ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANTI-INFECTIVE DRUGS ADVISORY**
>
> **COMMITTEE (AIDAC) MEETING**
>
> Tuesday, March 4, 2003
>
> 8:00 a.m.
>
> Marriott Washingtonian Center
>
> Grand Ballroom
>
> 975 Washington Boulevard
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> James E. Leggett, Jr., M.D., Acting Chair
>
> Tara P. Turner, Pharm.D., Executive Secretary
>
> MEMBERS
>
> Alan S. Cross, M.D.
>
> Mary P. Glode, M.D.
>
> Celia J. Maxwell, M.D.
>
> Jan E. Patterson, M.D.
>
> Ellen Wald, M.D.
>
> ACTING INDUSTRY REPRESENTATIVE (NON-VOTING)
>
> Kenneth R. Brown, M.D.
>
> CONSULTANTS
>
> N. Franklin Adkinson, Jr., M.D.
>
> Michael E. Bigby, M.D.
>
> John S. Bradley, M.D.
>
> Hari S. Conjeevaram, M.D.
>
> Lynn A. Drake, M.D.
>
> Roselyn E. Epps, M.D.
>
> Joan F. Hilton, Sc.D.
>
> Judith R. O\'Fallon, Ph.D.
>
> Donald M. Poretz, M.D.
>
> Michael Proschan, Ph.D.
>
> L. Barth Reller, M.D.
>
> Keith A. Rodvold, Pharm.D.
>
> Maria H. Sjogren, M.D.
>
> FDA
>
> Renata Albrecht, M.D.
>
> Edward Cox, M.D., M.P.H.
>
> Mark Goldberger, M.D., M.P.H.
>
> John Powers, M.D.
>
> Maureen Tierney, M.D., M.Sc.
>
> [C O N T E N T S]{.underline}
>
> Call to Order, James E. Leggett, Jr., M.D. 4
>
> Introduction of the Committee 4
>
> Conflict of Interest Statement, Tara P. Turner, Pharm.D. 7
>
> Opening Remarks, Renata Albrecht, M.D. 10
>
> Adverse Cutaneous Drug Reactions, Michael Bigby, M.D. 17
>
> Antimicrobial Resistance in [Streptococcus pneumoniae]{.underline},
>
> John H. Powers, M.D. 36
>
> SPONSOR PRESENTATION
>
> Parexel International, U.S. Agent for Life Sciences, Ltd.
>
> Introduction, Gary Patou, M.D. 73
>
> Unmet Medical Need, Donald E. Low, M.D. 78
>
> Efficacy, Lionel A. Mandell, M.D. 95
>
> Safety, Gary Patou, M.D. 110
>
> Cutaneous Manifestations, Neil H. Shear, M.D. 119
>
> Risk-Benefit and Risk Management, Gary Patou, M.D. 150
>
> Questions and Answers 156
>
> FDA PRESENTATION
>
> Introduction, Edward Cox, M.D., M.P.H. 166
>
> Microbiology, Peter Dionne 167
>
> Community-Acquired Pneumonia, Regina Alivisatos, M.D. 175
>
> Acute Bacterial Exacerbation of Chronic Bronchitis,
>
> Eileen Navarro, M.D. 189
>
> Safety, Maureen Tierney, M.D., M.Sc. 199
>
> Summary, Edward Cox, M.D., M.P.H. 227
>
> Questions and Answers 229
>
> Charge to the Committee, Mark Goldberger, M.D., M.P.H. 232
>
> Committee Discussion 238
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order**
>
> DR. LEGGETT: Good morning. Welcome to the Anti-Infective Drugs
> Advisory Committee. We are here today to talk about Factive,
> gemifloxacin tablets.
>
> We will go around the table and introduce ourselves. One little piece
> of information I would like you to try to remember is these
> mikes\--only four of them can be on at one time so, after you are done
> talking, please remember to switch it off.
>
> Let\'s start down there.
>
> **Introductions**
>
> DR. ALBRECHT: Good morning. I am Renata Albrecht, Director of the
> Division of Special Pathogens and Immunological Drug Products.
>
> DR. COX: Good morning. I am Edward Cox, Deputy Director, Office of
> Drug Evaluation IV.
>
> DR. TIERNEY: Maureen Tierney, medical officer, Division of Special
> Pathogens, FDA.
>
> DR. BRADLEY: John Bradley, Division of Infectious Diseases,
> Children\'s Hospital, San Diego.
>
> DR. PORETZ: I am Don Poretz in private practice of infectious diseases
> in Fairfax, Virginia.
>
> DR. PATTERSON: Jan Patterson, Infectious Diseases, University of Texas
> Health Science Center, San Antonio.
>
> DR. O\'FALLON: Judith O\'Fallon, statistician, Mayo Cancer Center
> Statistics Unit, Mayo Clinic, Rochester, Minnesota.
>
> DR. RELLER: Barth Reller, Infectious Diseases, Clinical Microbiology,
> Duke University Medical Center.
>
> DR. RODVOLD: Keith Rodvold, professor at the Colleges of Pharmacy and
> Medicine, University of Illinois, Chicago.
>
> DR. TURNER: Tara Turner, executive secretary for the Committee.
>
> DR. LEGGETT: Jim Leggett, Infectious Disease, Health Sciences
> University at Oregon and Providence Portland Medical Center.
>
> DR. WALD: Ellen Wald, Pediatric Infectious Diseases, University of
> Pittsburgh School of Medicine.
>
> DR. CROSS: Alan Cross, Infectious Diseases, Center for Vaccine
> Development, University of Maryland.
>
> DR. PROSCHAN: I am Mike Proschan. I am a statistician at the National
> Heart, Lung and Blood Institute.
>
> DR. GLODE. Mimi Glode, Pediatric Infectious Disease, Children\'s
> Hospital at the University of Colorado, Denver.
>
> DR. BIGBY: Michael Bigby, Department of Dermatology, Harvard Medical
> School and Beth Israel Deaconess Medical Center in Boston.
>
> DR. EPPS: Roselyn Epps, Chief, Division of Dermatology, Children\'s
> National Medical Center, George Washington University.
>
> DR. ADKINSON: Franklin Adkinson, Allergy and Immunology, Johns Hopkins
> School of Medicine.
>
> DR. HILTON: Joan Hilton, Biostatistics, University of California at
> San Francisco.
>
> DR. CONJEEVARAM: Hari Conjeevaram, Division of Gastroenterology and
> Hepatology, University of Michigan, Ann Arbor.
>
> DR. SJOGREN: Maria Sjogren, Gastroenterology and Hepatology at Walter
> Reed Army Medical Center.
>
> DR. LEGGETT: Thank you.
>
> I think we will start the morning first by Tara with the conflict of
> interest statement.
>
> **Conflict of Interest Statement**
>
> DR. TURNER: Thank you. The following announcement addresses the issues
> 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 the submitted agenda for the meeting and all financial
> interests reported by the committee participants, it has been
> determined that all interests in firms regulated by the Center for
> Drug Evaluation and Research present no potential for an appearance of
> a conflict of interest in this meeting with the following exceptions:
>
> In accordance with 18 U.S.C. 208(b)(30, Dr. James Leggett has been
> granted a waiver for his pending consulting for a competitor on an
> unrelated matter. He will receive a fee of less than \$10,001.
>
> Dr. Celia Maxwell has been granted a waiver for her speaker\'s bureau
> and possible membership on an advisory committee for a competitor on
> unrelated matters. Her fees are less than \$10,001.
>
> Dr. Lynn Drake has been granted a waiver for her role as a member of
> an advisory board for a competitor on an unrelated matter. She
> receives a fee of less than \$10,001 for this activity.
>
> Dr. Ellen Wald has been granted a waiver for her employer\'s contract
> with a competitor on an unrelated matter. Funding received is less
> than \$100,000.
>
> Dr. Jan Patterson has been granted a waiver for her role on the
> speaker\'s bureaus for two competitors on related matters. She
> receives fees of less than \$10,001 for these activities. Dr.
> Patterson has also been granted a waiver for her memberships on an
> advisory board and a visiting professor program for two competitors on
> unrelated matters. She receives fees of less than \$10,001 for these
> activities. Finally, Dr. Patterson has been granted a waiver for her
> spouse\'s consulting for a competitor on an unrelated matter. Her
> spouse receives a fee of less than \$10,001 for this activity.
>
> Dr. John Bradley has been granted a waiver for his role as a
> consultant for two competitors on unrelated matters. He receives fees
> of less than \$10,001 for these activities.
>
> Dr. N. Franklin Adkinson has been granted a waiver for his role as a
> consultant for two competitors on unrelated matters. He receives fees
> of less than \$10,001 for these activities.
>
> Dr. Keith Rodvold has been granted a waiver for his role as a
> consultant for two competitors on unrelated matters. He receives fees
> of less than \$10,001 for these activities.
>
> Dr. Donald Poretz has been granted a waiver, 21 U.S.C. 355(n)(4)
> amendment of Section 505 of the Food and Drug Administration
> Modernization Act, for his ownership of stock in a competitor valued
> between \$5,001 to \$25,000.
>
> A copy of the waiver statements may be obtained by submitting a
> written request to the agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building.
>
> In addition, we would like to disclose that Dr. Kenneth Brown is
> participating in this meeting as an acting industry representative,
> acting on behalf of regulated industry. Dr. Brown reports that he owns
> stock in Johnson & Johnson and Pfizer. Dr. Brown also serves as a
> consultant to Wyeth.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for 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. Thank you.
>
> DR. LEGGETT: Thank you. I think we will begin with opening remarks by
> Dr. Renata Albrecht. I would like to remind all speakers to try to
> stay on time. At the end of each presentation we will take one or two
> major questions and save the rest of the questioning to sort of do as
> a group at the end of each particular session before the break. Dr.
> Albrecht?
>
> **Opening Remarks**
>
> DR. ALBRECHT: Thank you, Dr. Leggett.
>
> \[Slide\]
>
> Good morning, everyone. On behalf of the Division and the Office I
> would also like to add my words of welcome to everyone for today\'s
> session of the Anti-Infective Advisory Committee during which we are
> going to be talking about the fluoroquinolone gemifloxacin.
>
> First of all, however, I would like to thank the members of the
> committee, as well as the consultants and guests, for taking time from
> what we know are your very busy schedules to join us for these
> discussions and to provide us with your advice. I would also like to
> thank the applicant, LG Life Sciences, as well as their agent, Parexel
> International, for their willingness to bring this application to the
> committee, and their cooperation in providing additional information
> in preparation for this meeting and, of course, our staff in the
> Division and the Office who have worked very hard despite unexpected
> adversities, like the blizzard of 2003, to try to put this advisory
> committee together. Finally, let me acknowledge Mrs. Karin Klunk and
> Dr. Yon Yu for their invaluable help in making the handouts that you
> all have available and running the presentations for the FDA this
> morning.
>
> \[Slide\]
>
> Let me go ahead and turn to some basic comments and try and give you a
> perspective of how we reviewed this application, and the thoughts that
> were going through our minds as we planned for this advisory
> committee.
>
> As you are very well aware, the fluoroquinolone drug class is not a
> new one. Many drugs in this class have been developed, submitted to
> the agency and, in fact, approved. We also have examples of ones that
> have not been approved or after approval, withdrawn, limited in scope
> and so forth.
>
> \[Slide\]
>
> Over time we have learned a great deal about the efficacy of this
> class and we know that as a class it does work in a broad range of
> indications. We have, of course, also learned quite a bit about the
> safety profile and, again, as a class fluoroquinolones are labeled
> with various contraindications, warnings, precautions and adverse
> reactions in their product labeling. As might be expected, each
> fluoroquinolone presents its own unique characteristics and, in making
> regulatory decisions on these issues, we have, in fact, brought some
> of the fluoroquinolones to this advisory committee for input. The most
> recent examples include moxifloxacin and levofloxacin.
>
> \[Slide\]
>
> What about gemifloxacin makes us bring it to you for your input and
> for your deliberation? What are the unique aspects that we wish you to
> provide us advice on?
>
> Clinical studies with gemifloxacin have actually demonstrated that
> gemifloxacin is not inferior to the FDA approved comparison in the
> indications of community-acquired pneumonia, acute exacerbation of
> chronic bronchitis and, in fact, a couple of indications that we will
> not be talking about at length today.
>
> \[Slide\]
>
> As far as safety, clinical studies have demonstrated that the
> incidence of rash is somewhat higher in the gemifloxacin arm than in
> the comparator arm, and this was found for the study population as a
> whole and also in specific subsets, most notably in females under the
> age of forty.
>
> \[Slide\]
>
> This is the only data that I will be showing for the introduction.
> This is actually a slide that I have borrowed from Dr. Maureen
> Tierney\'s presentation and you will see it again when she gives the
> full safety presentation later this morning. This demonstrates the
> gender and age relationship of rash.
>
> If you look on the X axis, at the left-most corner the bars represent
> the incidence of rash in control patients. Moving from left to right
> are different durations of gemifloxacin therapy, ranging from 3 days
> to 5, 7, 10 and 14 days. The Y axis represents the percent of rash
> reported by patients. If we look at the color coding for the bars, the
> blue bars are males greater than 40; the purplish ones are males under
> 40; the white ones are females greater than 40; and these light
> turquoise are females less than 40. As you examine the graph, I think
> you can appreciate the increased rate of rash reported by increasing
> duration of therapy and, again, in the light turquoise bar the
> relatively higher rates of rashes in women under the age of 40.
>
> So, as you listen to the detailed presentations by both the company
> and FDA you will learn more both about the safety profile and the
> efficacy profile of the drug product.
>
> \[Slide\]
>
> Let me also add that before the company presentations and the FDA
> presentations, we are actually truly fortunate to have Dr. Michael
> Bigby, from Harvard, join us to give a presentation about adverse
> cutaneous reactions to drugs to give you more background on these
> reactions in patients. That presentation will then be followed by Dr.
> John Powers, from the Office of Drug Evaluation IV, who will be
> speaking about [Strep. pneumoniae]{.underline} and resistance in that
> organism.
>
> Dr. Powers\' presentation is applicable to today\'s advisory committee
> because the company has asked us to consider penicillin-resistant and
> other resistant Strep. pneumo. as part of the indications, but I think
> it is also a preview to tomorrow\'s advisory committee which will talk
> at length about resistant organisms and topics relevant to that.
>
> So, having mentioned some of the issues that we have been considering
> regarding gemifloxacin, what is it that we are going to be asking of
> you today? I think the questions that we will be posing to you come in
> two categories. One, we will be asking you about the risk-benefit
> considerations as far as the approval of gemifloxacin. The second is
> risk management considerations.
>
> \[Slide\]
>
> We will be asking actually three questions. Dr. Goldberger will review
> these in much greater detail during the charge to the committee this
> afternoon, but we wanted to give you just a brief overview of the type
> of advice we will be seeking so that you will keep this in mind as you
> hear the presentations.
>
> The first question will basically be to ask whether, based on the data
> you have heard and your clinical and scientific opinion, the benefits
> of gemifloxacin therapy outweigh the risks for the proposed
> individuals with community-acquired pneumonia and acute exacerbation
> of chronic bronchitis.
>
> \[Slide\]
>
> The second question, assuming the answer to the first one is yes, will
> be to ask you to give us some thoughts about the type of information
> that should be provided to physicians and patients, also your
> suggestions about caveats on what patients should receive gemifloxacin
> and any discussion on either risk management or risk communication
> strategies that you might find useful.
>
> \[Slide\]
>
> Just to complete the questions we ask, if the answer is no, what
> additional information you would recommend be obtained for either or
> both of the indications.
>
> So, with those remarks, I will turn it back to you, Dr. Leggett.
>
> DR. LEGGETT: Thank you. Dr. Bigby, could you please help us out?
>
> **Adverse Cutaneous Drug Reactions**
>
> DR. BIGBY: Good morning.
>
> \[Slide\]
>
> What I thought I would try to do in the half hour allotted is to just
> talk basically about adverse cutaneous reactions to drugs and try to
> keep it mostly focused on the questions that have been raised about
> gemifloxacin.
>
> \[Slide\]
>
> These are the common drug rashes, exanthem, urticaria and fixed-drug
> eruption. By far, drug exanthem is the most common adverse cutaneous
> reaction to drugs. Its description I think is important and very
> germane to the discussions that will occur here today. It is generally
> a fine, papular eruption, meaning that patients develop very small,
> 1-3 mm bumps on the skin that have generally a sort of erythematous,
> quite pink color. They are often numerous. They generally start on
> areas of trauma so that in ambulatory patients most commonly you see
> that the rash starts on the legs and will spread up from there. In
> patients that are hospitalized, on their back, often the rash will
> begin on their back and spread from there. It can be quite localized
> as well as quite generalized. It is commonly mis-described as a
> macular eruption or a maculopapular eruption but, in general, most
> patients that get rashes from drugs have this drug exanthem.
>
> Urticaria is a lot less common but is the second most common reaction
> and those lesions are hives. It is basically an area of edema in the
> skin. Almost always there is associated redness or erythema.
> Fixed-drug is actually irrelevant for today\'s discussion so I will
> skip it.
>
> \[Slide\]
>
> I think this is one of the major concerns that has been raised about
> this drug and whether or not it could potentially be a cause of more
> serious drug reactions. The three serious drug reactions are toxic
> epidermal necrolysis, Stevens-Johnson syndrome and what is called a
> drug hypersensitivity syndrome.
>
> TEN and Stevens-Johnson syndrome are probably a spectrum of the same
> disease in which patients develop full thickness necrosis of the
> epidermis that leads to blister formation, sloughing of the skin and,
> depending on the area of involvement, is quite serious and has a
> mortality rate up to over 50 percent in some studies for TEN. The
> mortality from Stevens-Johnson syndrome is much less. Luckily for all
> of us, this is a very infrequent reaction and in the best estimates
> available for drugs that have been well studied the rate is somewhere
> around 0.5 to 1.0 cases per million of exposures.
>
> An important thing and a question raised about this drug is whether or
> not one could go from one of these, exanthem or urticaria, to
> something more serious. I would say that there is no evidence that
> that transition occurs, and I think it is not something that is
> described or that one would in general have to worry about.
>
> \[Slide\]
>
> The drug hypersensitivity syndrome is similarly rare. The rash
> associated with it is the exanthem that I have already described.
> Patients also have fever, hepatitis, they are very ill, almost always
> wind up hospitalized, usually in intensive care units, and the
> mortality rate is actually quite high. There is a lot of controversy
> about how such patients should be handled.
>
> \[Slide\]
>
> When a patient develops a drug eruption, how do you know what is
> responsible? It is basically done in the majority of clinical cases by
> the timing of the rash; some knowledge about how commonly drugs cause
> rash; what happens when you withdraw the drug; and usually in this
> country what happens if patients are accidentally rechallenged to the
> drug. Deliberate rechallenge is something that is rarely done here but
> is done actually fairly frequently, particularly in experimental
> studies in Scandinavia.
>
> \[Slide\]
>
> In general, the drug exanthem and urticaria occur within the first 3
> days after a drug is started. There are several very notable
> exceptions to this, again germane to our discussion today, that can
> occur up to 2 weeks after a drug is started for many antibiotics and
> allopurinol. This means that actually you can have the drug given for
> 1, 2 or 3 days, stop the drug and people can develop drug eruptions 2
> weeks later, or if they are continually treated for that duration of
> treatment, 2 weeks, you will often see or not infrequently see drug
> rash develop late. In fact, I was struck by looking at the figures on
> onset of rash for this drug that it really paralleled a lot of the
> eruptions that we observed when we did a study trying to determine
> rates of reactions to drugs based on consecutively monitored
> hospitalized patients, and I will show you some of that data as well.
>
> \[Slide\]
>
> In terms of getting actual rates of drug reactions, I published in
> June of 2001 a systematic review of available studies looking at rates
> of reactions to drug. The kind of data that is available\--the best is
> prospectively collected data on monitored patients. These were very
> big studies that were conducted between the late \'60s and mid to late
> \'80s. There are also data from retrospective studies, usually based
> on computerized medical records. Lastly, there are some data, not
> quite as useful, on spontaneous reports and consumption of drugs.
> Again, I will show you some of that data.
>
> \[Slide\]
>
> I did some assessment of the quality of the studies, and the best
> studies had well-defined, representative samples and sufficiently long
> and complete follow-up. It was clear how the researchers linked drug
> reactions and the drug. The temporal relationship was correct and you
> could calculate rates based on the data provided, as well as their 95
> percent confidence intervals.
>
> \[Slide\]
>
> Not to bore you with a lot of numbers, but this is data collected on
> something like 38,000 patients. I am just presenting rates for drugs
> that were more than 1 percent and were taken by more than 1000
> patients. The only point I want to make here is that in this list of
> things that produce rashes more than 1 percent of the time, the list
> is dominated by antibiotics, with the exception of transfusions, and
> amoxicillin and ampicillin are very high up on the list and I think
> those are drugs that were used as comparators for gemifloxacin. So, we
> are talking about comparators that actually have very high rates of
> cutaneous reactions. I think you should pay some attention to the rate
> number because I think these are really pretty much the most accurate
> estimates of how frequently drugs cause rash. For amoxicillin and
> ampicillin it is around 5 percent in the real world.
>
> \[Slide\]
>
> This one I will skip. But, you know, that study also generated a list
> of drugs that hardly ever cause rashes but I don\'t think that is
> germane for this talk.
>
> \[Slide\]
>
> This is a study that was done in Switzerland in three teaching
> hospitals. Again, roughly 40,000 patients were monitored. Estimates
> were made for rates at which drugs cause rashes and, again, the big
> take-home point is that antibiotics predominate. They have rates over
> 1 percent, and the aminopenicillins were among the highest reactors.
> The estimates here are pretty comparable to what we obtained in the
> BCDSP, so a reaction rate of 5 percent or higher for the
> aminopenicillins is something that you want to have stuck in your
> mind.
>
> \[Slide\]
>
> More recently fluoroquinolones were studied. This data was based on
> about 19,000 patients. It was retrospectively collected on the basis
> of computerized records. You will notice again that the
> fluoroquinolones were the highest reactors relative to amoxicillin and
> Augmentin, which is a combination drug. The rate is considerably lower
> than what I showed you on the previous slides and I think it had to do
> with the methodology involved.
>
> It is interesting, there was a study done in Italy based on
> spontaneous reports and consumption that showed that there was marked
> variability in the rate at which specific fluoroquinolones produce
> rashes, and some produce rashes as much as three times as others in
> that same class. So, it is not a uniform class of drugs in terms of
> the rates at which they produce reactions.
>
> \[Slide\]
>
> I think this may be the last data slide. This is from a study of about
> 15,000 patients based on pediatric records. I only include it to show
> you that with more recently introduced antibiotics, like Cefaclor, you
> can pick up a signal for them causing rashes. Again, the rash rate for
> Cefaclor is actually quite high, higher than the sulfonamides in this
> study.
>
> \[Slide\]
>
> In summary, the common exanthem producers are on this slide,
> predominated by antibiotics. The aminopenicillins are high on the list
> and fluoroquinolones certainly have lately gotten onto the list of
> common exanthem producers.
>
> \[Slide\]
>
> The drugs that can produce urticaria are similar. In addition,
> histamine releasers like contrast dye and morphine by directly causing
> histamine release, can cause urticaria.
>
> \[Slide\]
>
> This is irrelevant.
>
> \[Slide\]
>
> The drugs that cause TEN and Stevens-Johnson syndrome, with the
> exception of sulfonamides, is a pretty different list of drugs and you
> don\'t see those antibiotics, most of which we will be talking about
> today, on this list of drugs that are associated with TEN and SJS. I
> am actually not aware of any sort of big signal having been detected
> in terms of fluoroquinolones producing either TEN or Stevens-Johnson
> syndrome.
>
> \[Slide\]
>
> For the drug hypersensitivity syndrome, again, sulfonamides are the
> one antibiotic that is associated but it is mostly the anti-seizure
> drugs that are deemed responsible for most cases.
>
> The last thing I would like to say is that in a randomized, controlled
> trial it is actually a fairly rare thing to pick up a signal of
> frequent drug rash production, and when you do pick up such a signal
> in a randomized, controlled trial it is almost always clinically
> relevant when the drug is introduced into the market.
>
> That is the end of what I had to say. I am happy to answer questions.
>
> DR. LEGGETT: Thank you, Dr. Bigby. Only one or two questions. Yes, go
> ahead, Donald.
>
> DR. PORETZ: Can you explain, in these two different charts that you
> gave us, one with the BCDSP and one with van der Linden et al., the
> difference in reaction of skin rash? Amoxicillin in the BCDSP was
> reported as 5.1 percent and 1.2 percent in the other. That is a huge
> difference.
>
> DR. BIGBY: Yes, it is actually not such a huge difference in that it
> is entirely a question of methodology. The methodology in the BCDSP
> study is that it was a funded study. Patients who were hospitalized
> were monitored by a group of nurses who followed the patients through
> the course of their hospitalization and they were looking for all
> adverse drug reactions, including skin reactions. So, the
> ascertainment of the numerator, the number of patients who had rashes,
> and the denominator, the total number of patients exposed to any and
> every drug was very high. So, I would say that among the data that I
> have shown you the BCDSP data and the data from the teaching hospitals
> in Switzerland is the most accurate.
>
> On the other study you referred to where the rate was 1.2 percent the
> data were collected from electronic medical records in which the
> patients developed a rash and were also reported to have been exposed
> to the drug. Charts were pulled and reviewed on that basis, and I
> would say that the ascertainment of patients that had rashes would
> only have occurred if they saw a physician and the physician wrote
> down that they had a drug reaction, which I would say in general would
> be a very small minority of the actual patients who had rashes because
> most patients, if it is just a little bit of a rash, won\'t report it
> to a doctor.
>
> So, I think that the difference is solely explainable on the basis of
> the methodology and the 1.2 estimate is probably much lower than the
> reality.
>
> DR. RELLER: When one is doing a drug study, like the one being
> presented today, do you think that would reflect the potential highest
> chance of having rash or a lower chance?
>
> DR. PORETZ: No, that is why I actually made that closing statement. I
> think if you pick up a signal in a randomized, controlled trial the
> actual use rate will be much higher.
>
> DR. LEGGETT: Dr. Reller?
>
> DR. RELLER: For the clinical indications that we will be discussing,
> co-trimoxazole or amoxicillin which you gave rates for are used in
> adults; doxycycline as well which is perceived, especially with sun
> exposure, to be a source of cutaneous reactions. Do you have any data
> from your studies as to where doxycycline would fit into the spectrum
> of frequency that you shared with us?
>
> DR. BIGBY: I don\'t remember which but in one of the slides
> tetracycline had a rate of 1 percent relative to the amoxicillin which
> was about 5 percent. I mean, if you want a number I would say it would
> be 1 percent or less.
>
> DR. LEGGETT: Dr. Maxwell?
>
> DR. MAXWELL: I just had a question on your slide, Table 5, about the
> fluoroquinolones. Was there a time period where the fluoroquinolones
> seemed to produce the rash? Was it early on, within the first 3 days,
> or was it usually later, after a week or so, that the rashes were seen
> that were reported here? The reason for the question is that in the
> drug that we are looking at, gemifloxacin, the patients seemed to
> develop the rashes as they took more of the drug, so later on in the
> course as opposed to earlier. So, I wanted to know if that sort of
> thing was seen for the fluoroquinolones that were reported here, or if
> that is even known.
>
> DR. BIGBY: The two places that fluoroquinolone data were prominent
> were the van der Linden study and the study by Naldi that looked at
> spontaneous reports and consumption. Off the top of my head, I don\'t
> remember that that phenomenon was discussed by either one. But I also
> know from a lot of the other data and also from BCDSP data that late
> onset rashes with antibiotics was actually a fairly common pattern and
> I don\'t find it at all surprising.
>
> DR. LEGGETT: Dr. Cross?
>
> DR. CROSS: I would like to ask a question on methodology in terms of
> cross-sensitization, which we will address later on. Assuming that we
> challenge with a drug that initially caused a rash but does not 100
> percent of the time cause a rash on subsequent rechallenge, how does
> one assess the capacity for cross-sensitization between, let\'s say,
> the drug under discussion and another fluoroquinolone?
>
> DR. BIGBY: Well, I think I am going to avoid answering this question
> because I don\'t have any data upon which to base an answer.
>
> DR. CROSS: But is there any methodology that one uses? For example,
> early on in my training we were told that if one reports a sensitivity
> or allergy to penicillin, if you then rechallenge that patient with a
> cephalosporin you would expect to see a rash about 10 percent of the
> time.
>
> DR. BIGBY: Yes, that is actually a bad example because I think that
> that figure in that data is actually totally incorrect. But what you
> are asking about is drugs in the same class, and if you want my
> opinion about it, I would say that if a patient developed a rash to a
> fluoroquinolone they should never be given another one because I think
> that the rate of reaction that you would get in that scenario is
> unacceptably high. I mean very high, unacceptably high. For example,
> if somebody developed a drug reaction to a cephalosporin, I think that
> probably in the real world it would preclude the use of another
> cephalosporin for that patient unless you had no choice.
>
> DR. CROSS: So, a rechallenge would have an unacceptably high\--
>
> DR. BIGBY: Right, for a drug in the same class, yes.
>
> DR. LEGGETT: Dr. Rodvold?
>
> DR. RODVOLD: My understanding is there are like two rashes. You can
> get it more acute but then there is also like an ampicillin-related
> rash that kind of accrues later in the course of therapy?
>
> DR. BIGBY: No. The only thing I would say about that is that in
> general, with the exception of antibiotics and allopurinol, almost
> always when you get a drug exanthem it occurs in that first 3-day
> window. For many antibiotics and allopurinol and actually some of the
> anti-epileptic drugs you can see drug reactions as far out as 2 weeks
> after the drug starts. It is not a separate entity; it is the same
> drug reaction. It can occur in that 1-3-day window and it can occur
> all the way out to 14 days. That data is very, very clear and very
> reproducible so it is not an unusual phenomenon.
>
> DR. LEGGETT: Two questions. In general clinical practice the word of
> mouth is sort of that if you have an allergic reaction to penicillin
> you shouldn\'t get it again. But we all know that if someone got a
> rash to penicillin 30 years ago you can give it again orally and
> oftentimes nothing happens. Indeed, some of the data here suggests
> that when people got a second exposure they did not get a rash. So,
> how ironclad is that and what is the mechanism of exanthem? Do we
> know? Are there sort of memory half-lives that then subside?
>
> DR. BIGBY: There have been a lot of studies on the clinical
> predictability of history of drug allergy and the general result is
> that the history of drug allergy has very little predictive value
> because what people remember from 30 years ago often wasn\'t a drug
> reaction at all. So, I think that the explanation of why somebody can
> say they had a rash to penicillin 40 years ago and then you give it to
> them with impunity is that if you actually have the data from 40 years
> ago it was not a drug reaction, and if they really had a drug reaction
> to penicillin the likelihood that they would have a reaction again is
> very high.
>
> DR. LEGGETT: My second question, do you know of any IgE-mediated
> allergic responses to fluoroquinolones?
>
> DR. BIGBY: There is almost no sort of hard data knowledge about the
> pathophysiology of the drug exanthem, although everybody involved in
> drug eruptions thinks that it is an immune complex disease. Urticaria,
> on the other hand, is thought to be predominantly an IgE-mediated
> disease, and off the top of my head I don\'t remember what percentage
> of the rashes to fluoroquinolones were urticaria but I know it is in
> here.
>
> DR. LEGGETT: Thank you. Dr. Glode?
>
> DR. GLODE: I just have a quick question about the methodology of the
> Boston Collaborative Drug Study. Since I work mostly in inpatient
> medicine I have never seen anyone on only one medicine. So, if you
> were receiving amoxicillin and were on pheno. barb. and got a blood
> transfusion and developed a rash, was the methodology such that the
> best attempt was made to ascribe it to just one or did you put it in
> all three columns?
>
> DR. BIGBY: No, no, no. The methodology here was actually quite
> creative and it was sort of made up by Herschel Jick. There is no
> standard way to do this. What he did at first blush was that for every
> drug we had graphs of counts of patients developing rashes after the
> drug was started. So, you had a graph of that for every drug and you
> had a sort of mean reaction rate as well as a confidence interval for
> that drug. What he did, and I thought it was actually brilliant, was
> as a first cut of the data just to take drugs that had reaction rates
> more than twice the sort of overall average rate, and also a pattern
> where the reactions occurred within the first 3 days after the drug
> was started, and those drugs were just sort of arbitrarily identified
> as high rash producers. Then, once you had those, you eliminated that
> from the data set and then you looked at the rest of the drugs, and
> you did this in progressive stages. Then, at the end, to answer your
> question, the average number of drugs each patient took was 9, and to
> settle those cases where there was more than one high rash producer
> what you did was to divide the cases proportionally. For example, if
> the rate for ampicillin was 5 and for tetracycline was 1 and there
> were 6 such patients, you gave 5 of them to ampicillin and 1 to
> tetracycline. So, that is how it was done.
>
> DR. LEGGETT: One final question. Mike?
>
> DR. PROSCHAN: I was wondering if the late onset rashes are more
> serious than the early ones.
>
> DR. BIGBY: As far as I know there is no correlation.
>
> DR. LEGGETT: Thank you, Dr. Bigby. I would like to take this moment to
> have folks who arrived late introduce themselves.
>
> DR. GOLDBERGER: Mark Goldberger, from the Office of Drug Evaluation
> IV.
>
> DR. DRAKE: Lynn Drake, from Massachusetts General Hospital Harvard
> Medical School.
>
> DR. BROWN: Ken Brown, representing industry, University of
> Pennsylvania.
>
> DR. MAXWELL: Celia Maxwell, Howard University.
>
> DR. POWERS: John Powers, lead medical officer for antimicrobial drug
> development in ODE IV.
>
> DR. LEGGETT: Are you ready to go?
>
> **Antimicrobial Resistance in**
>
> **[Streptococcus Pneumoniae]{.underline}**
>
> DR. POWERS: What I would like to talk to you about today is a
> continuation of a discussion that we began back in the January
> committee meeting. At that time, the sponsor for that drug requested
> an indication for community-acquired pneumonia and a few other
> diseases due to penicillin-resistant [Streptococcus
> pneumoniae]{.underline} and macrolide-resistant [Streptococcus
> pneumoniae]{.underline}.
>
> Today the drug sponsor is requesting an indication that includes both
> those two resistance patterns and cefuroxime-resistant [Streptococcus
> pneumoniae]{.underline} as well. So, this seemed like a good
> opportunity to actually discuss where we are going with antimicrobial
> resistance in [Streptococcus pneumoniae]{.underline} and its
> implication for prescription drug labeling.
>
> \[Slide\]
>
> What I would like to talk to you to start off about is our historical
> background on how we have approached antimicrobial resistance labeling
> claims in the past, and then to try to tie together what we have seen
> has been done in labels in the past with some rationale of why we have
> done what we have done, then present some data to you that we have
> acquired on cross-resistance among [Streptococcus
> pneumoniae]{.underline} strains of various antimicrobials, and then
> put forward for the committee a proposal for future labeling of
> antimicrobial resistance claims for [Streptococcus
> pneumoniae]{.underline}.
>
> As Dr. Albrecht said, this discussion is relevant to this drug today
> because of what the sponsor is requesting but it really does also
> dovetail very well into tomorrow\'s discussion on drug development for
> antimicrobially resistant pathogens.
>
> \[Slide\]
>
> If we look back at the labels that the FDA has issued in the past,
> most of these drug resistance claims deal with resistance to drugs
> within the same class which we have termed \"in class\" resistance.
> This would include things like a number of cephalosporins for
> beta-lactamase producing organisms like [Haemophilus
> influenzae]{.underline} and [Moraxella cetarrhalls]{.underline} in
> various infections. The label for nafcillin also reads for severe and
> serious infections in penicillinase-producing staphylococci.
>
> \[Slide\]
>
> On the other hand, the FDA has not granted several claims for \"out of
> class\" resistance, meaning resistance to a class outside of that
> particular drug class, such as in the past when fluoroquinolones were
> asked for indications for penicillinase-producing [Neisseria
> gonorrhoea]{.underline} infections. That has been denied. As well as
> there are no labels that include beta-lactamase producing [H.
> influenzae]{.underline} or [Moraxella catarrhalis]{.underline} in the
> quinolone labels.
>
> On the other hand there are approved \"out of class\" resistance
> claims and here are a couple of examples. For example, vancomycin is
> indicted for serious or severe methicillin-resistant [Staph.
> aureus]{.underline} infections and, more recently, linezolid was
> approved for hospital-acquired pneumonia and complicated skin and skin
> structure infections with methicillin-resistant [Staph.
> aureus]{.underline}, and also carries a claim for vancomycin-resistant
> [Enterococcus faecium]{.underline} infections.
> Dalfopristin-quinupristin also carries an indication for
> vancomycin-resistant [Enterococcus faecium]{.underline} bacteremia.
> Then, most relevant to our discussions today, levofloxacin and now,
> last Friday, moxifloxacin are both approved for community-acquired
> pneumonia with penicillin-resistant [Streptococcus
> pneumoniae]{.underline}.
>
> \[Slide\]
>
> Well, what ties all these together, the \"in class\" and the \"out of
> class\" resistance? What are we trying to do when we grant a
> resistance claim? Really, the benchmark is that the information in
> labeling should aid clinicians in their ability to make clinical
> decisions and in choosing drugs to treat their patients.
>
> We have divided this up into five characteristics that would enable a
> clinician to make that decision. The first is that the organism is
> unique and distinguishable. In other words, is there cross-resistance
> across drugs such that one cannot differentiate between these
> organisms? For instance, if we look at vancomycin and methicillin
> resistant [Staphylococcus aureus]{.underline} we know that MRSA
> organisms are resistant to a number of other drug classes, including
> the quinolones, and yet we don\'t grant separate indications for
> methicillin-resistant [Staph. aureus]{.underline} and
> quinolone-resistant [Staph. aureus]{.underline}.
>
> Secondly, the drug to which organism is resistant is commonly used to
> treat the infection under study. For instance, we don\'t grant
> indications for, say, streptomycin-resistant gram negative rods for
> urinary tract infections because people don\'t use that drug to treat
> that particular infection.
>
> The third thing is that there are few alternative therapies to be able
> to treat that drug \[sic\] and that is why this information is
> important to put in the labels so that the clinicians know that this
> particular drug is available to treat that kind of infection.
>
> The fourth thing is that [in vitro]{.underline} resistance actually
> correlates with increased clinical failures, and we had a long
> discussion about this at the last advisory committee meeting related
> to macrolide-resistant [Streptococcus pneumoniae]{.underline} and the
> state of the data there.
>
> Finally, the other important thing is that allowing a drug sponsor to
> put a resistance claim in the label provides incentive for that
> sponsor to actually acquire data on the efficacy and safety of the
> drug in infections due to that resistant organism.
>
> \[Slide\]
>
> Let\'s apply these principles and look at some of what we have done in
> the past to see if this makes sense. For vancomycin and MRSA, MRSA
> clearly is a unique and distinguishable organism with different
> characteristics but, as I said, methicillin resistance correlates with
> resistance to other drugs which are not separately designated in the
> label. For instance, resistance to cephalosporins and resistance to
> quinolones are not given separate designations in addition to
> methicillin resistance.
>
> At the time of approval, methicillin and other anti-staphylococcal
> penicillins were commonly used, as they are still commonly used today,
> in the treatment of staphylococcal infections although methicillin
> itself has fallen out of common usage. At the time of vancomycin
> approval there were few alternative therapies for serious
> methicillin-resistant [Staph. aureus]{.underline} infections and some
> data, although this is controversial, indicate worse outcomes with
> methicillin-resistant [Staph. aureus]{.underline} compared to
> methicillin sensitive [Staph. aureus]{.underline} infections and,
> certainly, if one receives a drug to which the organism is resistant
> the outcome appears to be worse.
>
> \[Slide\]
>
> Now let\'s apply this to levofloxacin and penicillin-resistant
> [Streptococcus pneumoniae]{.underline}. At the time of approval,
> penicillin-resistant [Streptococcus pneumoniae]{.underline} was
> considered a unique, new organism for which clinicians desired
> treatment information.
>
> Penicillin was a previously commonly used antimicrobial to treat
> community-acquired pneumonia, and also penicillin resistance is used
> in clinical laboratories as a marker for resistance to other drug
> classes as well. In these organisms that are resistant to many drug
> types in [Streptococcus pneumoniae]{.underline} there appear to be
> limited treatment options and I am going to show you some data on the
> cross-resistance amongst these various types of classes.
>
> At the time of levofloxacin approval there was very little data in the
> clinical literature on outcomes with community-acquired pneumonia in
> people who were infected with penicillin-resistant [Streptococcus
> pneumoniae]{.underline}.
>
> \[Slide\]
>
> But since that time we have acquired some information on the
> cross-resistance patterns of penicillin-resistant isolates and their
> resistance to other drug classes. Also, there is accumulating clinical
> data that the outcome in patients who are infected with
> penicillin-resistant [Streptococcus pneumoniae]{.underline} is no
> worse in most cases of community-acquired pneumonia as long as the
> minimum inhibitory concentration to penicillin of that infecting
> organism is less than 4 mcg/ml, which is the majority of PRSPs in this
> country which have less than 4.
>
> \[Slide\]
>
> Before I go on to present some data about cross-resistance among
> various antimicrobial classes for [Streptococcus
> pneumoniae]{.underline}, one could ask the logical question of what
> degree of cross-resistance among drug classes is clinically
> significant.
>
> \[Slide\]
>
> When you try to look this up, there is actually little scientific data
> that actually addresses this question of at what degree does this
> become relevant. The Infectious Disease Society of American guidelines
> for some infections suggest that clinicians should use alternate drugs
> when resistance is 10-20 percent for a drug class. The IDSA guideline
> for community-acquired pneumonia doesn\'t address this question but
> the one for urinary tract infection does specifically say 10-20
> percent. However, this is based on expert opinion, not really data.
>
> But since the time that that IDSA guideline was issued, one model
> based on a cost estimate, estimated that this clinically relevant
> degree or resistance to the drug trimethoprim-sulfamethoxazole, which
> is commonly used in urinary tract infections\--when that level
> approaches 22 percent, then that becomes clinically relevant at least
> in terms of how much cost is spent and it didn\'t really address it in
> terms of what the clinical outcomes are as well. So, one could
> actually say perhaps that that level of 20 percent could be used as a
> benchmark, although that still remains controversial.
>
> \[Slide\]
>
> Since the January advisory committee we have been trying to get data
> on the cross-resistance patterns amongst various antimicrobials for
> purposes of drug development. We obtained a contract to get
> surveillance data from Focus Technologies for the purposes of
> identifying and tracking resistant organisms of public health
> importance for drug development.
>
> \[Slide\]
>
> The surveillance network of Focus Technologies encompasses 317 U.S.
> laboratories. They are directly connected via computer to these
> laboratories and it is updated continuously. This surveillance
> includes community, government and university laboratories and
> includes hospitals that have bed sizes from less than 99 to 500 beds.
> The surveillance network gives us access to greater than 65 million
> antibody susceptibility testing results, and these are not active
> surveillance but they are based on cultures which the clinicians
> order. There are greater than 500 microbial taxa included in this and
> susceptibilities to greater than 100 individual types of drugs. This
> covers almost 3 million patients in the United States and includes
> both inpatient and outpatient data.
>
> The data I am going to show you today is pooled information although
> we are planning on separating this out into inpatients and outpatients
> once we have a chance to look at the data in more detail. This gives
> us access to about 2.6 percent of all isolates tested per year in the
> United States, and some of the other surveillance programs are
> actually less than 1 percent.
>
> \[Slide\]
>
> What I am going to show you now is a couple of graphs on
> cross-resistance. This is a blank slide to show you what we are trying
> to look at here. So, what we have done is to look at one drug and show
> increasing MICs across the X axis compared to a second drug with
> increasing MICs across the Y axis. What you will see here is some red
> dotted lines, here. These vertical lines, here, are the intermediate
> susceptibility breakpoint for drug X, and the second vertical line
> will be the breakpoint for a high level resistance to this drug, X.
> The two horizontal lines are the intermediate susceptibility
> breakpoint to drug Y, and this higher dotted horizontal line will be
> the high level susceptibility breakpoint to drug Y.
>
> What this will do is divide this up into nine different boxes. Some of
> these drugs don\'t have intermediate susceptibility breakpoints so you
> will see that some of these boxes are missing when I show you some of
> these. But what we will have then is that in the lower left-hand
> corner will be organisms that are susceptible to drug X and
> susceptible to drug Y. In the upper right-hand corner you will see
> organisms that are resistant to drug X and resistant to drug Y. This
> diagonal line, here, will be organisms that are concordant, meaning
> they are either susceptible, intermediate or resistant to these two
> drugs and the rest of the boxes are discordant.
>
> \[Slide\]
>
> What I wanted to show you was an example of an organism and two drug
> classes that we know are concordant. We know that most
> methicillin-resistant [Staphylococcus aureus]{.underline} are
> resistant to quinolones as well. So, if we look here, across the X
> axis we have increasing MICs of oxacillin. The Y axis is increasing
> MICs to ciprofloxacin. This is a total of 234,000 isolates that are
> tested and, actually, these dots represent 10 results each because if
> we put them all in here the entire slide turns black. So, it is just
> to make it a little easier for you to look at. This vertical line,
> here, is the breakpoint for oxacillin to methicillin-resistant
> [Staphylococcus aureus]{.underline}, and this is the intermediate
> breakpoint for cipro. and the high level breakpoint for cipro. They
> are a little off because when you shine these things up on Power Point
> all the lines move around so this is the best we could do with this.
>
> What I wanted to show you was that essentially when there is
> correlation in cross-resistance you can almost draw a diagonal line
> here, and you see that there is clustering of the organisms here,
> meaning that if this organism is oxacillin susceptible it also tends
> to be susceptible to ciprofloxacin. If the organism is oxacillin
> resistant, it also tends to be resistant to ciprofloxacin as well.
>
> \[Slide\]
>
> Let\'s apply this to looking at [Streptococcus
> pneumoniae]{.underline}, looking at penicillin and cefuroxime. Again
> we see the same kind of pattern here. There is a clustering in the
> lower left-hand corner which shows that if an organism is susceptible
> to penicillin it is likely to be susceptible to cefuroxime, and if an
> organism is resistant to penicillin it is likely to be resistant to
> cefuroxime as well.
>
> \[Slide\]
>
> Let me show you the opposite of a lack of correlation. Here, if we
> look at penicillin on the X axis and levofloxacin on the Y axis you
> can see that if an organism is penicillin susceptible, it tends to be
> susceptible to levofloxacin; if an organism is penicillin resistant we
> see the clustering in the lower right rather than the upper right. If
> there was a correlation between levofloxacin and penicillin resistance
> we should see the clustering up here, however we see it down here,
> meaning that penicillin organisms for the most part still retain their
> susceptibility to levofloxacin.
>
> \[Slide\]
>
> We did this for any number of drug combinations, looking at resistance
> in [Streptococcus pneumoniae]{.underline}, and we did this in two
> ways. First we took penicillin-resistant organisms and tried to see
> what their resistance was to other drug classes. Then we flipped it
> around and looked at it the other way and said let\'s take organisms
> resistant to the other drug classes and see how often they are
> resistant to penicillin, trying to make sure that the correlation goes
> in both directions.
>
> \[Slide\]
>
> The first slide that I will show you is the first example for
> penicillin-resistant [Streptococcus pneumoniae]{.underline} and we
> tried to look at the rate of resistance to other drug classes. As you
> can see here, the rate of resistance of penicillin-resistant
> [Streptococcus pneumoniae]{.underline} to second generation
> cephalosporins is almost 98 percent; trimethoprim-sulfa almost 88
> percent; erythromycin 82 percent; tetracycline is about 46 percent;
> clindamycin 23 percent; third generation cephalosporins 98.6 percent
> and then levofloxacin 1.4 percent. So, if we say that cut-off point is
> about 20 percent we can say that clearly second generation
> cephalosporin, trimethoprim-sulfa, erythromycin and tetracyclines are
> above that line. Clindamycin and third generation cephalosporins is
> debatable, and levofloxacin is clearly below that cut-off.
>
> \[Slide\]
>
> Now let\'s take it and turn it around the other way. Let\'s take
> organisms that are resistant to second generation cephalosporins and
> see how often they are resistant to penicillin. So, this becomes a
> clinically relevant question for clinicians. If I have resistance to
> one of these classes, how often can I use one of the other drugs?
>
> You can see that the correlation really goes in both directions.
> Second generation cephalosporins 60 percent; trimethoprim-sulfa 50;
> erythromycin 50 percent; and tetracycline is around 50 percent. Then
> you will see that these bottom three, when you start off with
> clindamycin, third generation cephalosporin or levofloxacin resistance
> the level of penicillin resistance actually shoots up. So, 50 percent
> of clindamycin-resistant isolates are resistant to penicillin; 93
> percent of third generation cephalosporin-resistant isolates are
> resistant to penicillin; and a third of levofloxacin-resistant
> isolates are resistant to penicillin, leaving you not much of a
> treatment choice when we get down to a levofloxacin-resistant bug.
>
> The other thing I want to point out to you is how often clinical
> laboratories actually test for these, which goes to sort of the idea
> of how often do people actually use these various drug classes. These
> numbers correlate to when a lab tested penicillin resistance and
> tested for that drug resistance simultaneously. You can see that
> 32,000 isolates were tested for both third generation cephalosporins
> and penicillin, but we get all the way down to less than 6000 isolates
> tested in labs against second generation cephalosporins and
> penicillin.
>
> \[Slide\]
>
> What do we make out of all this information? There was a discussion at
> the last advisory committee in January about labeling organisms to
> just say susceptible pathogens only. In other words, a label would
> read something like drug X is indicated for community-acquired
> pneumonia in susceptible strains of [Streptococcus
> pneumoniae]{.underline}. But when we look at that, it actually
> doesn\'t address what we have been doing in the past with resistance
> labeling, and that is actually conveying some important information to
> physicians.
>
> There are also a couple of other issues. If we do not grant these
> claims to other drugs that are approved in the future, it may place
> those drugs at an unfair competitive disadvantage. One can say, well,
> that wouldn\'t be the case if we went back to the levofloxacin label
> and withdrew the penicillin-resistant [Streptococcus
> pneumoniae]{.underline} indication. However, from a regulatory
> perspective that is actually very difficult to do.
>
> The other thing that is a real key issue here though is, is this
> information that would be important to convey to clinicians that these
> organisms are not just resistant to penicillin but if you have an
> organism that is resistant to penicillin then it is going to be
> resistant to these other drug classes as well? Again, that is the
> benchmark we use, are we educating clinicians here?
>
> The other point that is really important to keep in mind here is that
> this drug label is not just written for infectious disease specialists
> who may be well informed about these cross-resistance patterns; it is
> for all kinds of clinicians who may not have as much information on
> cross-resistance.
>
> The other issue is that if we don\'t grant resistance labeling claims
> and just put susceptible pathogens only, this really gives drug
> sponsors no incentive at all to go out and acquire clinical data on
> treatment with these resistant pathogens.
>
> \[Slide\]
>
> So, what do we see here? We see a high rate of cross-resistance among
> penicillin-resistant classes and other drug classes, including second
> generation cephalosporins, macrolides, tetracyclines and
> trimethoprim-sulfa resistance. Therefore, based on what we said about
> vancomycin and MRSA, these organisms do not appear to be unique. If
> you have a PRSP organism it is likely to also be resistant to these
> other drug classes as well.
>
> The second criterion used is are these drugs commonly used in the
> infection under study? Yes, all 5 of those drug classes, penicillin,
> cephalosporins, macrolides, tetracyclines and trimethoprim-sulfa are
> commonly used to treat respiratory tract infections. It also conveys
> information about cross-resistance to clinicians in prescription drug
> labeling, especially because these drugs are often prescribed
> empirically. First of all, we don\'t always even get cultures in
> outpatients but, even so, we usually prescribe these drugs empirically
> for at least 48 hours when we do get culture information. Again, it
> also provides an incentive to the sponsor to obtain clinical
> information on treatment of these multi-drug resistant organisms.
>
> \[Slide\]
>
> So, the proposal that we would put before the committee today, which
> would apply to this drug under discussion today but also to future
> drug labeling claims as well as going back to previous drugs and
> changing their labels, would be to define a term called multi-drug
> resistant [Streptococcus pneumoniae]{.underline}, similar to what we
> did with multi-drug resistant tuberculosis.
>
> \[Slide\]
>
> Not to say this is how scientists and authors should define this, but
> for the purposes of drug labeling we would define this as resistance
> to penicillin, second generation cephalosporins, macrolides,
> tetracyclines and trimethoprim-sulfa. Doing this would maintain the
> distinct nature of non-cross-linked resistance such as that to the
> pneumococcal quinolones. So, that would be a separate indication as
> well.
>
> This definition could change over time. If other resistance does
> become linked, we could go back to those labels and add in more things
> to this definition of multi-drug-resistant [Streptococcus
> pneumoniae]{.underline}. This serves the purpose of informing
> clinicians that the organism is not just resistant to one drug class
> but is resistant to all of these drug classes where, if we designate
> them separately such as PRSP and MRSP, clinicians who are not informed
> in this area may assume that an MRSP still might be susceptible to
> penicillin. However, drug sponsors would still need to obtain clinical
> data to garner this resistance claim.
>
> \[Slide\]
>
> But are we raising the bar here by doing that? Actually, we are not.
> We are trying to streamline drug development by doing this. For
> example, a drug sponsor would need the strongest supportive data for
> \"in class\" resistant strains because that is what we are really
> worried about.
>
> Let me give you an example. Suppose someone came in with a
> tetracycline type drug. They would need the strongest supportive data
> on tetracycline-resistant organisms. But does that mean they need a
> whole lot of penicillin-resistant organisms, macrolide-resistant
> organisms, etc.? Well, for \"out of class\" resistance one could make
> the scientific argument why should we be worried that this drug
> wouldn\'t work if the mechanism of resistance is different than that
> particular drug class?
>
> The other thing is that from what I showed you we already know that a
> good proportion of, say, the tetracycline-resistant organisms are
> already going to be resistant to penicillin, second generation
> cephalosporins, macrolides and tetracyclines so if they had a good
> number of tetracycline-resistant organisms they would already have a
> good number of isolates that were resistant to these other drugs as
> well in their database.
>
> The other benefit of \"out of class\" resistance is that one may be
> able to use susceptible isolates to support the data on resistant
> isolates. For instance, we know that for, say, the anti-pneumococcal
> quinolones for the most part the MICs to penicillin resistant and
> penicillin susceptible isolates are pretty close. That would be a
> benchmark that we have to look at though, that there is no appreciable
> difference in MICs for penicillin susceptible and resistant isolates
> so that one could use the efficacy in penicillin susceptible isolates
> to support the penicillin resistant isolates for, say, a tetracycline
> type drug, given that alterations in penicillin binding proteins
> wouldn\'t have a whole lot to do with tetracycline afflux pumps.
>
> \[Slide\]
>
> But this gets to another issue, and that is something that sponsors
> ask us all the time, how many do I need? The numbers game\--my
> favorite. Sponsors love to have this number to shoot for when they are
> garnering a resistance claim and this makes logical sense. If you are
> going to invest in a drug development program you want to know when
> you have won and when you have lost.
>
> But it is not that easy when you are on our end and you have to
> actually review this clinical information, and we ask the basic
> question should resistance claims be based on quality of data rather
> than quantity of data? And, how would one define a high quality case?
>
> Well, there are three things that we can think of. One would be that
> the disease is unlikely to remit spontaneously. For instance, if one
> looks at acute bacterial meningitis and you show that the drug works
> in meningitis, that is different than looking at, say, acute
> exacerbations of chronic bronchitis where the placebo cure rate in
> that disease may be as high as 50 percent.
>
> The second thing we look at is the certainty of the diagnosis.
> Isolates from a normally sterile body site, like cerebral spinal
> fluid, tend to provide us more information than, say, isolates from a
> non-sterile body site, such as sputum.
>
> One of the other things that is very difficult, especially in serious
> disease, is that we look for little confounding in assessment of the
> drug\'s contribution to efficacy. Again, if we go back to, say, a
> meningitis trial and you show that you had 5 cases of meningitis and
> all 5 of them got better but then, when we evaluate the cases, we see
> that all these people got vancomycin and ceftriaxone and on day 5 they
> had new drug X added and on day 6 we raise the flag of victory and
> say, look, the patient got better and it is all because of drug X,
> that is very difficult for us to actually piece together.
>
> Finally, there is the efficacy rate in the disease in question. So, if
> someone comes in with 5 cases of meningitis and four of them are
> failures and one of them was a success, what do we make out of that
> information?
>
> So, when we talk about coming up with a number for sponsors to shoot
> for, what I am just trying to show you here is that it is very
> difficult to just draw a line in the sand and say X number of cases
> gets you an indication because it is really the quality that we are
> looking at as well as the number of cases.
>
> \[Slide\]
>
> In conclusion, what I would like to leave you with is something for
> the committee to discuss here, again referable to this drug as well as
> to other drugs in the future, which is that an indication would read
> something like this: Drug X is indicated in the treatment of
> community-acquired pneumonia due to [Streptococcus
> pneumoniae]{.underline}, including multi-drug resistant strains,
> meaning resistance to penicillin, second generation cephalosporins,
> macrolides, tetracyclines and trimethoprim-sulfa. Again, as we
> continue to gather information on this over time that definition of
> multi-drug resistance may change.
>
> Then, what we would also suggest doing is listing the actual clinical
> trials data on which this resistance claim is based in the clinical
> studies section of the label. Therefore, if a sponsor studied more
> patients they would be able to show in the label that they had a
> stronger body of evidence than someone else did.
>
> I will stop at that point and I would be happy to answer any
> questions.
>
> DR. LEGGETT: Thank you, Dr. Powers. Dr. Poretz?
>
> DR. PORETZ: Obviously, most physicians are in practice and not
> infectious disease doctors. In different hospitals in the country you
> get reports of an antimicrobic sensitivity pattern that is either
> sensitive or resistant sometimes or MICs, depending upon the hospital
> or lab that is used. I have always wondered whether the average
> physician understands MICs. Is it confusing? Is it worthwhile
> reporting that? Actually, my microbiologist tells me it is cheaper,
> because it is automated, to do MICs than it is to replate sensitive or
> resistant. Does the average doctor know the difference? Does it make
> any difference in antimicrobic selection or is it confusing?
>
> DR. POWERS: That is probably a question I am not qualified to answer.
> We have debated whether we should put MICs in the label or not. We
> have done so for some drugs. For instance, Augmentin does include an
> MIC in the label for where we think this drug is effective up to a
> particular MIC. So, we have done it.
>
> Again, this is a tricky thing when you are writing a label. It
> doesn\'t mean that you should exclude information that an infectious
> disease physician might find helpful, but we should also write it in
> such a way that people who are not infectious disease physicians can
> understand it as well. My personal opinion is that I agree with you, I
> don\'t know that the majority of non-infectious disease physicians
> would understand what those MICs actually mean.
>
> The other point is that as far as labeling goes, we know that these
> breakpoints keep shifting around. For instance, the NCCLS just changed
> the breakpoints for third generation cephalosporins for non-meningeal
> isolates. So, that is a moving target for us as well.
>
> DR. LEGGETT: Dr. O\'Fallon?
>
> DR. O\'FALLON: Of course, I want to know are the MICs at one place the
> same as the MICs at the other place. So, do you have a problem with of
> shifting values?
>
> DR. POWERS: That is a good point. After the last advisory committee
> meeting Dr. Leggett sent an e-mail showing how some resistant
> pneumococci were actually misidentified based on the methodology. So,
> we know that those things exist but that is why we went out and tried
> to gather this information with 317 different labs, trying to get a
> more broad-based approach to this.
>
> DR. O\'FALLON: This looks really good to me, knowing what has been
> around here before, but putting a number in the label will be a
> problem unless the MICs are the same across the country.
>
> DR. LEGGETT: Dr. Reller, could you address that point?
>
> DR. RELLER: We recognize that laboratories, like clinicians, vary in
> their prowess but laboratories are very highly regulated and to be
> accredited, they are supposed to follow NCCLS standards and the
> numbers are very precise. They change because the science changes and
> an attempt is made, with documents coming out each January, to keep up
> with the science and change the breakpoints when additional data are
> available or clinical information about failures related to previous
> breakpoints.
>
> The comments about how much information is conveyed with an MIC and
> automated methods in the laboratory\--in reality most MIC reports from
> laboratories, in fact, are not MICs. They are based on breakpoint
> panels and they, in truth, convey no more information than an SINNR.
> There are few exceptions and I think, Dr. Poretz and all other
> infectious disease clinicians here, there are a few places where
> numbers are very important where an exact MIC is crucial to care, like
> the less than 0.06 for penicillin in the treatment for meningitis with
> [Streptococcus pneumoniae]{.underline}. But to get that precise MIC
> requires different methodology, actually doing an exact MIC which is
> not on automated system, through, for example, E-testing or other
> exact MICs. In the treatment for endocarditis an exact MIC to an
> infectious disease clinician for streptococcal endocarditis means
> something. There are a few situations where an exact MIC is necessary
> but most MICs on reports coming from clinical laboratories, in fact,
> are based on breakpoints and do not give any more additional
> information than an SINNR.
>
> DR. LEGGETT: Thank you. Dr. Bradley?
>
> DR. BRADLEY: I think that the vast majority of clinicians for the vast
> majority of infections look at the lab report to see whether the
> organism is interpreted as sensitive, intermediate or resistant. When
> interpretation of the breakpoints change, like what happened with
> enterococcus a few years ago and what just happened with the third
> generation cephalosporins, the understanding of why that change
> occurred is missing among the general clinicians. All they do, they
> see that the bugs are now all intermediate or resistant or now, with
> the third generation cephalosporins in pneumococcus, a lot more
> susceptible.
>
> So, I think the SINNR are critical pieces of information for the
> clinician and the NCCLS has done a very nice job of continuing to get
> new information to change the breakpoints if that becomes applicable.
>
> The [in vitro]{.underline} susceptibility, to go back to your initial
> point, John\--our training is to look at [in vitro]{.underline}
> susceptibility when we get an organism. When you approve a drug to
> treat that organism there is a disclaimer that treatment is based on
> [in vitro]{.underline} susceptibility. So, the giving of special
> indications for organisms based on different [in vitro]{.underline}
> susceptibilities doesn\'t make much sense and I think it has been used
> a lot for marketing as opposed to scientific usage in order to treat
> patients.
>
> But the points that you make certainly are very well made in that
> there are a lot of resistant organisms that are present now, and for
> the doctor to know that it is the old-fashioned susceptible strain
> versus one that is tougher to treat, susceptible versus multi-drug
> resistant, is a very interesting concept. In putting together your NDR
> for [Strep. pneumo]{.underline}. I would suggest perhaps that you say
> resistant to penicillin plus two others because, as you mentioned, in
> addition to macrolides there are ketolides, oxazolidones and God knows
> what is going to come up next, and if you say it is resistant to all
> of them, then that actually represents only a very small percentage of
> all the resistant isolates, just the worse ones. Indeed, I think the
> concept you are trying to get across is the fact that there are some
> which have multiple drug resistance, not maybe to everything but to
> many, and to get drug approval and an indication in the label for
> those more resistant strains is quite reasonable.
>
> DR. LEGGETT: Dr. Hilton?
>
> DR. HILTON: I have a comment on your correlation plots. I like the
> comment at the end where you talked about the quality of the efficacy
> rate data, and I think it applies to the correlation plots. You
> mentioned that the data for those plots came from isolates that
> clinicians sent to labs. Of course, there could be multiple isolates
> from a single patient and they would weight the findings by that
> patient\'s severity of disease.
>
> DR. POWERS: That we ruled out. There are not multiple isolates per
> patient in this database. We took care of that. You do raise an
> important point though of who gets cultured. It may be skewed towards
> people that are sicker.
>
> I will give you a good example. I am going to show some information on
> this cross-resistance for other types of organisms tomorrow when we
> talk about drug development. We looked at something like gonorrhea. I
> showed you that there are about 230,000 [Staph. aureus]{.underline} in
> this database; there are 1500 [Neisseria gonorrhoeae]{.underline},
> which says that people aren\'t culturing for those. That doesn\'t mean
> it is not important; it just means people aren\'t looking.
>
> No way did I mean to make this the be-all and end-all but it is the
> best thing we could get our hands around when we were trying to look
> at this problem.
>
> DR. LEGGETT: One last comment. Dr. Brown?
>
> DR. BROWN: John, that was a great presentation and I appreciate it.
>
> DR. POWERS: Are you going to ask me what I think this time, Dr. Brown?
>
> DR. BROWN: No, I am going to ask you for a very specific question,
> either you or Dr. Goldberger. The numbers game is very important to
> everybody. I think high numbers in the thousands of patients are
> important for assessing safety. However, for efficacy I think the
> numbers game becomes important and I would like to ask you, folks, if
> I had \"wondermycin\" and I was looking for a claim for penicillin
> susceptible or \"wondermycin\" susceptible pneumococcal pneumonia
> where I knew what the organism was either from a trans-trach. or a
> blood culture, I had X-ray diagnosis and I had a good cure rate, how
> many patients should I study to get that claim?
>
> I have to tell you that more is not a sufficient answer, but that is
> the most common answer that we tend to get. As an example, when I was
> working up a drug for gonorrhea and we kept getting the answer more,
> and more, and more, we wound up studying a thousand patients with
> uncomplicated gonorrhea. That seems unreasonable. On the other hand,
> the number which we worked with at the time was in a given box, that
> is, one organism by one disease, and we tried to get at least 10
> patients with a 70 percent cure rate. But I would like to hear a
> specific answer for what the FDA accepts now.
>
> DR. POWERS: I think there are two questions within your question. One
> is how many patients who are infected with a resistant isolate do you
> need? The second one, the broader question you asked, was how many do
> you need to study?
>
> Let me answer the first one first. There are benchmarks for what we
> have done in the past. For instance, the database that levofloxacin
> had for penicillin-resistant organisms was about 15 isolates depending
> upon how you count it. But that is not an exceedingly large number for
> people with community-acquired pneumonia. When we asked this question
> of people in industry at the February, 2002 meeting, Dr. Goldberger
> asked Dr. Frank Tally how many isolates do you think we need and his
> answer was 15. So, it just happened to correlate with what we had
> looked at for penicillin-resistant [Streptococcus
> pneumoniae]{.underline} and levofloxacin.
>
> Now, the second question you asked was how many patients do they have
> to study to find those 15? But there is a hidden thing in that
> question and that is who you choose to study. So, they had to study
> about 3000 patients to find those. There are two issues there. One is
> that levofloxacin was doing studies at a time when penicillin
> resistance was not as widespread as it is today. The second thing is
> that when you look at the original levofloxacin application and the
> licensing study for that, 57 percent of those people were outpatients
> who were not particularly ill.
>
> So, if you choose to use a development program where you guide your
> treatments towards patients who are less likely to harbor resistant
> organisms, you are going to have to study a whole lot of people to
> find those cases. That is not up to us. What we have told sponsors is
> that if you want to look for resistant organisms you should probably
> gear your development program towards patients who are most likely to
> harbor those. We had this discussion again in July at an advisory
> committee about otitis media and about how to gear your development
> program towards patients who are most likely to harbor that.
>
> We saw this development program in Augmentin where they had 50
> isolates of penicillin-resistant [Streptococcus
> pneumoniae]{.underline} in kids with otitis media in one respiratory
> season because they gauged their development program towards the kids
> who were most likely to harbor those organisms.
>
> DR. GOLDBERGER: If I could follow-up also on that, I think the other
> component in terms of thinking about the numbers, and again, I think
> levofloxacin is an example of this as is moxifloxacin, is collecting
> information about the effectiveness of the drug in penicillin, for
> instance, susceptible pneumococci since penicillin-resistant
> fluoroquinolones is clearly very much \"out of class.\"
>
> Again, we were very comfortable with, as John describes, what I think
> is a very reasonable and certainly a low number of cases of PRSP in
> fluoroquinolones because of buttressing our understanding of how
> fluoroquinolones perform in pneumococcal infections, using
> levofloxacin as an example, was about 250 patients with pneumococcal
> infection, including 55 patients with pneumococcal bacteremia which is
> considered to be a severe manifestation, that is, pneumococcal
> bacteremia and pneumonia with an overall cure rate of 100 percent.
>
> So, that information as to how a drug performs overall, including
> susceptible isolates plus some additional data, a relatively modest
> amount of additional data in resistant isolates to just tell us that
> if the patients who harbor resistant isolates are in some way
> different and the drug still works formed a very nice package. And,
> the model that we have used for levofloxacin we think is a useful way
> to proceed in developing drugs for \"out of class\" resistance claims.
> That is the model today and we have articulated these similar thoughts
> at meetings like this, as well as meetings directly one-on-one with
> sponsors.
>
> DR. LEGGETT: Thank you. We will now take a break for eight to ten
> minutes max. Thank you.
>
> \[Brief recess\]
>
> DR. LEGGETT: We would like to get started now on the sponsor
> presentation. What we will do is try to stay on time so there will be
> plenty of time for questions. I am going to ask the speakers to go one
> after the other and for the panel and committee members to save
> questions until the very end of the sponsor\'s presentation, and we
> will try to do likewise for the FDA presentation and then reconcile
> any questions that still may linger at the very end before going to
> lunch and giving the sponsor some time to bring back answers, or the
> FDA to bring back answers, if they cannot be answered before lunch,
> during that open public hearing if time remains.
>
> I would like to introduce Dr. Gary Patou, the president of GeneSoft
> Pharmaceuticals.
>
> **Sponsor Presentation**
>
> **Introduction**
>
> DR. PATOU: Good morning, members of the advisory committee and the
> FDA.
>
> \[Slide\]
>
> Ladies and gentlemen, I am Gary Patou, president of GeneSoft
> Pharmaceuticals. I led the development of gemifloxacin through its
> Phase I through III clinical trials, and I will lead you through the
> presentations today on gemifloxacin.
>
> Many of you have been involved in the approval process for other
> fluoroquinolones and, considering this, I think you will appreciate me
> getting straight to the point. We believe there are two primary issues
> on the table here today. The first is why do we need another
> respiratory fluoroquinolone? Well, we are going to show you that
> gemifloxacin is not just another fluoroquinolone. It is uniquely
> potent and this translates into clear clinical and microbiological
> benefits.
>
> The second issue is the high incidence of rash that we saw in the
> clinical trials. Who gets the rash? When do they get it? How long does
> it last? But, most importantly, is it serious?
>
> To answer these questions we conducted a Phase I volunteer study in
> 1000 subjects. This was a study agreed upon with the FDA. The rash was
> evaluated by a team of dermatologists, dermatopathologists and
> clinical pharmacologists. Many of them are here today to help address
> any questions the advisory committee may have. A substantial part of
> our presentation today will be addressing and asking questions of that
> particular study.
>
> \[Slide\]
>
> That is by way of introduction. Let me summarize gemifloxacin for you.
> The chemical structure of gemifloxacin is shown below. It is a member
> of the fluoroquinolone class. It is the most potent gram positive
> fluoroquinolone, with an MIC-90 against [Streptococcus
> pneumoniae]{.underline} or 0.03. It is dual-targeting in patients and
> unique amongst the fluoroquinolones in being active against the
> majority of [Strep. pneumoniae]{.underline} organisms that are
> resistant to other fluoroquinolones.
>
> \[Slide\]
>
> Turning now to the pharmacokinetics, gemifloxacin is rapidly absorbed.
> Oral bioavailability is high, on average 70 percent. It has a long
> half-life, allowing for once daily dosing, and it is 55-65 percent
> protein bound with a large volume of distribution. Greater than 70
> percent of the drug in plasma, urine and feces is unchanged
> gemifloxacin. So, metabolism plays only a minor part in the
> elimination of the drug. There are no significant drug-drug
> interactions with gemifloxacin since it is neither metabolized by nor
> an inhibitor of the cytochrome p450 system which is the major system
> for drug elimination in the body. Consequently, it has predictable
> pharmacokinetics. The drug is eliminated by both the renal and the
> hepatic routes with 20-40 percent of the drug going out through the
> kidney, the rest through feces. This means no dosage adjustment is
> necessary in any severity of hepatic deficit and only in the most
> severe instances of renal impairment.
>
> \[Slide\]
>
> The original NDA was filed by GSK in 1999 for a broad range of
> indications. A non-approvable letter was issued in December of 2000
> and additional studies were conducted to address the issues that had
> been raised in that letter. This included study 344, a 1000 volunteer
> Phase I study designed in cooperation with the FDA. The NDA was
> resubmitted in October of 2002 by a new sponsor, LG Life Sciences, in
> collaboration with GeneSoft Pharmaceuticals and Parexel International
> acting as LG\'s U.S. agent.
>
> LG Life Sciences discovered gemifloxacin and is Korea\'s largest
> R&D-based healthcare company. GeneSoft is an emerging pharmaceutical
> company also dedicated to anti-infectives.
>
> The two indications that we are now seeking, acute exacerbations of
> chronic bronchitis, AECB, and community-acquired pneumonia, CAP, are
> those where the greatest unmet medical need exists and which we
> believe gemifloxacin can help address.
>
> \[Slide\]
>
> To date, gemifloxacin has been assessed in nearly 10,000 subjects and
> just under 7000 subjects at the proposed therapeutic dose.
>
> \[Slide\]
>
> We are seeking approval for a 320 mg dose of gemifloxacin given once
> daily orally for 5 days for AECB and 7 days for CAP, all severities of
> disease. Please remember these short durations when we review the data
> on prognostic factors for rash.
>
> We will also show you two types of efficacy data during the course of
> our presentations. The first are primary endpoints of clinical trials.
> We will also show you prospectively defined secondary endpoints that
> were agreed upon with the FDA during the protocol development.
> Examples of these secondary endpoints include bacterial eradication
> and duration of hospitalization in AECB. It is really important for me
> to point out that we are not seeking indication claims based upon
> secondary endpoints, but we do think that it is important to share
> these data with you as you consider the attributes of gemifloxacin.
>
> \[Slide\]
>
> Here you see our agenda and additional speakers for today\'s
> presentation. Dr. Low is Chief of Microbiology at Mount Sinai Hospital
> and professor of medicine at the University of Toronto. Dr. Low has
> published widely on [Strep. pneumoniae]{.underline} drug resistance
> and is on the NCCLS committee that determines antibiotic breakpoints
> for the United States.
>
> Dr. Mandell is Chairman of the joint IDSA American Thoracic Society
> Treatment Guidelines Committee which recommends standard of care for
> community-acquired pneumonia in the United States.
>
> Dr. Shear is professor of dermatology at the University of Toronto
> where he runs a clinic for patients with cutaneous drug reactions. Dr.
> Shear is at the forefront of research in the cutaneous effects of
> drugs.
>
> \[Slide\]
>
> As you can see on this screen, we also have a multi-disciplinary team
> of experts to answer questions in other ares of interest to the
> advisory committee. These specialists are drawn from dermatology,
> dermatopathology, immunology, hepatology, cardiology, pharmacokinetics
> and toxicology.
>
> With that, I will turn the podium over to Dr. Low.
>
> **Unmet Medical Need**
>
> DR. LOW: Thank you.
>
> \[Slide\]
>
> Thanks very much, Gary. Let me just say that it is a privilege to be
> able to present before this committee. I see the task that I have at
> hand is to convince you of three things.
>
> One, that emerging fluoroquinolone resistance is a serious concern, an
> issue. Two, one of the solutions to that problem is to use the most
> potent fluoroquinolone and the most potent fluoroquinolone, I believe,
> is gemifloxacin.
>
> \[Slide\]
>
> Gemifloxacin is a functionally dual-targeting quinolone. Not that
> other quinolones aren\'t dual-targeting but gemifloxacin is the most
> potent dual-targeting fluoroquinolone, and I will explain a bit what
> that means in a few moments. It has unique activities against
> [Streptococcus pneumoniae]{.underline} as evidenced by its PK/PD
> parameters, parameters which correlate with clinical efficacy and, not
> surprisingly, it has excellent activity against the other respiratory
> pathogens.
>
> \[Slide\]
>
> Briefly, let me define the problem of pneumococcal resistance or
> multi-drug resistant pneumococci. I think, first of all, we recognize
> that the pneumococcus is the most common and important cause of
> respiratory tract infections, including pneumonia; that it is the one
> associated with the greatest morbidity and mortality and, if not
> treated appropriately, the one that is most likely to be associated
> with clinical failures.
>
> I think what we have heard this morning is that over the last decade
> we have seen the emergence of antimicrobial resistance to the commonly
> used antimicrobials, including the beta-lactams, macrolides,
> tetracyclines and sulfamethoxazole.
>
> \[Slide\]
>
> So, it has been a challenge to both academia and industry to come up
> with solutions to this problem. One of them is the development of new
> antimicrobials. One solution has been the development of
> fluoroquinolones, such as levofloxacin, that have enhanced gram
> positive activity against [Streptococcus pneumoniae]{.underline} while
> retaining superb activity against [H. influenzae]{.underline} and the
> other respiratory pathogens. Unfortunately, what we are seeing is the
> emergence of fluoroquinolone resistance in pneumococci.
>
> \[Slide\]
>
> The next four slides are important to understand why this problem is
> emerging. The first slide shows you the problem of pen resistance in
> pneumococci. It took 50 years to get to the rates of resistance that
> we see today. In the 1980s we saw a low-level resistance, that we
> didn\'t pay much attention to, appear and emerge. In the 1990s we saw
> a high-level resistance emerge, as shown here in the yellow bars, and
> this high-level resistance is more likely to be associated with
> clinical failures. Obviously, that is why we are concerned.
>
> \[Slide\]
>
> On this slide you see a similar pattern with macrolide resistance.
> Macrolides were introduced in the 1950s. It wasn\'t until 15 years
> later that we saw the first macrolide-resistant pneumococci. It
> wasn\'t until the 1990s that we saw the worldwide dissemination of
> macrolide resistance in pneumococci. In fact, it has only been in the
> last year that we have seen peer reviewed published reports that have
> documented clinical failures that occur in patients who are infected
> with macrolide-resistant pneumococci and treated with macrolides.
>
> \[Slide\]
>
> As you can see here, this is not true for pneumococcal resistance in
> the fluoroquinolones. Remember that ciprofloxacin was introduced in
> 1987 for indications which included pneumococci, and they are still in
> the package insert, but within four years we saw high-level resistance
> and, more importantly, we saw clinical failures. I am sure most of us
> remember that letter to the editor in [The New England Journal of
> Medicine]{.underline} which described about 8 cases of pneumococcal
> pneumonia or infections that failed ciprofloxacin therapy.
>
> \[Slide\]
>
> So, why this discrepancy? I think you can understand it if you
> understand what the mechanisms of resistance are, how bacteria become
> resistant. The way the macrolides and the way the beta-lactams become
> resistant. The way the pneumococci become resistant to these classes
> is that they have to acquire complex pieces of DNA from other
> bacteria, thousands of kilobytes. Whereas, with fluoroquinolone
> resistance all it can take is a point mutation in one nucleotide to
> reduce the susceptibility of a pneumococci to one of the
> fluoroquinolones. So, there is a completely different mechanism of
> resistance and I think this explains why we have seen the rapid
> emergence of fluoroquinolone resistance despite the fact that these
> drugs have only recently been introduced.
>
> \[Slide\]
>
> This is the disturbing slide. This is data from Hong Kong. Philip Ho
> and his colleagues have been doing surveillance. They showed, in 1995,
> that levofloxacin\--MICs of 8 or greater\--levofloxacin resistance was
> less than 2 percent, rates that we see currently in North America, but
> within 5 years rates of resistance increased to greater than 13
> percent, that is by the year 2000.
>
> \[Slide\]
>
> This is data from a recent U.S. surveillance program that was
> presented at ICAAC this year. I think this is the opportunity.
> Although the rates are still only 0.8 percent overall to levofloxacin
> in the United States, there are variations from 0-5 percent rates of
> resistance in some states and 0-22 percent in some cities.
>
> What concerns me is that this is the pattern similar to what we saw
> with pneumococcal resistance to penicillin in the 1980s. That is,
> overall low rates of resistance with pockets of high prevalence of
> resistance such as occurred in Tennessee and Kentucky, and were
> published in MMWR in the early 1990s. My concern is that we can see
> the very same rates for fluoroquinolone resistance if we don\'t do
> something with this window of opportunity that we have.
>
> \[Slide\]
>
> What does it mean clinically? I think that we all appreciate that
> there has been a debate about the relevance of beta-lactam or
> macrolide resistance in pneumococci and what it means clinically is a
> difficulty in showing that resistance correlates with clinical
> failures. Let me say that this is not the case with the
> fluoroquinolones. Within only a few years of fluoroquinolone use for
> the treatment of pneumococcal infections, especially pneumonia where
> you have big burdens of infections, large numbers of organisms, we
> have already seen a number of clinical failures associated with
> resistance. In fact, there are over 25 reports either in abstract form
> or published form of levofloxacin failures.
>
> \[Slide\]
>
> In the past three years we have seen five published reports that have
> described 8 patients that had pneumococcal infections treated with
> levofloxacin that failed therapy. Three of these patients died. I will
> show you data that explains not only why this happened but why it will
> continue to happen unless we adopt a new strategy for the treatment of
> pneumococcal infections with the fluoroquinolones.
>
> \[Slide\]
>
> To explain why clinical failures have resulted and a solution to this
> problem it is essential that you understand how fluoroquinolones work
> and how resistance develops. Fluoroquinolones kill bacteria, and they
> do this very well. They kill bacteria by targeting enzymes that are
> essential for DNA replication. There are two targets within the
> bacteria that the fluoroquinolones bind to, ParC and GyrA, and
> resistance develops as a result of a spontaneous point mutation in
> either ParC, GyrA or both of these targets. In fact, all clinical
> isolates that have been reported to date from patients that have
> failed clinically or developed resistance on therapy with
> fluoroquinolones have had mutations in both of these targets.
>
> \[Slide\]
>
> Let me show you an example of resistance in an isolate of pneumococci
> and, at the same time, demonstrate to you the uniqueness of
> gemifloxacin in the face of emerging resistance. This is a strain of
> pneumococci that has an MIC to levofloxacin, this is an exceptionally
> low MIC to levofloxacin of 0.038, and a typical MIC to gemifloxacin of
> 0.016. If there is a mutation in ParC you can see a 32-fold increase
> in MIC to levofloxacin as compared to only a 4-fold increase in MIC to
> gemifloxacin. A mutation in ParC results in a 20-fold increase in MIC
> to levofloxacin but only a 1.4-fold increase in MIC to gemifloxacin.
> If you have mutations in both ParC and GyrA you can see that the
> levofloxacin MIC increases by greater than 1000-fold, but only by
> 64-fold to gemifloxacin.
>
> I think the key point here to take away is that the MIC is still only
> 0.25, and after you, guys, get over arguing about breakpoints, this is
> not resistant; 0.25 will not be resistant and I think that is a unique
> characteristic of gemifloxacin.
>
> \[Slide\]
>
> So, why is it important then to have a dual-targeting fluoroquinolone?
> Why is it important to have a fluoroquinolone at therapeutic doses
> that is able to bind to both targets and to inhibit and kill the
> bacteria? It is important because these mutations are being found in
> the lungs of patients with pneumococcal pneumonia when they first
> present to the doctor\'s office or the emergency department with
> pneumococcal pneumonia.
>
> Why is that? Well, you can calculate it. We know from numerous
> publications that the frequency of first step mutations is about 1 in
> 10^7^. We also know that the second step mutations actually occur more
> frequently about 1 in 10^5^. We know that patients with pneumococcal
> pneumonia\--and these are studies done in the \'40s where they
> literally took lungs and did colony counts on those patients that died
> of pneumococcal pneumonia\--have about 10^12^ to 10^14^ bacteria in
> that lung. Therefore, it is not surprising that we see in somebody
> with pneumococcal pneumonia, prior to the onset of therapy, that about
> 10^5^ to 10^7^ isolates will have a first step mutation and up to 100
> isolates will have a first and second step mutation.
>
> You could argue, well, that is crazy because every patient then would
> fail therapy if you used a drug like ciprofloxasin. Well, there are
> many reasons why a patient responds to treatment and gets over
> pneumonia. One of those is host defenses. Another is the activity of
> the drug and is the drug getting to the site of infection. But this
> helps explain, helps us understand why failures have occurred and
> resistance has developed in a period as short as over 3 days.
>
> \[Slide\]
>
> The problem of emerging resistance of fluoroquinolones is analogous to
> a problem that we saw several decades ago, and we addressed that
> problem by using drugs appropriately. That is, emerging resistance to
> anti-tuberculosis drugs.
>
> \[Slide\]
>
> Like some of the fluoroquinolones currently on the market, anti-TB
> drugs were only effective against one target in the bacteria. Just as
> the fluoroquinolones though, resistance was the result of the [de
> novo]{.underline} spontaneous point mutations in the drug target.
>
> \[Slide\]
>
> I think what I would like to get into now is to present you data on
> how does it differentiate from moxifloxacin and the other
> fluoroquinolones. This slide shows you the results of [in
> vitro]{.underline} experiments where a pneumococcal isolate was
> exposed to sub-inhibitory concentrations of trovafloxacin,
> ciprofloxacin and gemifloxacin.
>
> As you can see, despite daily passages up to 15 days, the gemifloxacin
> MIC only increased by 32-fold as compared to greater than 100-fold for
> ciprofloxacin and greater than 500-fold increase in MIC for
> trovafloxacin.
>
> \[Slide\]
>
> More importantly, if we look at clinical isolates and compare
> gemifloxacin\'s activity with the activity of currently available
> fluoroquinolones you can this collection of isolates. These are
> clinical isolates from patients where they have reduced susceptibility
> to the fluoroquinolones. In fact, they have mutations in both ParC and
> GyrA. On the far right-hand side you can see that gemifloxacin clearly
> has the most active [in vitro]{.underline} activity against these
> non-susceptible strains, with an MIC-90 of 0.25. That I think is not
> resistant compared to an MIC-90 of moxifloxacin of 4 which is
> resistant; gatifloxacin of 8 and levofloxacin of 16. That is a 4-fold
> lower MIC for gemifloxacin.
>
> \[Slide\]
>
> I think another characteristic of gemifloxacin is its unique activity
> that is not only reflective of low MICs but ability to kill organisms.
> This is an [in vitro]{.underline} synergy time-kill experiment. What
> you see here is the ability of gemifloxacin, in the yellow line, to
> not only rapidly be bacteriocidal against pneumococci that are
> non-susceptible\-- and I would point out that this is free drug
> concentrations that were used to simulate these experiments\--it was
> not only rapidly bacteriocidal but, in fact, at 24 hours it was the
> only fluoroquinolone that was bacteriocidal with a greater than a
> 3-log reduction.
>
> \[Slide\]
>
> So, not only [in vitro]{.underline} but [in vivo]{.underline}
> gemifloxacin has better activity than the other fluoroquinolones,
> including moxifloxacin. Remember that the first-step mutants are
> essential to kill those first-step mutants if we are not going to have
> resistance emerge. You can see here in an animal model that
> gemifloxacin was statistically better than both gatifloxacin and
> moxifloxacin in reduction in pneumococcal log count and statistically
> better against gatifloxacin in strains causing the infection that had
> two mutations.
>
> \[Slide\]
>
> Let me show you activity of gemifloxacin against clinical isolates
> that were not selected for resistance to show you its activity. Again,
> you can see exceptional activity of gemifloxacin with MICs of 0.032,
> 4-fold better than moxifloxacin at 0.25 and gatifloxacin.
>
> \[Slide\]
>
> When we look at the other respiratory pathogens, gemifloxacin does not
> lose any of its activity. It is either equal to the other
> fluoroquinolones or it actually has better activity than the other
> fluoroquinolones.
>
> \[Slide\]
>
> As you know, an important consideration today is another parameter,
> and that is PK/PD parameters. This is a concentration dependent
> killing that we are seeing here so it is important to remember that.
> One of the values that we use is the maximum serum concentration of
> the drug, that is, the C-max divided by the MIC. The optimal C-max to
> MIC ratio is 1 that has been calculated to be greater than 10.
>
> Another measurement of activity is AUC to MIC ratios, that is, area
> under the concentration curve, and here the target for gram negatives
> is greater than 100 for [H. flu.]{.underline} and [E.
> coli]{.underline} but for gram positives the target is greater than
> 25.
>
> I think another point to remember about pharmacokinetics here is that
> more is better than less. That is, maybe with time-dependent killing
> it is not so important but here more is better than less.
>
> \[Slide\]
>
> So, what is the evidence that these optimal PK/PD parameters actually
> make any difference in preventing the emergence of resistance? In
> fact, I think we have excellent data already available that these
> things work and we have examples where they don\'t work.
>
> Here I think is an important example where the use of ciprofloxacin
> for the treatment of [H. influenzae]{.underline} and [M.
> catarrhalis]{.underline} in patients with acute exacerbation of
> chronic bronchitis, despite 10 years of the use of ciprofloxacin and
> other fluoroquinolones for this indication, resistance is almost
> unheard of. I think the reason for that is the exceptional AUC to MIC
> parameters and C-max to MIC ratio that we have not seen resistance
> emerge in [H. flu.]{.underline} and [M. catarrhalis]{.underline}.
>
> \[Slide\]
>
> If you look at gemifloxacin and its activity against pneumococci, you
> can see it has similar exceptional parameters with AUC to MIC ratios
> from 97 to 127. Remember, this is free drug to calculate these ratios,
> and remember there is more than one parameter when we are looking at
> PK/PD parameters. AUC to MIC ratio of greater than 10, that is, a
> ratio from 19 to 24.
>
> \[Slide\]
>
> In fact, when we compare gemifloxacin PK/PD parameters with the other
> fluoroquinolones it clearly comes out on top. Yes, it is similar to
> moxifloxacin when we look at free drug but it clearly has better C-max
> to MIC ratios. Some would argue that this is a better predictor. In
> Preston\'s and Drusano\'s paper in JAMA, looking at levofloxacin
> therapy of community-acquired pneumonia C-max to MIC ratio was as
> important as AUC to MIC ratio, if not better.
>
> \[Slide\]
>
> Probably more importantly though, what does this mean clinically?
> Might it have made any difference for those patients who failed
> therapy with levofloxacin? In fact, we have been able to glean from
> the literature the susceptibility data on 8 patients who failed
> levofloxacin therapy. All isolates at baseline were susceptible to
> gemifloxacin. Five out of the 8 patients\' isolates remained
> susceptible to gemifloxacin while becoming non-susceptible to
> levofloxacin, gatifloxacin or moxifloxacin. Finally, we found that an
> isolate from one of the patients that died remained susceptible to
> gemifloxacin.
>
> \[Slide\]
>
> In summary, gemifloxacin has demonstrated excellent [in
> vitro]{.underline} activity and maintains this activity [in
> vivo]{.underline}. So, the question is, is it any better than
> moxifloxacin? I think that it is better than moxifloxacin. I think its
> [in vitro]{.underline} activity clearly shows that against
> non-susceptible strains as well as susceptible strains it has 4-8-fold
> more activity. It has bacteriocidal activity that is better than
> moxifloxacin both [in vitro]{.underline} with time-kill studies and in
> the [in vivo]{.underline} animal model. Although its AUC to MIC ratios
> are similar, it has superior C-max to MIC ratios.
>
> \[Slide\]
>
> Thanks for your attention. I would like to introduce Lionel Mandell,
> who will talk about clinical efficacy.
>
> **Efficacy**
>
> DR. MANDELL: Good morning. I am Lionel Mandell, and it is a pleasure
> and an honor for me to address this committee.
>
> You have just heard from Dr. Low about gemifloxacin\'s excellent
> activity against resistant pathogens [in vitro]{.underline}. Let\'s
> now move into the realm of clinical medicine.
>
> \[Slide\]
>
> Infectious diseases differ from all other medical specialties since
> the implications of treatment go far beyond the individual patient.
> With other medical specialties, such as cardiology or neurology for
> example, if an inappropriate drug is given the issue ends with that
> patient. With infectious diseases, however, an incorrect choice of
> antibiotics can lead to resistance problems which then affect many
> patients. So, with infectious diseases, when prescribing an
> antibiotic, ideally the physician must consider not only the patient
> at hand but society as well. Some drugs, like gemifloxacin, allow us
> to do both.
>
> \[Slide\]
>
> I will begin by talking about the impact of AECB and CAP. Then I will
> describe the challenges we face today in the treatment of these
> conditions, and then for each condition I will pose two questions.
> One, has clinical effectiveness been demonstrated? Two, are there
> unique or differential features that the drug has shown for that
> indication? Then I will review the data that answer both these
> questions.
>
> \[Slide\]
>
> Now let\'s look at the impact of both AECB and CAP. At any given time
> there are at least 13 million cases of AECB in the United States.
> [Haemophilus influenzae]{.underline} and [Streptococcus
> pneumoniae]{.underline} are major pathogens and emerging resistance is
> a major issue. The mortality rate in hospitalized AECB patients can be
> as high as 30 percent.
>
> \[Slide\]
>
> As for CAP, there are 3 to 4 million cases of CAP in the United States
> annually and the impact of this is tremendous. There are at least
> 600,000 hospitalizations yearly, 64 million days of restricted
> activity and over 64,000 deaths. In fact, pneumonia is the seventh
> leading cause of death overall and the number one cause of death from
> infection.
>
> \[Slide\]
>
> As I mentioned a few moments ago, one of the biggest challenges we
> face in treating AECB and CAP is resistance to commonly used
> antimicrobials including some of the newer fluoroquinolones. As Dr.
> Low described, we are beginning to see treatment failures and even
> deaths on fluoroquinolone therapy.
>
> We are also concerned about the enormous growth in the population of
> patients most vulnerable to AECB and CAP, namely the elderly.
> Incidence and severity of disease, as well as antibiotic resistance,
> all correlate with increasing age. The elderly often have comorbidity
> that requires additional medications and maintaining mobility of those
> patients and reducing hospitalization is particularly important in
> that vulnerable age group.
>
> \[Slide\]
>
> Please keep these challenges in mind as I review the data on
> gemifloxacin, beginning first with AECB. Let me remind you also that
> standard antibacterial clinical studies are sized for non-inferiority
> to the comparator. But even in this context gemifloxacin demonstrates
> differentiable benefits, as I will show you.
>
> \[Slide\]
>
> So, 1267 patients received 5 days of gemifloxacin in 5 main AECB
> clinical trials. All were randomized, controlled trials and the first
> four were double-blind, while study 207 was an open-label trial. All
> the studies were non-inferiority trials. The primary outcome measure
> was per protocol clinical success at follow-up but I will also be
> showing you intention-to-treat data.
>
> Gemifloxacin was studied against three well established comparators in
> three major antibiotic classes, the beta-lactams, the macrolides and
> the fluoroquinolones. Most patients had severity equivalent to
> Antonison Class I disease which has been demonstrated to benefit from
> antibiotics.
>
> \[Slide\]
>
> This graph shows the estimated treatment difference with 95 confidence
> intervals for clinical success in both the per protocol and
> intention-to-treat populations for the three principal clinical
> trials. Here we can see that in each trial the treatment difference
> was no less than the predefined non-inferiority limit. In all cases
> the confidence limit included zero. Results across these studies
> provide consistent evidence that 5 days of gemifloxacin is as
> effective as 7 days of comparator whether that comparator was a
> beta-lactam, a macrolide or another quinolone.
>
> \[Slide\]
>
> The analysis of the bacteriological response at follow-up supported
> the clinical results just shown on the previous slide.
>
> \[Slide\]
>
> In summary, three out of three principal studies meet the
> non-inferiority criteria demonstrating the effectiveness of
> gemifloxacin in AECB. In addition, the secondary endpoint of
> bacteriologic success shows high rates for gemifloxacin across all
> three studies. In each of these studies gemifloxacin was shown to be
> as effective when given for 5 days as the comparator given for 7 days.
>
> \[Slide\]
>
> Having shown you that the drug is effective in AECB, let me now show
> you gemifloxacin\'s attributes in the AECB clinical trial program.
>
> \[Slide\]
>
> Gemifloxacin results in faster bacterial eradication than does
> clarithromycin. Significantly more gemifloxacin-treated patients
> remained relapse free and fewer were hospitalized than with
> clarithromycin. When gemifloxacin was compared with an IV/oral
> cephalosporin switch regimen, it was statistically better in terms of
> clinical response for the intention-to-treat population, and subjects
> had statistically significantly shorter hospital stays in the analysis
> of the intention-to-treat population.
>
> Also, in a head-to-head trial against a highly potent fluoroquinolone,
> trovafloxacin, gemifloxacin was statistically significantly better
> than trovafloxacin in terms of clinical response for the
> intention-to-treat population.
>
> \[Slide\]
>
> In study 068 we see gemifloxacin\'s rapid eradication of [Haemophilus
> influenzae]{.underline} compared with clarithromycin. Gemifloxacin
> eradicated [Haemophilus influenzae]{.underline} in 100 percent of
> those cultured by the first day of treatment, while clarithromycin
> still hadn\'t demonstrated complete eradication of [H.
> flu.]{.underline} by day 6. This rapid eradication is particularly
> important since longer regimens generally promote antimicrobial
> resistance.
>
> \[Slide\]
>
> Generally the major endpoint we look at in antibiotic trials is 2
> weeks after completion of therapy. However, we wanted to see if
> gemifloxacin provided a longer-term outcome benefit. Study 139 was a
> 6-month follow-on to study 068. The prospectively defined primary
> endpoint was the proportion of patients in the intention-to-treat
> population who remained relapse free at 26 weeks. Employing the
> Bonferroni correction for multiple visits, the relapse rate was
> statistically significantly better in favor of gemifloxacin, with a p
> value of 0.048. The study also found a trend toward fewer
> hospitalizations with gemifloxacin, only 2.3 percent compared with 6.3
> percent with clarithromycin.
>
> Two related studies, however, failed to replicate these effects. Study
> 112 measured time to relapse as opposed to the relapse rate but
> relapse rates in both treatment groups were low probably because the
> study was run during the summer months. Study 105 had baseline
> imbalances between the two groups. Twice as many patients in the
> gemifloxacin arm were on steroids, suggesting more severe disease in
> this group.
>
> \[Slide\]
>
> Study 207 is one of the supportive studies comparing 5 days of oral
> gemifloxacin with 10 days of IV/oral cephalosporin for patients
> requiring hospitalization. This graph shows the clinical and
> bacteriological success rates for both per protocol and
> intention-to-treat analyses. Gemifloxacin was as effective as
> cephalosporin in the per protocol populations, and in the
> intention-to-treat analytical was statistically superior for clinical
> success.
>
> This is very important because keeping patients off IV can maintain
> mobility which is crucial in elderly patients. I will be going into
> more detail on this when I discuss the CAP studies.
>
> \[Slide\]
>
> Length of hospital stay was a prospectively defined secondary endpoint
> evaluating an important outcome measure. The percentage of patients
> discharged at follow-up was higher with gemifloxacin although not
> statistically significant. The time to discharge, however, was
> significantly shorter for gemifloxacin, 9 days as opposed to 11 days
> for comparator and the result was statistical significant, with a p
> value of 0.04.
>
> \[Slide\]
>
> In study 069 5 days of gemifloxacin was compared to 5 days of a very
> potent quinolone, trovafloxacin. In the per protocol population
> gemifloxacin was found to be as effective as trovafloxacin. In the
> intention-to-treat population, however, gemifloxacin was significantly
> better than trovafloxacin for clinical success.
>
> \[Slide\]
>
> Turning now to the CAP indication, let\'s look at whether clinical
> effectiveness has been demonstrated.
>
> \[Slide\]
>
> The clinical program consisted of 4 randomized, controlled studies
> with non-inferiority design and two uncontrolled studies to help
> assess the efficacy of the 7-day regimen. Three of the 4 controlled
> trials were double-blind and one was open and 1349 patients received
> gemifloxacin at a daily dose of 320 mg for 7-14 days. The primary
> outcome measure for 5 of the 6 trials was per protocol clinical
> success at follow-up. For study 287 the primary outcome was
> bacteriological response at follow-up.
>
> \[Slide\]
>
> Fifty-eight percent of study subjects were either ill enough to
> require hospitalization, were bacteremic or had severe CAP according
> to defined criteria. Again, no significant differences were noted
> between the regimens. A high proportion of the patients were elderly,
> assuring us that gemifloxacin was effectively assessed in this growing
> but very vulnerable population.
>
> \[Slide\]
>
> The primary endpoint for clinical studies was success at follow-up in
> the per protocol population. Also shown here is the pooled analysis
> across the studies. In study 012 the lower 95 confidence interval was
> minus 10.1 percent, which was only 0.1 percent outside the predefined
> delta. The confidence intervals for the intention-to-treat population
> are also lower, failing to indicate equivalence. Except for the one
> small difference in this study, all the study showed gemifloxacin to
> be as effective as the comparators.
>
> \[Slide\]
>
> This graph shows how effective gemifloxacin is against the pooled
> comparators in all CAP studies for eradication of select bacterial and
> atypical pathogens.
>
> \[Slide\]
>
> In summary, three of the four principal studies meet the
> non-inferiority criteria for the primary endpoint.
>
> \[Slide\]
>
> Now I will address the question of whether gemifloxacin demonstrates
> differentiable features in the CAP program.
>
> \[Slide\]
>
> It is effective when given for 7 days of treatment in all severities
> of the disease, both in the hospital and out in the community. Oral
> gemifloxacin is as effective as an IV/oral cephalosporins switch
> regimen for hospitalized CAP patients. As in AECB, gemifloxacin again
> shows statistical superiority in the intention-to-treat analysis
> against trovafloxacin, another very potent quinolone. And, it is
> effective in eradicating pneumococci resistant to penicillins,
> macrolides, cephalosporins and ciprofloxacin.
>
> \[Slide\]
>
> Analyzing data from all the CAP studies, we see that in trials
> specifically looking at 7 days treatment only gemifloxacin
> demonstrated high clinical response rates. It was as effective as the
> comparator in both the randomized, controlled trial and the 7-day data
> pooled from the 7-14 day clinical trials.
>
> \[Slide\]
>
> This is a similar analysis of patients with severe CAP according to
> the defined criteria. Gemifloxacin is as effective as comparators in
> both the 7-day fixed regimen and in the 7-14-day regimen. These data
> confirm other recent studies showing that severe pneumonia can be
> effectively treated with shorter regimens.
>
> There is a growing body of data, recognized by the IDSA and the ATS
> Treatment Guidelines Committee, that even in infections as severe as
> ventilator-associated pneumonia the pathogens are eradicated and the
> parameters reflecting infection have resolved within the first several
> days of treatment, and adding a second week of treatment does nothing
> more even in these severely ill patients with VAP than lead to
> colonization with resistant pathogens.
>
> \[Slide\]
>
> The shorter treatment regimen was also highly effective in
> hospitalized patients. More than three-quarters of the hospitalized
> patients in the gemifloxacin group received only 7 days of therapy.
> Although not shown here, gemifloxacin also appeared to be as effective
> as comparators for treating bacteremic patients.
>
> \[Slide\]
>
> Study 185 was specifically designed to compare oral gemifloxacin with
> IV/oral cephalosporin in hospitalized patients and 21 percent of these
> patients were defined as severe, defined as Class IV and V. Oral
> gemifloxacin was as effective statistically as its comparators for
> both clinical and bacteriological response.
>
> This is very important because there is a very common misconception
> that we have to treat hospitalized patients with IV antibiotics. This
> simply is not true. One of the worst thing you can do to a patient who
> is fighting to avoid the use of a walker is bring him or her into
> hospital, hook them up to an IV and then make them a prisoner in their
> own bed. After a week of being immobilized like this you can virtually
> guaranty that that older patient is going to need a walker and
> rehabilitation. There is a growing trend toward using oral agents to
> encourage and to maintain mobility.
>
> Generally, I strongly recommend IV drugs only if the patient is
> vomiting, is being mechanically ventilated or is hemodynamically
> unstable, and these conditions exist in only a very small percentage
> of CAP patients.
>
> \[Slide\]
>
> As in AECB, gemifloxacin was assessed in a head-to-head trial against
> one of the most potent fluoroquinolone, trovafloxacin. Looking at the
> clinical and bacteriological responses for the per protocol and
> intention-to-treat post-approval study, we see that gemifloxacin was
> as effective as trovafloxacin in the per protocol population and,
> again, was statistically clinically superior to trovafloxacin in the
> intention-to-treat population.
>
> \[Slide\]
>
> Looking at all of the CAP clinical trials, we see that 7 days of
> treatment with gemifloxacin is also highly effective in eradicating
> [Streptococcus pneumoniae]{.underline} resistant to penicillins,
> macrolides and cephalosporins. In addition, there were patients with
> ciprofloxacin noon-susceptible isolates with MICs of 2 or 4.
> Gemifloxacin showed a high success rate against these organisms, as
> anticipated from Dr. Low\'s excellent discussion of gemifloxacin\'s
> potency and spectrum of activity.
>
> \[Slide\]
>
> In conclusion, we have a clear need for more potent, more effective
> drugs for both AECB and CAP. In AECB gemifloxacin has demonstrated
> clinical effectiveness and shows a number of very important attributes
> and outcome benefits. The drug is also clinically effective in CAP and
> oral gemifloxacin was comparable to an IV/oral switch regimen of a
> cephalosporin. I believe that oral therapy, given for shorter
> durations, will soon be standard treatment for most patients with CAP
> and AECB.
>
> Finally but importantly, gemifloxacin shows effective activity against
> [Streptococcus pneumoniae]{.underline} resistant to antibiotics,
> including the penicillins, the macrolides, the cephalosporins and
> ciprofloxacin. Gemifloxacin\'s efficacy and unique features that I
> have described make it extremely valuable for the treatment of both
> AECB and CAP.
>
> \[Slide\]
>
> Now I would like to turn the podium back to Dr. Patou.
>
> **Safety**
>
> DR. PATOU: Thank you, Dr. Mandell. I will now being our presentation
> of the safety data.
>
> \[Slide\]
>
> I am going to tell you about the overall frequency of adverse events.
> Then I will show you the serious adverse events and withdrawals. Then
> we will walk you through gemifloxacin\'s safety record in terms of the
> key class effects of quinolones, including hepatic safety. Then Dr.
> Shear will address the data on cutaneous manifestations.
>
> \[Slide\]
>
> Shown here are the most frequently occurring adverse events reported
> on gemifloxacin treatment. Gemifloxacin is associated with a low
> incidence of adverse events, generally similar to or lower than the
> adverse event rates seen in comparators and of mild to moderate
> severity. The exception is rash. The frequency of rash was 3.6 percent
> versus 1.1 percent in the comparator group.
>
> \[Slide\]
>
> As you can see on this slide, the serious event rate, withdrawal rate
> and death rate with gemifloxacin is similar to the rates seen with the
> pooled comparator group. I have broken out for you the serious adverse
> events related to rash and Dr. Shear will review each one of these
> cases in turn with you during his presentation.
>
> \[Slide\]
>
> As a class, other quinolones have demonstrated specific side effects.
> Gemifloxacin was rationally designed to reduce or effectively
> eliminate some of those class effects, such as phototoxicity and CNS
> stimulation.
>
> \[Slide\]
>
> The only drug interactions observed with gemifloxacin were the class
> interactions observed with all fluoroquinolones, namely the ones
> associated with antacids and sucralfate. Gemifloxacin has low
> phototoxicity potential comparable to ciprofloxacin, and there is no
> dysregulation of glucose homeostasis as we have seen with other
> fluoroquinolones such as gatifloxacin.
>
> \[Slide\]
>
> QTc prolongation is another important class effect of fluoroquinolones
> and the patient study showed that gemifloxacin increased the QTc by a
> mean of 2.6 milliseconds. There were no reports of Torsade de pointes,
> the clinical consequence of very prolonged QTc. None of these cases
> were observed in gemifloxacin-treated patients. For comparison, we
> have included the data for other fluoroquinolones on this slide, taken
> either from the package insert or from publication.
>
> Co-medications capable of prolonging QTc interval which compete for or
> inhibit cytochrome p450 are potentially an issue with this class of
> drugs. Gemifloxacin does not inhibit and is not cleared by the
> cytochrome p450 mechanism. Therefore, this type of drug-drug
> interaction is not of concern with gemifloxacin.
>
> \[Slide\]
>
> I will now discuss the drug\'s hepatic safety.
>
> \[Slide\]
>
> I am going to break the analysis into a number of parts. I am going to
> first look at patients who have a normal pretreatment alanine
> transaminase or ALT, which is a sensitive marker of hepatocellular
> liver injury. I will then look at subjects who had an elevated ALT
> value pretreatment. That is, they had some underlying liver problem at
> least biochemically. Then I am going to review the incidence of
> hepatic adverse events in subjects with underlying liver disease, and
> the clinical trial database has been reviewed independently by Dr.
> Paul Watkins and Dr. Jim Lewis, both noted hepatologists. They are in
> the audience to take questions and my presentation is a consensus of
> both their reviews.
>
> \[Slide\]
>
> Shown on this slide is the incidence of ALT elevations on therapy for
> subjects receiving 320 mg of gemifloxacin. Moth stayed within normal
> range and comparable rates of elevation were observed with both
> gemifloxacin and pooled comparator. No patients on gemifloxacin
> therapy had elevations greater than 6 times the upper limit of normal.
>
> \[Slide\]
>
> We also looked at subjects receiving 640 mg of gemifloxacin, twice the
> proposed recommended dose. There is a slightly higher number of cases
> of ALT elevations in the gemifloxacin group compared to comparator.
> One patient had an ALT elevation greater than 10 times the upper limit
> of normal, and there was a second patient that had an ALT elevation
> just under 8 times the upper limit of normal. In both cases the
> changes were rapidly reversible and the patients were asymptomatic.
>
> \[Slide\]
>
> We then went back and mined the database for any signals for potential
> serious hepatocellular injury, and we applied two criteria which are
> commonly considered predictive of severe drug-induced liver injury.
>
> The first is so-called Hy\'s rule, described by Hy Zimmermann, and
> this is a distinctive pattern of LFT, liver function test, changes
> with both an elevated bilirubin of 3 mg/dl or greater and a very high
> ALT, generally considered to be greater than 20 times the upper limit
> of normal. Hy observed that 10 percent of subjects meeting these
> criteria either died or required liver transplantation.
>
> The second criterion was to look at eosinophilia associated with any
> ALT elevation greater than 2 times the upper limit of normal as a
> marker for hypersensitivity reactions.
>
> We also went back and searched the database again, using more
> stringent search criteria than Hy\'s rule implies, to screen for any
> other subjects that we thought merited further review by Drs. Watkins
> and Lewis.
>
> \[Slide\]
>
> There were no cases of patients meeting Hy\'s rule or demonstrating
> eosinophilia at either the 320 mg or 640 mg dose levels. Using the
> very conservative database search parameters, there were 2 cases with
> a bilirubin of greater than 1.5 mg/dl and with an ALT greater than 2
> times the upper limit of normal. In both these cases the ALT was less
> than 3 times the upper limit of normal and both bilirubins were less
> than 2.
>
> The cases were reviewed by hepatology experts. They noted that the
> serum alkaline phosphatase was also elevated and, therefore, the
> rising serum bilirubin was not the result of hepatocellular injury.
> Dr. Watkins and Dr. Lewis concluded that there were no liver signals
> with the 320 mg dose in patients with normal baseline liver chemistry.
>
> \[Slide\]
>
> We next looked at subjects with ALT elevations at baseline. This
> table, which can be found in your FDA briefing book, shows the
> frequency of ALT abnormality on therapy with pretreatment abnormal ALT
> levels. The FDA noted that there appears to be a higher number of
> gemifloxacin-treated subjects with an ALT elevation above 2 times the
> upper limit of normal in these subjects. However, this table by itself
> is inconclusive because it only shows ALT levels at one moment in
> time. It doesn\'t show what the ALT levels were prior to treatment,
> nor does it measure whether they increased or decreased on therapy. In
> order to analyze whether gemifloxacin did, in fact, change the ALT
> levels of these patients we did a dynamic analysis.
>
> \[Slide\]
>
> We looked at the patients who had a greater than 2 times the upper
> limit of normal ALT at baseline and we followed the patients over time
> to see if their values increased, decreased or stayed the same. We
> compared their ALT values at the on-therapy visit with baseline and
> also at the end of therapy visit with baseline.
>
> Importantly, 93 percent of patients at the on-therapy visit and 96
> percent of patients at the end of therapy visit showed either a
> decrease in ALT or no change in ALT. There were only 6 patients who
> showed an increase at either visit.
>
> \[Slide\]
>
> Let\'s take a closer look at those 6 patients. Shown here are the
> actual values for ALT and bilirubin. Bilirubin was normal pretreatment
> and did not rise in any patient. In fact, in 5 of the 6 patients the
> bilirubin actually fell. The highest ALT attained was 501 in the last
> listed patient, which represents a 5-fold increase from baseline and,
> in fact, was coming down again by the end of therapy. In the other
> subjects the ALT elevations were 3-fold or less. So, none of these
> patients came anywhere close to meeting Hy\'s rule and none of them
> showed any evidence of eosinophilia. The hepatologists did not find
> these liver function changes of concern.
>
> \[Slide\]
>
> We also looked at hepatic adverse events reported in subjects with
> underlying liver disease. All of these reports were descriptions of
> liver enzyme changes. There were no clinical findings, and none of
> these adverse events were reported as SAEs. Importantly, there were
> fewer subjects withdrawn from the gemifloxacin-treated group related
> to these AEs than in the comparator group.
>
> \[Slide\]
>
> Serious adverse events related to the liver were reported in 4
> gemifloxacin-treated subjects. All of them were from an unblinded
> study, study 185. All were reported as liver function test
> abnormalities. In fact, the ALT values were not more than 5 times the
> upper limit of normal in any of these cases. All of them were
> asymptomatic. There were no clinical reports associated with these
> biochemical changes. All have already been reviewed included in the
> biochemical analyses I have just described to you. Specifically, none
> of them met Hy\'s rule; none of them demonstrate any eosinophilia. We
> think that the investigators, knowing that the patients were receiving
> an investigational drug, were cautious and reported these as serious
> adverse events.
>
> \[Slide\]
>
> In summary, the hepatic profile of gemifloxacin at the recommended
> dose was devoid of any defined signals for serious hepatotoxicity
> potential. No subject met criteria for treatment emergent Hy\'s rule.
> There were no signals of acute liver failure or irreversible liver
> injury or of hypersensitivity.
>
> At the 640 mg dose there is a higher frequency of ALT increases,
> however, no subjects met Hy\'s rule and there were no signals for
> irreversible liver injury.
>
> Finally, when we looked specifically at subjects with preexisting
> liver disease we found no evidence that these preexisting conditions
> represented a safety concern.
>
> \[Slide\]
>
> With that, I will turn the podium over to Dr. Shear for his analysis
> of the dermatological effects of gemifloxacin. Thank you.
>
> **Cutaneous Manifestations**
>
> DR. SHEAR: Good morning.
>
> \[Slide\]
>
> I am going to be reviewing the rash issue which is obviously of
> interest here, and I am going to be giving my presentation in three
> parts. First, Dr. Bigby presented very nicely \"drug rash 100\" and I
> guess what I am going to present is \"drug rash 101\" just to put this
> in perspective, with a few pictures and to make sure we are all
> talking about the same terms and it is not because of your lack of
> knowledge in this area, I think it is because it is an area that has
> been very poorly defined over the years and we are just starting to
> get somewhere with it. This is the kind of approach that I used to
> teach other dermatologists about rashes, and I will be using that
> little yellow triangle in the corner to explain what I am talking
> about.
>
> Secondly, I will show the study data from the clinical trials and
> tease out the rash issues that we see and look at the data there.
>
> Then I am going to be presenting this very special study, 344, which
> looked at the rash in a most incredibly intense study ever done just
> for a drug rash.
>
> \[Slide\]
>
> I call this the rash diagnostic triangle. The fact is that we need to
> have an approach to drug rashes that goes beyond just looking and
> trying to describe what we see. When one looks at analyzing drug data
> you really need to look at each corner of this triangle.
>
> First you need to look at the appearance, and I think this is
> something we see all the time but normally we just see descriptions of
> the appearance. Some people use the term urticaria and different
> people might even disagree about what that is. So, even that is faulty
> and even with pictures you can try your best but that is not enough.
>
> You also need to know if there is systemic involvement with the rash
> because that is going to change your assessment of what the rash
> means. Finally and ideally, you would like to have the histology of
> the rash.
>
> None of these stands alone. I think if you only have one or two
> corners of the triangle you really can\'t make a full assessment. It
> doesn\'t mean you can\'t make one; it just means you have to realize
> you don\'t have everything you need.
>
> \[Slide\]
>
> This slide shows a variety of drug eruptions and basically are some
> pictures of what Dr. Bigby showed before. But the rash of interest
> here with gemifloxacin is this exanthem. This is an example using
> amoxicillin. As he showed, the aminopenicillins are the ones that most
> commonly have been reported to cause this in terms of incidence but
> also because these drugs are very commonly used. Probably overall they
> are the most rashes that we see.
>
> It is also important to note that this clinical appearance can be
> interpreted by different terms by different people. I think
> historically it was not as clear and most recently, in the data that
> Dr. Bigby showed, it is clear that we are starting to agree on at
> least some of the terms and descriptions.
>
> \[Slide\]
>
> In this next one, these are the terms that we use as exanthem, which
> is by no means an ideal term. Exanthem usually refers to an external
> manifestation of an infection, as most of you obviously know, but
> urticaria and other eruptions can do that as well so one could say
> they are potential exanthems.
>
> The other term, maculopapular eruption\--I certainly agree with Dr.
> Bigby, I don\'t like that term at all but it is a term used by many
> clinicians in many environments, and I am sure many of you here use
> that term. No offense, but we don\'t like it in dermatology but we
> don\'t have a better term. This is often just called drug rash and
> these are all called drug rash. Usually when I am finished with this
> part when I am giving a lecture or teaching people, I usually say this
> may be something called \"Shear\" syndrome but right now it doesn\'t
> have a good name so it is wide open. If anybody wants to make a name
> for the most common drug rash and probably the most common side effect
> from drugs, especially antibiotics, it doesn\'t have a name and that
> makes it very difficult.
>
> Down the line you have what is really a classic urticaria and I use
> urticaria because it is really descriptive. We don\'t know everything
> about this patient just by looking at the picture. I apologize because
> this is difficult to see but this is a patient who was on isoniazid
> for TB prophylaxis and she has about 30 pustules on each cheek, which
> are very uniform in the aciniform eruptions that you get fro
> isoniazid.
>
> This is a patient who has a blister of a fixed drug eruption that Dr.
> Bigby mentioned. It is not always bullous but it can be blistering
> sometimes and this is from tetracycline and he has about 9 lesions on
> his body.
>
> \[Slide\]
>
> I mentioned that we look at the appearance and that is a beginning to
> the assessment. The second thing is to look at whether there is
> systemic involvement. One of the key markers we have been impressed by
> in doing this work for the past 20 years is how important fever is.
> So, when we see fever we also look for systemic involvement. If we
> have an exanthem with fever and systemic involvement we are thinking
> about possible hypersensitivity syndrome. Usually, by definition at
> least in the studies we do and whenever we are reporting these, we are
> also looking for concomitant internal organ involvement. It doesn\'t
> have to be hepatitis but in the big series we did with dilantin, in
> the [Journal of Clinical Investigation]{.underline} in 1988, about 50
> percent of those patients had hepatitis but 25 percent can have
> nephritis and there can be other organs that are involved as well but
> less commonly.
>
> An urticarial eruption with fever and arthralgia could represent serum
> sickness like reaction. It is not serum sickness. In fact, it is not
> even like serum sickness\--another bad name. This is not an immune
> complex mediated disease but these patients will have fever, this sort
> of urticarial rash, and they have arthralgia and Cefaclor is a classic
> for that.
>
> If one has generalized pustules with high white count, this is
> emergent drug eruption which we probably years ago called pustular
> psoriasis by mistake but now understand it as AGEP or acute
> generalized exanthematous pustulosis, and that is not relevant to
> today\'s discussion.
>
> Then, of course, there is the one that is very rare, as Dr. Bigby
> mentioned, Stevens-Johnson and TEN, and this is a spectrum of a
> blistering disease that is characterized clinically by mucosal
> involvement but that mucosal involvement is quite dramatic, and on the
> lips especially it is a hemorrhagic crusting that one sees on the lips
> and not just, you know, dryness or simple aphthae.
>
> We can get into the mechanistic part later. Dr. Werner Pichler is here
> who has done the seminal work in this area, and to go from this rash
> way over here to Stevens-Johnson/TEN, as Dr. Bigby mentioned, is not
> the way we see it happening.
>
> \[Slide\]
>
> The other important reactions when looking through a database are what
> might be serious reactions or what might be signals of serious
> reactions. Obviously, angioedema, hypersensitivity syndrome and
> Stevens-Johnson/TEN are ones that we are looking for.
>
> \[Slide\]
>
> As a bit of background on the relationship between Stevens-Johnson and
> TEN, and this is perhaps my perspective on this but there are issues
> that make one think that hypersensitivity syndrome reactions might
> have some association and coexistence with Stevens-Johnson and TEN.
>
> First of all, the pathogenesis is shared. There is a role of potential
> reactive metabolites, etc., and importantly, work that Dr. Pichler did
> showed that the T-cells that are infiltrating the skin\--there is a
> strong presence of CD8 positive cells in the dermis, which was not the
> case for the gemifloxacin-associated rash but that is an important
> marker in both of these diseases and one that allows you to think that
> perhaps both occur through a similar pathway.
>
> The reason that is important is when one looks at data like this
> hypersensitivity syndrome reaction for dilantin and Tegretol the
> reaction rate can be as high as 1/3000, and this is based on work that
> Rob Stern did, published in [Neurology]{.underline} several years ago,
> using the Saskatchewan database. They didn\'t really have enough cases
> to get a strong assessment here but they were seeing rates for
> dilantin and carbamazepine as high as 1/10,000.
>
> This suggests that perhaps this hypersensitivity syndrome reaction
> could be a signal or a harbinger of cases in the future perhaps of
> Stevens-Johnson/TEN. That wasn\'t the case here but I just mention
> this because I think it is important in understanding what these rare
> signals can mean.
>
> \[Slide\]
>
> The other part of the triangle I talked about was the histology, and
> histology should not be the definitive answer. Even our pathologist,
> Dr. Wedad Hamma, who led the pathology group for the 344 study is here
> and she will admit that pathology is part of the clinical story. It is
> not the definitive part of the story.
>
> Here is the histology of Stevens-Johnson/TEN and what one sees here is
> an attack of lymphocytes, especially CD8 positive cells, on the
> epidermis and hydropic changes. Over here, this is the epidermis but
> it is all pink which shows that it is necrotic. These CD8 cells are
> very good at elucidating things like fast ligands and other death
> signals to help kill the epidermis.
>
> Again, that was not seen in this study but I think it is important to
> note that if a pathologist just saw this picture he might not be able
> to tell this from even a fixed drug eruption because they can show
> similar pathology. So, the pathology is just part of the triangle and
> part of the whole picture.
>
> \[Slide\]
>
> I have shown you the triangle. I think that is the best thing we can
> do and really we are very fortunate to have the 344 study to allows us
> to address each part of this, and we have to remember what that means
> but I am going to go to the clinical trial data first and just show
> you how we work with that.
>
> \[Slide\]
>
> There are about 10,000 people in all the studies but 6775 patients, as
> Gary said, received the drug at the therapeutic dose of 320 mg per
> day. It is important to remember that overall when one is looking at
> rashes, and these were exanthems, 4 percent roughly, or less than 4
> percent, reported rash. So, we are looking at a prevalence of 3.6
> percent. That is more than the comparators but overall. What Dr. Bigby
> showed you was for aminopenicillins with rates of about 4-8 percent or
> 5-9 percent overall and this rate here was certainly below that. The
> median onset was 9 days and the mean duration was 5 days, which is
> actually the same finding as in the 344 study that I am going to show
> you so I think it just shows that this is a representative sample.
>
> There were some withdrawals due to the drug and that was fewer than 1
> percent of the patients because of rash and 1/1000 met the criteria
> for a serious adverse event and, as Gary said, I will go into those in
> detail.
>
> \[Slide\]
>
> There were 7 serious adverse events reported for rash in the 6775
> patients. These 4 are clustered here for a reason. Each of these
> patients was hospitalized and that is why it was recorded as an SAE.
> All of these cases were from eastern Europe and I know from speaking
> with colleagues who do work in eastern Europe that the standard of
> admission is very different there. There is a much lower threshold for
> admitting patients. We don\'t even have dermatology beds in Canada.
> They have units with 55 beds in Prague for admitting patients and it
> is a whole different approach.
>
> When you go back and read these case reports there is nothing that is
> anything more than a benign rash with these cases, some itchiness,
> truncal erythema. There was no mucosal involvement; no systemic
> concerns; and this is clearly something that would be treated perhaps
> only with topical corticosteroids or oral antihistamines if it was, in
> fact, treated at all in North America.
>
> \[Slide\]
>
> In these three cases from western Europe and North America we have
> first the case from Canada. This patient was afebrile and it was
> called serious in a decision by the investigator. We are not really
> sure what that is based on but the rash cleared in 2 days. So, there
> was nothing impressive there.
>
> The patient from the Netherlands was complex in that they were
> receiving 8 co-medications. The rash came up quickly, resolved by day
> 18 and all they were treated with was antihistamines, and they were
> not admitted to hospital.
>
> The case from the United States perhaps had more substance. This was
> reported as serum sickness but I think what the person was really
> trying to describe was a serum sickness like reaction. Serum sickness
> is different. It is from foreign proteins, an immune complex mediated
> disease, etc. but serum sickness like reaction is sort of what we saw
> here. This is a person who had rash, sore joints and fever. The odd
> thing was that it was about 13 days after the last dose of the drug,
> which is about 40 half-lives out, and usually, if we look at Ceclor as
> an example, it is about 5-10 days into therapy. But this might be a
> serum sickness like reaction.
>
> In summary, we have 7 reported SAEs, one that may be a serum sickness
> like reaction. I also reviewed 6 cases of facial edema because that
> might make one think of angioedema and might make one think of
> hypersensitivity syndrome. In all 6 of those cases, and the FDA agrees
> in the case book, if I remember, this was not a marker of anything
> else. These patients had no systemic symptoms.
>
> \[Slide\]
>
> The other issue the FDA asked the sponsor to look at were important
> questions regarding re-exposure to quinolones. Basically, going over
> that clinical trial database was one way to answer it. In patients who
> had a previous exposure to another quinolone and then got
> gemifloxacin, there were just over 180 people and 3 of them got minor
> rashes on gemifloxacin, which is a rate of less than 2 percent.
>
> The previous exposure with gemifloxacin for those who had no rash but
> then got gemifloxacin again perhaps months later in another study,
> there were 41 people who fit that criteria and none of those people
> got a rash.
>
> In subsequent exposure to another quinolone after a gemifloxacin rash,
> there were 11 people who gave a history of quinolone rash and then
> when they got gemifloxacin they had no adverse event in the skin.
>
> So, the question was looked at in these three different ways and each
> time there was no evidence of any important cross-reactivity.
>
> \[Slide\]
>
> Multivariate analysis was done from this clinical trial database and
> the covariates that were associated with rash are shown here: female
> gender, age under 40, as was mentioned in the FDA introduction, and
> longer duration of therapy which was also mentioned and shown in very
> nice graphic form. What one sees is around 10 and 14-day rates of
> about 6.4 percent and 7.4 percent. In addition, in women over 40 there
> was a slight increased risk in association with use of hormone
> replacement therapy.
>
> \[Slide\]
>
> Pulling out the main numbers here using logistic regression to
> identify the highest risk group, it defined a rash rate of 15.3
> percent in women under 40 who took the drug for 10 days, which is
> longer than the 5-7 days being asked for today. In the comparator the
> rash rate was around 2 percent.
>
> \[Slide\]
>
> It was this higher number in this subset and under these conditions of
> 10 days of exposure that prompted the idea to perhaps look at this in
> more depth. So, study 344 was designed to determine the
> characteristics of the rash. What was this rash? To really ensure that
> there were enough rashes to study, and when you try to think about
> doing this prospectively\--and this has never been done before to my
> knowledge, so it is unique opportunity to think about study design,
> interpretation of data, implications for approval, etc.\--so here we
> have a population that was defined that might give us a high enough
> rate of rash, especially if we look really hard.
>
> This was healthy women under the age of 40 in a Phase I setting. They
> took it for 10 days, as I said longer than you would take it for AECB
> or CAP, and they also looked at cross-reactivity in a second phase.
> So, people who got a rash were exposed to ciprofloxacin as a
> quinolone.
>
> Another part of this was to look at subclinical sensitization so if
> you got gemifloxacin once maybe you didn\'t get a rash, but what if
> you got it again? Finally, what about the relationship of drug and its
> major metabolite and acetyl gemifloxacin? Was there a relationship
> there?
>
> Just the answer to the last one since I have too many slides anyway,
> just to tell you that there was no relationship between the plasma
> levels, the AUC or the N-acetyl transferase activity in patients who
> got rash and who didn\'t.
>
> \[Slide\]
>
> Here is part A of the study. We are trying to get more than 3.6
> percent. So, what we do is take this at risk group of females who are
> 18-40 years old, weight it 5:1 in favor of getting gemifloxacin and
> they take 320 mg for 10 days because we know we have a higher rash
> rate at 10 days, and then see who gets rash and see who doesn\'t get
> rash.
>
> Now, in all there were 841 women who received gemifloxacin and 170 who
> received ciprofloxacin so there were over 1000 cases. That is very
> impressive for a rash study, I have to say.
>
> \[Slide\]
>
> This is part B of the study. What we are looking at here is the
> disposition of individuals to try and answer this question of
> sensitization. So, here we are seeing rash in part A and we are trying
> to characterize that rash. In part B we are not ignoring the people
> who get rashes but we just want to answer some of these questions
> about cross-sensitization.
>
> So, if you got gemifloxacin and you got a rash, then in you would get
> in part B, after washout, ciprofloxacin or a placebo. If you didn\'t
> get a rash you could look at subclinical sensitization by looking at
> gemifloxacin or placebo. Sort of as a background, ciprofloxacin rashes
> got placebo and ciprofloxacin who didn\'t get a rash the first time
> got ciprofloxacin again for sort of looking at this subclinical
> sensitization issue.
>
> \[Slide\]
>
> For further clinical assessment subjects were assessed by board
> certified dermatologist in 30 locations in 7 countries. Besides
> photographs and clinical assessments, the FDA had asked the sponsor to
> collect skin biopsies, which is a good thing because that is the third
> corner of my triangle.
>
> Ultimately, 288 subjects had biopsies taken from their rash. These
> include samples from the rash site but they also include samples from
> normal skin where there did not appear to be a rash. It is really
> unusual to do that but I think the reason there is to sort of look for
> a subclinical rash. By the time you see a rash maybe you are seeing
> something that, sure, is clinical but maybe there is something
> subclinical going on, and that is very unusual. We are going to review
> some of the pathology but this was sort of looked at in every way in
> blood and urine sampling and cardiograms, of course, were followed.
>
> \[Slide\]
>
> The numbers were remarkable. I have said this before but basically all
> aspects of this were unique, even the idea of doing a study like this.
> But when it was done, it was certainly done right. There were samples
> taken for routine histology, immunofluorescence, immunophenotyping to
> take a look for those CD8 positive cells, looking at drug levels and
> metabolite levels, and ended up with 1000 subjects, 10,000 slides and
> 16,000 samples. At the end of this there was no association with the
> drug or metabolite levels and only minimal inflammation in the skin.
>
> \[Slide\]
>
> The study did pick up, as expected, a high number of rashes. Here you
> will see 260 patients of the 800 or so, almost 32 percent, got a rash.
> When one looks at that data in that subset you wonder what that means,
> but that is comparable, if you want to look back at what was seen in
> the clinical trial database, to 15.3 percent in the clinical trial
> database. The cipro. rash was also more common, about 4 percent,
> compared to the background of around 2 percent in the clinical trials.
> There is no doubt when you see the rashes that ascertainment certainly
> plays a role. If you are going to look closely every day for 10 days
> you are going to see rashes that would often just be passed off as
> nothing. So, this is important.
>
> \[Slide\]
>
> Here is the timing. What one sees here is the day of onset. So,
> everybody gets 10 days of therapy. If they develop a rash the drug is
> stopped. Of the 100 percent of people who got rashes with gemifloxacin
> in part A, one can see that 42 percent of those occurred on day 9. Of
> those who got rashes, 82 percent of all the rashes occurred in these 3
> days. Very few rashes before day 8 and very few rashes after the drug
> was stopped.
>
> \[Slide\]
>
> So, to start looking at the aspects of what this means in study 344
> when you are looking beyond the numbers and starting to look at the
> cases and the case record forms for what was going on in the skin, we
> go back to this triangle idea. Here we are just going to look at the
> appearance.
>
> This is sort of an average type of rash. Most people on this study who
> got a rash, this is the kind of rash they had, little, tiny red
> papules scattered around. We are not going to show you the front and I
> am not going to show you the legs but pictures were taken all over.
>
> As far as the worst goes, as bad as it is, there is no name for this
> disease. There is no definition of \"worst\" and what we have done is
> we have reviewed all these pictures and since most of them look like
> this it is not very interesting, but there are about 5 or 6 rashes
> that would be around this sort of severity. So, the idea is you can
> see that there is deeper erythema. It is coalescing in areas and it
> seems to have a break here, which might be the bra straps, and one
> sees in a few patients.
>
> I just want to make a comment about that. Dr. Bigby mentioned
> sometimes pressure does induce rashes and sometimes I think it
> prevents rashes. People lying in bed in hospital often will get a rash
> on their back. I don\'t know if it is because of drug delivery,
> different heat, whatever, but in areas that have been under pressure,
> like belts, and bra straps, you often don\'t see as much of a rash and
> we will see that in a few people, but the pathology did not show any
> phototoxicity or changes associated with phototoxicity.
>
> \[Slide\]
>
> These are the severe cases. Seven percent of the rashes were coded as
> severe and the definition of severe was that it interfered with your
> daily activities. I just want to show you the appearance of the ones
> that we have photographs for, just so you get an idea, a bit of a
> gallery of what these look like because it is really hard to quantify
> these, and a picture is worth a thousand words and I want to spare you
> the seven thousand words or so.
>
> \[Slide\]
>
> Let\'s go on.
>
> \[Slide\]
>
> And again. You can see again this sort of appearance but really when
> you look at this closely you will see rash in there as well, it is
> just that the tanned area looks a little more impressive.
>
> \[Slide\]
>
> This is not a rash that a dermatologist would normally biopsy. I mean,
> it would only be a relative that would show you a rash like this, and
> if they did show you, you certainly wouldn\'t biopsy it and you
> probably wouldn\'t even treat it. Frankly, for some of these, even
> though these were recorded as severe, any less rash than this would be
> no rash at all.
>
> \[Slide\]
>
> The other issue that came up were other morphologies that might be
> signals. Two that come up are the issue of facial swelling and the
> term urticaria and what does this mean. In this study the term
> urticaria was meant to be a clinical description with a view that some
> rashes would be urticarial. None of these rashes had the annular
> appearance of true urticaria and basically just showed this papular
> appearance a little more strikingly. In some of the photographs,
> because you get blanching around some of these, they look as if they
> stand out even more but that is more an optical illusion that one
> sees. You often see this whitening of the skin probably because of a
> prostaglandin effect surrounding the rash.
>
> But the onset and duration of these so-called urticarias was the same
> as that seen with the typical exanthem. I am getting ahead with the
> histology but the histology is also similar to that seen with the
> typical exanthems. There was no swelling of the lips or tongue; no
> annular rashes on the skin; nothing that made it look truly urticaria
> but just urticarial.
>
> For the facial edema, this usually referred to the rash being on the
> face. We only have a few pictures of the face. It was not part of the
> study generally to take pictures. So, if anyone had anything severe
> that looked a little more red, that was taken and generally it wasn\'t
> urticaria and it wasn\'t generalized swelling; it was just the rash on
> the face that was swollen. So, that was reassuring. There was no true
> urticaria and nothing to support angioedema.
>
> \[Slide\]
>
> Continuing with the diagnostic triangle, we are also looking at the
> systemic appearance. I mentioned that mucosal changes could be
> important, and specifically we are interested in hemorrhagic crusting
> or more erosive changes and those were not seen. But there were
> changes like dryness of the lips and typical aphthae, and one person
> had macular erythema. Wheezing was seen in one patient but they had no
> signs of any type-1 or hypersensitivity reaction associated with that
> and it seems to be just an isolated finding.
>
> Six patients who had fever with rash, in reviewing the CRFs there was
> nothing of concern except there was one that had lymphadenopathy
> associated with this, and all we have in the check box is
> lymphadenopathy. The patient\'s rash cleared in a couple of days. They
> weren\'t admitted to hospital, and the histology did not show CD8
> positive predominance like one sees with hypersensitivity syndrome,
> and they did not have any liver or urine changes that, again, would
> suggest systemic involvement. So, we were quite reassured in looking
> back on that one. The rash looked a little redder but the pathology
> was as benign as all the others. It cleared quickly and there was no
> systemic involvement so we don\'t think that is a true
> hypersensitivity syndrome.
>
> \[Slide\]
>
> Looking at liver enzymes, there were no clinically significant changes
> in this study; no differences in ALTs between women with rash and
> those who didn\'t have rash; and no changes in the eosinophilic count
> that were of importance.
>
> \[Slide\]
>
> Now the histology. This is the final part of the triangle. Assuming
> that you are not all horribly familiar with skin biopsies, let me just
> show you. This dark part, here, is the epidermis. One of the things
> one would look for, of course, would be either changes at the
> interaction between the epidermis and the dermis, like one sees in
> Stevens-Johnson or other reactions, and, no, there aren\'t.
>
> Is there necrosis or changes in the blood vessels, like vasculitis?
> No, there aren\'t. In fact, what you see here is lymphocytes which are
> predominantly CD4 positive, which is what one sees in the mildest of
> drug rashes. This is what was seen in 278 of the 288 biopsies\--this
> picture, slightly more or slightly less over and over and over again.
>
> This is sort of the worst one because the ones which were at the mild
> end, which is 80 percent of them, you can hardly even see the
> lymphocytes.
>
> When you look at the 10 cases that had moderate superficial and deep
> lymphocytic infiltrate, again they were CD4 positive and, in reviewing
> these cases, there was nothing that was striking about them
> clinically.
>
> In the skin that was normal that was biopsied there were no
> subclinical rash changes. There was no pathology in the normal skin.
>
> \[Slide\]
>
> The immunohistochemistry, as I said, showed that these were T-cells
> and they were CD3 positive. There was a mixed population,
> predominantly CD4 positive, which is what one sees in these mild
> exanthems. This is a reassuring sign. There was no hint of erythema
> multiforme, epidermal necrosis or vasculitis. This all fits with just
> a general mild drug rash.
>
> \[Slide\]
>
> Now part B, looking at the issue of sensitization potential, and this
> has taken a complicated study and made it even more complicated but
> what one looks at here is three groups. I am going to go through these
> individually to make it easier to follow.
>
> This group is people who got a rash on gemifloxacin and then were
> exposed to ciprofloxacin or placebo. In about 10 percent of people,
> which is about 6 percent more than the placebo rate so about 6
> percent, if you will, overall got a rash on ciprofloxacin. There was
> one site that was considered an outlier and I see the FDA has taken
> that site out of theirs. We took a more conservative approach of
> including it here, but if you take that out one sees an increased
> attributable risk of about 4 percent.
>
> I think this is remarkable. We have heard things about \"in class\"
> issues and from our drug safety clinic and others who do drug safety
> clinics we have heard that people will react to Pan G and not to Pan
> V, let alone react to amoxicillin and not react to penicillin,
> oxacillin or others. So, it is very, very specific to the drug and
> there are good immunological reasons for that. I think the reason we
> tend to think of a class effect is based on the premise that these
> drugs work through the same way but the reason they work through the
> same way is we only pick the drugs to develop that are going to work.
> So, if a quinolone doesn\'t block these enzymes that Dr. Low showed
> you, it is not going to go on to development. So at the end of the day
> they all look the same but they are not really all the same. The ones
> that are different have dropped out because of efficacy and we are
> left with a legacy that we think they are the same but they are not.
>
> I think anybody who is afraid of this would be surprised to say that
> if you took all the people who got a rash and 4 weeks later gave them
> a quinolone and 4 percent of them, if you will, had a rash above
> placebo you would be really surprised. That is a very low number and I
> think that is very useful, and no other drug has this data so that is
> also very useful.
>
> \[Slide\]
>
> Looking at people who maybe had subclinical sensitization\--you got
> gemifloxacin once and you didn\'t get a rash, what if you got it again
> and there is no difference between placebo or not. So, if you got gem.
> and you are okay, you are okay.
>
> \[Slide\]
>
> This was to look at some of the background, and what is interesting
> here is people who got ciprofloxacin once and didn\'t get a rash but
> got ciprofloxacin again, about 5 percent of them, or 3.5 depending on
> the data you use, got a rash on ciprofloxacin. The background rate
> with gemifloxacin actually was lower for people who got it twice.
>
> \[Slide\]
>
> When we looked back on the rashes in part B, we also wanted to look at
> what these rashes were. You might say, well, the rate was low but
> maybe these rashes were really scary. We didn\'t get a lot of them but
> maybe they were scary.
>
> They were all less than 10 percent of the body surface area. I have to
> say that when you read these case record forms body surface area is
> overstated, which is a problem and it was a problem we faced when we
> did the big study that was in [The New England Journal]{.underline}
> looking at TEN. We had to have pictures of bodies to show you because
> if you got a couple of dots all over the place people tend to
> overestimate that. But this did not have much of the body surface
> area. No reports of mucus membrane involvement; nothing suggestive of
> IgE-mediated reaction; no systemic involvement; no elevated liver
> enzymes; and the rash came on a little earlier but was benign. So, I
> think what we found in part B was just a lot of very bland eruptions.
>
> \[Slide\]
>
> To summarize study 344, this was a remarkable study and after 10-day
> exposure in a population that is known to have an increased risk of a
> rash, the rash that was seen was generally very bland. It was a
> classical exanthem that one sees. There was no evidence of
> hypersensitivity syndrome; no markers of Stevens-Johnson toxic
> epidermal necrolysis.
>
> \[Slide\]
>
> In the clinical trials the rash rate was 3.6 percent overall. The rash
> was higher in younger women after 10 days. After 7 days it was 10
> percent, as you saw, and about 2 percent at 5 days.
>
> There was one case of serum sickness like reaction in the database of
> 6,775 people and exposures and no cases that really fit the definition
> of a clinically serious rash like Stevens-Johnson/TEN or
> hypersensitivity syndrome. Those were not seen.
>
> \[Slide\]
>
> In conclusion, the rash rate with gemifloxacin in the general
> population that is exposed for treatment is 3.6 percent and that is a
> rate consistent with that commonly seen with many antibiotics, as you
> heard earlier. It did occur with an increased frequency in a subset of
> people who are not really the target treatment population and when the
> drug was taken for longer than is being asked for.
>
> Study 344 was the largest and most comprehensive drug rash study that
> I have ever seen in 20 years in the business of looking at drug safety
> in skin. What was found was conclusively clinically and systemically
> and histologically to be a mild inflammatory exanthem. There were no
> cases in the 10,000 subjects in the overall database of
> hypersensitivity syndrome of Stevens-Johnson.
>
> So, this is a rash that may occur more frequently than seen with the
> comparators in the clinical trials, but I am very reassured from the
> clinical trial database and especially from this 344 study that the
> safety questions have been investigated extensively and have been
> answered clearly. Thank you.
>
> **Risk-Benefit and Risk Management**
>
> DR. PATOU: Thank you, Dr. Shear.
>
> To sum up, gemifloxacin has been extensively examined in studies
> involving nearly 10,000 patients. The data show no clinically
> significant liver or QTc problems. The rash rate in CAP and AECB is
> greater than that seen with comparator, however, there was no evidence
> of significant morbidity observed. There is a low rate of
> cross-sensitization and there is no evidence for subclinical
> sensitization with gemifloxacin usage.
>
> \[Slide\]
>
> I will now describe the benefit-risk for gemifloxacin. Really no
> assessment of benefit-risk would be complete without first reviewing
> the limitations of current medical treatment for these conditions.
> Because of resistance to the older classes of antibiotics, physicians
> have become increasingly dependent on the newer fluoroquinolones. As
> we have heard, there is now increasing resistance to these quinolones
> also.
>
> \[Slide\]
>
> As shown on this slide, each of the fluoroquinolones currently on the
> market comes with its own set of problems. With gatifloxacin
> life-threatening hyperosmolar coma has been reported. Moxifloxacin
> carries a warning for QTc prolongation. As Dr. Low has published and
> described today, levofloxacin resistance, which is now emerging, has
> been associated with pneumococcal pneumonia treatment failure and even
> death. Thus, there is a critical need for additional treatment choices
> in AECB and CAP, and we believe gemifloxacin is well suited to meet
> that need.
>
> \[Slide\]
>
> Looking at the benefits of the drug, gemifloxacin is uniquely potent
> against respiratory pathogens and has favorable PK/PD correlates. We
> have demonstrated that this allows us to treat patients with shorter
> courses of therapy. This would likely lead to better patient
> compliance and, importantly, would expose the commensal bacterial
> flora to less resistance pressure.
>
> The dual targeting of the drug and its potency means that it is active
> against antibiotic resistant respiratory pathogens, including
> fluoroquinolone resistant pathogens. As Dr. Powers mentioned in his
> talk earlier, by the time the organisms are resistant to levofloxacin
> there really are very few treatment choices available.
>
> The spectrum of its activity means that the drug is likely to be
> effective in empiric treatment in the community, regardless of whether
> the infective respiratory pathogen is antibiotic resistant. We have
> also demonstrated that the benefits of this drug extend beyond the
> acute treatment period, manifested as reduced relapse rate and
> duration of hospitalization in AECB, fully recognizing that these are
> secondary endpoints in those clinical studies.
>
> \[Slide\]
>
> Gemifloxacin\'s excellent oral bioavailability, coupled with its
> potency, means this drug can effectively be used when physicians may
> otherwise have used intravenous therapy to treat their patients. We
> have demonstrated that oral gemifloxacin is equivalent in
> effectiveness to IV comparator regimens and obviates the need to
> immobilize patients.
>
> The lack of significant drug-drug interactions with gemifloxacin is
> important because many of the patients affected with these conditions
> are elderly and on co-medications which complicate the choice of
> antibiotic. No dose adjustments are required, except in severe renal
> impairment, with gemifloxacin.
>
> \[Slide\]
>
> On the risk side, gemifloxacin has a good adverse event profile and
> was well tolerated, as reflected in the low withdrawal rates from
> studies. There are few quinolone class effects. There is no hepatic
> safety signal and we see a shorter QTc prolongation than with other
> quinolones.
>
> There was an overall rash rate of 3.6 percent and clearly higher in a
> susceptible subpopulation that we studied. However, it was not
> associated with significant morbidity and had low cross-sensitization
> potential and no subclinical sensitization potential. As you heard Dr.
> Shear say earlier, it is a clinically manageable, typically mild drug
> rash.
>
> \[Slide\]
>
> I want to say a few words about risk management. We have obviously
> thought a lot about risk management. We have a twofold risk management
> strategy. The first is managing risk and the second is anticipating
> the worst case scenario.
>
> First, we know that most of the rashes occurred in women younger than
> 40. Our target label population is patients with CAP and AECB and
> these tend to be an older patient population. In study 344 the rash
> occurred when the women took the drug for extended periods, that is,
> more than the 5-7 days that we are intending in our treatment
> indications of CAP and AECB.
>
> We will provide the drug only in a 5- or 7-day fixed dosage pack. This
> means that we believe physicians will be unlikely to prescribe more
> than the intended course. As we explained in an appendix in our
> briefing book, we have analyzed the impact of a fixed dosage pack and
> we believe that this strategy would be effective.
>
> However, even in the event that none of these procedures is followed,
> study 344 clearly demonstrates that this observed rash is benign and
> uneventful for those patients who might get it. You recall what Dr.
> Shear said, never before has he seen a study as thorough and
> exhaustive as study 344 and he found no evidence in the study that the
> observed rash was anything other than a mild, benign drug rash.
>
> The adverse events noted on gemifloxacin will be fully described in
> the package insert to the drug. In addition, we will provide physician
> education and we have proposed to the FDA, and we have been in some
> discussions with Rob Stern and others who are experts in this area,
> the study design for a Phase IV study to study the safety of the drug
> in the marketplace.
>
> \[Slide\]
>
> We conclude that gemifloxacin in the treatment of AECB and CAP would
> be a valuable, indeed a critically needed addition to the physician\'s
> armamentarium in the treatment of these diseases. I thank you for your
> attention.
>
> **Questions and Answers**
>
> DR. LEGGETT: Thank you. Are there any immediate questions over the
> next five minutes or so before we take a break, and then we will come
> back. First Dr. Maxwell and then Dr. Bigby.
>
> DR. MAXWELL: I have three questions related to the same issue, and
> that is the issue of women and estrogens. Firstly, although the
> reports are that most of the women that were affected were under the
> age of 40, what I wanted to know is were there any older women that
> were on estrogen replacement therapy that developed the rash?
>
> The second part to my question was on slide number 32 where there were
> some aphthous buccal ulcers noted. I wanted to know if there was any
> other mucosal involvement in any of the women, vaginal or anywhere
> else.
>
> The last part of my question, Dr. Bigby stated that you could develop
> a rash up to several weeks after exposure to some drugs. I want to
> know if there were any of the patients developing a rash that received
> the drug for the 5- or 7-day period that developed this rash greater
> than 2 weeks after exposure to the drug.
>
> DR. SHEAR: Can I have slide R36? Actually, we can probably show 35 as
> well.
>
> \[Slide\]
>
> As I mentioned verbally, there was an association with hormone
> replacement therapy that showed a higher risk. What we are looking at
> here is the odds ratios and the 95 percent confidence intervals. So,
> we are looking at hormone replacement therapy use. It was around two.
> So, there was an increased risk with hormone replacement therapy, not
> as high as with the other risk factors.
>
> \[Slide\]
>
> This is our contraceptive use, which I think is relevant to the
> question. Here there was no statistically significant association. It
> was slightly higher but the confidence intervals crossed 1 and so it
> was not considered that oral contraceptive use was relevant.
>
> The question about mucosal involvement, there was one case report in
> 344 that mentioned labial involvement. Now, I don\'t know if that
> meant that it was on the lips, but the implication I think was that it
> may have been on the vulva but there was just some erythema and
> possible erosions but nothing striking. At least, there were no
> details there that made us think it was anything severe. That was in a
> patient who had some other changes and I think that will be discussed
> later.
>
> \[Slide\]
>
> In study 344 we had the chance to follow people very carefully. This
> is a complicated slide so let me walk you through it. It is not
> something we see very commonly. This is from the clinical trial
> population because we know in 344 people didn\'t get the rash much
> after the 10 days. But if you look at the trial population, what we
> are doing here is this is the number of days after therapy was
> stopped. The yellow is the gemifloxacin and the blue is the
> comparator. What we have here is that this number represents, if you
> added up all these, 100 percent of people who got a rash after the
> drug was stopped. We know what the rash looks like, but if 100 percent
> of those people got a rash after the drug was stopped, about a third
> of them were on the first day after the drug was stopped and about a
> quarter of them were 2 days later. Then, there were a few cases that
> came up later but there were no late surprises later on.
>
> DR. LEGGETT: Dr. Bigby?
>
> DR. BIGBY: The duration of treatment for those patients in this slide
> is what?
>
> DR. SHEAR: The duration of treatment is a mixed bag. It is primarily 5
> and 7 days. There are some 10 and the odd 14 because 14 wasn\'t used
> much.
>
> DR. LEGGETT: Dr. O\'Fallon?
>
> DR. O\'FALLON: This is more of a comment. I thought the rash study was
> very impressive. I wish you had presented confidence interval
> estimators on a lot of those things because when you have done a
> really big study you can get a lot of mileage out of that.
>
> DR. LEGGETT: Dr. Adkinson?
>
> DR. ADKINSON: Dr. Shear, I certainly share your belief that the
> clinical significance of rash is perhaps inferred from evidence of
> systemic involvement in reaction. So, I would like to ask for a little
> further information about these 7 severe adverse reactions that were
> attributed to rash. You have told us I think that the histology and
> the pictures taken of those rashes were quite benign and unimpressive.
> But I wonder if you could say a little more about other systemic
> features that might have been present during those hospital stays,
> particularly fever and eosinophilia.
>
> DR. SHEAR: There are a couple of bits of data that are important. In
> the 7 SAEs that were reported from the clinical trial database, 6 of
> those had really no important signs of systemic involvement. As far as
> eosinophilia goes, I don\'t have that. We don\'t know about the
> eosinophilia in those. The rashes were very mild, lasted a couple of
> days and went away. There was nothing to suggest urticaria and nothing
> to suggest systemic involvement. Are those the ones you are talking
> about?
>
> DR. ADKINSON: And also with regard to the 6 cases that had fever and
> rash in the 344 study. Can you say something about the time course and
> the persistence of fever in those cases? Was it an isolated fever
> spike? Did it correlate with the rash? Did it persist after the rash
> disappeared? I am particularly worried about this group because if I
> understand it correctly the 344 study was conducted in normal
> subjects. Right? So, there shouldn\'t be other common causes for
> fever.
>
> DR. SHEAR: Well, I think there are certainly issues when you are
> looking at 1000 people. Some people are going to get a fever. Having
> said that, fever was defined as a temperature above 37.5 so it was a
> pretty low threshold for diagnosing fever. The way it was scored was
> just on a check box so they checked off that that was the temperature.
> The drug was stopped if people had rash, and the rashes lasted maybe 5
> days, just like the others. There was nothing different in terms of
> the duration. But the fever was hard to chart. In follow-up visits 2,
> 3 days later people were generally recovered.
>
> DR. ADKINSON: And was eosinophilia looked for in these cases?
>
> DR. SHEAR: No, eosinophilia was not part of that.
>
> DR. ADKINSON: Was not part of that? So it was looked for and not
> found?
>
> DR. SHEAR: It was looked for and not found.
>
> DR. LEGGETT: Dr. Epps?
>
> DR. EPPS: I just have a brief question at this point. What was your
> ethnic breakdown in study 344? The reason I ask is that a 2-5-day rash
> can sometimes result in months of hyperpigmentation or
> hypopigmentation, which is what ends up at the dermatologist\'s
> doorstep, and certainly something that is benign from this aspect or
> your consideration may be prolonged and very distressing for a
> patient.
>
> DR. SHEAR: My apologies, what was the very first part of the question?
>
> DR. EPPS: The ethnic breakdown.
>
> DR. SHEAR: In 344? I can get you some information but in the clinical
> trials there were rashes and the rate in people with white skin was
> 3.8 percent, which was similar to the overall. In the non-white
> skinned or darker skinned individuals, there were about 1000 people
> who were involved in the studies and the rash rates ranged between 1.3
> and 2.9 percent. In fact, it was less than in the white individuals.
>
> In 344 as part of the exclusion criteria the darker skinned
> individuals were excluded, mostly for reasons of ascertainment, but
> the clinical trial database was very reassuring that, if anything,
> there may have been a lower rate.
>
> DR. LEGGETT: Dr. Wald?
>
> DR. WALD: In any of the clinical trials was the drug continued in
> patients who developed a rash? If so, what was the outcome?
>
> DR. SHEAR: It was. Gary, do you want to comment on that?
>
> DR. PATOU: Yes, many of the patients in the original clinical trials
> actually continued therapy after they developed a rash. It was at the
> time when we were not aware of an increased rash rate on study. In
> fact, 75 percent were actually treated through rash and we looked to
> see if there was any increased severity or adverse events that were
> associated with treating them through the rash in that regard, and
> there were not.
>
> DR. LEGGETT: Dr. Poretz?
>
> DR. PORETZ: The rash associated with amoxicillin is exacerbated in
> people who have concurrent viral infections like EBV. I saw that you
> obtained EBV serologies. I don\'t know what they showed but in the
> patients that you studied, you obviously went to great care to make
> sure that they had bacterial infections. They had sputa collected or
> whatever. Were patients put on gemifloxacin who had coexistent viral
> illnesses, and was there a greater incidence of rash? Because in a
> younger population, young women below the age of 40, I will bet you in
> the community people will be put on a drug like this when they have a
> viral illness and not necessarily a bacterial problem.
>
> DR. SHEAR: Just to reinforce that, in study 344 these were healthy
> volunteers who did not have infection and who were given the drug and
> it was done in a very controlled way, which actually made it easier
> because you didn\'t have to worry about how they were doing
> clinically.
>
> Epstein-Barr, EBV, was looked at and there was no positive EBV. One
> could argue that maybe other infections should be looked at as being
> reactivated, or whatever. That is an area that is still very much
> investigational in trying to understand exanthems, but that wasn\'t
> found in that study. As far as in a larger clinical trial database,
> Wayne, did you want to speak to that? Wayne Danker is the senior
> medical advisor for Parexel.
>
> DR. DANKER: In the clinical trial database the only pathogens that
> were looked for were the typical respiratory pathogens that one would
> seek for a claim for the antibiotic. So, specimens were not
> specifically looked at for viruses or cultured for viruses.
>
> DR. PORETZ: But in individuals who have been treated in some parts of
> the world, Europe or somewhere, there must be data on those people who
> had coexistent viral infections perchance.
>
> DR. DANKER: It wouldn\'t have been captured on the CRF-1. The only
> things that were captured on the CRF-1 were the sputum culture results
> from the AECB and the CAP patients.
>
> DR. LEGGETT: Dr. Proschan?
>
> DR. PROSCHAN: I have a comment that is not about rash. I don\'t know
> whether you want to delay that.
>
> DR. LEGGETT: Can we delay that?
>
> DR. PROSCHAN: Sure.
>
> DR. LEGGETT: Dr. Patterson?
>
> DR. PATTERSON: Since the anti-pneumococcal quinolones are more similar
> in structure to each other than, say, cipro., would
> cross-sensitization be more likely if gem. was compared to, say, gati.
> than to cipro.? I guess the corollary to that is do you know what part
> of the gem. molecule is associated with this rash? Is it present in
> the other anti-pneumococcal quinolones?
>
> DR. SHEAR: That is a very good question. I think perhaps Dr. Werner
> Pichler, who has worked with the quinolones and rash and has done some
> very good work on that, could come and speak to that.
>
> DR. PICHLER: Patients who were treated with ciprofloxacin and
> generated T-cell clones against these compounds were analyzed for
> cross-reactivity with 7 different fluoroquinolones. We found that the
> majority of the T-cell clones reacted only with the original compound
> which was ciprofloxacin or norfloxacin. But some clones reacted also
> with a variety of different fluoroquinolones. So, in principle there
> is the chance that there is cross-reactivity but the cross-reactivity
> becomes clinically manifested only if you have a very strong immune
> reaction to first line and if you have many, many clones which react
> with these compounds. The majority of clones react only with the
> original compound. It is quite complicated.
>
> DR. LEGGETT: Good. Can we take a break now and come back in ten
> minutes? Could I please speak with a representative from the company?
>
> \[Brief recess\]
>
> DR. LEGGETT: Hello again. The next part of today\'s proceedings will
> be the FDA presentation. To give us a brief introduction will be Dr.
> Ed Cox.
>
> **FDA Presentation**
>
> **Introduction**
>
> DR. COX: Good morning and almost good afternoon. I am Ed Cox. I am the
> Deputy Office Director for the Office of Drug Evaluation IV.
>
> \[Slide\]
>
> Today what I am going to do is to just review the structure of the FDA
> presentation just to orient folks. We will start out with a
> presentation by Mr. Pete Dionne who will be reviewing the
> microbiology; followed by Regina Alivisatos who will be talking about
> community-acquired pneumonia; and then Eileen Navarro will be talking
> about acute bacterial exacerbation of chronic bronchitis; followed by
> Dr. Maureen Tierney who will be talking about safety. Then I will just
> come back and make some brief remarks at the close of the
> presentation.
>
> With that, I will turn the microphone over to Mr. Dionne. Thank you.
>
> **Microbiology**
>
> MR. DIONNE: Good morning. I guess it is still morning.
>
> \[Slide\]
>
> I am Pete Dionne and I get to start off FDA\'s presentations on
> gemifloxacin. In the next few minutes we will be talking about
> gemifloxacin\'s microbiology from the FDA viewpoint.
>
> First of all, we will look at the activity of gemifloxacin to compare
> to some of the other quinolones, mainly against the major respiratory
> tract infections. After that we will look at the activity of
> gemifloxacin and compare it against certain resistant [Strep.
> pneumoniae]{.underline} strains. Then we will look at the comparative
> activity against genetically defined mutants of [Strep.
> pneumo.]{.underline} Lastly, we will look at the efficacy of
> gemifloxacin and some comparative quinolones in a rat pneumonia model.
>
> \[Slide\]
>
> On this first slide I have listed the MIC-90s for gemifloxacin and
> some of the other comparative quinolones. As you will notice, against
> the gram positive organisms gemifloxacin\'s MIC-90s are considerably
> lower than most of the other quinolones. Against the gram negative
> organisms the MICs are comparable to most of the other ones.
>
> Another point you might want to consider is against [E.
> coli]{.underline} and [Klebsiella]{.underline}, gemifloxacin\'s MIC is
> higher for these two organisms. That may affect how well it works
> against these two organisms in clinical efficacy.
>
> \[Slide\]
>
> As you know, looking at MICs alone is only one part of the thing we
> have to look at. If we look at the AUC, which most people think with
> quinolones is the important PK parameter, we notice that
> gemifloxacin\'s MIC is about 4-8 times lower than those for the other
> comparative quinolones. It is basically about 6 times lower than that
> for moxifloxacin.
>
> \[Slide\]
>
> Let\'s see what we have just reviewed here. We noticed that
> gemifloxacin\'s MICs are lower against the gram positive bacteria
> compared to other quinolones. Then we have noticed that
> gemifloxacin\'s MICs are about equal to other quinolones against the
> gram negative bacteria. Gemifloxacin\'s PK parameters weaken the
> significance of the lower MICs against the gram positives.
> Gemifloxacin\'s PK parameters may affect the efficacy against the
> enterobacteriaceae.
>
> \[Slide\]
>
> On this slide we have looked at Pen-resistance to [Strep
> pneumo]{.underline}. The thing to notice here, as has already been
> presented this morning, is the MIC values and the Pen-resistant ones
> are basically equal for all the quinolones.
>
> \[Slide\]
>
> On this slide we look at quinolone resistant [Strep
> pneumo]{.underline}. Notice that there is a difference here, as you
> would expect. The quinolone-resistant ones for gemifloxacin have
> MIC-90s of 0.25-1.0 with a median MIC-90 of 0.5 as compared to 0.06
> for the quinolone susceptibles. Notice this is only one study.
> Moxifloxacin has an MIC-90 about 4 in this study and levofloxacin and
> ciprofloxacin have considerably higher MICs against these
> quinolone-resistant ones.
>
> \[Slide\]
>
> On this slide we look at some genetically defined [Strep.
> pneumo]{.underline}. mutants. As was pointed out this morning, ParC
> doesn\'t affect gemifloxacin\'s MICs too much. They go up about 2-4
> times. Moxifloxacin\'s run about the same, but levofloxacin\'s go up
> considerably. The shaded value here represents the double mutant. As
> you can see, gemifloxacin\'s MIC is 0.25, moxifloxacin\'s is about
> 2.0, levofloxacin and ciprofloxacin are greater than 32.
>
> \[Slide\]
>
> On this slide we have some ciprofloxacin [Strep. pneumo]{.underline}.
> and we have done MIC testing against them. We have also genetically
> defined the mutations. What you might want to notice here is that this
> one is ciprofloxacin intermediate. It also has no mutations. So, that
> may indicate that ciprofloxacin is probably one of the better drugs
> for [Strep. pneumoniae]{.underline}. The ones shaded here are the
> double mutants. Once again, gemifloxacin\'s MIC is 0.12 to 0.25;
> moxifloxacin\'s is around 2, gatifloxacin is 4; levofloxacin is 8 and
> ciprofloxacin is 60.
>
> \[Slide\]
>
> This experiment we saw a little bit of this morning. What happened,
> there were 44 [Strep. pneumoniae]{.underline} second step mutants. In
> this slide I have listed, out of the 44, the numbers of each of the
> MICs. As you can see, most of the ones for gemifloxacin are around
> 0.25. Moxifloxacin\'s majority was 2; gatifloxacin was 1 higher and
> levofloxacin and ciprofloxacin were considerably higher than that.
>
> \[Slide\]
>
> Now if we look what we have learned in the second part, we see that
> [Strep. pneumo.]{.underline} MICs, as expected, against the
> Pen-resistant ones were the same as the Pen-susceptible for all the
> quinolones. When we get to the quinolone-resistant [Strep.
> pneumo.]{.underline} gemifloxacin\'s MICs are in the range of 0.25 to
> 1.0 and moxifloxacin\'s\--granted, it was only one study\--was around
> 4. The [Strep. pneumo.]{.underline} double mutants had gemifloxacin
> MICs, once again, of 0.25. Moxifloxacin\'s were around 2 and
> levofloxacin\'s was 32. If you consider that gemifloxacin\'s value is
> about 6 times the AUC, about 6 times lower than the moxifloxacin\'s
> and you multiply 0.25 by 6 you get 1.25, which is approximately what
> moxifloxacin\'s MIC is for these double mutants.
>
> \[Slide\]
>
> Lastly, we are going to look at the efficacy of gemifloxacin and
> comparative quinolones in a rat pneumonia model, [Strep.
> pneumoniae]{.underline} being the infecting organism. On the first
> slide all the gemifloxacin MICs are less than equal to 0.03 mcg/ml.
> Some of them are Pen-resistant, some are macrolide resistant. If you
> notice gemifloxacin, the level of detection in this experiment was
> less than or equal to 1.7 CFUs per lung.
>
> Also, dosing in this experiment was once daily and started 24 hours
> after the infection was started. This will be significant when we go
> to the other slide. Dosing was once daily because most of the
> quinolones, as you know, are dosed once daily and they tried to
> represent the same AUC values in this experiment as what would happen
> with a normal human dose.
>
> When they tried this experiment with gemifloxacin\'s MICs of 0.125,
> they didn\'t get efficacious results. So, they looked at it and they
> said, well, the half-life in the rat is about half of what it is in
> humans so they went to twice a day dosing, kept the dose per day the
> same but just went to twice a day dosing. The shaded area represents
> gemifloxacin\'s MICs of 0.25 and there were 5 of those. For 3 of them
> gemifloxacin wasn\'t any better than the control.
>
> Once again, you might want to notice that in this experiment
> gemifloxacin never got down to the level of detection for most of
> these. They were better than levofloxacin for almost all cases.
>
> \[Slide\]
>
> The last slide in this series compares gemifloxacin with moxifloxacin
> and gatifloxacin. Once again, dosing was b.i.d. As you can see, when
> you get the gemifloxacin MICs of 0.03 or less once again you get to
> the level of detection for gemifloxacin but moxifloxacin and
> gatifloxacin were pretty much the same. Gemifloxacin beat moxifloxacin
> in a couple of cases. It was better than gatifloxacin also in other
> cases. But overall, the efficacy in this experiment appears to be
> pretty equal for all three of them.
>
> \[Slide\]
>
> In this rat [Strep. pneumoniae]{.underline} infection model isolates
> for gemifloxacin MICs less than or equal to 0.03 mcg/ml were able to
> be dosed once daily, and the CFUs reached close to the level of
> detection. Isolates with gemifloxacin\'s of 0.125 mcg/ml had to be
> dosed twice a day and the efficacy never got down to the level of
> detection. In most cases in these experiments gemifloxacin appeared to
> be better than levofloxacin and gemifloxacin appeared to be about the
> same as moxifloxacin and gatifloxacin.
>
> \[Slide\]
>
> The summary that I have is that gemifloxacin, at least from the
> microbiological viewpoint, looks to be about equal to moxifloxacin and
> looks to be better than levofloxacin.
>
> With that, I will turn the podium over to Dr. Alivisatos to talk to
> you about community-acquired pneumonia.
>
> **Community-Acquired Pneumonia**
>
> DR. ALIVISATOS: My name is Regina Alivisatos and I will be presenting
> the FDA perspective on the efficacy of gemifloxacin in the treatment
> in community-acquired pneumonia.
>
> \[Slide\]
>
> The sponsor\'s proposed indication is community-acquired pneumonia
> caused by [Streptococcus pneumoniae]{.underline}, including
> penicillin, clarithromycin and cefuroxime-resistant strains,
> [Haemophilus influenzae]{.underline}, [Haemophilus
> parainfluenzae]{.underline}, [Moraxella catarrhalis]{.underline},
> [Mycoplasma pneumoniae]{.underline}, [Chlamydia
> pneumoniae]{.underline} and [Legionella pneumophila]{.underline} and
> [Staphylococcus aureus]{.underline}. The proposed dose and duration of
> treatment is one 320 mg daily for 7 days.
>
> The sponsor is requesting duration of treatment of 7 days primarily
> for two reasons: One, because the incidence of rash increases with
> durations of treatment greater than 7 days. Two, because of the
> movement toward shorter durations of treatment in respiratory tract
> infections.
>
> \[Slide\]
>
> I would like to start off by saying that the FDA is in general
> agreement with the sponsor\'s efficacy analyses. The FDA presentation
> will concentrate on efficacy in relation to the duration of treatment
> and to the severity of disease. I will also present the data that was
> reviewed by the agency in support of the sponsor\'s claim of efficacy
> versus [Streptococcus pneumoniae]{.underline}, including
> penicillin-resistant, macrolide-resistant and cefuroxime-resistant
> [Streptococcus pneumoniae]{.underline}. I will also briefly mention
> data submitted regarding quinolone-resistant [Streptococcus
> pneumoniae]{.underline}.
>
> \[Slide\]
>
> As seen in the sponsor\'s presentation, there were 6 studies that
> comprised the clinical studies data set, 4 controlled and 2
> uncontrolled. One uncontrolled study, number 287, is ongoing and an
> interim report was part of the submission. Three of the controlled
> studies, number 011, 012 and 0149, were randomized, double-blind,
> parallel group studies and one study, number 185, was an open,
> controlled trial.
>
> Of interest to the agency was the duration of treatment. As you can
> see, only study 011 of the controlled studies, as well as the 2
> uncontrolled studies, have a fixed 7-day duration of treatment.
> Whereas, in 3 of the controlled studies, 012, 049 and 185, the
> decision to allow dosing to continue to 14 days was made in a
> non-randomized fashion based on post-randomization efficacy
> information. Treatment could have been extended at the investigator\'s
> discretion at the on-therapy visit, for example if the pneumonia was
> confirmed or if it was due to an atypical pathogen such as
> [Legionella]{.underline}.
>
> \[Slide\]
>
> The agency, although in general agreement with the sponsor\'s
> analyses, determined that combining the 7-day data from the subjects
> enrolled in the fixed 7-day trials with those that received 7 days in
> the 7-14 day trials should not be done because the 7-day data from the
> fixed 7-day trials contain information from all patients enrolled in
> those studies, while the 7-day data from the 7-14 day studies have
> patients removed who were considered by the physicians to have needed
> more treatment and could, in general, represent a more ill population.
> This would cause the 7-day efficacy data from these studies to be
> biased most likely upwards.
>
> In our presentation of the data we will not combine these 2 groups of
> 7-day duration subjects. Since the sponsor is interested only in a
> 7-day regimen, we considered the data from the 7-day fixed regimen as
> primary data, with the 7-14 day data as supportive. Although the
> sponsor didn\'t mention this today, they did have it in their
> submission, as cautioned by them, the 7-day efficacy data should not
> be directly compared to the 14-day efficacy data. Each group of
> gemifloxacin patients should only be compared to their respective
> controls.
>
> \[Slide\]
>
> There were 1349 intent-to-treat patients treated with gemifloxacin and
> 927 treated with an active comparator, and 947 patients were treated
> with gemifloxacin in the controlled studies and 402 patients were
> treated with gemifloxacin in the uncontrolled studies; 569 patients,
> 1167 from study 011 and 402 from the uncontrolled studies, had a fixed
> 7-day duration of treatment; 468 patients from the controlled 7-14 day
> studies received 7 days of treatment and 312 patients received greater
> than 7 days and in some cases up to 14 days. Overall, 312 of 947, or
> about a third of the controlled study patients received greater than 7
> days of treatment.
>
> You have seen the sponsor\'s primary efficacy analyses and we are not
> going to repeat them all. I will be presenting additional analyses
> that the FDA performed that handled the fixed 7-day duration alongside
> those that received a duration of 7-14 days.
>
> \[Slide\]
>
> The FDA performed analyses of clinical response at the test of cure or
> the follow-up visit by age, race and gender, as well as by study and
> duration of treatment. As can be seen in these analyses of clinical
> response by duration of treatment, when the allowed comparisons were
> made between treatment groups for both the 7-day fixed and the 7-14
> day studies, clinical success rates were similar to those of
> respective comparators.
>
> Again, I would like to remind you that because the sponsor is
> requesting a 7-day treatment duration it is most appropriate for us to
> base our regulatory decisions on the data from the 7-day fixed
> studies, and the data from the 7-14 day studies should be considered
> as supportive.
>
> \[Slide\]
>
> For the purposes of this submission, severity was determined by
> categorizing patients according to the mortality risk classes
> published by Dr. Fine. These criteria were applied retrospectively
> except for ongoing open study 287 where they are being applied
> prospectively. Patients were assigned to one of five classes with
> respect to the risk of death within 30 days, first according to an
> algorithm to class I, and then on the basis of the total point score
> to classes II through V. A prediction rule assigned points based on
> age and the presence of coexisting disease, abnormal physical findings
> and abnormal laboratory findings at presentation.
>
> Based on assigned risk class, patients were classified as having mild,
> or classes I and II, moderate, class III, or severe, classes IV and V,
> disease. Patients in risk classes I through III can often be managed
> as outpatients, whereas those in classes IV and V are at higher risk
> of death and often required hospitalization.
>
> \[Slide\]
>
> Demographics were also assessed on all patients by degree of severity.
> And, 996 or 7.14 percent of patients had mild disease. In this group
> there were more females than males. The mean age of this category of
> patients was 46.6 years. Those patients with moderate and severe
> disease were predominantly males and older, with a mean age of 69.4
> years for the moderately ill gemifloxacin-treated patients and a mean
> age of 76.3 years for the severe group of gemifloxacin-treated
> patients.
>
> The severe group of patients represented 7.2 percent of the 7-day
> fixed population, 9.6 percent of the 7-day group of the 7-14 day
> population, and 13.8 percent of the 14-day population. Thus, there was
> an increased number of severely ill patients in the more prolonged
> duration treatment group and there were fewer severely ill patients in
> the fixed 7-day treatment group.
>
> Of the 129 intent-to-treat patients categorized as having severe
> disease, 125 had class IV disease and 4 had class V disease. The
> sponsor provided further details on these patients regarding
> intubation status, use of pressors or respiratory treatments at the
> time of enrollment and none of the subjects had documented use of any
> of these at that time. Six subjects ultimately did require at least
> one of the concomitant treatments during the study and all of those
> patients ultimately failed treatment.
>
> \[Slide\]
>
> When clinical response was assessed at the test of cure by severity,
> success rates for those patients with mild and moderate disease were
> similar to those of the overall population. Although efficacy in the
> severely ill patients was high, there were very few patients, 26 in
> total, treated with a 7-day fixed regimen.
>
> As noted previously, the 7-day group of the 7-14 day studies should
> not be added to the fixed 7-day patient population and, again,
> comparisons should not be made between the 7 and the 14 day regimens.
> So, in the agency\'s viewpoint, the data currently available on severe
> patients are limited.
>
> \[Slide\]
>
> In addition to the classification of subjects by defined criteria, the
> sponsor also assessed clinical response in hospitalized subjects, thus
> using hospitalization as criteria to assess the effectiveness of
> gemifloxacin in severe cases of community-acquired pneumonia. However,
> as the decision to hospitalize or not was investigator driven and may
> have varied according to geographic location, it would not appear that
> the presence or absence of this factor can be used as a sole
> determinant of severity of illness.
>
> Only in open, controlled study 185 were all patients hospitalized for
> at least the first 24 hours of treatment. In that study, 36 of the 172
> gemifloxacin-treated patients were classified as having severe disease
> or Fine classes IV and V, whereas approximately 80 percent of the
> patients in that study had mild to moderate disease, again raising the
> question of the appropriateness of using hospitalization alone as
> criteria for severe community-acquired pneumonia. When allowed
> comparisons were made between gemifloxacin and the comparator
> regimens, clinical response rates were similar.
>
> \[Slide\]
>
> The sponsor provided a separate analysis of clinical response in
> bacteremic patients. There were 48 gemifloxacin-treated patients or
> 4.7 percent of the combined all studies data set with a positive blood
> culture at screening. In the agency\'s analysis of bacteremic
> patients, although clinical response rates were comparable between
> treatment arms, the sample size was too small to allow for valid
> comparisons. Clinical response for all bacteremic patients receiving
> the fixed 7-day regimen was 91 percent, whereas for all 7-14 day
> patients it was 96.3 percent. In that group 4 subjects received a
> 7-day treatment regimen.
>
> \[Slide\]
>
> The clinical review team requested that the sponsor provide tables of
> risk class specific mortality for all intent-to-treat patients.
> Overall mortality was similar between the gemifloxacin and comparator
> treated groups, as well as between the gemifloxacin controlled and
> uncontrolled study patients, with 12 deaths, or 1.3 percent, in the
> gemifloxacin controlled study patients; 13 deaths, or 1.4 percent, in
> the comparator treated patients; and 5 deaths, or 1.2 percent, in the
> gemifloxacin-treated uncontrolled study patients. There was a total of
> 17 deaths, or 1.3 percent, in all gemifloxacin-treated patients.
>
> When deaths were assessed by Fine class, it appeared that mortality
> rates for classes I, II and III patients were consistent with what was
> expected based on the publication by Dr. Fine. In class IV patients
> the mortality rates in the clinical studies, which are here, appeared
> to be somewhat less than what was reported for Fine class IV patients.
> There were too few class V patients in the data set to draw any
> conclusions for this class.
>
> \[Slide\]
>
> With regards to regulatory precedents, there are two quinolones at
> present, levofloxacin and moxifloxacin, that have a severe disease
> claim and both have oral and intravenous formulations. The criteria
> for determining severity differed in both applications but in both
> they were applied at the time of randomization and were used to
> determine the mode of treatment as well as the duration of treatment.
> Almost all of the severe patients in the levofloxacin NDA received
> intravenous treatment and the moxifloxacin claim was granted after FDA
> review of the intravenous formulation.
>
> \[Slide\]
>
> To turn to another issue, the sponsor is requesting approval for
> penicillin-resistant, macrolide-resistant and cefuroxime-resistant
> [Streptococcus pneumoniae]{.underline}, and has also submitted data
> regarding quinolone-resistant [Streptococcus pneumoniae]{.underline}.
> At present, levofloxacin and now moxifloxacin have the indication of
> penicillin-resistant [Strep. pneumoniae]{.underline} and no
> antimicrobial currently has a macrolide-resistant indication, although
> it has been discussed.
>
> As you heard earlier, Dr. Powers, of ODE IV, gave some introductory
> remarks regarding the FDA perspective on the issue of multi-drug
> resistant [Streptococcus pneumoniae]{.underline} to this committee.
> Points that were raised in his presentation today, as well as at the
> January, 2003 Anti-Infective Advisory Committee meeting, and that
> continue to need to be addressed are what is the clinical relevance of
> macrolide-resistant [Streptococcus pneumoniae]{.underline}? Should it
> be treated as a separate entity from penicillin-resistant
> [Streptococcus pneumoniae]{.underline}? Should an approval be granted
> for both or for multi-drug resistant [Streptococcus
> pneumoniae]{.underline} or only for penicillin-resistant
> [Streptococcus pneumoniae]{.underline}?
>
> In addition to these questions, the issue of cefuroxime-resistant
> isolates also now needs to be addressed. What is the clinical
> relevance of this organism? As you will see, all penicillin-resistant
> [Strep. pneumoniae]{.underline} isolates in this submission were also
> cefuroxime resistant and these isolates represented 67 percent of the
> total number of cefuroxime-resistant isolates. Also, 83 percent of
> cefuroxime-resistant isolates were also macrolide resistant.
>
> \[Slide\]
>
> The agency and the sponsor are in general agreement with regard to
> numbers. We had 12 per protocol gemifloxacin-treated patients who had
> [Strep. pneumoniae]{.underline} isolates with penicillin MICs of
> greater than or equal to 2 mcg/ml and 3 of these had MICs of 4 mcg/ml.
> The clinical success and bacteriological eradication rates in patients
> with PRSP were 100 percent. Four comparator arm patients had
> penicillin-resistant isolates with 100 percent clinical success in
> bacteriologic eradication rates.
>
> \[Slide\]
>
> We are also in agreement that 25 gemifloxacin-treated per protocol
> patients with [Streptococcus pneumoniae]{.underline} had
> macrolide-resistant isolates, defined as clarythromycin MIC of greater
> than or equal to 1 mcg/ml. Clinical success and bacteriological
> eradication rates were 88 percent, and 10 of these isolates, or 40
> percent, were also penicillin resistant.
>
> There were 12 comparator treated per protocol patients found to have
> macrolide-resistant [Streptococcus pneumoniae]{.underline}, with
> clinical success and bacteriologic eradication rates of 91.6 percent.
> Three of these isolates were also penicillin resistant and 2 of those
> 3 were successfully treated.
>
> \[Slide\]
>
> Eighteen patients had cefuroxime-resistant [Streptococcus
> pneumoniae]{.underline}, defined as a MIC of greater than or equal to
> 4 mcg/ml. Clinical success and bacteriological eradication rates at
> follow-up were 94.4 percent. Twelve out of the 18 cefuroxime-resistant
> isolates were also penicillin resistant, or 67 percent, and 15 of 18
> cefuroxime resistant isolates were also clarythromycin resistant, or
> 83 percent. On the comparator\'s arm there were 7 patients with
> [Streptococcus pneumoniae]{.underline} isolates resistant to
> cefuroxime that were all successfully treated.
>
> \[Slide\]
>
> Finally, regarding quinolone-resistant [Streptococcus
> pneumoniae]{.underline}, in the gemifloxacin group of the combined
> studies population there were no pathogens resistant to ofloxacin and
> levofloxacin. There was one resistant isolate in the all comparators
> arm that was a failure. In the gemifloxacin group there were 4
> isolates with [Streptococcus pneumoniae]{.underline} with an MIC
> against ciprofloxacin of 4 mcg/ml. All 4 of these were successfully
> treated.
>
> With that, I will turn it over to Dr. Navarro.
>
> **Acute Bacterial Exacerbation of Chronic Bronchitis**
>
> DR. NAVARRO: Good morning.
>
> \[Slide\]
>
> My name is Eileen Navarro, and I am here to present the agency\'s
> perspective regarding the efficacy of Factive for the indication of
> acute bacterial exacerbation of chronic bronchitis.
>
> Before I proceed, I would like to acknowledge the assistance of our
> statistical colleagues in understanding the sophisticated statistical
> analyses that were unique to this indication.
>
> \[Slide\]
>
> The applicant\'s NDA seeks to establish that Factive is efficacious in
> the treatment of acute bacterial exacerbations of chronic bronchitis,
> which I will refer to in the rest of the talk as ABECB, being due to
> [H. influenzae]{.underline}, [M. catarrhalis]{.underline}, [S.
> pneumoniae]{.underline}, [H. parainfluenzae]{.underline} and [S.
> aureus]{.underline}. There are three things to note that separate this
> indication from CAP. You will note that the applicant does not seek an
> indication for resistant isolates in this indication. As has already
> been alluded to by Dr. Low regarding the prevalence of resistant
> isolates in chronic bronchitis, this is appropriate to consider.
>
> Another thing that distinguishes this indication is the fact that a
> shorter duration of 5 days is sought compared to community-acquired
> pneumonia, and that is important to consider when one looks at the
> adverse event rates for rash.
>
> The other thing to note is that the applicant submits data regarding
> additional findings outside of the efficacy for the larger population
> with ABECB, and one of these findings is actually a claim being made
> in the label of earlier eradication of [H. influenzae]{.underline}
> from the sputum. So, within the context of this indication, we are
> being asked to understand the significance of the eradication of
> bacteria from the sputum.
>
> \[Slide\]
>
> The applicant\'s additional findings, for which no claims are made in
> the label, are described in the applicant\'s background package. This
> includes superior clinical efficacy in the intent-to-treat analysis;
> prolonged exacerbation-free intervals; and several findings that
> relate to efficacy in severe hospitalized ABECB, including efficacy in
> hospitalized patients obviating the need for intravenous therapy;
> earlier time to hospital discharge; and reductions in hospitalization
> due to respiratory tract infections.
>
> Particularly for an indication where there are several treatment
> alternatives, it is important, and in fact it is innovative to look at
> what the additional benefits may be due to a drug and that has been
> rightly described by the applicant. We will, however, attempt to
> describe these findings in the context of the study design and the
> study objectives; describe whether the finding is one prespecified
> primary endpoint or one of several secondary endpoints and whether
> adjustments have been made for multiple comparisons. More importantly,
> we will look at the clinical implications of these findings and end
> with a discussion of additional considerations for antibacterial use
> for this indication.
>
> \[Slide\]
>
> The pivotal studies find that Factive was non-inferior to study
> comparators in the treatment of ABECB. The agency agrees with this
> conclusion based on point estimates that were well within the
> prespecified limits of inferiority. Two other supportive and several
> ancillary studies support the conclusion of non-inferior efficacy.
>
> \[Slide\]
>
> I will now move to the additional findings. The applicant\'s findings
> that Factive results in earlier bacterial eradication\--I am sorry, I
> think I have the wrong slide here. I am not used to this new mouse
> that we bought only a few days before this presentation.
>
> \[Slide\]
>
> The applicant\'s finding that Factive results in earlier bacterial
> eradication compared to clarythromycin was based on unadjusted
> analysis in the pivotal study 068 and in study 105. Were we to
> consider this analysis as statistically significant, although
> questions still remain regarding the relevance of earlier bacterial
> eradication in ABECB.
>
> We note that patients with [H. influenzae]{.underline} represented
> only a small proportion of patients who fulfilled the inclusion
> criteria for ABECB in the pivotal study. For example, please note that
> there were 24 patients out of the 600 patients in that study that
> actually led to this conclusion. Nevertheless, in the small subgroup
> of patients in whom eradication of [H. influenzae]{.underline} was
> proven, early eradication did not correlate with additional benefit
> over the comparator-treated patients in whom eradication of [H.
> influenzae]{.underline} was delayed.
>
> In addition, in study 105 early eradication may be related to the
> pharmacokinetic differences noted in that study between Factive and
> the comparator erythromycin. To also put this in a larger perspective,
> please note that bacterial eradication favored the other comparator,
> levofloxacin, in some of the pivotal studies presented earlier.
>
> \[Slide\]
>
> Now we are back to this slide. The finding of superior clinical
> efficacy in the intent-to-treat analysis is derived from studies 068
> and 207 where the point estimates favored Factive and the lower bounds
> excluded zero, with a value of 0.9 for study 068 and 0.7 for study
> 207.
>
> \[Slide\]
>
> The applicant\'s finding of superiority was limited to the ITT
> analysis in the supportive studies 068 and 207. In the same studies
> the primary analysis of clinical efficacy in the per protocol
> population showed that Factive was not inferior to the study
> comparators, and the secondary analyses of bacterial efficacy in the
> patients with pathogens showed similar efficacy rates. In the pivotal
> studies Factive was non-inferior in clinical efficacy for the analytic
> populations for ITT and per protocol, and the bacterial efficacy rates
> in both populations were also similar.
>
> \[Slide\]
>
> The finding that Factive was at least as good as parenteral therapy in
> severe ABECB is derived from study 207. Patients in study 207 were
> older, had more frequent ABECB exacerbations and more often required
> oxygen and corticosteroids than the patients that were described in
> the pivotal studies, supporting the finding that Factive was
> non-inferior to parenteral therapy in patients with these
> demographics. However, it is important to note that this open-label,
> non-U.S. study enrolled patients with severe ABECB who were able to
> tolerate oral medications. This is a population that is more
> restricted than all patients requiring parenteral therapy.
>
> Another question raised by the study is whether parenteral therapy is
> needed for patients who are able to tolerate oral medications, and
> whether patients so treated in this study would be analogous to a
> hospitalized patient population in the U.S.
>
> I think it was Dr. Shear who pointed out that hospitalization for a
> rash may be different in certain countries, and the question we raise
> is whether these findings from a non-U.S. study may be relevant to the
> way we hospitalize and treat our patients with ABECB.
>
> The applicant also shows that Factive-treated patients were discharged
> a mean of half a day earlier than patients that received parenteral
> therapy. This difference in mean time to discharge could be accounted
> for by the time required to insert and then remove intravenous access
> in patients that receive parenteral therapy. No difference was found
> in the primary outcomes of clinical efficacy.
>
> More importantly, related outcomes such as the rate of symptom
> resolution and indirect patient costs were no different between
> treatments, making it difficult to understand what the excess duration
> of treatment was related to. Furthermore, this analysis was only
> marginally significant using the Wilcoxon test, not significant using
> log rank test and the hazard ratio was not significantly different
> than 1.
>
> \[Slide\]
>
> Time to next exacerbation was evaluated in three studies. The findings
> from these studies were contradictory, with study 139 trending
> favorably for Factive and study 105 favoring the comparator. In study
> 112, where this analysis was the only primary outcome of interest and
> did not require adjustments, time to exacerbation for Factive was not
> significantly different from the comparator.
>
> Respiratory tract related hospitalization was similarly evaluated in
> these same three studies, although the applicant presents only the
> results from study 139. The finding of reduced hospitalization in
> Factive-treated patients was similarly unadjusted for multiple
> comparisons and other related outcomes do not buttress this
> conclusion.
>
> \[Slide\]
>
> This slide is a partial list for approved products for ABECB. It is
> important to note that, while in several classes antimicrobials
> limited to those that are used for oral therapy for ABECB are
> indicated for the treatment of ABECB, only three are registered as
> 5-day treatments for this indication. Moxifloxacin and gatifloxacin
> are both approved as 5-day therapies and as 7-day therapies for CAP.
>
> Please note further that quinolone antimicrobials listed here account
> for a good number of the available alternatives for ABECB. An issue
> that needs to be addressed in assessing the risk-benefit of Factive is
> the potential that a patient is labeled quinolone allergic on the
> basis of a rash, or becomes cross-sensitized to subsequent quinolone
> use. Elimination of the quinolones as a therapeutic alternative would
> significantly impact ABECB to a far greater proportion than it would
> patients with community-acquired pneumonia because patients with ABECB
> do have multiple recurrences, each requiring repeated exposures to
> antibiotics.
>
> \[Slide\]
>
> This slide compares the age-specific use of antibiotics for chronic
> bronchitis in the community to that in the clinical trials submitted
> by the applicant. The utilization data shown here represent a 3-year
> average of antibiotic use for bronchitis from the study by Scott and
> Levin, an appendix A of the applicant\'s background package.
>
> The study indicates that 33.5 percent of prescriptions for bronchitis
> would be written for patients under 40 years of age. Compared to this,
> the age distribution of patients in the pivotal ABECB studies was less
> than 1 percent of patients so treated in the clinical trials.
>
> In assessing the risk-benefit of Factive for ABECB, one consideration
> to take is the difference in the conditions of use within the context
> of a clinical trial and the anticipated broader use of the drug once
> it is available in the community.
>
> \[Slide\]
>
> We conclude that the clinical efficacy of Factive in ABECB is as good
> as its comparators. While we laud the applicant for their innovative
> analysis of trying to define additional benefits for the drug, we find
> that questions remain regarding the clinical relevance or
> applicability of the additional findings in the treatment of ABECB. In
> addition, the evidence supporting other findings is limited by the
> study design issues or could be attributed to chance alone.
>
> Finally, the antibiotic usage for bronchitis does have implications in
> the community far beyond just effectiveness, as Dr. Mandell has
> rightly pointed out, and the impact on available therapeutic
> alternatives is a relevant consideration in evaluating the data
> presented for the efficacy of Factive.
>
> **Safety**
>
> DR. TIERNEY: Hello.
>
> \[Slide\]
>
> My name is Maureen Tierney, and I am here to present the safety of
> Factive, or gemifloxacin, from the FDA\'s viewpoint.
>
> \[Slide\]
>
> This first slide shows the makeup of the safety population that was
> used to evaluate the safety of gemifloxacin. It was a combination of
> Phase II and Phase III clinical trials, totaling 6,775 patients for
> gemifloxacin and 5,248 patients for comparators, which included
> beta-lactams, macrolides and other quinolones.
>
> As has already been mentioned, these include patients only who
> received 320 mg of gemifloxacin. Individuals were enrolled in these
> studies for the treatment of a variety of conditions, but for the two
> indications being looked at here, ABECB was approximately 45 percent
> of the combined clinical population and CAP 17.5 percent. I will refer
> to this population as the combined clinical population unless I note
> otherwise looking at other clinical pharmacology studies of higher
> doses of study 344.
>
> \[Slide\]
>
> The demographics of the safety population show that approximately
> 20-25 percent of the individuals in total were under 40; about 45
> percent between 40 and 65; and between 30 and 35 percent over 65.
>
> \[Slide\]
>
> There was a mild preponderance of women in both arms.
>
> \[Slide\]
>
> The breakdown by race shows between 87 and 92 percent white; between
> about 3.5 and 4.5 percent black; 1 to 3 percent oriental and 4 to 6
> percent other, which includes individuals who are Hispanic.
>
> \[Slide\]
>
> I am going to concentrate my talk today on four areas: Adverse events
> of special interest and that will include withdrawals and serious
> adverse events; QT prolongation; the hepatic safety profile of
> gemifloxacin; and rash.
>
> \[Slide\]
>
> When looking at withdrawals due to adverse events, rash was the most
> common cause of withdrawal from the gemifloxacin arm, causing 0.9
> percent of the patients to be withdrawn versus 0.3 percent for
> comparator. Related cutaneous events of urticaria reveal 0.2 percent
> or 15 being withdrawn from the gemifloxacin arm versus 4 or 0.1
> percent for comparator. The other more common causes of withdrawals,
> nausea, diarrhea and vomiting\--gastrointestinal side effects were
> more common in comparator as compared to gemifloxacin.
>
> \[Slide\]
>
> Serious adverse events that were considered by the investigator to be
> of suspected relationship to drug medication showed that rash was the
> most common cause of the serious adverse events in the gemifloxacin
> arm for 7 cases, as has already been described by Dr. Shear, versus 1
> for comparator.
>
> LFTs being increased were the cause of serious adverse events in 3
> patients receiving gemifloxacin versus none for comparator. Pneumonia
> was pretty even between the 2 groups. No patients were removed from
> the gemifloxacin arm for severe diarrhea but 3 from comparator.
>
> \[Slide\]
>
> We will talk about QT effects for some of the reasons already
> mentioned. It is a known side effect for the quinolone class. There
> was some mild prolongation noted in the database and it would be a
> serious event if it occurred, but I would like to note now that there
> were no cases of Torsade de pointes noted in the gemifloxacin
> database.
>
> \[Slide\]
>
> When looking at QT effects trying to assess preclinically the
> potential of a drug for QT prolongation, several assays are looked at,
> including Perjinki and inhibition of hERG. This slide is shown not to
> give a ranking of the variety of quinolones but in this and other
> assays gemifloxacin was in the mid range or the ball park of other
> quinolones for its potential for QT prolongation.
>
> \[Slide\]
>
> The mean changes in QTc in the clinical pharmacology population, a
> large percentage of which were women in study 344, was 4.9
> milliseconds of increase and in the combined clinical population, 2.6
> milliseconds.
>
> \[Slide\]
>
> This slide looks at changes in QTc from baseline. In the end, where
> you see sort of larger increases from baseline, 50-60 and over 60,
> there is a trend towards a few more patients in the gemifloxacin arm.
>
> \[Slide\]
>
> This slide shows the relationship of gemifloxacin dose and QTc. It is
> the result of a meta-analysis of five studies. These are five Phase I
> studies looking at both old and young healthy individuals receiving
> 320 mg, 480 mg or 640 mg doses of gemifloxacin. In single doses there
> was no dose effect seen, but in multiple doses\--
>
> I would just like to orient you. On the X axis is the dose of
> gemifloxacin and here is the maximal change in mean QTc, so the
> average maximal change in mean QTc. At 320 mg there is a change noted
> of minus 5 milliseconds; at 480, plus 5.5 milliseconds; and at 640 the
> increase is plus 16 milliseconds.
>
> \[Slide\]
>
> As Dr. Patou mentioned, when you talk about QT it is important to
> discuss issues of drug interactions. There is no inhibition or
> induction of CYP450 enzymes by gemifloxacin nor is it dependent upon
> its metabolism by the CYP450 enzymes. It also has a dual route of
> elimination.
>
> \[Slide\]
>
> I would now like to move to the hepatic safety profile of
> gemifloxacin. We will talk about four areas, the preclinical findings
> with the drug; LFT increases that were seen at higher doses; LFT
> increases in those with hepatic impairment or more comorbidity; and
> ALT and/or bilirubin elevations.
>
> \[Slide\]
>
> When looking at preclinical hepatic findings in dogs, and these were
> in repeat oral dose studies for 28 days, for 3 months or 6 months,
> cholangitis and pericholangitis with hepatocellular degeneration and
> single cell necrosis was seen at high doses. This was associated with
> crystalline deposits of drug in the bile canaliculi and was associated
> with concomitant elevated ALT and alk. phos. These elevations,
> however, did return to normal after 4 weeks.
>
> \[Slide\]
>
> When looking at individuals who got higher doses and, remember, these
> are not the individuals in the combined clinical populations, there
> was an uncomplicated UTI study looking at mostly younger women who
> were randomized to receive gemifloxacin 640 mg in a single dose versus
> ciprofloxacin 250 mg b.i.d. for 3 days. Of the 592 individuals who
> received gemifloxacin, 9 or 1.6 percent had ALT elevations greater
> than 2 times the upper limit of normal and 4 had greater than 6 times
> the upper limit of normal. There were no similar ALT elevations seen
> in comparator. There were no significant bilirubin elevations in
> either group.
>
> Similar results were seen in the 480 and 640 dose clinical
> pharmacology studies, in particular study 005 which was a PK study in
> healthy elderly individuals, 4 of 16 of whom were required to be
> withdrawn because of elevated ALTs, with ALTs ranging from 121 to 33
> on therapy.
>
> \[Slide\]
>
> Dr. Patou also discussed the issue of hepatic side effects in
> individuals with baseline liver disease. This slide shows adverse
> events of the liver and biliary system in patients with baseline liver
> disease who were defined as individuals who had a history of liver
> disease and, in addition, had elevated ALTs at screening.
>
> The gemifloxacin N of 235 does include some patients who were in
> non-comparative studies. These are adverse events of hepatic enzyme
> increase seen in 3.4 percent for the gemifloxacin arm and none for
> comparator; 4.3 percent in alkaline phosphatase elevations for
> gemifloxacin versus none for comparator, and 2.1 percent bilirubin
> increase versus 0.6 percent for comparator.
>
> \[Slide\]
>
> When looking at individuals who may have higher comorbidity, there are
> 2 studies I would like to mention. Study 185 is a study looking at
> patients with CAP requiring hospitalization so, in general, a more ill
> population. Of the patients who received gemifloxacin there were 6
> with LFT elevations greater than 3 times the upper limit of normal,
> with 4 of those being withdrawn; and 3 with LFT elevations greater
> than 3 times the upper limit of normal in the comparator arm but none
> requiring withdrawal.
>
> In study 287, which is not a study in the combined clinical database
> but is an ongoing clinical study which is trying to enroll patients
> only with pneumococcal pneumonia, there were 2 individuals seen who
> had ALTs greater than 3 times the upper limit of normal with a
> concomitant bilirubin greater than 1.5 mg/dl.
>
> \[Slide\]
>
> I would now like to look at things just from the biochemical
> standpoint. As a result, I may repeat some of the data in prior
> slides. When looking at combinations of ALT and bilirubin, as Dr.
> Patou mentioned, the combination is supposed to be more suggestive of
> hepatocellular damage. What exactly is the right threshold to look at
> is unclear and I have seen a variety of different Hy\'s rules
> mentioned.
>
> When looking at ALTs greater than 3 times the upper limit of normal
> with a bilirubin greater than 1.5, there were no patients in the
> combined clinical database who received gemifloxacin who met that
> criteria; and 2, as I just mentioned in study 287; and there was 1 in
> the comparator arm. That is in the combined clinical population.
>
> If you lower your threshold to a very conservative ALT greater than 2
> times the upper limit of normal with a bilirubin greater than 1.5
> mg/dl you find additional 3 patients in the gemifloxacin arm in
> comparative clinical trials and none for comparator.
>
> \[Slide\]
>
> When looking at bilirubin elevations in isolation, there was 1 healthy
> male in a clinical pharmacology study whose bilirubin bumped from 0.8
> to 7.5 mg/dl. He was asymptomatic and eventually his bilirubin came
> down to close to normal. But it is interesting to note that he
> received ofloxacin, for unclear reasons a few months before, whether
> it was for a clinical indication or another drug study, and had an
> elevation, though not quite as high, on ofloxacin. There were 3
> isolated bilirubin elevations to greater than 2 but less than 4 times
> the upper limit of normal in patients who were in range at screening
> but not for the comparator in the combined clinical population looking
> at comparative studies.
>
> \[Slide\]
>
> For ALT elevations alone, there was no patient who was in range at
> screening who received gemifloxacin who had an ALT elevation greater
> than 8 times the upper limit of normal on the 320 mg dose. One patient
> who had an abnormal ALT at baseline of 110 elevated his bilirubin to
> 501. But there were 2 patients on the 640 mg dose who were in range at
> screening and who had elevations close to or above 8 times the upper
> limit of normal.
>
> \[Slide\]
>
> Lastly, I would like to discuss rash. We are discussing rash today for
> the reason that it occurred at a higher incidence than all
> comparators; that there was a higher number of serious adverse events
> and withdrawals than on all comparators. There was a markedly high
> incidence in an enriched and carefully studied population of 31.7
> percent in study 344 where we saw a large percentage of the body
> surface area involved, perhaps more urticaria and 6 percent more mucus
> membrane involvement, and how these issues would affect clinical
> practice.
>
> \[Slide\]
>
> The overall incidence of rash in the combined clinical population was,
> as you have already heard, 3.6 percent for gemifloxacin versus 1.1
> percent for all comparators. There were 7 serious adverse events
> secondary to rash on the gemifloxacin arm versus 1 for comparator.
>
> Thirty-six patients were reported to have urticaria, or 0.5 percent,
> in the gemifloxacin arm versus 2 percent for comparator and 64
> patients were withdrawn because of cutaneous adverse events from
> gemifloxacin versus 15 for comparator.
>
> \[Slide\]
>
> When looking at the severity of rash and the breakdown of that for
> gemifloxacin versus comparator, I would just like to concentrate on
> the last line. The rashes were determined to be severe in 13.6 percent
> of the gemifloxacin arm versus 6.7 percent for comparator. My
> understanding is that these were severities that were clearly
> determined by investigator.
>
> \[Slide\]
>
> You have already seen time and rash. Two-thirds of the gemifloxacin
> rashes began after day 7, with most of it on days 8, 9 or 10, whereas
> the comparator rashes in general began on day 7 or before.
>
> \[Slide\]
>
> The risk factors for rash development are female gender, age less than
> 40, and a planned duration of treatment of greater than 7 days. The
> indication appears to be primarily related to these first three
> explanatory variables and also HRT in women greater than 40 years of
> age.
>
> \[Slide\]
>
> I would just like to orient you to this slide. This axis is the
> percentage of individuals reporting rash and this duration of therapy
> on the left for gemifloxacin, and on the right for all comparators.
>
> I will discuss based on all the categories, first looking at females
> under 40 years of age, which is this very light green column. As one
> increases duration, beginning at 7 days, the rash incidence increases
> markedly to over 20 percent at 14 days in women under 40 years of age.
>
> I would next like to look at males under 40 years of age, this maroon
> column, because their incidence appears to go up even more than women
> over 40 as one increases from 7 to 14 days of therapy.
>
> Females greater than 40 years of age, which is this yellow bar, again
> start to increase to produce a rash rate probably between 7-8 percent
> at 14 days. Only the males greater than 40 years of age appear to have
> a flat incidence regardless of duration.
>
> In the comparator arm rash rates begin to go up to some degree, and
> even more so at 14 days but, clearly, the impact of duration is not as
> impressive.
>
> \[Slide\]
>
> We are looking at the rash rates by indications here. For ABECB the
> rash rate is 1.5 percent versus 0.8 percent for comparator. For CAP,
> 4.7 percent versus 2.1 percent for comparator.
>
> \[Slide\]
>
> I think this slide will show you a little bit why the rash rate of 1.5
> percent is seen in ABECB. When looking at the numbers of individuals
> who were studied, as Dr. Navarro mentioned, we really have very small
> numbers of women less than 40 years of age, only a total of 8
> patients, and for males less than 40 years of age only 7 patients.
> Clearly, their rash rates are high but the numbers are really quite
> low.
>
> \[Slide\]
>
> When looking at females greater than 40 years of age, the total rash
> rate is 1.9 percent but over 4 percent at 10 days, and for males
> greater than 40 a total rate of 1.1 percent.
>
> \[Slide\]
>
> When looking at CAP differentiation by age and by duration in this
> chart format, clearly there are many more female and male patients
> under the age of 40 which gives us a more balanced perspective.
> Looking at females under 40, the rate is 11.6 percent; females greater
> than 40, 4.6 percent; 5.1 percent for males under 40 and 2.7 percent
> for males greater than 40. The increase almost doubles, if not more
> so, going from 7 to 14 days for all of those categories, with the
> exception of males greater than 40 whose rate appears to stay flat.
>
> \[Slide\]
>
> HRT use and the risk of rash shows that the incidence approximately
> doubles with the use of HRT in women over 40, which has already been
> mentioned, and gives you an odds ratio of 1.9 which is statistically
> significant.
>
> \[Slide\]
>
> The sponsor also looked at prior or subsequent quinolone usage and has
> already presented this data showing that of 181 patients who received
> a prior quinolone and then were enrolled in a gemifloxacin study and
> received gemifloxacin, only 3, or 1.7 percent, developed a rash.
>
> However, this data is subject to a selection bias. Since an individual
> did not have rash on prior exposure to a quinolone they would be less
> likely to have rash on subsequent exposure to a quinolone. Secondly,
> 12 patients who developed a rash on gemifloxacin subsequently received
> another quinolone for one reason or another. None of those 12 patients
> developed a rash but this may also be subject to selection bias
> because had the rash been very severe upon exposure to gemifloxacin,
> it is less likely they would have received another quinolone.
>
> \[Slide\]
>
> Now I would like to turn to study 344. The model has already been
> shown to you so I will just briefly mention that, again, it was over
> 1000 healthy women who were randomized in a 5:1 ratio to receive
> gemifloxacin or ciprofloxacin for 10 days and then, based on which
> drug they received and whether or not they developed a rash, were
> further randomized in part B after a 4-week washout period.
>
> \[Slide\]
>
> The demographics of this show that it was overwhelmingly Caucasian
> women who were enrolled in the study, 92 percent.
>
> \[Slide\]
>
> The overall results show that of the 819 women who received
> gemifloxacin and were evaluated, 260 developed a rash, for a rate of
> 31.7 percent, with the confidence intervals that are present here. For
> ciprofloxacin, of 164 women who received cipro., 7 developed a rash,
> for a rate of 4.3 percent, with this confidence interval.
>
> \[Slide\]
>
> Withdrawals and severe adverse events that occurred in study 344
> showed that of the 819 women receiving gemifloxacin, 26 were withdrawn
> for a cutaneous adverse event, or 26 out of the 260 who developed a
> rash, so a 1 percent withdrawal. That is withdrawal from entering part
> B; it is not withdrawal from part A since the drug would be stopped in
> part A. There were none for ciprofloxacin.
>
> There were no rash-related serious adverse events reported in either
> arm but severe cutaneous adverse events were determined to be present.
> Again, these were determined by the investigator, 20 out of 260 for
> gemifloxacin and 0 of 7 for ciprofloxacin.
>
> \[Slide\]
>
> Time and rash similarly, a later day of onset and a longer mean
> duration for gemifloxacin related to ciprofloxacin.
>
> \[Slide\]
>
> The severity of rash, similar to what I just mentioned, 19 patients
> were determined to have a severe rash, or 7 percent of the
> gemifloxacin arm; zero for the ciprofloxacin arm, but since there are
> only 7 patients it is hard to make that comparison.
>
> \[Slide\]
>
> When looking at the extent of the body surface area that was involved
> in this rash, the breakdown is shown here but in particular I would
> like to point out that over 25 percent of the women who experienced a
> rash to gemifloxacin had over 60 percent of their body surface area
> determined to be involved. Of the 7 patients who developed a rash to
> ciprofloxacin, no one had a rash over 60 percent and they were pretty
> evenly divided, 4 at 6-10 percent and 1, 11-20 and 1, 21-40.
>
> \[Slide\]
>
> Looking at the characteristics of the rash, as was described on the
> rash case report form, clearly, the gemifloxacin rash was
> overwhelmingly a pruritic rash with erythematous macules and papules.
> The ciprofloxacin rash description stopped there. No one was described
> as having any other involvement but in gemifloxacin patients some were
> described as having plaques, skin tenderness, and 11.5 percent as
> having urticaria.
>
> I would just like to mention here that of the patients who developed
> the gemifloxacin rash in part A, there were actually 7 patients who
> were reported to have fever, 4 who were reported to have eosinophilia,
> and 1 person who had fever and eosinophilia.
>
> \[Slide\]
>
> When looking at mucus membrane in part A, of the 7 women who developed
> a rash to ciprofloxacin, none reported mucus membrane involvement. Of
> 260 women who developed rash to gemifloxacin, 16 were reported to have
> mucus membrane involvement. Just to remind you, all of these patients
> were evaluated not only by the main investigator but by a
> dermatologist and a very specific form was filled out where the extent
> of the rash, the description of the rash, the presence of mucus
> membrane involvement, other systemic signs were requested to be
> checked or not checked. So, 16 of those case reports included
> observations of some mucus membrane involvement.
>
> Three of 260 reported eye involvement but on review of those case
> report forms there were no discrete ocular lesions. It was all dry
> eyes or very itchy eyes, maybe crusty eyes but no particular ocular
> lesions. The one person who had genital lesions described was someone
> who had what was described as a total body rash, and it may have just
> been extension of that rash as opposed to particular genital lesions.
>
> \[Slide\]
>
> But 12 of 260 were described as having mouth lesions. These were
> described as follows: There were 5 women who were described as having
> one to a few ulcerations, erosions, papules or vesicles inside the
> mouth or on the lips; 2, as having erythema on the lips or inside the
> mouth; 2, as having petechiae on the lips. There were 3 who clearly
> had mucus membrane mouth involvement checked but either the
> description is unreadable or unavailable. No pictures were taken of
> any mucus membrane lesions.
>
> \[Slide\]
>
> One other aspect of the rash that we looked at was the treatment of
> gemifloxacin-associated rash both in study 344 and the combined
> clinical population and, clearly, many women got antihistamines and
> topical steroids but systemic steroids might be a marker for what an
> investigator thought was a more concerning versus less concerning
> rash. Of the 160 women who developed a rash in study 344, 12 of then
> were treated with systemic steroids, all of which were oral steroids,
> and 27 of 241 individuals who developed a rash in the combined
> clinical study were treated with systemic steroids, mostly oral but on
> occasion with intravenous or IM steroids.
>
> \[Slide\]
>
> I would now like to turn to discussing a few cases. These cases have
> been chosen, I would like to say, either because they are more severe
> cases, there was mucus membrane involvement, steroid treatment was
> given or a particular histopathologic finding was found. So, they are
> clearly on the more severe end of the spectrum but since that is what
> we are concerned about we thought it appropriate to present these
> cases.
>
> \[Slide\]
>
> Case one is a 24-year old white female with no past medical history
> who had onset on day 8 of her rash with associated fever. It was a
> pruritic rash with erythematous macules and papules covering greater
> than 60 percent of the body surface area. There were lesions
> determined to be present in her mouth but were not described. She was
> treated with Zyrtec and a Medrol pack and the duration of her rash was
> 6 days. In the quality of life questionnaire that was included for all
> patients in this study, she determined this very much affected her
> life.
>
> \[Slide\]
>
> Her rash is seen here. I believe you may have seen this earlier today,
> and her closeup is seen here.
>
> \[Slide\]
>
> The next case is a 20-year old white female with no past medical
> history who had onset on day 8 of a pruritic rash with erythematous
> macules and papules covering greater than 60 percent of her body
> surface area, also with plaques and mild facial edema. She had
> erythematous macules present on her lips. She was treated with
> benadryl and oral prednisone. The duration of her rash was 12 days and
> her quality of life was moderately affected.
>
> \[Slide\]
>
> This rash does not project very well but up close one can see that
> there is quite an extensive rash on her back.
>
> \[Slide\]
>
> Case three, a 21-year old white female with a history of child asthma,
> who had onset on day 6 of a pruritic urticarial rash with erythematous
> macules and papules covering greater than 60 percent of her body
> surface area. She did not have mucus membrane involvement, was treated
> with benadryl and oral Solumedrol.
>
> \[Slide\]
>
> Her rash lasted for 6 days and some aspects of her life were very much
> affected.
>
> \[Slide\]
>
> Case four is a 21-year old white female who had onset on day 8 of a
> non-pruritic rash with erythematous macules and papules covering
> greater than 60 percent of her body surface area, with ulcers in her
> mouth and pharyngitis. But she was not withdrawn from the study, nor
> received systemic therapy and the duration of her rash was 7 days. Her
> quality of life was reported as being minimally affected.
>
> \[Slide\]
>
> This is the rash on the back of her legs, and a closeup of her
> shoulder.
>
> \[Slide\]
>
> Case five is a 39-year old white female with a history of hives to
> sulfa, who had onset on day 9 of a morbilliform urticarial eruptions
> with 40-60 percent of her body surface area involved, with erythema on
> the labial mucosa, and by labial I mean lips; this is not a genital
> lesion.
>
> \[Slide\]
>
> She was treated with acetaminophen only and her rash lasted 30 days,
> and there was no quality of life assessment made.
>
> \[Slide\]
>
> Before I mention this case, I would like to mention briefly another
> case of a 21-year old female who had 5 percent of her body surface
> area with a pruritic rash, and this was the one individual who had
> associated fever and eosinophilia, with an eosinophil level of 0.62
> with an upper limit of normal of 0.55. She had itchy eyes but no
> discrete mucosal lesions, and was treated with Allegra, with the
> duration lasting 8 days. But pictures of this rash are not available.
>
> \[Slide\]
>
> The last case is a 20-year old white female with no past medical
> history who had onset on day 6 of a pruritic rash with erythematous
> macules covering 20-40 percent of her body surface area. This rash
> lasted 4 days and no photographs of this rash were taken for unclear
> reasons, but the biopsy showed a linear deposition of IgM along the
> dermal basement membrane.
>
> \[Slide\]
>
> That is present here.
>
> \[Slide\]
>
> The other histopathologic findings have already been mentioned and in
> most cases mild, superficial perivascular infiltrates were seen, with
> moderate or deep infiltrates seen in 10 specimens; eosinophils noted
> in 10 specimens, with no particular pattern for CD4 cells or
> immunofluorescence. There were some faint deposits of IgM and/or C3 in
> dermal vessel lumina and in one case, which you just saw, along the
> basement membrane. But there was no evidence of vasculitis, bulla or
> necrosis.
>
> \[Slide\]
>
> I would like to move to study 344, part B now. I will not go over the
> randomization pattern because Dr. Shear already went over it. It was
> to determine whether or not there was cross-sensitization or
> subclinical sensitization. So, if you developed a rash to gemifloxacin
> in the first part you got either cipro. or placebo. If you didn\'t,
> you got either gemifloxacin again or placebo. Excluding the 027
> center, you get a rash rate of 5.9 percent for individuals who
> received cipro. after having developed a rash from gemifloxacin.
>
> \[Slide\]
>
> These results really show us that there is a suggestion of a minor
> cross-sensitization with ciprofloxacin but it is not really conclusive
> data, nor can we really extrapolate about cross-sensitization with
> other quinolones. There is really no significant evidence of
> subclinical sensitization with gemifloxacin.
>
> \[Slide\]
>
> One thing I would like to mention before concluding is a brief
> literature review looking at the association of quinolones with severe
> cutaneous reactions. In a review by Roujeau et al., which I believe
> includes Dr. Stern, there was a multivariate crude relative rate
> developed. This was not just looking at quinolones but looking at all
> drugs in association with risk for development of Stevens-Johnson
> syndrome or toxic epidermal necrolysis. Crude relative rates were
> developed for a variety of drugs and, clearly, sulfonamides have a
> very high relative risk but for quinolones the relative risk was 10,
> with aminopenicillins at 6.7. A very recent literature review came up
> with 13 case reports of Stevens-Johnson or toxic epidermal necrolysis
> occurring secondary to a variety of fluoroquinolone agents.
>
> \[Slide\]
>
> In summary, the safety findings for gemifloxacin include a minor
> increase in mean QTc. There were some LFT elevations seen,
> particularly in those with liver disease or more comorbidity. With
> rash there was an increased overall incidence, with a large percentage
> of the body surface area involved and some severe rashes with mucus
> membrane involvement in study 344.
>
> \[Slide\]
>
> So, looking at the risk-benefit for the different indications being
> sought, for ABECB the considerations include the efficacy of the drug
> in the treatment of this condition; the length of therapy; the fact
> that it is a chronic condition often requiring recurrent therapy; what
> the rash rates would be in a population actually prescribed drug; the
> possible limitation of future quinolone availability in those who
> experience rash; and the fact that there were small increases in liver
> function tests and minor increases in mean QTc.
>
> \[Slide\]
>
> The risk-benefit considerations for community-acquired pneumonia
> include efficacy again in the treatment of this condition; the fact
> that it is an oral therapy; what prescriber compliance would be with
> 7-day regimens. One thing not here, importantly, is the incidence of
> rash; the possible limitation of future quinolone availability in
> those who experience rash; possibly more hepatic effects in those with
> more comorbidity; and minor increases in mean QTc.
>
> With that, I would like to take it over for conclusions to Dr. Edward
> Cox.
>
> **Summary**
>
> DR. COX: Just quick summary slides of a few of the items that have
> been discussed in the FDA presentation.
>
> \[Slide\]
>
> First you heard from Mr. Dionne about the microbiology review, and he
> noted and described some of the [in vitro]{.underline} data and also
> some of the data from the animal models, and also provided some
> information about the pharmacokinetic indices to help put the MIC in
> context.
>
> Then Dr. Alivisatos provided a discussion of the data for the
> community-acquired pneumonia studies. In this, she talked about
> duration of treatment of 7 days versus 7-14 days in light of the
> proposed dose duration of 7 days. She also discussed the issue of
> severity of disease in the community-acquired pneumonia studies, and
> then provided some information and discussion of the data for isolates
> of [Streptococcus pneumoniae]{.underline} from the clinical studies,
> including data on the resistant isolates for [Streptococcus
> pneumoniae]{.underline}.
>
> With regards to acute bacterial exacerbation of chronic bronchitis,
> Dr. Navarro provided an initial discussion of the principal studies
> and, in general, these studies support the efficacy in the treatment
> of acute bacterial exacerbation of chronic bronchitis. Then she also
> went on to talk about some of the statistical and clinical
> considerations for some of the other findings in the ABECB studies.
> She closed with a brief slide that talked about some of the population
> differences with regards to the antimicrobial usage data compared to
> the data from the clinical studies population.
>
> \[Slide\]
>
> Dr. Tierney provided information about gemifloxacin-associated rash
> and provided details about the rates, the characteristics of the rash
> and also some of the risk factors.
>
> With regards to some of the remaining questions, we have already had
> some discussion today and I expect we will have more but the issues of
> the risk for more serious dermatologic manifestations, the likelihood
> of cross-sensitization to other quinolones, and then some practical
> issues such as for patients who do develop a rash, the clinician\'s
> response to that and what the future antimicrobial options might be
> that would be available to such patients.
>
> Then she talked about the hepatic safety profile of gemifloxacin and
> provided some information about perturbations in liver function tests
> in patients who receive doses in excess of the 320 mg daily dose, and
> provided some discussion about cardiac repolarization, and then
> provided some of the considerations in the overall risk-benefit
> profile for the indications of community-acquired pneumonia and acute
> bacterial exacerbations of chronic bronchitis.
>
> So, just as a recap I will end there and turn it back over to the
> Chair.
>
> **Questions and Answers**
>
> DR. LEGGETT: Thank you. Are there any pressing questions that can\'t
> wait?
>
> DR. BRADLEY: Just a very quick one. In terms of the under 40 female
> age group that is at risk for the rash, does either the FDA or the
> sponsor have information on the incidence of rash by decade? Is this a
> straight line which has the highest incidence perhaps in the 20s or is
> it estrogen-related so that at the time of menopause the risk drops?
> So instead of a 40 cut-off, perhaps a 50-year old cut-off would be
> better? So, if there was some way to see by decade what the incidence
> of rash would be, it might be easier to put something into the
> labeling.
>
> DR. TIERNEY: I have never seen a breakdown, other than under 40 or
> over 40. One thing that may help with that is the use of HRT. Over 40
> HRT use does increase the risk. It might be related to that. But in
> terms of a breakdown by decade, I haven\'t seen data.
>
> DR. LEGGETT: Dr. Patou is saying that that analysis has not been done.
> Any other questions?
>
> \[No response\]
>
> As far as I know, there is no open public hearing statement. So, why
> don\'t we reconvene here at 2:00 p.m.? We will answer some questions
> left over from the morning and then hear the charge to the committee
> from Dr. Goldberger. Thank you.
>
> \[Whereupon, at 1:20 p.m., the proceedings were recessed for lunch, to
> resume at 2:00 p.m.\]
>
> \- - -
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> DR. LEGGETT: This afternoon will be spent in discussing questions
> regarding the risks and benefits of gemifloxacin, but before that I
> would like to make sure that there is no one who showed up at the last
> minute, because of the snow, who wishes to speak at the open public
> forum.
>
> \[No response\]
>
> Before we get to hear the charge by Dr. Goldberger, were there any
> questions that the sponsor wanted to bring up in terms of the
> questions we had in terms of things that were left over from this
> morning? Anything that you wanted to say to address any of those?
>
> DR. PATOU: The only piece of data that I think was requested was the
> confidence intervals from study 344. The FDA showed the confidence
> intervals from part B. f that addresses your question we are fine.
>
> DR. LEGGETT: Thank you very much. Dr. Goldberger?
>
> **Charge to the Committee**
>
> DR. GOLDBERGER: I will try to make my comments brief. We have three
> questions. The first is, based on the data presented and in your
> scientific and clinical opinion, do the benefits of gemifloxacin
> therapy outweigh the risks for the proposed indications of, (a)
> community-acquired pneumonia and, (b) acute bacterial exacerbation of
> chronic bronchitis?
>
> It is worth noting that FDA agrees with the firm that efficacy has
> been demonstrated in both of those indications. I believe you have
> gotten the sense that there are probably some differences in exactly
> how we would describe the degree of efficacy, and we will come back to
> that in a second, but there is agreement that efficacy has been
> demonstrated.
>
> In addition, activity in penicillin-resistant [Streptococcus
> pneumoniae]{.underline} has been demonstrated. That is why we have not
> asked a specific question with regards to that. We believe how exactly
> that claim ought to be placed in product labeling, should you
> recommend approval for community-acquired pneumonia, is something that
> we will have a better handle on after discussion tomorrow, but we
> don\'t think actually there is enough doubt about that to really
> warrant a question.
>
> As you discuss this, we want you to include as part of your discussion
> the clinical and microbiological benefits of gemifloxacin. As I said
> before, there is agreement that the product is efficacious. As we all
> know, even though there is no statutory requirement that a product be
> better than what is out there or add value to what is out there in
> order to get approved, realistically when we look at the efficacy of
> the product, we need to do it in the context of the severity of the
> illnesses in question, the availability of alternative therapies and,
> in particular, what safety issues are posed by a product.
>
> In this case, there has been some discussion obviously about some
> potential safety issues, and we will come back to those in a second.
> As a result, we feel it is important to talk about the efficacy and
> take into account these potential safety issues. So, one of the first
> steps is to talk some about the clinical and microbiologic benefits of
> gemifloxacin. As you know, the company has made a strong statement
> about the advantages from a microbiologic point of view in terms of
> enhanced activity against resistant pneumococci, and I think there is
> recognition that such organisms are important, and has tried to make
> the case with regards to some benefits in some of agreed upon
> secondary endpoints in some of the trial. We think it is important,
> you know, to hear your perspectives on those different issues.
>
> We also, obviously, think that it is important to talk about some of
> the safety issues. It is no accident that we have such a huge
> collection of dermatologists here today. I kept thinking if I had any
> dermatologic problem that I needed any advice on, this would be ideal.
>
> \[Laughter\]
>
> In any case, we want you to talk a little bit about the significance
> of the rash and, first of all, its frequency but, in addition,
> particularly as it relates to the likelihood of more severe
> dermatologic manifestations when the drug is prescribed to many more
> people and the likelihood of cross-sensitization to other
> fluoroquinolones. This is obviously a concern. Fluoroquinolone
> antimicrobials are important drugs for a wide range of infections,
> ranging from respiratory infections to severe systemic infections,
> urinary tract infections, etc. Getting a better feeling for these
> issues we think is essential in understanding how to proceed with this
> product.
>
> We would also like to have some discussion about the hepatic toxicity
> profile of the drug. You have heard analyses presented by the firm.
> You have heard some analyses presented by the FDA. As much as is
> possible, we would like to get some kind of consensus as to whether
> this is likely to pose a problem in actual use.
>
> Question two is, if the answers to question 1(a) and/or 1(b) are yes,
> please discuss types of information that should be provided to
> physicians and patients. Please focus on elements outlined in question
> one, as well as any other issues you believe relevant. Please include
> as part of this discussion any caveats as to how and to whom the drug
> should be administered. For any risk communication or management
> strategies that may be appropriate, please comment on how practical
> and/or effective you think such strategies would actually be.
>
> These are obviously issuers about putting statements in labeling about
> how long the product should be prescribed for, any cautions about if
> it doesn\'t appear to be working as well as about prescribing another
> course; what to do about repeated prescribing and is that a concern?
> Perhaps even more to the point, what should somebody do if a rash
> develops? Should therapy be stopped? Can the drug ever be used again?
> What recommendations ought there be, if any, to patients for future
> use of fluoroquinolones, etc.?
>
> The more information like that that could be put in labeling, the more
> helpful it is to physicians and patients to understand how a product
> like this can reasonably be used; the less confusion there is and,
> hopefully, the less likelihood of potentially more severe adverse
> events if, in fact, that is a risk; and concerns about an impact on
> future use of fluoroquinolones.
>
> So, any useful comments you have about this, as well as any comments
> you may have regarding issues related to the efficacy, particular
> patient groups who would be felt to particularly benefit from the
> drug, etc., those are the kinds of things we would like to hear some
> comments about because a lot of those issues can potentially find
> their way into product labeling.
>
> Finally question three, if the answers to 1(a) and/or 1(b) are no,
> please recommend what additional studies or information should be
> obtained for both those indications, community-acquired pneumonia and
> acute bacterial exacerbation of chronic bronchitis.
>
> We didn\'t specifically ask one other question that I just want to
> follow-up with, if you believe that the drug should be approved for
> one or both of these indications, we would also like to hear any
> comments you have about additional studies in the postmarketing period
> that you think might be helpful in better understanding both efficacy
> and/or safety issues. Those basically are my comments.
>
> **Committee Discussion**
>
> DR. LEGGETT: What I would like to have us try to do, given that
> charge, is to try to address these issues, starting off first of all,
> talking about the efficacy part of this in the first discussion
> session. If you want to say something about pneumonia or bronchitis,
> that is okay, we will try to link it up. Everybody, start thinking
> about what your answers are going to be because not only is it going
> to be yes/no at the end; it is going to be why yes or why no.
>
> After we talk about the efficacy and, hopefully, if there are
> questions either the FDA or the sponsor can elucidate them a little,
> then we will pass on to the safety part of it and have another
> discussion regarding the various safety aspects. During that part, for
> sure, I would like to hear at relevant time points what
> gastroenterologists, panel members and dermatologists and allergists
> have to say for the specific points involved.
>
> Who would like to start either talking or asking a question, let\'s
> say, about what this drug is going to be for. Dr. O\'Fallon?
>
> DR. O\'FALLON: In reading through the results of this, I was struck by
> the fact that no matter how sick the patients were, and there weren\'t
> all that many that were sick, really sick, and no matter what kind of
> bug they had, something on the order of 75, 80, 85 percent of them
> were improved or were considered successes. I can\'t see it in any
> package, what percentage of patients get better on no treatment at
> all, or placebo, or ineffective therapy in both of those diseases and
> I need to know.
>
> DR. LEGGETT: Dr. Patterson, could you give us a little help with
> chronic bronchitis?
>
> DR. PATTERSON: Well, based on earlier discussions, the acute
> exacerbation of chronic bronchitis has been somewhat controversial as
> to whether antibiotics really make a difference in that disease. In
> fact, that is one of the diseases that we talked about in earlier
> discussions, that it might even be reasonable to do a
> placebo-controlled trial with that because it is not clear that
> antibiotics make a big difference.
>
> \* DR. LEGGETT: As a follow-up to that question, a statement was made,
> and I can\'t remember whether it was Dr. Mandell or who it was this
> morning, about efficacy was better in the gemifloxacin group in terms
> of either the time to relapse or hospitalization. I believe I asked
> Dr. Patou whether the trials were stratified according to steroid use,
> given the data that if you don\'t stratify for steroid use antibiotics
> make a difference in bronchitis case but if you do, they don\'t, at
> least in some studies.
>
> DR. MANDELL: If I could just make a brief comment before addressing
> this, with ABECB in relationship to that question, and it is a good
> question, you really have to stratify according to severity.
> Unfortunately, there isn\'t a stratification scheme that everyone
> agrees to but the Antonison is one approach. With that, the Antonison
> I or II, and Antonison I unfortunately means all three of the signs
> and symptoms, those patients do benefit. There have been a number of
> studies now that show quite clearly that those patients benefit. The
> Antonison III, which the mild, I don\'t think there is much argument,
> those patients may not benefit from antibiotics but the sicker ones
> definitely do.
>
> \[Slide\]
>
> On your question about steroids, this is the gemi. group, this is the
> clary. group and 25 percent of the patients and 24.6 percent of the
> patients. So, steroid use was even in the two arms.
>
> DR. LEGGETT: That was within the last year. What about while they were
> being treated during that month or two afterwards? Do you have data on
> that? That looks like baseline data. I was wondering in terms of the
> actual treatment course.
>
> DR. MANDELL: Do we have that data?
>
> DR. LEGGETT: You can deal with that later. Mike?
>
> DR. PROSCHAN: Yes, I wanted to get back to the 7-14 day issue. Isn\'t
> it true that even the people who went to 14 days you still have
> outcome data at 7 days. So, why can\'t you look at all the 7 days, not
> just ones who only completed 7 but everyone? I mean, that eliminates
> the bias problem.
>
> DR. LEGGETT: Does somebody want to tackle that?
>
> DR. COX: I think the issue is that in the studies where there is a
> choice of 7 or 14 days it is not determined at the time of randomized
> whether somebody gets 7 or 14 days of therapy, but it is actually
> something that is determined on therapy.
>
> DR. PROSCHAN: Right, I understand that but even if they go on to 14
> days you still have their 7-day outcome. So, why can\'t you just look
> at everyone at 7 days, not just the ones who only went 7 days but the
> 7-day outcomes in everyone? Then you don\'t have the bias problem.
>
> DR. ALBRECHT: I think in the evaluation of a trial of an infectious
> disease if we looked at a study where a patient received a certain
> duration of therapy, and then it was determined by some investigator
> criteria that that patient required additional therapy, i.e., up to 14
> days, then our assessment of that patient\'s progress at that 7-day
> time point would be that the patient was not successful because he or
> she required the additional 7 days. So, I think if we were to go back
> and do that, and I will defer to our statistical colleagues here but
> one of those analyses would have to be a sensitivity analysis assuming
> that all of those that received 14 days, in fact, would have been
> failures if they stopped at 7. That might actually bias the results
> the other way, making the success rate seem artificially lower than it
> really happened.
>
> DR. PROSCHAN: So, there was not an outcome measured at 7 days? Is that
> what you are saying?
>
> DR. COX: The primary outcome assessment would have been thereafter,
> and I think it is around day 21 with a window around it. That would
> have been the same for patients despite the course of therapy.
>
> DR. LEGGETT: Dr. Maxwell?
>
> DR. MAXWELL: Just to follow-up on that question, you could get safety
> data though after 7 days.
>
> DR. TIERNEY: We did assess the safety for all those patients, both on
> therapy and after therapy. So, if they had a safety problem on therapy
> that would still have been determined regardless whether it was 7 or
> 14 days.
>
> DR. LEGGETT: Yes?
>
> DR. HILTON: I have a different question on the efficacy. I wonder what
> the non-inferiority margin was. I see that some of the confidence
> intervals go down to as low as 10 percent inferiority and I wonder
> what was the cut point used to design the study and to think about
> non-inferiority.
>
> DR. COX: For most of the studies the lower bound of the confidence
> interval is minus 10. There were some I think that were minus 15.
>
> DR. ALIVISATOS: Some of the CAP studies were minus 15 and some of them
> were minus 10. In the sponsor\'s analysis, I think what they said, you
> know, post studies they tried to go to a delta of minus 10.
>
> DR. HILTON: Okay. There was just a lot of focus on the mean rather
> than the lower bound and I wondered if attention had been paid to
> that.
>
> DR. LEGGETT: Dr. Proschan?
>
> DR. PROSCHAN: The reason I brought up that earlier question is that I
> am not sure the FDA would agree that efficacy has been shown based on,
> you know, if you only consider study 11 as the primary study and the
> others as supportive, then one, namely 12, is not supportive. I mean,
> it is supportive of the opposite; 49 is supportive. So, I am not sure
> that it is true that the FDA would concede efficacy if you take the
> point of view that only study 11 is really the primary valid study.
>
> DR. COX: Can you just restate the last part of your question there?
>
> DR. PROSCHAN: Yes. I mean, the FDA\'s position, as I understand it, is
> that study 11 is really the only valid study of a 7-day course because
> the others have these biases. Then, the others are supposed to be sort
> of supportive. While one of them looks quite supportive, another one
> looks supportive of the opposite, namely that the competitor is
> better. I don\'t know whether it suffices to show that, you know, in
> at least one trial it is better or what the level of evidence required
> is. This is page 69. In particular, I am just looking at the ITT
> population but a similar pattern is in the PP population. Study number
> 49 is certainly supportive but study 12 is going the other way.
>
> DR. COX: For study 12, if memory serves me correctly, the lower bound
> of the confidence interval was minus 10.2. In some of the discussions
> earlier on during the drug development there was discussion of a
> confidence interval that would even be beyond the 10 percent, during
> the time when the NDA was being discussed. So, you know, I believe
> that lower bound, 10.2, is just beyond the 10 percent.
>
> DR. LEGGETT: Go ahead, Mark.
>
> DR. GOLDBERGER: It is also worth keeping in mind that one needs to put
> the issue of the confidence intervals sort of in a broader
> perspective. Clearly meeting a previously agreed upon confidence
> interval is the easiest way to get an approval absent any unusual
> safety or other issue. The fact that you may in one of the studies be
> just over the confidence interval doesn\'t, of itself, mean that study
> does not indicate that the drug had activity. I don\'t think, looking
> at the data, we would conclude that gemifloxacin is without activity
> perhaps in community-acquired pneumonia.
>
> However, it raises the broader concerns when we are then obliged to
> look at the overall activity as it has been demonstrated in clinical
> trials, and then link that to some of the potential safety issues that
> we need to talk about as well. That is where being on the borderline
> with some of the confidence intervals may prove to be, you know, a
> little bit more problematic.
>
> DR. LEGGETT: I have a couple of questions regarding kinetics and the
> mechanism of action. Maybe someone can help me from the sponsor.
>
> Much mention was made of the dual targets with the relative affinity
> being the same. When I look at the actual data, which in the FDA is on
> page 20, Table 14 and Table 15, to me, when I look at the difference
> between the wild type and then either the Par or the GyrA or the dual
> resistant mutants, to me it looks like gemi. and moxi. certainly aver
> very similar in terms of their fold range rise for those two things. I
> am wondering how much of a qualitative difference there really is
> between moxi. and gemi., rather than sort of just a purely
> quantitative change and calling 4-fold not significant and 8-fold
> significant and vice versa. When I look at the rat data I see that
> when the MIC becomes 0.25 or so the CFU declined in presumably the rat
> pneumonia model, really dropped off sharply for gemi. At least for
> those three strains, basically moxi. and gemi. did pretty much the
> same. I was wondering whether you could sort of overall comment about
> those issues.
>
> Not to beat a dead horse but the breakpoints will obviously play a big
> role in terms of how things are marketed, and I would hate to see a
> breakpoint pushed high, as was done with levo., which makes things
> there still labeled as intermediate or even susceptible, not being
> clinically susceptible.
>
> DR. PATOU: I would like to ask Dr. Steve Brown to comment on that
> question with particular reference to the table you referred to.
>
> DR. BROWN: Could I have slide M63, please?
>
> \[Slide\]
>
> This is the sponsor\'s version of essentially the same table as the
> one that you referenced. Yes, indeed, there are some marked
> similarities between gemifloxacin and moxifloxacin in the rat lung
> model.
>
> There are a couple of things that I would point out to you, one of
> which you have already observed. There is marked similarity between
> gemifloxacin and moxifloxacin in the majority of the cases. However,
> there are three distinct issues here. In this instance, in which case
> there is a statistically significant difference between both
> gemifloxacin and moxifloxacin or gatifloxacin, in this particular
> instance there is a second step mutation and there is a statistical
> difference between gemifloxacin and moxifloxacin. Finally, in this
> case there was a statistically significant difference between
> gemifloxacin and gatifloxacin.
>
> Yes, there are some similarities there. That cannot be denied.
> However, there are no instances in which moxifloxacin is more active
> than gemifloxacin. We have those two out of eight instances where
> gemifloxacin is slightly more active than moxifloxacin.
>
> In a semi-related matter, if I could call up FDA slide 10, please?
>
> \[Slide\]
>
> This was presented earlier by the FDA. These are looking at the 44 bad
> bugs. These are 44 strains of [Strep. pneumoniae]{.underline} with
> second step mutations. Even using the FDA\'s very conservative
> breakpoint of 0.125 I think that you can visually see that there is
> quite a difference between gemifloxacin and moxifloxacin in terms of
> the [in vitro]{.underline} activity. This is also very clearly
> reflected in the MIC-90.
>
> What we did during the lunch break was go back to the line listing and
> look at these individual paired data, pairing up gemifloxacin results
> with moxifloxacin results. Subjecting those paired data to statistical
> analysis using the Nieman\'s test for binary paired data on these 44
> strains, we found that there were 25 strains that were resistant to
> gemifloxacin\--these strains. Of those 25 strains, and you cannot
> appreciate it from this slide; you have to look at the paired data. Of
> those 25 strains, none of them was susceptible to moxifloxacin.
> Looking at 11 of these 19 strains that were susceptible to
> gemifloxacin, 8 of those were also susceptible to moxifloxacin.
>
> So, when you do this paired statistical analysis, you get a p value of
> 0.00098. So, the differences between gemifloxacin and moxifloxacin
> are, indeed, statistically significant. It was reflected in two of the
> eight rat lung models and reflected in the [in vitro]{.underline} MICs
> quite clearly.
>
> DR. PATOU: I think Dr. Klugman could address the affinity question
> that you asked about the binding at the two sites.
>
> DR. KLUGMAN: Keith Klugman, from Emory University. I think the issue
> of affinity does go more towards direct measurement of MIC. So, the
> drug affinities of gemi. are likely to be significantly higher and
> that is what has led to the lower MIC.
>
> I think that the context of this is important because I have been
> listening to the discussion and, clearly, it is a great concern to me
> that we need to consider where one goes beyond the fluoroquinolones
> for these indications. I think that the data we saw of the rat lung
> model got me thinking that for those strains where there really was no
> good efficacy of either agent, what is left?
>
> So, one of the arguments I would make in favor of this agent would be
> perhaps a lower propensity, because of this higher affinity for
> selection of resistant mutants so that one could come to an analysis
> of a condition like acute exacerbations of chronic bronchitis where
> you have a need for multiple rounds of therapy. So, at the moment my
> feeling is that clinical consensus is that once you have had a
> fluoroquinolone, any fluoroquinolone, you are at risk for subsequent
> resistant disease. In fact, many guidelines are now going to say that
> if you have had any fluoroquinolone for AECB you shouldn\'t have any
> other fluoroquinolone for at least four months. The argument then
> would be in favor of using perhaps the most active agent so you
> wouldn\'t have this development of resistance.
>
> DR. LEGGETT: A quick follow-up, what is the reason for the much higher
> MICs for gram negatives if this really is a dual target and the MIC is
> the marker of choice?
>
> DR. KLUGMAN: I think it is a question of the affinity of the enzyme;
> it is different in different organisms. So, we are really talking
> about gram positive topoisomerase. There is a greater affinity for
> this drug for that particular topoisomerase and less so for the gram
> negatives.
>
> DR. LEGGETT: Has anybody looked at what happens to the gram negative
> flora while we are taking this drug to treat our respiratory flora?
>
> DR. KLUGMAN: That is a good question and, clearly, there is a quid pro
> quo on both sides of this equation. Clearly, if you use less active
> fluoroquinolones against gram positives you are in danger of selecting
> resistance, say, in the pneumococcus. You could equally argue that
> using any of these agents may be less useful than using, say,
> ciprofloxacin against the gram negatives. So, you have a trade-off on
> either side of the equation, in my view.
>
> DR. LEGGETT: Thank you. Alan?
>
> DR. CROSS: I was interested in Dr. Low\'s data where you showed that
> if you had a mutation in both the ParC and GyrA with the gemi. you
> still had an MIC of less than 1; it was 0.25. I was just wondering,
> first of all, if it is known how these isolates are killed and, second
> of all, is it known whether or not gemifloxacin has any other
> antibacterial effects, other than on the killing, much like
> clindamycin affects the amount of capsule in bacteroides, for example?
>
> DR. LOW: To answer your second question first, there is no other
> evidence that it has other beneficial effects with regard to reducing
> virulence or decrease protein or toxin reduction. I guess I wouldn\'t
> be surprised that really it just affects DNA replication.
>
> Why is this drug still able, even in the face of mutations, to bind to
> these targets? It is called a cleavable complex. So, the way it works
> is that you literally have the topoisomerase enzyme wrapped around the
> DNA which allows it to open up and so you can replicate. The
> fluoroquinolone comes in and locks that together so it can\'t
> dissociate and it causes loose ends of the DNA which kills the
> bacteria. Presumably, it is the structure that allows\--you can
> literally see it on the molecule where the mutations occur how it
> affects binding affinity. So, you get a mutation and that mutation may
> disproportionately affect levofloxacin but gemifloxacin is still able
> to bind to and hold these two together and be bacteriocidal, as I
> showed in that one killing slide. So, it is just the structure of the
> compound.
>
> DR. LEGGETT: Thank you. Could I hear some comments perhaps from the
> committee members about their feelings about the number of severe
> community-acquired pneumonias that were in the trials, or lack
> thereof? Dr. O\'Fallon, you are really good for this one.
>
> DR. O\'FALLON: I was trying to find the data and I just did. I am
> looking at the FDA packet, page 10. Take a look at the numbers, 13 in
> one group; 11 in another; 31 and 26, 34, 30. There aren\'t very many
> in any of the treatment groups that were classified as having severe
> disease. So, those are small sample sizes.
>
> One of the things that concerned me is the response rates. They are
> still up in the 85 and 95 range for the most part. You know, if there
> is supposed to be more severe disease\--this is true for the
> comparators as well\--that is what makes me wonder whether any
> treatment will do. So, it really doesn\'t matter what you treat them
> with, they are going to get better, most of the people. If that is
> true, then is this evidence for the activity of any drug? If the
> underlying disease is going to basically get well no matter what you
> give them, then is this evidence for any of them being active?
>
> DR. LEGGETT: I guess one question that people tried to address was the
> difference in mortality between in the Fine study either in the
> validated or the initial modeling of the difference between the two
> groups.
>
> Going through here in my reading, I only saw mention of six intubated
> patients. Is that correct? And, all six were considered failures? Or,
> you know, was I just falling asleep?
>
> DR. ALIVISATOS: At the time of enrollment there were no patients that
> were intubated or on pressors, things like that. During the study,
> during the course of treatment six patients altogether did
> ultimately\--actually, there were two that were intubated, two that
> required pressors, and those were all failures.
>
> DR. LEGGETT: But not big numbers.
>
> DR. ALIVISATOS: No.
>
> DR. LEGGETT: Dr. Poretz?
>
> DR. PORETZ: Those patients who were seriously ill who were intubated
> were maintained on gemifloxacin during that period of time?
>
> DR. COX: They were put on alternative therapy.
>
> DR. PORETZ: Because in actuality, someone who is admitted to the
> hospital with a Fine I or IV even, in all honesty, is going to be put
> on parenteral antibiotics for practical reasons, whether it be
> insurance coverage or whatever. Many people won\'t pay for putting a
> patient in a hospital on oral medications. So, the sicker people will
> have to be on parenteral medications.
>
> DR. LEGGETT: And I would be worried about their absorption anyway.
>
> DR. PORETZ: Yes.
>
> DR. LEGGETT: Barth?
>
> DR. RELLER: There are several pieces of data that support less
> severely ill, not only the Fine scores, but the overall mortality and
> also the proportion of bacteremic patients, which is substantially
> less than most studies. So, I think that there are real limitations on
> excessive exuberance about the efficacy of this drug in CAP. Clearly,
> the sponsor\'s request for inclusion of [Staphylococcus
> aureus]{.underline} in particular but even [Haemophilus
> influenzae]{.underline} and [Moraxella catarrhalis]{.underline}\--over
> and above the majority of information is about [Streptococcus
> pneumoniae]{.underline}. I just don\'t see the numbers and certainly I
> don\'t see any numbers where one is absolutely sure that patients have
> those entities, apart from the pneumococcus, and even with the
> pneumococcus the number of bacteremic cases is less than 50.
>
> DR. LEGGETT: Can we pass on to the question of efficacy against
> multi-drug resistant pneumococci since you brought up pneumococci?
> Anybody want to give it an opening volley?
>
> To follow up on what Dr. Reller said, when I looked at the bacteremic,
> I think it was 37 of the 48 bacteremic cases were pneumococcus and 16
> of the 17 bacteremic pneumococci did respond but it is still smaller
> numbers than what we saw in the others.
>
> DR. RELLER: I was thinking about the query earlier about how many are
> required to be certain. I recall at multiple meetings ago when
> ofloxacin was presented there were over 100 bacteremic cases of
> pneumococcal pneumonia. People are pretty certain that they had
> pneumococcal pneumonia when the blood culture is positive, which leads
> to an additional question that there was not the time to ask earlier.
> Were there any other attempts, given the limitations of sputum
> cultures in the confirmation of the diagnosis of pneumococcal
> pneumonia since these are all adult patients and we don\'t have the
> difficulties of specificity with children, was pneumococcal antigen
> assessed in the urine of these patients? As published from New Zealand
> it is actually a reasonable test to augment the objectivity beyond the
> positive blood cultures where, you know, all of us would agree, as Dr.
> Brown was mentioning earlier, chest infiltrate, sputum production at
> least after being hydrated and a positive blood culture for the
> pneumococcus was certainly what we had, and a relatively small number
> of those with efficacy with this or any other compound, it seems to
> me, is a lot more powerful than large numbers of questionable severity
> by several accounts with a relatively small number of bacteremic
> patients. So, are there any data on pneumococcal urinary antigen
> detection in any of these studies?
>
> DR. ALIVISATOS: Two of the studies, the open study which is still
> ongoing, number 287 which is an enrichment study, one of the inclusion
> criteria is to have a positive urine pneumococcal antigen. Also, in
> study 011, which again was sort of an enrichment study, I mean, they
> tried again to enroll people that probably had pneumococcal disease
> and you had to have gram positive cocci on the sputum gram stain and,
> in other words, there were some clinical criteria there.
>
> Just to clarify first, for the 37 of the 48 bacteremic patients that
> had [Strep. pneumo.]{.underline} bacteremia, the success rate for the
> group of patients that received treatment for greater than 7 days was
> 95 percent. The success rate for the people who received less than 7
> days was 94 percent, even though you shouldn\'t look at it like that.
>
> DR. LEGGETT: I had a little question regarding what was stated a
> couple of times, first by Dr. Mandell and then later by the FDA and
> then what I saw in our FDA packet on page 57. On page 57, I don\'t
> want to fault anybody\'s grammar but I couldn\'t understand what you
> were saying. Were four out of four cipro. resistant pneumococci
> strains treated successfully? Or, how many were \"others\" were
> associated with clinical failure? I got lost. I think Dr. Mandell, if
> I heard him right, said 26 of 28 cipro. resistant strains were cured
> and I am having trouble with the numbers.
>
> DR. ALIVISATOS: There were four patients with cipro. isolates that had
> an MIC of greater than or equal to 4, which is considered resistant.
> The rest were intermediate.
>
> DR. LEGGETT: So, there were 22 intermediate and four resistant. Did
> you want to say something, John?
>
> DR. BRADLEY: It has to do with emergence of resistance because as
> quinolones are used more, particularly if there is ever a pediatric
> approval for one of the quinolones, we may see more resistance. So,
> looking to the future and knowing [in vitro]{.underline} the activity
> of the drug and the types of mutations that you need in pneumococci in
> order to develop resistance, in gram negative pneumonias there have
> been pharmacodynamic models which look at an AUC to MIC. If you get
> below an AUC to MIC of 100, the likelihood of emergency of resistance
> goes up dramatically. If you are above 100, then you tend not to get
> any resistant organisms. I am wondering if the company has done
> pharmacodynamic modeling perhaps in the rat, because you certainly
> don\'t have these same kinds of data in people, on what AUC to MIC
> ratio you would require to prevent emergence of resistant organisms.
>
> DR. LEGGETT: To follow-up with that, do you have kinetics and then a
> Monte Carlo simulation of patients at all?
>
> DR. BRADLEY: This would just be supportive data to show that the
> mutational resistance is very low, and if you have a certain drug
> exposure at 320 mg a day that you would be unlikely, given the current
> MIC-90, to develop resistance, and then compare that with other
> agents.
>
> DR. PATOU: We haven\'t done the specific AUC to MIC modeling that you
> described on gram negative organisms, but I think that Dr. Jacobs has
> worked in this area and might have a comment to say on this.
>
> DR. JACOBS: I think I can give you a general answer to that. There is
> some data showing that you prevent resistant mutants at an AUC to MIC
> ratio of free drug of 100 or greater, whereas for efficacy, especially
> for gram positives, you probably need 25-30 as a lower number.
>
> There is also some controversy as to whether 100 is needed for gram
> negatives and 30 for gram positives, or whether you need 100 for
> immunocompromised patients and only 25-30 for immunocompetent
> patients. I think a lot of that still needs to be dissected out as to
> which factors come into it, but I think, to me, the bottom line for
> gemifloxacin is, whichever parameter you look at, against either
> susceptible or quinolone-resistant [Strep. pneumo.]{.underline}, it
> has the highest parameter, higher than any other drug including
> ofloxacin.
>
> DR. LEGGETT: Although I would hasten to add that 97-128 is no
> different than 96 in terms of these numbers because of the huge
> difference that the MIC makes. That is where most of your
> pharmacodynamic variability is. So, going from 0.125 to 0.25 shoots it
> in the foot, for instance.
>
> DR. JACOBS: No, if you are just looking at pure ratios, if you are
> looking at ACU to MIC ratio gemifloxacin is about 20 percent higher
> than moxifloxacin. I think that is what you were referring to. But if
> you look at peak to MIC ratio for both susceptible and resistant
> strains you see an even bigger difference. For susceptible pneumococci
> gemifloxacin is over twice that of moxifloxacin for free drug. When
> you look at resistant strains the ratio increases to five-fold. The
> peak to MIC ratio for ofloxacin, based on MIC-90 of
> quinolone-resistant strains is 0.55, whereas for gemifloxacin it is
> 2.6.
>
> DR. LEGGETT: At least this year.
>
> DR. JACOBS: Sure, but as the MICs go up for one, they are going to go
> up for the other.
>
> DR. LEGGETT: Sure. Just couldn\'t let you off the hook that easily!
>
> If we have beaten community-acquired pneumonia to death, could
> somebody make some comments about the secondary endpoint issues that
> were brought up with the chronic bronchitis issues? Do you keep people
> out of the hospital? Is there a longer time to relapse and those sort
> of things? Anybody care to make any comments about the efficacy data
> as far as that is concerned?
>
> DR. PROSCHAN: Yes, I, for one, don\'t believe the hospitalization
> results. I am trying to find that picture in the FDA document that
> shows the log rank curve.
>
> DR. LEGGETT: The hazards ratio?
>
> DR. PROSCHAN: Yes, page 67. To me, we often go by log rank and I
> don\'t see much of a difference here, a p value of 0.16. You know,
> there also do seem to be some pretty big jumps near about 10 days, and
> I don\'t know whether that is some kind of important cut point as far
> as insurance is concerned but it looks like something might be
> happening there. So, taking all that into account, I tend to discount
> that particular claim of benefit.
>
> DR. LEGGETT: I might only add in terms of the time to the next
> infection or rehospitalization or relapse there is some data apropos
> of this with steroids in the last couple of years, in [The New England
> Journal of Medicine]{.underline}, looking at steroids and chronic
> bronchitis exacerbations and the time that you can prevent
> rehospitalizations, reinfections and that, of course, diminishes over
> time so that by the time you are out to six months or longer there is
> really no difference. It is a very short time frame. So, I would hate
> to carry out the data too far in terms of a five-day course of they
> when giving influence on relapse rates two, three and four months
> later. Don?
>
> DR. PORETZ: The slide was shown a little while ago about the number of
> drugs approved by the FDA for ABECB. There are at least half a dozen
> cephalosporins on the market, a bunch of quinolones on the market,
> macrolides on the market. The fact is there are so many drugs, I
> can\'t believe this is any better or any worse than any of those other
> drugs that have already been approved by the FDA for bronchitis.
>
> DR. LEGGETT: So, you are suggesting we jump from efficacy to toxicity?
>
> DR. PORETZ: Yes.
>
> DR. LEGGETT: Okay. Why don\'t we bite into the big one first, rash?
> Oh, sorry, Barth?
>
> DR. RELLER: I would like to come back to Dr. O\'Fallon\'s earlier
> query. Since these patients with acute exacerbations of chronic
> bronchitis were not stratified before entry and, by my reading, better
> than 95 percent of them or, let\'s put it another way, fewer than 5
> percent of them were in category III, the more severe, in previous
> discussions of the committee I think legitimate queries have been
> raised as to not only being ethical but perhaps obligatory to have
> placebo-controlled trials to assess the efficacy in acute
> exacerbations of chronic bronchitis. Particularly when better than 95
> percent of these patients are not in the severe category, I am not
> certain now to interpret this information, the bacteriologic data.
> There are actually as many or more with some of the putative agents
> that most people don\'t think cause, or are not important in acute
> exacerbations of chronic bronchitis, namely [Staphylococcus
> aureus]{.underline}, is they are all for [Streptococcus
> pneumoniae]{.underline}.
>
> So, what is proposed is a leading pathogen and we are going to
> diminish resistance and we are going to have a great effect because of
> the efficacy of this compound [in vitro]{.underline} against
> [Streptococcus pneumoniae]{.underline}. When you look at the
> microbiology data with these milder cases of acute exacerbations of
> chronic bronchitis the numbers simply aren\'t there.
>
> Now, does it work as well as the other compounds? It probably does.
> How it works versus placebo in these patients I would like to know
> because you get into the safety issue in terms of not does it work as
> well as other comparators but, given the numbers of patients, does it
> work sufficiently well over placebo to encounter the risk? One could
> say, well, the rashes are mostly in the younger patients who don\'t
> have acute exacerbations of chronic bronchitis. On the other hand, in
> the touted 344 study, and it was impressive, there were all of these
> challenges that people had rash and didn\'t have rash with
> ciprofloxacin but, unless I missed it, I didn\'t see the gemifloxacin
> rash and gemifloxacin again. Given the frequency of use of agents and
> repeated, recommendations not withstanding of not repeating any
> fluoroquinolone within X period of time, what is the reality of people
> getting gemifloxacin again? I think there are a lot of questions with
> acute exacerbation in chronic bronchitis in the data presented to us.
>
> DR. LEGGETT: I would like to add to that. From my own real-world
> perspective, the fact that it is approved for AECB means that it is
> automatically used in acute bronchitis and the numbers there are
> overwhelmingly young. Also, in community-acquired pneumonia if you
> look at the Fine data, 67 percent of those people are under 40 and
> they are outpatients.
>
> DR. RELLER: Actually, in the six or so patients that were listed as
> having severe reactions, most of them admittedly overseas, I, maybe
> incorrectly, assumed that EBS, which was the diagnosis, was acute
> bacterial bronchitis. Maybe I didn\'t get that straight. Guideline
> after guideline, you know, from IDSA has come out that that is not an
> entity that warrants antimicrobial therapy.
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: I have a comment but it is actually not related to
> that. It is about the multi-drug resistant indication that you brought
> up before.
>
> DR. LEGGETT: Sure. Oh, go ahead.
>
> DR. PATOU: Just to provide clarification for the committee. Just two
> quick points. One is that all of the AECB studies that were conducted
> were studied according to the existing guidelines for the assessments
> of acute exacerbation of chronic bronchitis. They were conducted over
> a three- or four-year period and they were conducted to the standard
> that is expected of a sponsor for the assessment of the efficacy of
> the drug in AECB, and we were not asked to include a placebo in those
> studies.
>
> The second point is that the definition of AECB in these studies did
> meet the accepted criteria for AECB. If there is a reference on a
> slide, and I think it may have been a safety slide, to EBS that was
> referring to a patient in an acute bacterial sinusitis study, not an
> AECB study.
>
> DR. LEGGETT: Dr. Powers?
>
> DR. POWERS: I want to make a comment about where we are going with
> AECB trials. It is true that gemifloxacin\'s development program was
> long before we brought up some of these issues and we would never hold
> them to something that we had, you know, discussed just recently. But
> in November there was a workshop being co-sponsored by the IDSA, the
> pharmaceutical industry and the FDA where we discussed just these
> issues of acute exacerbations of chronic bronchitis trials, and there
> was a consensus among the representatives there that
> placebo-controlled trials would be something that folks would want to
> see, given this idea that the placebo rate in patients treated in that
> disease would be very high. Again, that is not something we would hold
> a development program that is already completed to, but to say that
> that is the current guidance I don\'t think is true anymore and, from
> this point forward, we would be really looking towards more
> placebo-controlled trials.
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: Related to the multi-drug resistance issue that you
> brought up before, and we have discussed this before, I think, as Dr.
> Powers was proposing, the multi-drug resistance indication makes more
> sense, especially, as he pointed out, the data is accumulating that
> really for isolates that have penicillin MICs less than 4 there
> doesn\'t seen to be a significant difference in clinical outcome, and
> actually macrolide resistance is more important than what we are now
> calling penicillin resistance on the label. That may change when we
> have more isolates with MICs greater than 4. But rather than, you
> know, adding on drug after drug to penicillin resistance, second
> generation cephalosporin resistance, macrolide resistance, perhaps we
> should say multi-drug resistance and define that as at least three
> classes of drugs.
>
> DR. LEGGETT: So, in AECB we are going to go against placebo. If there
> is more toxicity and they don\'t have a multi-drug resistant
> pneumococcus they are not going to get\--it doesn\'t make sense. It is
> getting complicated.
>
> Can we pass on to toxicity issues? Perhaps the first question would be
> rash. I was rather intrigued that some people in 344 who developed
> rash the first time around did not get the second, especially from
> your comments earlier, Dr. Bigby, about if someone had a cephalosporin
> rash that you wouldn\'t want to give it again. Is there something
> fundamentally different about a fluoroquinolone rash that you or
> anybody else knows?
>
> DR. BIGBY: I guess the only thing that I would say about this is that
> I was surprised by this result, the gemifloxacin rash and then
> ciprofloxacin and the point estimate rate was 5.6. I would just point
> out that the N is small and that doesn\'t exclude the possibility of a
> reaction rate as high as 9 patients out of 100.
>
> DR. LEGGETT: Dr. Rodvold?
>
> DR. RODVOLD: Would you anticipate it would be different in patients
> versus a volunteer study? In patients do you think it would be higher?
>
> DR. BIGBY: There is no way to know.
>
> DR. LEGGETT: Dr. Epps, anything to add to that in terms of your
> interpretation of rashes?
>
> DR. EPPS: I guess just a general comments. I certainly appreciate the
> company\'s work and the additional study that was performed. I was
> very happy to see pathology and histopathology, and it was very
> reassuring that there was no vasculitis. There didn\'t seem to be
> immune complex diseases. That is very reassuring.
>
> I was impressed by their data on MICs, although some people don\'t
> think it maybe as pertinent but I thought it was interesting. What I
> guess concerns me is the high incidence of eruptions in people who
> were normal. In women under 40, 31 percent had eruptions. Now, if they
> were ill I have no idea what the rash rate would be but 31 percent is
> quite high. The mean onset was 9 days, which is beyond the 7 days and
> it certainly lasted at least a week in over half the cases.
>
> So, certainly, you know, one would wonder what it was about women
> below 40, what hormonal influences were there. There was discussion
> about oral contraceptives. What about people who use Norplan? What
> about people who use Depo-Provera, older women who are on hormone
> replacement therapy? There seems to be some kind of a theme there.
> Whether it needs more investigation I don\'t know but the rate is very
> concerning to me. Certainly, you know, I would consider something
> different if it were a woman under 40. So, maybe some adjustments
> could be made for that.
>
> DR. LEGGETT: Wear an anti-drug bracelet?
>
> \[Laughter\]
>
> Dr. Drake?
>
> DR. DRAKE: Well, I too want to compliment the sponsor because the 344
> study is terrific in dermatology. It is long needed and we need more
> of it so we can start to sort some of this out.
>
> Maybe I am not reactionary enough. It seems to me that we have other
> drugs that give us these kind of non-specific rashes. In absence of
> vasculitis and in absence of immune complex disease, gee, if I see a
> rash and I don\'t know what it is I get a biopsy and get it frozen and
> kind of find out what is going on. But in the absence of those things,
> it is not uncommon\--and I think it is a standard in dermatology\--it
> is not uncommon to what we call treat through some of the rashes. It
> is particularly true for some of the antifungals. You just treat right
> on through. People get these rashes and you treat them and keep on
> going and pretty soon the rash resolves all by itself anyway.
>
> Now, that doesn\'t mean that you are not prudent. It doesn\'t mean
> that you don\'t think about what is underlying the rash and exactly
> what the pathophysiology is. But, in fact, I am not terribly alarmed
> by this. If you have a good drug that might treat a patient who might
> otherwise not be treatable by something else, in other words, if this
> is a nice alternative or nice addition to the therapeutic
> armamentarium, then I wouldn\'t let the rash preclude me from using it
> or considering using it.
>
> I do think that one can address this issue by looking at the labeling
> and a Phase IV study to further separate it out a little bit. In all
> honesty, you are not going to get much answer on the rashes in
> clinical studies. The power is just too low. You are just simply not
> going to have it. You are going to have to get it out in the
> real-world use and then follow them and monitor the rashes and monitor
> the patients and see what happens. So, I think as a practical matter,
> if that is the only limiting factor it makes more sense to get it out
> there and get it in real-world use and then monitor it in Phase IV and
> tease it out at that time.
>
> DR. LEGGETT: Yes, go ahead, Dr. Bigby.
>
> DR. BIGBY: I believe that gemifloxacin has been licensed in several
> countries in Europe and I wonder whether there is any postmarketing
> surveillance data vis-a-vis its frequency of producing rashes and the
> duration at which it is used in the countries where it has already
> been licensed.
>
> DR. LEGGETT: They are shaking their head, no.
>
> DR. PATOU: I mean, the drug has not been launched anywhere at this
> point in time.
>
> DR. LEGGETT: Could I get an opinion from Dr. Adkinson and the three
> dermatologists about if you get this rash, is it going to become
> anything different the second, the third or the fourth time around? If
> that is the case, to me, the clinical paradigm in the United States is
> if somebody comes in and you have seen their penicillin rash, they
> don\'t get penicillin again. If I have seen their fluoroquinolone or
> cipro. rash, I don\'t give it again. Could the committee get your
> opinion about that?
>
> DR. ADKINSON: Could I put that off for just a second and just comment
> more generally about the rash issue as I see it?
>
> If you just look at the clinical trial data, the rate of this
> apparently benign, late occurring maculopapular rash is about 3.6
> percent versus 1.1 percent in the comparator group. If you look even
> more specifically at those that were considered by the investigator to
> be probably drug related, the rate of rash is 2.8 percent compared to
> 0.6 percent. So, there is a drug specific excess rate for sure, but I
> don\'t think that would have garnished very much attention except for
> this demographic factor of a very high prominence rate of this rash in
> young women. It is young as opposed to women and it seems to be the
> important factor.
>
> The rate of reaction is going to be a little more in the chronic
> bronchitis, about 1.5 percent, and somewhat higher in CAP, about 4.7
> percent because of the demographic factors, and the fact that
> bronchitis is a disease of older men I guess and community-acquired
> pneumonia has a much larger fraction of younger women. So, we are in a
> range where other antimicrobial drug preparations commonly induce rash
> rates in this area.
>
> So, for me the issue is, does this rash portend something about this
> drug that is different from other similar appearing rashes that occur
> with comparable frequency, putting aside for a moment this issue of
> gender and age risk factors? From what I have heard today, I am
> reassured I think, especially by this very large 344 study, that this
> rash behaves very much like the diamino-penicillin rashes that we have
> become familiar with and that we know occur with high frequency and
> that, with appropriate co-factors, can approach 100 percent in cases,
> as you know, where there is coincident infection with EB virus or even
> other proven viral infections, or the co-administration of
> allopurinol.
>
> So, high rates of rashes don\'t necessarily portend a substantially
> worrisome clinical outcome, it seems to me, judging from what we have
> learned to tolerate and to deal with clinically in the case of the
> diamino-penicillins.
>
> Coupled with that, I am reluctant to make too much of the incidence of
> rash in study 344. I mean, everybody is a bit wowed by this 31 percent
> rash rate in the participants in this study, but part of this very
> high rash rate is due to the surveillance factor that Dr. Bigby talked
> about today. The patient population chosen for study were young
> females who were taking the drug for ten days or more. If you go back
> and look at the clinical trial data, the rate of rash expected or
> observed in that group was 15 percent. Once you set up a prospective
> study aimed at looking at rash, the rash rate goes from 15 percent to
> 32 percent.
>
> Since we don\'t have any other studies that I am aware of, of this
> type of large-scale, prospective study of rash from drugs, this may
> not be as unique or as unusual as we might otherwise, just looking at
> the numbers on the surface of things, believe. It has taken me a while
> to sort of see that, but to me, that helps to assuage the numbers a
> bit with the fact that we don\'t really have comparison groups. I
> don\'t know how we interpret these numbers and then I have to fall
> back to the issue of the clinical consequences.
>
> As much as I have tried to, you know, search the database here and
> probe our presenters today about evidence for systemic findings
> associated with these rashes, I am not convinced that we really have
> anything that is above the background level of noise that we would see
> in a clinical trial of this type. There is certainly no red flag or
> worrisome data here, in my mind, to suggest that these rashes are
> going to turn into something to be clinically very worrisome if the
> drug is given to a much larger number of patients.
>
> To go back to your question, Dr. Leggett, I don\'t know the answer to
> that question but you are absolutely right in making the observation
> that once a patient is pegged as having nominally a hypersensitivity
> reaction to a drug, the usual clinical course is that that drug is
> withheld for the duration of that patient\'s life unless a particular
> physician has some belief that allows him to readminister or
> rechallenge patients or to move beyond the standard of practice, which
> is to withhold drugs generally that have caused problems in the past
> under the presumption that they are going to be a problem again.
>
> DR. LEGGETT: Do the three dermatologists concur in general lines with
> that statement?
>
> DR. BIGBY: Which statement?
>
> \[Laughter\]
>
> DR. LEGGETT: The most recent one, treating again or withholding
> treatment.
>
> DR. BIGBY: I would agree with that, yes.
>
> DR. DRAKE: I don\'t. As I said, in dermatology, frankly, we haven\'t
> done a very good job of sorting all this out and I think we are pretty
> good doctors so I don\'t want to disparage my specialty. I just think
> this is an area that hasn\'t perhaps gotten as much attention as it
> deserves.
>
> I would like to compliment the FDA for putting this issue on the
> table. This is really an important issue because people should not be
> labeled\--I was labeled allergic to penicillin as a kid because of a
> slight ampicillin rash. I mean, it is ridiculous; I am not allergic to
> penicillin. I think people miss out on good things and I think this
> reaction of if you have ever had any kind of a thing on your skin we
> don\'t ever give it again is probably inaccurate.
>
> I think we have to be more thoughtful and that is why I say I cheat. I
> tend to get biopsies and get frozen sections. I want to know what is
> going on underneath the skin and then make a better educated decision.
> But I don\'t think you can say, just because you had some kind of a
> \"rash\" without defining that, that you can tell a patient they
> can\'t ever have that drug or that category of drug again. If the FDA
> does approve this, I think it begs the question of sponsors trying to
> educate physicians on what we can do and what we can\'t do, and what
> is a reasonable approach to this type of patient.
>
> DR. LEGGETT: Dr. Bigby? Everybody is raising their hands. Folks who
> want to jump in on this, please raise your hand again.
>
> DR. BIGBY: I just want to say if a patient develops, while they are
> taking a drug, a drug exanthem and you don\'t have another explanation
> for it, I think it would be a big mistake to give it back to them.
>
> DR. LEGGETT: Dr. Epps, can we say that this is maybe not universally
> shared on either side? Dr. Adkinson?
>
> DR. ADKINSON: I just wanted to call our attention to the fact that the
> only data that I am aware of that deals with this directly were nice
> studies done in the late 1960s and early \'70s with amoxicillin in
> which patients who had late-appearing maculopapular rashes, very
> similar to the ones we are talking about today, were intentionally
> either treated through or rechallenged. Two of these studies were
> pediatric populations. They showed that the rate of rash with the
> first exposure was, I think in this case, about 10 or 12 percent. They
> took reactors and re-exposed them to the same drug again and got
> another 10 or 12 percent reaction.
>
> So, when it has been done, in a very limited way admittedly, and it
> involves the presumption that the rash we are dealing with today is in
> some ways similar, other than its clinical phenotype which is very
> similar I think to the amoxicillin rash, it gives us some suggestion
> that clinical practice here may be very conservative with regard to
> what is possible if one is willing to do provocational challenges and
> gather the data to support readministration.
>
> DR. LEGGETT: Dr. Bigby?
>
> DR. BIGBY: The best rechallenge data actually was done by a group in
> Scandinavia. The lead author is Cal Pinin. They did rechallenge
> studies to exanthems to fixed drug eruptions, and I think that the
> rate of sort of identification of culprit drugs is actually much
> higher than 10 percent.
>
> DR. LEGGETT: Dr. Wald?
>
> DR. WALD: I think that this study provided the data about rechallenge
> so the gemi. rash-gemi. was 2.4 percent, substantially less than 31
> percent the first go around. I think this is really such reassuring
> data that, in fact, we should tell people that if a patient gets a
> rash it is not a contraindication specifically with this drug to get
> the drug again.
>
> DR. TIERNEY: Dr. Leggett, can I just clarify? Dr. Wald, no one who
> received gemifloxacin and developed a rash got gemifloxacin again.
> Those are people who had not developed a rash to gemifloxacin and then
> got gemi., they had a 2.4 percent rash.
>
> DR. LEGGETT: Yes, go ahead.
>
> DR. SHEAR: That is not completely true. In 344 nobody was supposed to
> get gemifloxacin again but two individuals did get gemifloxacin again,
> as was found out when the mask was broken. One received just one dose
> I think and the other actually got a complete dose, and neither had a
> rash.
>
> DR. BIGBY: But an N of two\--
>
> DR. SHEAR: No, no, I am just telling you\--
>
> DR. BIGBY: Why bring that up then?
>
> DR. SHEAR: I showed you the data which is quite convincing\--
>
> DR. BIGBY: Yes, but it is zero out of two. What does it tell you? The
> reaction rate could be as high as two-thirds.
>
> DR. SHEAR: It tells you less than the four percent that I showed you
> here but that is more than no other data for any other drug.
>
> DR. LEGGETT: Thank you. Dr. Rodvold?
>
> DR. RODVOLD: In the aspect that you would go to all kinds of patients
> that could have pneumonia, is there anyone that you would say don\'t
> give the drug to because of the rash? I mean, any risk patient? Any
> type of group of patients? Any disease? Other drugs that you would be
> worried about in the sense that, you know, lots and lots of different
> types of patients get pneumonia?
>
> DR. LEGGETT: Anybody you would say not to use this drug? Use another
> one? I think the answer is no. Dr. O\'Fallon?
>
> DR. O\'FALLON: A comment, I notice in looking at the incidence of
> events, again from the FDA slides on page 25, the incidence is roughly
> three times higher in the gem. group than in the comparators, and that
> is true for any of the events, and the severity seems to be about
> three times higher at every level\--mild, moderate, severe.
>
> What I found intriguing was on the next page where there is rash by
> indication, it shows that rash in CAP seems to be about three times
> higher than the rash rates in ABECB. I am curious. Why would that
> happen?
>
> DR. LEGGETT: That was the age.
>
> DR. O\'FALLON: Was that the age deal? Okay, fine. DR. LEGGETT: Dr.
> Patterson?
>
> DR. PATTERSON: Well, I think it is a good idea to do the five-day and
> seven-day pack thing because the rash incidence goes up so high after
> seven days. But a concern is that in atypical pneumonia, or really any
> kind of pneumonia but especially atypical pneumonia it is very common
> to have a persistent cough after the pneumonia has cleared, just from
> reactive airway disease. I know that very often that gets treated by a
> repeated course of antibiotics rather than an inhaler. A good example
> is the Z-pack. I know people who have taken two, three and four just
> for a persistent cough.
>
> So, I think it should be a very big part of the education and/or
> marketing that, you know, if someone has a persistent cough you don\'t
> give them another refill of the seven-day pack, not because the rash
> is medically significant\--I think we have kind of answered that
> question, but, for one thing, I think it is significant to the patient
> to have a pruritic rash for a week. Maybe I am biased because several
> weeks ago I got my small pox vaccine and it itched like crazy for a
> week and I couldn\'t sleep well.
>
> The other thing is that just with the rash, as we have already talked
> about, even though there may not be cross-sensitization, physicians
> are afraid just medically-legally these days to give the same class of
> drug to people who have had a rash and patients are afraid too. I
> mean, I have had a patient who said he was allergic to penicillin but
> he tolerated Augmentin for two weeks in the past and when I suggested
> using it he thought I was trying to kill him. So, I mean, I think
> there is a very big perception by the physician as well as the patient
> that these rashes are significant even though there may not be
> cross-resistance. So, I think that is another good reason to try to
> avoid them by not giving more than seven days.
>
> DR. LEGGETT: Dr. Maxwell?
>
> DR. MAXWELL: Just two point. I think that the sponsor did a nice job
> in showing histopathology. That was really helpful. On the other hand,
> I think that the way we were taught I don\'t believe that I have any
> time rechallenged a patient, and most of my patients don\'t want to be
> rechallenged. I feel that when you weigh in the balance this severity,
> let\'s say, of acute exacerbation of chronic bronchitis it is probably
> not worth it and most patients and physicians will feel that way
> because the patients that developed the rash felt that it altered
> their life significantly. So, one way perhaps to handle this would be
> in the labeling and also intense provider education.
>
> DR. LEGGETT: Dr. Proschan?
>
> DR. PROSCHAN: So, is this largely a psychological problem?
>
> \[Laughter\]
>
> I ask partly because I get rashes sometimes for no apparent reason and
> I just ignore them and they always go away.
>
> DR. LEGGETT: That is why the rate in men is lower in these studies!
>
> \[Laughter\]
>
> DR. PROSCHAN: What are the doctors and patients worried will happen if
> they just don\'t do anything? What is the concern?
>
> DR. ADKINSON: It is worth pointing out that the rash for placebo
> treatment in the 344 study was 3.9 percent. So, just
> hyper-surveillance for rash will produce a fairly high rate of them. I
> think in this 344 study we have seen large numbers because people were
> looking very carefully and observing something that might otherwise in
> many cases have been ignored and certainly never have come to medical
> attention.
>
> DR. LEGGETT: Dr. Cross?
>
> DR. CROSS: I practice in a cancer center and I just want to bring up a
> point which perhaps is slightly off the point but related, and that is
> that perhaps most abused drugs in a situation of, let\'s say,
> neutropenic host are the quinolones. The practice has been that as
> long as a patient remains neutropenic, if they are on antibiotics,
> they remain on the antibiotics until they cure their neutropenia. We
> have lots of patients who resolve their fever; they are stable and are
> sent home, off-label, on quinolones and stay on that. I have a real
> fear if it is used in this way, although it is not with the blessings
> of the sponsor or the FDA. Is it possible to even have something in
> the insert that this drug is approved for CAP; that it is not to be
> used for prolonged treatment of neutropenia in immunocompromised
> patients because these are the ones where I am sure you will see skin
> reactions triple and all the other complications. I am not sure we
> have ever had in a package insert that a drug is not to be used for a
> certain indication, but in view of the prevalence of the problem I
> think it is worth considering.
>
> DR. LEGGETT: Dr. Drake?
>
> DR. DRAKE: Who asked the question about any group of patients where
> you would not use it? Was it you? I started to say something very
> respectful and say lawyers\--
>
> \[Laughter\]
>
> \--but I do think that the legal issues become very, very dicey in
> this arena. On the other hand, I think as professionals it is our
> responsibility to do what is right for the patient and to be
> thoughtful about how we make our decisions. That is why I have said
> what I have said, that we shouldn\'t just automatically be reactive
> and say they should never have the drug because they had a rash once
> because that is not an indicator in my opinion.
>
> But the second thing I wanted to be sure and mention is in terms of
> Phase IV studies, if it should go that way. I don\'t think there was a
> lot mentioned about mucus membranes. You know, Stevens-Johnson and TEN
> often appear initially, I mean sometimes it is your first clue.
> Frankly, when you are dealing with diseases of the eye, they can go
> south pretty quick. You know, two or three days and you can have some
> visual impairment. So, I would like to have some special\--I am sorry
> there weren\'t pictures or biopsies of mucus membranes in this
> wonderful study that they did, but I would like to strongly recommend
> that special attention be paid to people who might have a mucus
> membrane reaction. I can tell you that in that group I would be
> particularly cautious about rechallenging.
>
> DR. LEGGETT: Before we leave the rash, between the lines I got the
> impression that none of you were very worried about what has been
> manifested so far so could I have you speak about definitely showing
> an increased rash risk that you could identify from the data,
> recognizing that the numbers are small?
>
> DR. BIGBY: I would say that the rash that has been manifested is not
> one that I would worry about.
>
> DR. LEGGETT: Dr. Drake?
>
> DR. DRAKE: And I would say that too with one exception, and that is
> the patient who had the fever. I would pay careful attention to that
> type of thing.
>
> DR. LEGGETT: Dr. Rodvold?
>
> DR. RODVOLD: Most of these people are going to have fever if they have
> an infection.
>
> DR. DRAKE: Details, details, details! Picky, picky, picky!
>
> \[Laughter\]
>
> DR. PATTERSON: Probably not by day seven or eight.
>
> DR. LEGGETT: John?
>
> DR. BRADLEY: I have a question for Dr. Poretz. I have mostly a
> hospital-based practice and, as a pediatrician, certainly don\'t take
> care of many women under 40. But as someone who is trying to give
> recommendations for treatment, what I would like to do is to ask
> someone who is actually in an office, writing these prescriptions
> every day, how the incidence of rash in the under 40 women would
> impact his prescribing practices, assuming that the drug does get
> approved.
>
> DR. PORETZ: I will try to answer that. You know, medicine is never
> black or white. We always have to make decisions every day. We see
> people all the time for whom, for various reasons, you want to use
> certain drugs. For example, sulfa-trimethoprim is a commonly used
> drug. We like to use it because it is inexpensive. I realize it has a
> significant amount of drug eruptions associated with it but, you know,
> many times prescribe it anyway because it is good; it works under
> certain circumstances and it is cheap. So, you realize that X percent
> of people develop a rash.
>
> Well, this particular drug has a higher incidence of rash in certain
> populations. So, to be crude, I would probably not use it in women on
> birth control pills commonly and use it in older guys who smoke a lot.
> Okay? I mean, it seems to have a nice niche for people who have
> chronic lung disease, people who smoke a lot and people who have
> community-acquired pneumonia. Maybe that will be patients in nursing
> homes and maybe it will be people in extended care facilities. I am
> not sure you are going to use this drug that much in the hospital, in
> all honesty, because of the reason we said before, people tend to be
> on parenteral medications.
>
> But in answer to your question, in selective groups of individuals it
> looks like, because of the MICs\--and people can argue that\--it will
> be a very nice drug to add to our armamentarium to treat
> community-acquired pneumonia particularly.
>
> DR. LEGGETT: Dr. Epps?
>
> DR. EPPS: Just one last brief group for education would be the
> pharmacies, particularly when they go to the pharmacy and they get a
> page-long explanation of what the complications are and what your
> potential side effects could be and it may not agree with what the
> prescriber believes.
>
> DR. LEGGETT: Go ahead, Keith.
>
> DR. RODVOLD: Actually, on the slide it really only said educating
> physicians. I would broaden this way up because the triage is lots of
> other healthcare people. So, when you look at this educational
> program, once you get to it, it is going to have to be huge, in my
> mind, and I mean lots and lots and lots of education and lots and lots
> and lots of people.
>
> DR. LEGGETT: Jan?
>
> DR. PATTERSON: I was just going to say before we leave the rash issue,
> regarding postmarketing or Phase IV studies, I had some concerns that
> Dr. Epps brought up earlier about people of color. At least, in that
> 344 study there were a fair number of Hispanics, about five percent,
> but there were only two African-Americans, or 0.2 percent. While there
> wasn\'t a difference in the overall studies, I think that would be
> something to focus on in postmarketing.
>
> DR. LEGGETT: Go ahead.
>
> DR. CONJEEVARAM: From the perspective of not treating these patients
> on a regular basis, a question I have is that it is true that the
> current standard of practice for most physicians is that if someone
> develops a rash you don\'t rechallenge them. You can talk all you want
> about that this is safe. We do that in our specialty too with some of
> the medications we give and we go through the rash, but in general,
> especially with antibiotics, my impression is that if you do treat
> someone and they get a rash you don\'t rechallenge it.
>
> If you take the setting of acute exacerbation of chronic bronchitis,
> which is a recurrent phenomenon, and as we make guidelines would you
> use this antibiotic as first line knowing that if there is a high
> incidence of rash you will never be able to use that again in that
> setting? That might actually be quite clinically important at a later
> time.
>
> DR. LEGGETT: That was the reason for my comment about the niche of the
> resistant bugs. Go ahead.
>
> DR. ADKINSON: If we are treating, for example, acute bronchitis and
> consider using this drug, the expected rash rate will be lower than if
> one chooses to use amoxicillin. So, I think we have jumped to
> conclusions about the clinical significance of this that are far
> beyond what is practically the case when you are in a prescribing
> situation. I mean, I don\'t see any particular reason to be concerned
> about the use of this drug for these two indications. If there are
> high risk groups that can be easily identified, then one would
> naturally stay away from those groups but for these particular
> indications the rash rate is not going to be substantially different
> from the alternatives, it seems to me.
>
> DR. LEGGETT: Dr. Bigby?
>
> DR. BIGBY: Well, in the actual data in the study in head-to-head
> trials with amoxicillin and Augmentin the rate that is higher, more
> than twice as high in the head-to-head studies that they presented. I
> mean, that is clearly not going to be the case.
>
> DR. LEGGETT: If it is okay with everyone else, it is 3:30 and we have
> two members who have to leave at 5:00, we will skip the afternoon
> break. If folks have to skip out, that would be fine as long as they
> come back. Can we move on to the hepatotoxicity issue? Hari, could you
> give us your view?
>
> DR. CONJEEVARAM: I think in general, at least from the data presented
> and from the point of using it for five or seven days, it seems very
> safe in that it is reversible. None of the findings suggest that they
> are at risk of going on to acute liver failure, using the Hy\'s rule.
>
> The only two concerns I have, and maybe Jim Lewis or someone can
> comment on this, is that if, for whatever reason, you do use a higher
> dose or you prolong the dosage, if you look at the data from using the
> 640 mg, it is associated with increased ALT plus increased alkaline
> phosphatase which is cholestatic hepatitis. So, those patients are not
> really at risk necessarily of liver failure, which we all worry about
> but. As we know, there are antibiotics where one of the other
> potential risks is irreversible bile duct injury where they go on to
> have prolonged cholestasis, sometimes going on to liver failure.
>
> So, that would be one concern. That is where I think really education
> about use of this drug for a limited time period might be important
> and also surveillance post-approval, if it is approved, to really
> follow these patients, especially patients who are being treated for
> longer than what is prescribed. Again, I think probably in a certain
> number of patients it will be prolonged beyond one week or two weeks
> and really I think it is very important to follow those patients.
>
> The other issue is patients with underlying liver disease. I am not
> sure if among those patients there were patients with actual
> cholestatic liver disease included in the studies. We don\'t have the
> details on that. Again, maybe someone can help us with that.
>
> I am really not too worried about the fact that there was a higher
> rate of further increase in these patients because when we see
> patients who already have chronic liver disease, we are really looking
> at their baseline ALT which is usually abnormal, two or three times
> abnormal as the baseline cut-off. You really cannot compare with a
> normal ALT in that setting. You really have to say, well, what was the
> patient\'s baseline and then how many times beyond that has it
> increased. The data presented here again shows that though you do have
> a further rise, they all come back to their baseline, if not even
> better actually. So, I don\'t have much concern from that perspective.
>
> DR. LEGGETT: Are there any populations that you know of, other than
> sort of idiopathic, that are at increased risk of severe cholestatic
> hepatitis?
>
> DR. CONJEEVARAM: As far as we know, no. At least there doesn\'t seem
> to be any risk when you look at gender, though in general females are
> a bit more higher prone for drug-induced liver disease. No information
> on race, not that I know of.
>
> DR. LEGGETT: Dr. Sjogren, could you please put in your two cents?
>
> DR. SJOGREN: Yes. First I want to congratulate the sponsor and the FDA
> for the analyses of the data. It made it very easy for my review in
> terms of liver tests. Looking at the group of people with normal ALT
> and then the group with abnormal ALT, I can make some congruent
> decisions and opinions.
>
> I agree with my colleague that it doesn\'t alarm me. It is something
> that is not unusual for me in the clinic to see these elevations, the
> percentages that the drug produced, and I was very comforted by the
> fact that the abnormal ALTs, when they discontinued the drug, went
> back to normal in one or two days after discontinuation. So, if people
> had a normal ALT to begin with I think this situation is not alarming.
>
> For people with abnormal ALT and presumably chronic liver disease, I
> am also very glad to see that the sponsor took steps to study those
> kind of patients because that is where we have to use our intuition
> most of the time because other drugs have not studied patients with
> chronic liver disease. So, I am very satisfied to see at least an
> effort in that regard. They had a couple of patients where the
> elevations were more sizeable and worrisome probably to clinicians at
> the time, but also when they discontinued the drug the ALTs went back
> to normal or to baseline, or in some cases improved.
>
> We have no information on the basic kind of diagnosis of those
> patients but I guess, you know, that may or may not be relevant. The
> fact that some patients had elevated alk. phos., yes, it points to a
> cholestatic type of liver condition which in general in our field we
> call bland cholestasis because it usually doesn\'t make you think that
> the patient is going to develop liver failure, which is what worries
> us the most.
>
> I would think that if a patient develops jaundice, Hari, the
> clinicians are going to take that patient off the drug. They just
> won\'t continue on it, especially when there are other antibiotics
> that they could use. So, I am not at all alarmed by what I have seen
> in the data that was presented today.
>
> DR. LEGGETT: Are there any postmarketing studies or any more data that
> either of you would like to see?
>
> DR. CONJEEVARAM: I would think only if it is being used for prolonged
> periods, otherwise I don\'t think so. The other issue is the issue of
> isolated hyperbilirubinemia, which doesn\'t concern me at all actually
> because usually isolated hyperbilirubinemia doesn\'t always suggest
> underlying liver disease. Some of these patients can have Gilbert\'s
> when they are under stress where, in fact, the bilirubin does go up. I
> suspect it is most likely that rather than real liver disease.
>
> DR. LEGGETT: Thank you.
>
> DR. SJOGREN: I would make a plea to continue on\--especially the
> FDA\--to continue on this path for other antibiotics or these kind of
> drugs to study patients with chronic liver disease because this was
> very valuable.
>
> DR. LEGGETT: Dr. Epps, go ahead.
>
> DR. EPPS: Do you have any recommendations about alcohol consumption or
> other drugs, or anything?
>
> DR. SJOGREN: In hepatology we don\'t want anybody to drink, of course.
>
> \[Laughter\]
>
> DR. LEGGETT: Does anyone have any comments on the QTc issue as regards
> gemifloxacin? It was my take that it sort of puts it right smack in
> the middle of the other fluoroquinolones. Any dissent? Go ahead.
>
> DR. GLODE: I wonder if now is the time to ask about a side effect that
> wasn\'t reported?
>
> DR. LEGGETT: Perfect.
>
> DR. GLODE: I am just interested and I have to ask this question as a
> pediatrician and it goes to the beagle puppies and their arthropathy.
> I am sorry, it is probably here and I missed it but I want to know if
> the study design was such that the sponsor attempted to capture all
> encounters with the medical system for some period of time after
> starting the drug. I wonder if that was 30 days or 60 days. I
> specifically want to know if there was any tendon rupture or
> tendinitis that was reported that we didn\'t hear about.
>
> DR. LEGGETT: Dr. Patou?
>
> DR. PATOU: There were no tendon ruptures or tendinitis in the clinical
> trial program.
>
> DR. GLODE: And what was the ascertainment for that? How long?
>
> DR. PATOU: I am sorry, the studies followed subjects for 30 days post
> therapy.
>
> DR. GLODE: Great, and you captured all medical encounters?
>
> DR. PATOU: Yes.
>
> DR. GLODE: Thank you.
>
> DR. LEGGETT: Dr. Maxwell?
>
> DR. MAXWELL: Just in the same vein, I didn\'t notice anything
> mentioned about neurologic abnormalities so I wanted to know did you
> notice anything.
>
> DR. PATOU: No is the answer. Although I didn\'t dwell on it, on the
> slide that I showed with the overall incidence of adverse events some
> of the CNS related adverse events were actually lower on gemi. than
> the pooled comparator. But certainly in terms of seeing any specific
> issue neurologically, that has not been the case with the drug.
>
> DR. LEGGETT: Could we spend maybe five or ten minutes at most to think
> about things on our \"want/wish\" for further studies that have not
> been mentioned, or address specifically the blister pack issue, those
> sorts of things? Dr. Maxwell?
>
> DR. MAXWELL: While I agree that the rash may not be life-threatening,
> it is certainly morbidity inducing and it is an additional doctor
> visit, probably several additional doctor visits and unhappy patients.
> Depending on what the patient does or does not do, it is physically
> disfiguring to some extent. So, I would like to see more emphasis to
> look at exactly why women seem to be more at risk, and what is it
> about estrogen, if it is estrogen, that seems to increase the risk and
> certainly labeling, if it is approved, should address this really
> clearly for the clinicians to be able to deal with it.
>
> DR. LEGGETT: Dr. Bigby?
>
> DR. BIGBY: As someone who does not treat CAP, I certainly won\'t tell
> the infectious disease people here about efficacy but I am always very
> interested in numbers with regard to the evidence that something
> either is or not efficacious. I think that Dr. Alivisatos has pointed
> out something very important, that the justification for its being
> efficacious in the treatment of CAP is based on a single randomized,
> controlled trial of only 228 patients.
>
> DR. LEGGETT: As you can tell from the looks, we have been down this
> road before. I don\'t see anybody jumping on blister packs. Go ahead,
> jump to wherever you want to go.
>
> DR. BRADLEY: I was going back to the under 40 age cut-off. In talking
> with Dr. Powers when he had reviewed the previous gemi. submission,
> the 40 cut-off was apparently something that had to do with acute
> exacerbation of chronic bronchitis so it seemed a natural cut to look
> at adverse events as well. If, for some reason, it is actually
> premenopausal women that have this high rate of reactions, then I
> think if there is going to be some package labeling which looks at
> adverse events, as per Dr. Patou\'s last slide in his presentation,
> perhaps that sort of information would go in rather than just under
> 40.
>
> DR. LEGGETT: Anything else? Dr. Goldberger, I was just going to ask if
> you wanted us to say anything more.
>
> DR. GOLDBERGER: Well, we still have all the dermatologists here so
> perhaps I can get them to do some of our work for us. As you know, if
> this drug is going to be recommended and ultimately approved, we are
> going to have to write a label so we have had a lot of discussion. But
> what I would like, if you don\'t mind, is if each of the
> dermatologists could give a line or so on these two questions in terms
> of what should go in the label.
>
> The first is for the person who develops a rash while on therapy, what
> the label should say about what should be done. Second, for the
> patient who has developed a rash on therapy, what the label should say
> about future exposure to this drug and drugs of the class, keeping in
> mind that at the end of the day we are obliged to do the best we can
> to make such information available to both practitioners and patients
> in a way that is clear to them and, hopefully, something that they can
> actually use. So, I wonder if we could sort of get each of the
> dermatologists just to briefly address what we should put in the
> label.
>
> DR. LEGGETT: Who wants to volunteer?
>
> DR. BIGBY: I think that in the description of the drug for the patient
> you would have to say that there is a relatively high rate of a mild
> drug rash that occurs, and you can sort of give a range of percentages
> based on trial data and also indicate that the rate is much higher in
> premenopausal women.
>
> I think the management of this type of drug eruption really is just
> withdrawing the drug and symptomatic therapy. With regard to what
> should happen to them thereafter, I think that for those patients in
> whom it is clear that it was a drug rash, I don\'t think that they
> should get that specific drug and I don\'t think we are actually in a
> position to make a rational statement about the entire class.
>
> DR. EPPS: I agree with those statements. I don\'t have enough
> information to say whether or not another drug from the same class
> could or could not be given. As far as his statements, I think that is
> appropriate. I might also add what percent were considered severe
> since they were dermatologist evaluated. That could be helpful.
>
> DR. GOLDBERGER: You would again also say that in a person who
> developed a rash while on treatment the drug should be stopped?
>
> DR. EPPS: Yes.
>
> DR. GOLDBERGER: Is that what you meant, that this particular drug but
> not necessarily other drugs of the same class should not be given
> again?
>
> DR. EPPS: Right. I don\'t think I have enough information to say
> don\'t give one of the others.
>
> DR. ADKINSON: I would disagree. I think it would be a mistake to put
> anything in the package information about the management of these
> drugs because we don\'t have any evidence-based data to make a
> recommendation, and to put it there makes it become standard of care
> and really is an impediment I think rather than a help to most
> physicians. As far as I know, there is no precedent for that. You
> don\'t have advice on management of adverse cutaneous reactions to
> other drugs that are licensed so why bring it up as a particular issue
> here? The management is going to be the same based on medical
> considerations regardless what the source of the rash is. I would
> argue against putting any specific advice if we don\'t have any
> evidence to recommend a particular course of action.
>
> DR. GOLDBERGER: Your recommendation then would be to describe or not
> to describe what was observed?
>
> DR. ADKINSON: Describe the risk factors so far as they are known, but
> leave the management of the rash to the physician.
>
> DR. GOLDBERGER: And say nothing about what should be done. Okay.
>
> DR. LEGGETT: Finally, Dr. Drake?
>
> DR. DRAKE: I have to think about it for a moment. May I start with a
> question first? The reason I was thinking about it is I don\'t recall
> any other drugs where you dictate\--not dictate but make
> recommendations on management in this particular arena.
>
> DR. GOLDBERGER: We certainly provide information about certain
> situations with regards to toxicities in general that may warrant
> discontinuing a drug. How much have we done? We certainly haven\'t in
> the anti-infective world had to deal a whole lot with the issue of
> what to do about the issue of rash.
>
> The reason in part why I am asking is at the end of the day, in spite
> of some of the comments we have heard, it seems to me the majority of
> the evidence here suggests that rashes, at least in some patient
> groups who under normal circumstances would be likely to be exposed to
> this drug are fairly high relative to other drugs. I have heard some
> people say that there was no comparator in the 344 trial and,
> therefore, the fact that it is 32 percent\--you know, we really can\'t
> interpret that. But, of course, there was a comparator, another
> fluoroquinolone, and the rash rate was six or seven times as high.
>
> So, our concern is if there is likely to be a common adverse event and
> we are silent, what it does in essence it sort of leave the burden
> then on the physician and the patient to figure out what to do. Maybe,
> in fact, at the end of the day, as Dr. Adkinson suggested, that is the
> best thing to do. Since we are not sure what to say, we just don\'t
> say anything and they are left to figure out what they are supposed to
> do with this, what they are supposed to do in the future, although
> that is not an easy thing for the average practitioner and patient to
> have to deal with.
>
> So, I think at the minimum we ought to have this type of discussion
> and get some feeling from people who at least have either, (a) a lot
> of experience in the area and/or, (b) at least have heard a lot of the
> information presented here in detail, and get some sense of what they
> think about this. Then, if we decide that it is sounds like people
> think we shouldn\'t say a whole lot, then at least it was on the basis
> of a lot of discussion. But I think it would be a mistake to just
> assume, well, let\'s not say anything even though we have a concern
> that some large groups of people might end up having a rash.
>
> Interestingly enough, one of the reasons to say something might be
> that many people seem to believe that the rash actually is not of that
> much consequence, and if you were to make a statement in the label
> saying that, that might, in fact, be reassuring to some people.
>
> So, those are some of the issues that I think should at least be
> addressed in terms of deciding how to proceed.
>
> DR. DRAKE: If I can get away with not giving my opinion, I am happy to
> do so.
>
> DR. LEGGETT: No.
>
> DR. DRAKE: I guess I tend to believe that you should keep it as
> factual as possible. We have observed this rash in a disproportionate
> amount in women under age 40, etc. Maybe I am coming from my own
> personal bias because I chaired the guidelines of the Care Committee
> for the American Academy of Dermatology for so many years and what I
> have learned is that it is very hard to mass dictate what an
> individual doctor does with the individual patient and I don\'t think
> you should put the physician in the position of not being able to
> prescribe something they think might really help that individual
> patient without being there at the bedside and understanding what is
> going on with that patient.
>
> So, I lean towards just giving the provider of care, whether it is
> your pharmacist, your nurse of your physician, whoever is providing
> that care, the facts. These are the factual issues as we know them.
> Then, I think anything beyond that should be\--I would vote for
> putting in a statement that this level of rash perhaps is\--you might
> even want to mention that this has not been seen in other drugs in
> this category so that will preclude the use of them. But, at the same
> time, I would hate to have you preclude the use of this drug when it
> might have a very important role. So, I think I would just leave it
> factual and let the patient and the care provider make that decision
> as individuals.
>
> DR. LEGGETT: Dr. Wald?
>
> DR. WALD: I agree with you entirely. Would it be helpful also to add
> data about the number of patients in the original clinical trials who
> did continue to receive treatment despite the fact that they developed
> a rash? I don\'t know if you have a number that you could attach to
> those who continued to receive treatment who did okay, in what
> proportion of patients that was. And then give the cipro. data because
> although it may not represent what would occur with any other
> fluoroquinolone, at least it would be a piece of data that suggests
> that at least for one the cross-reaction rate was quite low.
>
> DR. LEGGETT: Dr. Reller?
>
> DR. RELLER: Actually, Dr. Wald has probably already brought up perhaps
> the most important point, other than the relative increased frequency,
> and that is the data for lack of cross-reaction because the very group
> of patients who have the highest likelihood of a rash are the group of
> patients who are most apt to see a quinolone, for example for a
> urinary tract infection.
>
> DR. LEGGETT: Go ahead, Mark.
>
> DR. GOLDBERGER: I think that was very helpful. That provided us I
> think with at least enough information to get some idea how we might
> want to proceed.
>
> DR. LEGGETT: Ken?
>
> DR. BROWN: Mark, I was going to comment that the precedence for such a
> teaching statement goes back to nitrogen mustard where it says be
> careful and wear gloves if you are giving this drug and then the
> boiler plate for all beta-lactams which says what to do in case of
> anaphylaxis. But I think trying to turn the package circular into a
> teaching instrument or a Merck Manual would be a terrible mistake.
>
> DR. LEGGETT: But it doesn\'t have to go as far as the sort of QTc
> worry.
>
> DR. BROWN: Well, I have drafted some wording but I don\'t think it is
> important for me to share that right now.
>
> DR. LEGGETT: You can give that to him later. That would be great.
> Since it is now four o\'clock, why don\'t we pass on to addressing
> these three questions? Everyone here at the table, except Dr. Brown,
> is a voting member. As we go around, what I would like to do is hear
> your vote and then a brief summary of your reasons for a yea or a nay,
> understanding that there are many of us and there is only an hour
> left. Judging by the way the day has gone, I just thought I would make
> that clear.
>
> Though I do not think we necessarily need a vote for the FDA\'s
> purposes on questions two and three, I would like to address both two
> and three at least in brief terms so they get a better idea of what to
> do, no matter which way they take our 50-50 vote. John, do you want to
> write a little longer or do you want to be the one to start?
>
> DR. BRADLEY: I would vote for acceptance of community-acquired
> pneumonia, except for the severe category where I think that the data
> are insufficient at this time to give that approval.
>
> DR. LEGGETT: That is a yes for community-acquired pneumonia for mild
> to moderate?
>
> DR. BRADLEY: Exactly. Yes for acute exacerbation of chronic
> bronchitis. In terms of adverse events, to have the package labeling
> somehow document the increased risk of rash so that it is something
> that is understandable by clinicians for the appropriate age group and
> sex.
>
> Then, in terms of the specifics for the subsets of pneumococci that
> are resistant to other antimicrobials, my preference would be to turn
> the clock back and just go by [in vitro]{.underline} susceptibilities
> but if what Dr. Powers says is true and the cow is out of the barn,
> then I think simplifying the approval for multi-drug resistant [Strep.
> pneumo.]{.underline} based on criteria that I think we will be working
> on would be appropriate because it clearly recognizes the fact that
> gemi. is active against penicillin-resistant, macrolide-resistant,
> cefuroxime-resistant strains.
>
> DR. LEGGETT: So, that is a yes for NDRSP?
>
> DR. BRADLEY: Yes.
>
> DR. LEGGETT: Dr. Maxwell?
>
> DR. MAXWELL: I vote yes for community-acquired pneumonia, mild to
> moderate disease certainly, and I echo what John has said about the
> multi-drug resistant bugs.
>
> On acute bacterial exacerbation of chronic bronchitis I vote no. I
> think that while the issue of the other two adverse events, the
> hepatic toxicity profile and the cardiac toxicity, is really not of
> great concern. For me the rash still is a concern and I believe that
> it should be evaluated more in depth.
>
> Having said that, I also believe that even though the rash may not be
> life-threatening in the few patients that we have seen, I think it
> will impact on the practicing physician. I know that I would be
> hesitant to do so because most of my patients, once they develop a
> rash, and this is a generalized rash, develop great concerns. So, I
> would like to see more studies on why women seem\--
>
> DR. LEGGETT: We will get to that later. Dr. Poretz?
>
> DR. PORETZ: For community-acquired pneumonia I vote yes and for
> exacerbation of chronic bronchitis I vote yes, and I will explain why
> for both of those.
>
> I think the data that we are recognizing more and more with the
> fluoroquinolones and seeing the resistance to [Strep.
> pneumoniae]{.underline} is a real thing. I think the people from
> Canada showed that in the past. It is happening in the United States;
> it is happening in other parts of the world, and I think there is
> probably no reason to believe that it is not going to continue. If we
> don\'t approve this drug we could wake up in a year or two and have a
> significant amount of resistance to fluoroquinolones to [Strep.
> pneumoniae]{.underline}. For that reason, I think it is very important
> to get this drug on the market and use it for those indications.
>
> I like the concept of multi-drug resistance to [Strep.
> pneumo.]{.underline} I like that as an indication. I think that sums
> it up very, very nicely.
>
> DR. LEGGETT: Could you address in community-acquired pneumonia where
> you would include severe?
>
> DR. PORETZ: I think it is going to declare itself, in all honesty,
> because those people, as I said before, who are severely ill are going
> to be in the hospital and are going to get parenteral medication. I am
> not against leaving off the word \"severe\" but I think it is going to
> declare itself so I don\'t feel very strongly about it. That is going
> to be a clinical decision.
>
> DR. LEGGETT: Dr. Goldberger, if we forget to make sure that you have
> enough information about the why\'s or the why not\'s, jump in,
> please. Dr. Patterson?
>
> DR. PATTERSON: Based on the fact that there is activity against
> fluoroquinolone-resistant pneumococci, although it may be small if you
> consider the area under the curve, I would vote yes for the mild and
> moderate community-acquired pneumonia indication and for the acute
> bacterial exacerbation of chronic bronchitis indication.
>
> I would favor the term multi-drug resistant as defined by three
> classes of clinically used drugs rather than pen-resistant or
> macrolide resistant.
>
> The other caveat is that I would specify that it is not for prolonged
> use, particularly not for repeat therapy that would constitute more
> than seven days, and to specify that there is a high risk of rash in
> women under 40 years of age and high risk of elevated ALTs in patients
> with preexistent liver disease.
>
> DR. LEGGETT: Dr. Reller?
>
> DR. RELLER: Yes for CAP owing to mild to moderate [Streptococcus
> pneumoniae]{.underline}. Though it may work for other things, I think
> the data are insufficient to have a broad claim for all of the other
> etiologies.
>
> The data are sufficiently sparse in my view for acute exacerbation of
> chronic bronchitis, especially with the broad number of pathogens
> listed. In any individual group there are insufficient numbers so I
> vote no for that. Not that I don\'t think that it may work given the
> largely empirical therapy, and I recognize what has been brought up
> earlier about perhaps the unfairness of going back but I think the
> data are sufficiently sparse that I would like to see additional
> studies on this issue, and including a placebo-controlled trial, not
> in holding someone to a standard that is imposed after the fact but
> based on the relative smallness of the studies done to date that
> don\'t give me confidence especially for the broad range of
> indications.
>
> In contrast to others, I want to take the opportunity to voice a no
> for specific resistance mechanisms. Clearly, in the past and perhaps
> the present and future there may be promotional benefit to a sponsor
> to have a specific resistance indication. There may be political plus
> to the agency for doing something about resistant organisms. But I
> think some of the things we have done in the past are an ill-advised
> precedent and, despite the past well-intentioned actions on this
> issue, I think it creates a deepening dilemma for us. The reason I say
> that is because what is true today can\'t be assumed for tomorrow.
>
> In support of what Dr. Bradley mentioned earlier, I fail to see why we
> can\'t have indications for susceptible organisms and, to the extent
> that a given compound is active, regardless of whether or not a
> particular organism is resistant to penicillin, macrolide,
> cephalosporin or whatever the case may be, it enables one to treat.
> Indeed, the promotion of a compound could be based on the data [in
> vitro]{.underline}, PK/PD, etc. that a compound is active without
> regard to mechanisms of resistance and then one has a basis for
> continued use of a drug based on susceptibility even though the ground
> may shift in terms of resistance, and even within class.
>
> I think there is pretty interesting information presented to us, both
> on PK/PD as well as investigator susceptibility, and this drug may
> well be an agent one would go to for quinolone failure for empirical
> therapy. We don\'t have the data to specifically make that claim but
> as long as one had an isolate that was persistently susceptible, or
> even in a given institution in biograms where the prevalent organisms
> were susceptible, one could still use the drug empirically, getting
> around the argument that in reality you don\'t usually have an
> organism in these cases.
>
> So, I think that actually it is an issue that the agency should
> revisit, and we should emphasize the persistent robustness of some
> agents versus other agents in the face of increasing resistance and
> not get into the specific claims that are not apt to hold up for
> tomorrow necessarily.
>
> DR. LEGGETT: Dr. O\'Fallon?
>
> DR. O\'FALLON: I want to preface my remarks by saying that I was
> really impressed by what the company did. I think that this was a good
> piece of work.
>
> My problem is that when I looked through the information and saw what
> was going on, I think you have proved or I think the data support the
> decision that this is not inferior to the things that are out there
> now. That doesn\'t mean that any of them is effective. That is what
> isn\'t there. But, frankly, that is about as good as it is going to
> get as far as I am concerned; they are not worse.
>
> But I do think, given the fact that there is substantial toxicity
> associated not only with this but with any other of the rest of
> them\--they all have their adverse event profiles, if they aren\'t
> doing any better than, say, multi-vitamin capsules three times a day,
> then we are exposing patients to a lot of toxicity for no real benefit
> and I think that needs to be sorted out by the business here, the FDA
> and company. I don\'t think it is right to change the rules on the
> company because they did what they were told.
>
> I am not happy with the results but I think that there is the problem
> of treating people with these agents and then we are feeding the
> resistance. Every time we treat these patients with something they
> really don\'t need or even if it is something they do need, we are
> feeding the problem of multi-drug resistance or beefing up the
> resistant organisms.
>
> DR. LEGGETT: Judith, yes or no?
>
> \[Laughter\]
>
> DR. O\'FALLON: No, no, you said and I am going to do it.
>
> DR. LEGGETT: I said briefly.
>
> DR. O\'FALLON: Well, see, my problem is I can vote yes to saying it is
> not inferior. I can\'t vote to whether it is any good, and I think
> that is the problem.
>
> \[Laughter\]
>
> And, I think there is just not enough information about whether it
> works in severe disease. There is not enough information about whether
> it works in resistant organisms. So, a placebo trial is needed but
> that is not your problem; that is the FDA\'s problem.
>
> I suggest though when you go to publish your results, I think it is
> going to be very important to use confidence intervals. These points
> estimates are ridiculous. We cannot tell what the real range of values
> is likely to be. I think it is very important to publish the
> confidence intervals when you go to tell the rest of the world what
> happened in this study.
>
> DR. LEGGETT: So, we will take that as a yes for non-inferiority.
>
> DR. O\'FALLON: Non-inferiority is a yes. That is as far as we go. No
> on everything else.
>
> DR. LEGGETT: Keith?
>
> DR. RODVOLD: In community-acquired pneumonia I agree. In the mild to
> moderate indication I would be willing to vote yes. I agree that the
> data for severe wasn\'t there and historically we actually kind of
> voted for resistant pathogens when you had a very clear picture where
> there were [in vitro]{.underline} models, [in vivo]{.underline}
> models, patients, ICU, bacteremic, everything convinced and lit up so
> that you were really convinced that bacteremia with resistance, you
> were going to cover it. So, I am a little hesitant on giving
> resistance because we don\'t have a severe indication here.
>
> With that, I would also like to make a comment about the aspect of the
> cefuroxime-resistant pathogens. I don\'t even see that that language
> is needed because that is not a drug you put up in CAP that much at
> this point and penicillin is predicting a resistance anyway. So, I
> think that doesn\'t need to be there, or second generation
> cephalosporins. I think the penicillin data tells you that.
>
> The multi-resistant labeling, if you do go to it, my comment would be
> I would not list five or six drugs. I think that is going to be way
> too confusing to people. I would probably try to stay with penicillin
> and macrolides only but, again, I am not voting for that.
>
> The second indication of acute bacterial bronchitis, actually I am
> going to vote yes for it but if I was going to hold back on that
> indication and wanted more postmarketing safety data, this would be
> the one I would tell you to hold and get more postmarketing safety
> data if you thought you needed to do that, and then release it later
> on as we got convinced. You have done that before with other drugs
> that you have approved. You have held an indication waiting for more
> data to come. But I would approve it based on the basis that you
> followed the trials that you were told to do and you did it. The data
> could be more though. I think you need more data there and I think it
> needs to be done better but I think you did what you needed to do.
>
> DR. LEGGETT: I vote yes for mild to moderate; yes for exacerbations of
> chronic bronchitis. I see no reason from the MIC and other data to
> believe that this fluoroquinolone, which is a lot like other
> fluoroquinolones, should not work for [H. flu.]{.underline} in CAP but
> I have a lot of worries about community-acquired pneumonia due to [E.
> coli]{.underline} and [Klebsiella pneumoniae]{.underline} and I would
> definitely not allow the name [Staphylococcus aureus]{.underline} to
> go on the label for community-acquired pneumonia with this drug. I
> might have a little worry about even putting aspiration in there
> because I am a little worried about the anaerobic coverage. The
> reasons for all of the things are basically what everybody has stated
> so far.
>
> Regarding the fluoroquinolone multi-drug resistance, I like the
> concept at least how we have talked about it in the last couple of
> meetings. While scientifically I definitely agree with Dr. Reller, I
> think the cat is out of the bag, as he sort of mentioned, and I think
> that while we can sort of try to stay pure scientifically, this is a
> world of political and capitalistic compromise so I think that, given
> that, eventually I would be convinced that this is a multi-drug
> resistant drug because it is exactly in that small population of folks
> that I might use this drug, that have seen a lot of fluoroquinolones,
> that I am worried at least from what we have seen so far. I do not,
> however, think the numbers for all the different subgroups are big
> enough yet. So, I would put a yes vote contingent on how many sick,
> bacteremic, drug resistant folks in the 287 come in. I would also make
> a caveat not for long use.
>
> DR. WALD: I would vote yes for acute community-acquired pneumonia and
> yes for the acute exacerbations of chronic bronchitis.
>
> I would agree with some of the others in terms of multi-drug
> resistance. I think we can feel confident recommending the drug for
> the empiric management of community-acquired pneumonias. Most or at
> least many of those are viral. There is a relatively small proportion
> that are bacterial. Of the bacterial, there is a very small proportion
> that are really multiply drug resistant and we never know which those
> are when we begin therapy. So, I think what we are saying is that this
> is a drug that can be used comfortably for community acquired
> infections of the lower respiratory tree that can be managed as
> outpatients. That is sort of where I would draw the line.
>
> I don\'t know if this committee can exert any pressure on any AHRQ,
> NIH or CDC to fund the study that we are talking about, which is a
> placebo-controlled study, because it would be very brave for any of
> the drug companies to undertake that and I think really, in the end,
> if it turns out that most of the drugs we use are no better than
> placebo that would really be a tremendous advantage to the insurers
> and to the government. So, I think it really should be a
> government-sponsored study.
>
> DR. LEGGETT: Dr. Cross?
>
> DR. CROSS: I would vote yes for community-acquired pneumonia. I agree
> that there hasn\'t been a lot of data on severe pneumonia. There
> hasn\'t been anything on [Staph. aureus]{.underline} and I would also
> agree with Jim that we have no basis for actually including that.
>
> I think it does fit a real niche in terms of the increase in quinolone
> resistance. I think each of our locales ought to have some information
> on the degree of resistance. So, I think the idea of having an
> approval for multi-drug resistance is instructive if you know what is
> going on in your community. It gives a certain reassurance.
>
> In terms of the exacerbation of chronic bronchitis, I have mixed
> feelings about this. Seeing the long list of drugs that are already
> approved, this certainly doesn\'t appear to be any better or any
> worse, although I do have some doubts as to whether or not it is
> efficacious. But the thing I am concerned about is if any patients, by
> getting this for this indication, do have a rash and in practice once
> a patient does have a rash\--most physicians haven\'t had the benefit
> of the excellent dermatologic consultation we have had here and the
> reassurance and I think what will happen is that a patient will not
> get quinolones in the future. That is my main concern. Having said
> that, I don\'t think we can hold them to a higher standard although I
> wouldn\'t use it myself.
>
> DR. LEGGETT: Dr. Proschan?
>
> DR. PROSCHAN: I am teetering on the edge with respect to
> community-acquired pneumonia because I still believe that, you know,
> on page 69 of the blue book, it is no means a slam dunk. That
> confidence interval, by the way, for study 12 if you look at the
> intention-to-treat analysis, is actually minus 12.-something, not
> minus 10.-something. I tend to believe the intention-to-treat analysis
> more than per protocol anyway. So, it looks to me like the supportive
> evidence shows that it is better than at least one currently used
> drug. So, I guess that would tip me ever so slightly for voting yes.
>
> For chronic bronchitis, I agree with the FDA that multiplicity issues
> were definitely an issue here. I think when you are writing the
> results you have to be careful about some of those multiplicity
> issues. In particular, when I look, for example, at page 64 of the red
> book and you see the results at all these different visits, I think it
> can be explained by chance. But overall I felt like the evidence was
> pretty conclusive that it is at least as good so I would vote yes on
> that as well.
>
> DR. LEGGETT: Mike, could you give us a yea/no on severe
> community-acquired pneumonia? You can also abstain.
>
> DR. PROSCHAN: Yes, I think I probably should abstain because I don\'t
> know that much about the severity.
>
> DR. LEGGETT: Dr. Glode?
>
> DR. GLODE: I would vote yes for mild and moderate community-acquired
> pneumonia, again understanding this was designed as a non-inferiority
> trial. I think the data support non-inferiority but I accept your
> comments certainly.
>
> I would just have the caveat that I agree with 19 strains of [Staph.
> aureus]{.underline}, and who knows whether that was even the causative
> organism. That data is inadequate for staph. or [M.
> catarrhalis]{.underline}, possibly even for [Legionella]{.underline}
> with 14. So, the numbers are small when you do the subsets.
>
> I would also vote yes in terms of non-inferiority for acute bacterial
> exacerbation of chronic bronchitis. But I am persuaded by Dr.
> Reller\'s comments and his reluctance to allow a specific claim for
> multiply resistant [Strep. pneumo.]{.underline}
>
> DR. LEGGETT: Dr. Drake
>
> DR. DRAKE: Well, I feel completely inadequate. I learned a long time
> ago you don\'t get in the way of the ID guys or the pediatricians when
> you are a dermatologist.
>
> \[Laughter\]
>
> But I must tell you I learned a ton here today and I did read all the
> stuff you sent me, which is unusual. I read it better than I read the
> derm. stuff because I actually felt I had to read it because I didn\'t
> know what I was doing.
>
> I am going to vote yes on the community-acquired pneumonia but I would
> like to support what Mary said and what you said and what others
> around the table said. I think it is mild and moderate. I am not
> convinced it is adequate for severe. It may be; I just don\'t think we
> know.
>
> I am going to vote yes on the chronic bronchitis, and that is based
> mainly upon what I have heard here at the table, and I hesitate to
> cast that vote. It might be better to abstain because I don\'t think I
> have the depth of knowledge to comment on that.
>
> DR. LEGGETT: Dr. Bigby?
>
> DR. BIGBY: I guess my comments would be that I think that the drug
> will have a relatively high rate of producing drug rashes. I think
> these are predominantly of a minor type and that shouldn\'t preclude
> it from being marketed. I think it should contain some warning
> especially about high rates in premenopausal women, and I don\'t think
> I am going to vote because I don\'t treat patients with
> community-acquired pneumonia or with chronic bronchitis.
>
> DR. LEGGETT: Thank you. Dr. Epps?
>
> DR. EPPS: From what has been heard and what I have read, I guess I
> would be in support of mild to moderate community-acquired pneumonia,
> as well as the bronchitis indication. Certainly, I think clinicians
> need options. I would support many of the comments regarding facts
> regarding the 344 study, the brevity of the course as well.
>
> DR. LEGGETT: Dr. Adkinson?
>
> DR. ADKINSON: I would vote yes on both indications, largely deferring
> to what I think is a consensus of my infectious disease colleagues and
> I certainly accede to their views on the issue of multiple resistance,
> about which I know very little.
>
> My yes vote certainly includes my own assessment that I don\'t think
> this rash problem is sufficient to deny approval for a drug that
> otherwise has a clinical niche. I think that is especially true for
> the bronchitis indication where the expected rash rate will be very
> low.
>
> DR. LEGGETT: Thank you. Dr. Hilton?
>
> DR. HILTON: I feel that the high potency of the gemi. drug works
> strongly in its favor for me, and I feel that if I were the patient
> being treated getting over my community-acquired pneumonia would be
> much more important to me than experiencing a bout of rash. So, I vote
> in favor of the CAP but with the restriction on stage V of the Fine
> criteria.
>
> On the chronic bronchitis, I feel that the youngest patient studied
> was 34 years of age and I feel that there is essentially no data in
> young people and it should not be considered for approval for young
> people. The average age was 60 and higher for the patients in those
> studies.
>
> I also feel that even though the standards may have shifted and the
> drug company wasn\'t previously requested to do placebo-controlled
> trials, given what we know now, they are very important. So, I vote no
> on the chronic bronchitis.
>
> DR. LEGGETT: Thank you. Dr. Conjeevaram?
>
> DR. CONJEEVARAM: I would vote yes for community-acquired pneumonia,
> mild to moderate. I would vote yes for the acute exacerbation, but I
> would favor giving it as a second line, especially if they fail other
> regimens.
>
> Again, my concern is that this is a recurring disease and, to me, the
> risk of rash is still concerning. I would favor multi-drug resistance
> labeling. I would also, as some of my colleagues have already
> mentioned, really discuss on the label about the predictors of rash,
> who is at actual increased risk. I think that is very important for
> the physicians who are treating with this drug to know. I would also
> strongly emphasize the long-term use, that this is really for five to
> seven days.
>
> DR. LEGGETT: Dr. Sjogren?
>
> DR. SJOGREN: Yes, I am guided here by the comments from my colleagues,
> infectious disease colleagues although, you know, I have heard both
> sides, some pro and some against, and also based on my own opinions as
> a clinician at a hospital.
>
> I think I would like to vote yes for the community-acquired pneumonia
> and for the acute bacterial exacerbations of chronic bronchitis, mild
> to moderate. I think for the severe cases there is little data.
>
> About the drug resistance, I do feel that there is so much drug
> resistance nowadays that the drug has shown, at least in microbiology,
> to be quite good about it. I don\'t know why we have so much
> resistance to approve that label. For I think for the [Staph.
> aureus]{.underline} I am concerned that there was not enough data but
> for the rest of the organisms I thought it was adequate so I would
> vote yes for that as well.
>
> DR. LEGGETT: If I could make one sort of last point for the FDA, there
> was mention made, regarding this multi-drug resistance status, of
> substituting one drug to boost something else. But what we don\'t know
> from the data that was presented is how many of these bugs were
> actually the same bugs so we are seeing the same 12 all over again. If
> it is really 12 plus 10 plus 6 and we are coming up towards 50, that
> is one thing. But if it is the same 15, just in different ways, then I
> think our numbers are not as big as we would like.
>
> Instead of going to question two, since it is now 4:35, can we jump to
> question three? Let\'s just assume that our answer to 1(a) and 1(b) is
> no, what kind of things would people around the table think necessary
> to be done? One of the things that I would sort of throw out is that
> I, for sure, think that we need to finish 287 and increase the number
> of pneumococcal isolates and resistant data. I will shut up and let
> somebody else throw in their two cents. Barth, you were another
> hold-out.
>
> DR. RELLER: Well, I think additional data for 3(b) is a
> placebo-controlled trial, funded by whoever\'s arm can be twisted to
> do it for its potential benefits to the taxpayers, third party payers,
> consortia thereof, brave pharmaceutical philanthropist, anybody who is
> willing to do it, Bill Gates.
>
> DR. LEGGETT: There was mention made already of postmarketing studies
> and a study looking at photographing mucus membranes. We already
> talked about better data for AECB. Someone did mention, in terms of
> resistance gemi., rash, gemi. again, if more things can be done in
> that sort of subset. Then I think, of course, if the answer is no or
> approvable but, I think we would all like to see more cases of severe
> bacteremic community-acquired pneumonia in terms of that. John?
>
> DR. BRADLEY: In some of the earlier derm. presentations the risks of
> rash with the drug and the risk of Stevens-Johnson/TEN were listed,
> and the Stevens-Johnson is always less frequent than the regular
> exanthem. I am wondering if there could be any systematic way
> postmarketing, if we could track the incidence of Stevens-Johnson
> syndrome to see if it throws into the category of sulfa or phenytoin
> or whether it is something very, very small. I don\'t know if that is
> possible but that would be very helpful and would fold into this rash
> AE story.
>
> DR. LEGGETT: Dr. Reller?
>
> DR. RELLER: Another thought occurred to me. The 344 study has been
> lauded by many. I wonder if it would be possible, since our
> dermatology consultants were of divided opinion on the importance of
> this rash, as well as the probability of it happening again and, if I
> recall correctly, some diversity of viewpoint about whether a reaction
> was for life or for a period of months, is there any possibility of
> going back to the participants in the 344 study who had a rash to
> gemifloxacin and giving them a five-day exposure to gemifloxacin?
> Because if it is 100 percent, that is one thing. If it is five
> percent, like it was with ciprofloxacin, or ten percent that would be
> very useful information. Given the general consensus that no matter
> whether you should or shouldn\'t ever give the drug again and all of
> the other things for which I think there was consensus that it was not
> a serious reaction, certainly not a life-threatening one, nor was the
> exanthem, Dr. Bigby emphasized, necessarily a prelude to some more
> serious consequence.
>
> DR. LEGGETT: Dr. Cross?
>
> DR. CROSS: Barth, I like that idea. I think it is worth doing. I would
> just like to reemphasize the point made by Dr. Maxwell in terms of
> looking at the incidence of rash in minorities, especially
> African-American. I think there were only two subjects in the large
> study.
>
> DR. LEGGETT: Sorry, I forgot to include that. Yes?
>
> DR. ADKINSON: I was going to say I found it very intriguing and would
> endorse the proposal of the sponsor to try to manage the rash problem
> by packaging the drug in five unit doses so that extended courses of
> therapy cannot easily be given.
>
> DR. LEGGETT: Dr. Rodvold?
>
> DR. RODVOLD: I agree with the aspect of packaging but the problem I
> have with that is no one was proven to us that it works. I constantly
> hear about Z-packs being re-prescribed and ABC packs being redone, but
> I think I would also like to see data that proves this works because
> it is constantly coming up\--we are going to package it this way and
> this is going to be the save-all of this problem. So, I think that is
> something that really needs some science put behind it. I don\'t have
> a solution how to do it but I think it does tell us something with or
> not that is a really legitimate reason to put on the table.
>
> DR. LEGGETT: In that sense, could we have question number two flashed
> up? Keith, you already talked about information for everybody,
> especially the front office and the folks answering the phone, and you
> talked about the Z-pack. In my notes I didn\'t really notice anything
> except how long the treatment should be and what to do about repeated
> courses and how to handle the rash, that sort of thing, in terms of
> the packaging. Do you want to address that again?
>
> DR. RODVOLD: One of the other things that comes up that I would think
> could happen is that if, say, you developed a rash but you still
> wanted to use a quinolone, if you switched to another quinolone do you
> go into a problem? It goes away? I think there are going to be
> scenarios where people get into that. They are going to be up against
> the wall and they are going to switch out of this quinolone and go to
> the next one, and that would be very valuable information, to know
> whether or not you can or cannot do that. It is not going to happen a
> lot but it is going to happen.
>
> DR. LEGGETT: Working in a managed healthcare plan, I can tell you that
> we don\'t get the chance to choose any fluoroquinolone we want. So,
> that is going to come up again too. Go ahead, Hari.
>
> DR. CONJEEVARAM: I suspect that if this drug is used, especially for
> community-acquired pneumonia, and if it works for that particular
> patient and even if they do develop rash it might be used again for
> that patient. So, I think I would favor for the drug company to really
> keep track of that data. You are getting your rechallenge data,
> especially with the rash, in that setting. It will be very important.
> At the end of the day you can actually show that the drug is
> beneficial but the risk of rash is not that high or the same.
>
> DR. LEGGETT: Thank you. Any other comments before I ask Dr. Brown to
> read his statement? Go ahead, Ellen.
>
> DR. WALD: I would like to ask the dermatologists. A rule of thumb that
> I have used for alleged penicillin allergies when I am treating
> someone with amoxicillin or ampicillin is that if the rash doesn\'t
> itch and it is non-urticarial I use that as an indication to keep
> going, or if I get that history I feel comfortable repeating or using
> it again. Is that sound or crazy?
>
> DR. LEGGETT: Or does it just sound crazy?
>
> DR. BIGBY: Do you want a vote? I mean, I would say that there are lots
> of drug eruptions that don\'t itch and aren\'t urticarial and, under
> those circumstances, if you continue to give it the patient may or may
> not get worse, and if you let them clear and gave it again the rash
> would come back, not necessarily that it is a terrible thing. I mean,
> there are lots of drug rashes that are due to a drug that don\'t itch
> and are not urticarial.
>
> DR. LEGGETT: Mark?
>
> DR. GOLDBERGER: Just to ask again, similar to what I did before, about
> another issue, what kinds of statements\--some people have touched
> upon this already\--would you like to see in the label, ranging from
> very little to a lot, about duration of therapy and avoidance of
> re-prescribing, and even any comment about multiple courses over time?
> Some people have touched upon a few of these issues but it is another
> thing that is important in deciding what kind of information we ought
> to put in labeling. In other words, the duration and there has been a
> proposal for a five- or seven-day pack. Linked to that is how strong a
> statement about really discouraging re-prescribing and, finally, does
> there need to be any comment about multiple courses over time?
>
> DR. LEGGETT: I would think in the absence of data it would be better
> to keep our mouth shut. Is it possible to start off a label that sort
> of mentions the risk while these other studies might be pursued, and
> then go back and modify the label specifically at that point? I don\'t
> know if that is even plausible but that might be one approach to sort
> of not say too much until we at least have some data and then
> readdress it, just as the QTc wasn\'t put on the packages until we had
> some data, or the drug interactions with the macrolides and those
> sorts of things.
>
> DR. RODVOLD: I think when we did some of the other agents, linezolid
> and moxifloxacin, when we did that we really told people not to exceed
> the dose and do not exceed the duration. That was pretty much where we
> stopped at that point. But here you may want to say that longer
> durations of therapy were associated with a little bit higher risk in
> selected types of patients. You put it in the inserts because I was
> the one that made these comments during those times and Jim jumped in
> with me at least on one situation. We made them at that time because
> we only knew this amount of information at this point. If you can put
> it in multiple places in the insert so, hopefully, it gets read at
> least once, that is the best you can do.
>
> I would agree with Jim too that eventually you may end up modifying
> that. That may be a goal that the sponsor and the agency may want to
> work to be able to change this with time.
>
> DR. LEGGETT: I would also remind the sponsor that what they heard
> today about physicians being very reluctant to re-prescribe a
> medication to which there was a rash might be, in itself, enough of an
> incentive to try to sort out this question if they wanted the drug
> sold the second time around.
>
> The final point in terms of packaging things, linezolid was approved
> for 14 days but we now have people using it for months at a time and
> developing peripheral neuropathy. So, anything is possible. Dr.
> O\'Fallon?
>
> DR. O\'FALLON: With respect to the duration of treatment, there is a
> lot of evidence here. You provided us with a good bit of information
> about how the rash rate went up anywhere from five days to 15 days of
> treatment. I think you can simply explain that the rate, you know,
> tripled over that period of time. It is a statement of fact based on a
> very good study and I think you should put it into the label.
>
> DR. RODVOLD: In designing and implementing a clinical trial we
> typically take many safeguards to minimize the bias and estimate
> treatment effect.
>
> DR. O\'FALLON: But the warning should be to let the physicians know
> that this rate is going to go up rather substantially over time.
>
> DR. LEGGETT: Yes, Dr. Glode?
>
> DR. GLODE: I would just think as opposed to trying to capture in a
> Phase IV postmarketing study retreatment episodes and hope you got
> them, I would think if the dermatologic opinion is split or somewhat
> divided that maybe it would be worthwhile, in a sort of sequential
> phase, to take the patients from the study and take ten women who had
> rash, who had mild to moderate rash, and rechallenge those ten. If ten
> out of ten get a rash, at least you know. If it zero out of ten, you
> could proceed sequentially. You don\'t have to offer it to hundreds of
> people initially.
>
> DR. LEGGETT: Good thought. Unless you can think of anything else for
> us, Mark, I think we are done. Thank you, everyone, for coming and for
> sitting through a long day. For the committee, I believe tomorrow we
> start at 9:00 a.m.
>
> \[Whereupon, at 4:50 p.m., the proceedings were recessed to be resumed
> on Wednesday, March 5, 2003, at 9:00 a.m.\]
>
> \- - -