addition to cisapride, some of the other drugs that a number of patients are on, that the usual family practitioner, internist or other person prescribing this agent, doesnt know a lot about all the anti-psychotics, and frequently patients are on those medications and dont report being on those medications, so I would also study those as well.
		ACTING CHAIRMAN RELLER:  These comments reminded me of something that I also would be interested in, and I realize it may be difficult to obtain, and that is, there were very few clinical failures in the patients with pneumococcal pneumonia, but when there were failures either we dont have or the patients werent cultured, and I think it would be those patients that wed be particularly interested in finding out whether the organism that persisted, if there be any, is markedly different in its susceptibility to this or any of the newer compounds.
		Question four, do we have any recommendations regarding the parameters, both qualitative and quantitative, that might be most useful in assessing the significance of QT prolongation caused by anti-infective products, and Id like here to actually begin with our consultants, and just for consistency we can go to Dr. Battinelli and then to Dr. Ruskin and around for the voting members.
		DR. BATTINELLI:  I think some of these things have already been mentioned, that most interested in making sure that theres good data on concomitant drug use.  I think the sponsor has established the rigorous protocol by which prospective or potential patients who are normals, et cetera, are studied, but not enough data on people taking the additional medications.
		DR. RUSKIN:  I think weve hammered this pretty hard today, and I guess I would start by saying that what Bayer has done might serve as a model for working up a drug that affects the QT interval.  This is really a lovely evaluation all the way from the preclinical through the clinical.
		The important issue is, if you see a signal of an effect on a QT, to go back and do an Ikr screen, and then to look at single cells, usually guinea pig myocytes and hysperkingy tissue, isolated profused rabbit hearts, intact dog hearts, for a whole host of parameters, so that you look at a number of different models, one over a very wide range of drug concentrations and heart rates, be very careful to screen for metabolites and make sure that the clinical data are collected in a very careful and rigorous way, as detailed by Dr. Morganroth.
		So, I think it really is a package, and I would have to say that this is certainly among the best of them that Ive seen.  So, if FDA is looking for guidance, this is probably a very good place to start as a model.
		DR. GOLDBERGER:  You know, it wouldnt be uncommon to have potentially some of the preclinical data done first, or very early on, certainly before the Phase III trials.  Does the preclinical data, if a negative result occurs in that, is that sufficient even if you were worried because of the class of drugs to not have to do a lot in the Phase III trials, or are you basically saying that both preclinical and clinical data should always be obtained if theres any type of signal or suspicion?
		DR. RUSKIN:  I think the preclinical data is critical, and most of the experience would suggest that if the drug doesnt affect Ikr that you are probably pretty safe.  So, thats really the place to start.
		If the drug has Ikr blocking properties, then I think it opens Pandoras Box in terms of having to run the gamut.  I dont know how --
		DR. GOLDBERGER:  So, you would think thats a reasonable screening test?
		DR. RUSKIN:  Well, I think its a very good place to start.  The likelihood of having a significant clinical problem if you dont effect human Ikr is pretty minuscule.
		ACTING CHAIRMAN RELLER:  Dr. Temple.
		DR. TEMPLE:  We are actually actively looking at that.  Theres a lot of data on a lot of drugs, and there may be a difference, we dont know this for sure yet, it depends on what the concentration that inhibits the Ikr is.  Our dream, our hope, is that you can find a cutoff point above which you are not worried, because the concentration needed is so large, and theres at least some sense that it is breaking down that way, where the receptor is very sensitive, you have the class of drugs that cause trouble where its hardly sensitive at all, and you need a very large concentration to inhibit, those look more or less clean, and in the middle you have to do a lot of work.
		DR. GOLDBERGER:  Dr. Reller, could we also hear as part of this from Dr. Morganroth?
		ACTING CHAIRMAN RELLER:  Sure.
		DR. GOLDBERGER:  Okay.
		DR. MORGANROTH:  My only addition to it was just said, is that Id be very cautious to assume that Ikr data is simple, you know, black and white, like getting a serum potassium is.  As heard, its concentration dependent, model dependent, in whose hands it is.  So, if you are about to start a new drug and you set up the model in your lab in your company and you find it to be negative, you know, that would make me very comfortable.
		But, as Jeremy said, if you do it in a bunch of models and in a bunch of concentrations, et cetera, and you really work it up well and its negative, I still think that like doing liver function tests is an analogy, if you screen toxicologically and you dont think a drug affects the liver, how many of you would be comfortable going into a clinical drug development program and not obtaining in man liver function tests?  I mean, you wouldnt even raise that question, of course you would do that.
		In the past, weve not done electrocardiograms on every single drug ever taken into man in the non-cardiac field, because they dont affect the heart, they are non-cardiac.  But, weve now learned that so many drugs appear to affect the QT interval that were unexpected that I simplistically would suggest that the EKG, just like grabbing, you know, the CBC in a chemistry panel, its not irrational to include EKGs with every -- as a simple point of safety.  When do you do that?  Well, you dont do it before the drug is given, you know, and then after the drug is given, when would you do your CBC, liver function tests, you would do it during at least acute dosing, and then you would also want chronic exposure.  And, I think EKGs belong before, during acute exposure, and afterwards, and I think they should be centralized like most blood studies, and I think they have to be analyzed with the attempt to try to find three, six, ten milliseconds, rather than by eyeball where theres a lot of noise.
		So, my answer to number four is, you do need preclinical, you do need clinical. The preclinical only tells you what your risks are, and you may, even with a positive Ikr because of therapeutic benefit, go into man, but on the other hand if you are not so sure of the benefit risk you may pick another drug in that sequence or not move into man because of the risks involved, and that when you do it, and how you do it, should be very similar to any other safety test that you do and making this very simple.
		ACTING CHAIRMAN RELLER:  Dr. OFallon.
		DR. OFALLON:  Now, is the question, do you have any recommendations, et cetera, with these recommendations, is that the --
		ACTING CHAIRMAN RELLER:  Do you have anything to add in addition to whats already been said?
		DR. OFALLON:  No, I dont.  Thank you.
		ACTING CHAIRMAN RELLER:  And, Dr. Platt, I think I skipped over you when we diverted to Dr. Morganroth, whose comments we much appreciate.
		DR. PLATT:  Well, Ill comment from an epidemiologists perspective, to say that often what we -- another thing that is important to focus on is the absolute level of risk, not the relative risk, so that I think in the risk assessment for all drugs, and this class of QT prolonging drugs as well, its important to contemplate in the target population whats the number of people who are likely -- who might plausibly be adversely affected, as opposed to the percentage.
		And, the other comment Ill make is that, among drug safety problems, this is, I think, among the most difficult to tease out using traditional post-marketing surveillance methods, that the system that Dr. Brinker described, and some of the databases that draw on large populations that are very useful for understanding other kinds of adverse drug reactions, are not very good for these kinds of reactions.  And so, when theres a judgment to be made, theres more emphasis that will have to be put on the formal clinical evaluations.
		ACTING CHAIRMAN RELLER:  Thanks.
		DR. RODVOLD:  I have nothing to add.
		DR. CHRISTIE-SAMUELS:  I have nothing further to add.
		DR. SOPER:  Nothing to add except to amplify Dr. Platts comments.  I mean, I think that absolute risk and predictive values of some of these parameters that you are measuring with real patient outcome is an important target, and all of the money and work that goes into looking at measuring something, if its not predictive of poor outcome Im not sure its worthwhile.
		DR. DANNER:  Nothing to add.
		ACTING CHAIRMAN RELLER:  Julie, Barbara.
		Before they had to leave, Dr.s Archer and Norden affirmed, and I would like any comments from the committee, and this is, Mark, for you and your colleagues at FDA, and we can assume this would happen, but Id like for the voting members of the committee to give a sense of their feeling of need for it, and that is, as more has been learned and discussed about this specific agent, we together, Rhonda helped to just pull forth the package insert on specifically sparfloxacin, grepafloxacin and clarithromycin, and all of them have language different from what has been proposed, but related to the QTc issue.
		And, I would think it would be wise for fairness, for consistency, for understanding, realizing that some of these compounds, while these compounds were approved before we had the kind of database that is available here, to whatever, within the regulatory capabilities are possible, to go back and look at some of the questions that have been raised if the data are extant, including such things as what Dr. Ruskin pointed out, were patients with certain conditions excluded from the outset, so that there are no data and that the risks and the comments about the QTc intervals may be made on a patient population that is different from the ones that have been discussed so thoroughly here today.
		But, the essence of all of this is of trying to get consistency, equity, fairness and detecting real differences if there be them, which there have been for other values, between the compounds within a class and across classes that relate to a particular kind of safety concern.
		Dr. Murray, would you like to see that happen?
		DR. MURRAY:  Yes.
		ACTING CHAIRMAN RELLER:  Dr. Parsonnet.
		DR. PARSONNET:  Sure.
		DR. DANNER:  Yes.
		DR. SOPER:  Yes.
		DR. CHRISTIE-SAMUELS:  Yes.
		DR. RODVOLD:  Of course.
		ACTING CHAIRMAN RELLER:  Okay.
		DR. OFALLON:  Yes.
		ACTING CHAIRMAN RELLER:  Dr. Goldberger, we have tried to address the questions you posed, and a few additional ones, and have broken up, even added a few compounds that you never wanted us to consider, dropped quickly, or not so quickly, do you have any, or Dr. Kweder, any concluding -- any comments that you want to make?  We are about to wrap this up.
		DR. GOLDBERGER:  Yes, my only comment would be to thank the committee and the consultants for their comments and opinions, which I actually, I think have been quite useful.  Id particularly like to thank both Dr. Ruskin and actually Dr. Morganroth, even though he came here with Bayer, for their comments, which I think have helped a substantial amount in terms of our, you know, thinking about a possible framework for evaluating current and future compounds.
		ACTING CHAIRMAN RELLER:  Id like to thank everyones efforts to speak what they think and to do it succinctly, and this Anti-Infective Advisory Committee meeting is concluded.
		(Whereupon, the meeting was concluded at 3:32 p.m.)