FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

8:00 a.m.

Wednesday, January 8, 2003

Grand Ballroom

Marriott Washingtonian Center

9751 Washingtonian Boulevard

Gaithersburg, Maryland

ATTENDEES

COMMITTEE MEMBERS:

JAMES E. LEGGETT, JR., M.D., Chairman

Associate Professor of Medicine

Oregon Health Sciences University

5050 NE Hoyt, Suite 540

Portland, Oregon 97213

TARA TURNER, PHARM.D., Executive Secretary

Advisors and Consultants Staff, HFD-21

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, Maryland 20857

DAVID M. BELL, M.D.

Assistant to the Director for Antimicrobial Resistance

National Center for Infectious Diseases

Centers for Disease Control and Prevention

1600 Clifton Road, N.E. (C-12)

Atlanta, Georgia 30333

ALAN S. CROSS, M.D.

Professor of Medicine

Division of Infectious Diseases

Department of Medicine and

Greenebaum Cancer Center

University of Maryland

22 South Greene Street

Baltimore, Maryland 21201

CELIA J. MAXWELL, M.D.

Assistant Vice President for Health Affairs

Office of the Vice President for Health Affairs

Howard University

2041 Georgia Avenue, N.W., Suite 6000

Washington, D.C. 20060

JAN E. PATTERSON, M.D.

Professor of Medicine and Pathology

University of Texas Health Science Center

at San Antonio

Division of Infectious Diseases

Mail Code 7881

7703 Floyd Curl Drive

San Antonio, Texas 78229

ATTENDEES (Continued)

COMMITTEE MEMBERS: (Continued)

ELLEN R. WALD, M.D.

Chief, Allergy, Immunology and Infectious Diseases

Children\'s Hospital of Pittsburgh

3705 Fifth Avenue at DeSoto Street

Pittsburgh, Pennsylvania 15213

ACTING INDUSTRY REPRESENTATIVE (non-voting):

KENNETH R. BROWN, M.D.

Independent Consultant on Vaccines,

Antibiotics, and Tropical Medicine

8111 Winston Road

Philadelphia, Pennsylvania 19118

CONSULTANTS (voting):

JANET D. ELASHOFF, PH.D.

Director, Division of Biostatistics

Cedars-Sinai Medical Center

8700 Beverly Boulevard

Los Angeles, California 90048

WILLIAM M. LEE, M.D.

Meredith Mosle Distinguished Professor

in Liver Disease

Division of Digestive and Liver Diseases

Department of Internal Medicine

University of Texas Southwestern Medical School

5323 Harry Hines Boulevard

Dallas, Texas 75390

JUDITH R. O\'FALLON, PH.D.

Cancer Center Statistics, Kahler 1A

Mayo Clinic

200 First Street, S.W.

Rochester, Minnesota 55905

DONALD M. PORETZ, M.D.

Infectious Diseases Physicians, Inc.

3289 Woodburn Road, #200

Annandale, Virginia 22003

ATTENDEES (Continued)

CONSULTANTS (voting): (Continued)

L. BARTH RELLER, M.D.

Professor of Medicine (Infectious Diseases)

Director of Clinical Microbiology

Duke University Medical Center

Box 3938

Durham, North Carolina 27710

MARK E. RUPP, M.D.

Associate Professor, Infectious Diseases

Medical Director, Department of Healthcare Epidemiology

984031 Nebraska Medical Center

Omaha, Nebraska 68198

HHS FEDERAL EMPLOYEE (non-voting):

DAVID E. KLEINER, M.D., PH.D.

Director, Clinical Operations

Chief, Post-mortem Section

Laboratory of Pathology, NCI

Building 10, Room 2N212, MSC 1516

Bethesda, Maryland 20892

FOOD AND DRUG ADMINISTRATION STAFF:

JOHN ALEXANDER, M.D., M.P.H.

WILEY CHAMBERS, M.D.

CHARLES COOPER, M.D.

MARK GOLDBERGER, M.D.

TERRY PETERS, D.V.M.

JOHN POWERS, M.D.

C. GEORGE ROCHESTER, PH.D.

JANICE SORETH, M.D.

ATTENDEES (Continued)

AVENTIS PHARMACEUTICALS, INC. REPRESENTATIVES:

VIJAY BHARGAVA, PH.D.

STEVE CAFFE, M.D.

GRAHAM HARDING, M.D.

PAUL IANNINI, M.D.

STEPHEN JENKINS, PH.D.

PAUL LAGARENNE, M.D.

BRUNO LEROY, M.D.

JIM LEWIS, M.D.

EMANUEL RUBIN, M.D.

CRAIG PRATT, M.D.

ALSO PRESENT:

ITZHAK BROOK, M.D.

C O N T E N T S

NDA 21-144, Ketek (telithromycin),

Aventis Pharmaceuticals, Inc.,

Proposed for Treatment of Community-Acquired Pneumonia,

Acute Exacerbation of Chronic Bronchitis,

and Acute Maxillary Sinusitis

\* \* \*

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

By Dr. Tara Turner 9

HISTORICAL BACKGROUND OF KETEK NDA

By Dr. Janice Soreth 12

CLINICAL SIGNIFICANCE OF MACROLIDE RESISTANCE

By Dr. John Powers 26

SPONSOR PRESENTATION:

Introduction

By Dr. Steve Caffe 55

Medical Need

By Dr. Paul Iannini 58

Microbiology

By Dr. Stephen Jenkins 64

Clinical Efficacy

By Dr. Bruno Leroy 73

Human Pharmacology

By Dr. Vijay Bhargava 85

Clinical Safety

By Dr. Paul Lagarenne 95

Conclusions

By Dr. Paul Iannini 121

C O N T E N T S (Continued)

AGENDA ITEM PAGE

FDA PRESENTATION:

Efficacy of Telithromycin

By Dr. John Alexander 150

Safety Summary - Phase III

By Dr. Charles Cooper 159

Study 3014 - Safety

By Dr. C. George Rochester 168

Hepatic Pathology Discussion

By Dr. David Kleiner 182

Post-Marketing Information

By Dr. Charles Cooper 190

OPEN PUBLIC HEARING 234

COMMITTEE DISCUSSION AND VOTE 244

P R O C E E D I N G S

(8:00 a.m.)

DR. LEGGETT: Good morning. Welcome to this Anti-Infective Drugs Advisory
Committee meeting regarding telithromycin, presented by Aventis
Pharmaceuticals.

I think we will begin with introductions, and we\'ll go around the
table, beginning with Ken Brown.

DR. BROWN: Ken Brown. I\'m representing industry as a whole I guess. I
haven\'t heard from anybody telling me any more detail than that.

DR. PORETZ: I\'m Donald Poretz, an infectious disease practitioner in
Fairfax, Virginia.

DR. ELASHOFF: Janet Elashoff, biostatistics, Cedars-Sinai and UCLA.

DR. RUPP: Good morning. I\'m Mark Rupp, adult infectious diseases at the
University of Nebraska.

DR. WALD: I\'m Ellen Wald from the Children\'s Hospital of Pittsburgh,
infectious diseases.

DR. BELL: David Bell, National Center for Infectious Diseases, CDC in
Atlanta.

DR. MAXWELL: Good morning. Celia Maxwell, infectious diseases, Howard
University Hospital.

DR. RELLER: Barth Reller, infectious diseases, and clinical microbiology
Duke University Medical Center.

DR. O\'FALLON: Judith O\'Fallon, Cancer Center Statistics, Mayo Clinic.

DR. TURNER: Tara Turner, Executive Secretary for the committee.

DR. LEGGETT: Jim Leggett, infectious diseases, Oregon Health and
Sciences University.

DR. PATTERSON: Jan Patterson, medicine, infectious diseases, University
of Texas, San Antonio.

DR. LEE: Will Lee, hepatology, UT Southwestern in Dallas.

DR. KLEINER: Dave Kleiner, laboratory pathology, National Cancer
Institute.

DR. ROCHESTER: George Rochester, Office of Biostatistics.

DR. COOPER: Chuck Cooper, medical officer, Division of Anti-Infectives.

DR. ALEXANDER: John Alexander, medical team leader, Division of
Anti-Infectives.

DR. SORETH: Good morning. I\'m Janice Soreth, the Director of the
Division of Anti-Infectives at FDA.

DR. LEGGETT: Thank you.

Tara, would you please help us with the conflict of interest?

DR. TURNER: Thank you.

The following announcement addresses the issue of conflict of interest
with regard to this meeting and is made a part of the record to preclude
even the appearance of such at this meeting.

Based on 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 at this meeting with the following exceptions.

Drs. Steven Ebert and John Bradley have been recused from participating
in today\'s discussions and vote concerning Ketek.

In addition, in accordance with 18 U.S.C. 208(b)(3), the following
individuals have been granted waivers permitting their participation in
today\'s meeting.

Dr. Celia Maxwell has been granted a waiver for her consulting for a
competitor on an unrelated matter. She receives less than \$10,001 a
year.

Dr. Ellen Wald has been granted a waiver for her consulting for a
competitor on an unrelated matter ‑‑ she receives less than \$10,001 a
year ‑‑ and for her and her employer\'s participation in a trial funded
by a competitor involving a competing product on an unrelated matter.
This research is funded at less than \$100,000 a year.

Dr. William Lee has been granted a waiver for his role as a consultant
for a competitor on an unrelated matter. He receives fees of less than
\$10,001 for this activity.

Dr. Jan Patterson has been granted a waiver for her consulting for two
competitors on unrelated matters ‑‑ she receives less than \$10,001 a
year from each firm ‑‑ and for her spouse\'s consulting for a competitor
on an unrelated matter. He receives fees of less than \$10,001 for this
activity.

Dr. Donald Poretz has been granted a waiver under 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.

Dr. Mark Rupp has been granted a waiver under 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 less
than \$5,001.

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 on an issue unrelated to that coming before the
committee for consideration.

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 firms whose products they may wish to comment upon.

Thank you.

DR. LEGGETT: Thank you.

Let\'s begin today\'s proceedings with the historical background of
Ketek. Dr. Soreth.

DR. SORETH: Good morning. I\'d like to give a bit of an overview of the
new drug application brought by Aventis for telithromycin, or Ketek, as
this committee heard almost two years ago, efficacy and safety data in
the first cycle of that review, a little bit more about the regulatory
history and dates that surround that, an overview of the efficacy and
safety data presented in April of 2001, a few months later the FDA
action letter that followed asking for additional studies with regard to
safety and efficacy, and then a brief description of those studies.

The new drug application for telithromycin was submitted by Aventis
first in February of 2000, and this Anti-Infective Advisory Committee
met in April of that year to discuss the safety and efficacy data.

A few months later, the agency issued an approvable letter in June of
2001, outlining a request for additional studies to understand better
the risk-benefit profile of the drug.

And Aventis submitted to the agency an amendment in July of 2002 with
the data from those new studies.

In the meantime, the drug application had been approved in a number of
European countries and Central and Latin American countries, and
post-marketing exposure was also submitted to the agency.

Five-and-a-half months later, we\'re up to now.

In the initial application four indications were proposed:
community-acquired pneumonia, acute exacerbations of chronic bronchitis,
acute sinusitis, and tonsillopharyngitis. And for the first three
infections mentioned, pneumonia, bronchitis, and sinusitis, the company
included proposed labeling that would include efficacy against
penicillin- and erythromycin-resistant strains of Strep. pneumoniae.

In April of 2001, the clinical database in phase III at that time was
comprised of about 13 trials with at least two controlled trials in each
of the four indications requested and some uncontrolled trials in a few
indications as well.

By way of sweeping review, because you\'re going to see this data and a
lot more as the day unfolds, in CAP and bronchitis and sinusitis ‑‑ and
I\'ll stop for a moment so that you can look at the slide more carefully
‑‑ efficacy rates tended to run in the 80s and 90s for telithromycin and
comparator agents, and equivalence or noninferiority, by and large, was
demonstrated for pneumonia, for acute exacerbation of chronic
bronchitis, for sinusitis.

In April of 2001, we discussed briefly the results for a study in
tonsillopharyngitis and at that point spoke to the primary efficacy
parameter in this indication, being that of microbiologic eradication.
There was a comparative study that compared telithromycin to penicillin
with a success rate of 84 percent for teli and 89 percent for
penicillin. And our guidance on this issue I think is fairly clear, that
we look for at least a success rate of 85 percent for a first line
claim, and further discussion on this indication was then tabled.

With regard to the body of evidence in April of 2001 for drug-resistant
Strep. pneumoniae, we looked at the following data. Overall over 170
cases of Strep. pneumoniae of any susceptibility, with a 96 percent
success rate. Necessarily and usually the body of data for PRSP is
smaller, 17 cases with a success rate in the 80s, and then a further
subset of patients who were bacteremic with penicillin-resistant Strep.
pneumoniae in the setting of community-acquired pneumonia, a total of 6
cases with a success rate of 67 percent.

Similarly for patients with pneumonia, due to erythromycin-resistant
Strep. pneumoniae, these are not the exactly the same 17 cases. There\'s
about a 50 percent overlap, but success rates were the same, in the 80s,
in the 60s with a smaller experience for those who have concurrent
bacteremia.

In summary, the agency analyses were really consistent with those of
Aventis for pneumonia, bronchitis, and sinusitis. The discussion that
ensued around the data took into account not only efficacy, but also the
other side of the equation when we\'re considering drug approval, and
that is safety.

Our segue to safety then is just that, and at the time of April 2001,
the database for Ketek included in phase III a little bit over 3,000
patients, about 2,000 in the setting of controlled trials for Ketek,
another 1,200 patients in uncontrolled trials, together with various
comparators and 1,700 patients\' exposure.

There were no deaths in phase I trials. There were a total of 11 deaths
then in phase III, primarily in community-acquired pneumonia, primarily
in patients in higher risk categories, Fine category III or higher. None
of the deaths were directly attributed to drug.

In 6 of the 7 telithromycin deaths, there was a cardiovascular cause
listed as one of the causes of death, again none directly attributed to
drug, compared to 0 out of 4 comparator agents who had a cardiovascular
cause listed.

And with regard to serious adverse events in phase III, we saw the
following. Equal numbers roughly in both arms overall, and small numbers
of each of these cells for allergic reaction, liver damage,
gastroenteritis, et cetera.

With regard to overall adverse events, the common adverse events are
referable to the GI system, diarrhea, nausea, vomiting, whether one
looks at telithromycin or the comparators.

Although uncommon, I just want to draw your attention to the final line
of blurred vision, uncommon overall in the database, but when we did see
it, much more likely to be seen in the telithromycin arm versus
comparators.

The focus of the advisory then was on three areas in the realm of
safety: cardiac, hepatic, and visual. How did this come about? Well, we
look first to animal data, in vitro data, to give us some indication of
where to look, what might be the target organs potentially of toxicity.

Telithromycin inhibited IKr channels, prolonged action potentials in
isolated fibers, and prolonged QT in dogs. The numbers are here. You\'ll
hear more about this today. The effect is modest in phase I whether in
young patients or in elderly, on the order of a few seconds of QT
prolongation, a bit longer if one takes into account a CYP3A4 inhibitor.

In phase I, we discussed briefly nonlinear pharmacokinetics, with a mean
Cmax after a single dose of 800 milligrams, on the order of 2 milligrams
per liter; maximum Cmax, a little bit over 5 for those subjects who were
renally impaired. Similar numbers for multiple dose exposure. And in
phase III, the maximum observed concentrations ranged between
7-and-a-half and just under 10.

In elderly subjects, as well as subjects with renal impairment, Cmaxes
and AUCs were higher, ranging from 30 percent greater up to 100 percent.
In patients with hepatic impairment, area under the curve and Cmax were
quite similar to healthy subjects, as long as renal clearance was
normal. Although there were not specific data at that time to speak to
it, we raised the question of potential accumulation if creatinine
clearance was reduced in the setting of hepatic impairment.

In phase III, telithromycin had a small but consistent increase in
controlled trials. And I recall at that time, in Dr. Ruskin\'s
presentation in general on matters of QT and drugs that can affect
cardiac repolarization, the idea that in the setting of noncardiac drugs
that can have a small or modest effect on cardiac repolarization, it is
extremely rare to see clinical problems in the setting of healthy
subjects on that drug alone. Rather, the concern raised in the setting
that we have historically in the agency sometimes seen problems is the
setting where there\'s increased exposure of the drug that can have a
modest effect on QT and some perturbation, comorbid conditions, drugs
that compete for cytochrome P450 isoezymes, states that for one reason
or another increased exposure that may then lead to problems,
necessarily painting a picture that there will be lots of other
conditions and things going on when one might see a problem that becomes
a clinically significant problem with prolonged QT.

What about the hepatic body of data? Preclinically in the species tested
‑‑ dogs, rats, monkeys ‑‑ hepatotoxicity was noted by virtue of
increases in transaminases and liver necrosis in a 4-week rat study. In
phase I, there was a clustering of some hepatic adverse events in the
elderly who were given a single supratherapeutic dose but no clear dose
response for hepatic adverse events. And overall in phase III, similar
rates of reported adverse events for hepatic issues, telithromycin
versus comparators. No apparent drug-induced hepatic deaths.

There were, at the time of the April 2001 advisory, 2 hepatic serious
adverse events possibly, plausibly associated with telithromycin, and
there was at that meeting one liver biopsy discussed in a Finnish
patient read as centrilobular necrosis, eosinophilic infiltration which
could be consistent with a drug-induced picture. It could not be ruled
out. We will see that case again today, as well as another liver biopsy
review.

Overall in phase III, there were more AST and ALT elevations in
telithromycin-treated patients in the pneumonia trials, not seen in
non-pneumonia patients, and concomitant low-level transaminase and total
bilirubin elevations in telithromycin-treated patients.

Now to visual data. In phase I, about 4 out of 1,000 subjects reported
blurred vision with supratherapeutic doses, and in phase III, 14 out of
2,000, a tiny percentage, versus 1 out of 1,600 in a comparator. The
majority of patients were under 40 ‑‑ we\'ll say young ‑‑ and female.
The report of blurred vision was usually transient but variable,
minutes, days, hours. It was over the map.

In summary, the issues discussed at the April 2001 advisory about
potential QTc prolongation, a concentration-dependent effect of
telithromycin on QT, a concentration variation in special populations
like those with hepatic and renal disease, those with comorbid
conditions, potential for effects on the liver, raised questions of
increased exposure in the elderly and those with concomitant medications
and what effect that would have then on the safety picture.

There were limited data on subjects at risk, often the case because our
controlled clinical trials are designed in such a way that we have
exclusion criteria that sometimes give us not so much data when there
are many comorbid conditions or concomitant meds. And we reviewed this
data in the setting of a potential for wide population exposure, for we
know that in the United States each year we write many, many
prescriptions for patients on an outpatient basis for those with
respiratory tract infections like bronchitis or sinusitis or
pharyngitis, prescriptions in the millions.

The vote taken at that time was on these questions. Do the efficacy and
safety data presented support the use of Ketek, or telithromycin, in
community-acquired pneumonia, bronchitis, sinusitis? The majority of you
voted yes with regard to community-acquired pneumonia. The majority
voted no with regard to bronchitis or sinusitis. The discussion that
ensued around this was not one that questioned efficacy. Rather it was
one that raised questions about risk-benefit overall and about a desire
to have a better understanding of the safety profile.

With regard to drug-resistant Strep. pneumoniae overall, whether for
pen-resistant isolates or erythromycin-resistant isolates, the majority
of you did not feel that you had enough data to support the claim. You
raised questions to some extent as well about the body of evidence
available at that time to speak to the clinical impact of
macrolide-resistant Strep. pneumoniae. We\'ll hear more about that
today.

You made recommendations to us at that time that included a desire for a
larger number of patients to be enrolled in safety studies with
particular attention to special populations being targeted like the
elderly and patients with various organ impairment like hepatic
impairment or renal and to have a better understanding of the
pharmacokinetics in those populations, together with some more data on
drug-drug interactions.

On the side of efficacy, you also recommended the gathering of more data
in patients with drug-resistant Strep. pneumoniae, including hopefully
those with bacteremia.

In June of 2001, we issued an approvable letter for community-acquired
pneumonia, bronchitis, and sinusitis. We too asked for additional safety
and efficacy data to assess risk-benefit.

Aventis worked with us in the Division of Anti-Infectives in the design
of trials in phase I and phase III to gather those data.

In phase III then, study 3014, about which you\'ll hear quite a lot
throughout the day, was a randomized, open-label, multi-center trial
that compared telithromycin to amoxicillin-clavulanate in outpatients
who could enter with either pneumonia, bronchitis, or sinusitis. This
was a trial designed to simulate the usual care setting. It\'s a big
study. It\'s a big effort. 24,000 patients were enrolled. It was
designed as a large safety study to look at adverse events of special
interest, namely cardiac, hepatic, and visual.

In addition, other phase III studies were conducted to address a request
for additional efficacy data in community-acquired pneumonia on
drug-resistant Strep. pneumoniae. You\'ll hear the results of these
studies as well.

And finally in phase I, studies were conducted to examine cardiac issues
and QT interval changes when the system was taxed, when the deck was
stacked, with regard to patients having renal impairment and receiving
telithromycin or having renal impairment and receiving telithromycin as
well as ketoconazole.

In the visual realm, studies were designed to enable extensive
ophthalmologic evaluation in both young subjects, as well as older
subjects, in the setting of single doses, multiple doses, crossover
designs, looking as well at pharmacokinetics of telithromycin in plasma
and tears.

And finally in the setting of phase I studies referable to what was
going on with the liver, there\'s a multiple dose study of telithromycin
in patients with hepatic impairment versus healthy subjects.

As of October of 2002, there were 1 million to 1.5 million exposures in
Europe and Latin America of telithromycin; in Europe, largely in Germany
and France.

In closing, I wish to tell the committee that we get very excited in the
division when given the opportunity to review a new class of drugs. We
recognize that the pipeline for antibiotic drug development, for drug
development of new chemical entities is not overflowing, and I want to
recognize, applaud, and thank Aventis for a great amount of work that\'s
been done in the endeavor to develop a new compound for the treatment of
respiratory tract infections.

There is the potential to increase our armamentarium of agents to treat
respiratory tract infections, including resistant pathogens. I think
that\'s important. At the same time, with opportunity always comes
challenge. And in the review of any new drug application, maybe
especially in the setting of development of a brand new class, a first
in a class, one also has to carefully examine data to speak to potential
toxicities.

With regard to risk, I\'d like to read a very brief passage from a book
written by Peter Bernstein, Against the Gods: The Remarkable Story of
Risk. The ability to define what may happen in the future and to choose
among alternatives lies at the heart of contemporary societies. Risk
management guides us over a vast range of decision making, from waging
to war to planning a family, from paying insurance premiums to wearing a
seat belt, from planting corn to marketing corn flakes, from allocating
wealth to safeguarding the public health.

He goes on to say that the scientists who developed the Saturn V rocket
that launched the first Apollo mission to the moon put it this way. And
this is a quote from Arthur Rudolph. You want a valve that doesn\'t leak
and you try everything possible to develop one. But the real world
provides you with a leaky valve. You have to determine how much leaking
you can tolerate.

We ask the committee today to listen carefully to all of the data that
will be presented with regard to safety and efficacy and to assess in
the balance overall risk-benefit for telithromycin in the setting of
what we anticipate would be wide exposure, wide usage.

And with that, I will thank you and turn the microphone back over to Dr.
Leggett.

DR. LEGGETT: Thank you, Dr. Soreth.

Before I ask anyone if they have any questions, Alan, could you please,
for the record, introduce yourself?

DR. CROSS: I\'m Alan Cross, University of Maryland at Baltimore, Center
for Vaccine Development, a new address.

DR. LEGGETT: Thank you.

And I noticed Dr. Goldberger there too.

DR. GOLDBERGER: Mark Goldberger from the Office of Drug Evaluation IV.

DR. LEGGETT: Thank you.

Are there any questions for Dr. Soreth before we move on? Yes.

DR. ELASHOFF: Since I haven\'t been on anti-infective panels before, I
wanted to clarify whether that 85 percent rule which was applied to
decide that we weren\'t going to go for one indication, that that does
not apply to the other three or it would apply to the other three?

DR. SORETH: No, it does not apply to the other three.

DR. ELASHOFF: It does not apply. So those could be less than 85 and one
would still be interested.

DR. SORETH: Yes.

DR. ELASHOFF: Thank you.

DR. LEGGETT: Any further questions?

(No response.)

DR. LEGGETT: Thank you, Dr. Soreth.

Dr. Powers, could you please talk to us about the clinical significance
of macrolide resistance?

DR. POWERS: Today I\'d like to talk to you about, in asking a question
really, what is the public health impact of macrolide-resistant
Streptococcus pneumoniae? And this is one of those experiences, when you
look through the medical literature, that\'s very humbling in that
sometimes what we think we know we don\'t really know and the more you
read about it, the less clear sometimes something becomes. So I\'d like
to present to the committee today the information on the pros and cons
of whether macrolide-resistant Streptococcus pneumoniae is an organism
of public health importance at this point in time.

What I\'d like to do first is present you some information on background
on drug development for resistant pathogens that\'s been occurring
within the last year and then discuss the body of information that\'s in
the literature currently on the potential public health implications of
macrolide-resistant Streptococcus pneumoniae. What I\'d like to go
through is some characteristics that we\'ve come up with with an
organism that would be considered of public health importance that is
resistant to antimicrobials and then review those characteristics as
they relate to macrolide-resistant Streptococcus pneumoniae.

It\'s important to realize today there are two separate questions here.
The first one, as Dr. Soreth said, is is Ketek safe and effective for
the indications for which it\'s seeking approval. The second related,
though really separate question, is should Ketek, or any other drug for
that matter, garner a claim against macrolide-resistant Streptococcus
pneumoniae based on what we know about this organism at this point in
time. So the first question that we really have to tackle is whether
macrolide-resistant Streptococcus pneumoniae is an organism of public
health importance from what we know right now.

Several sponsors have requested indications for macrolide-resistant
Streptococcus pneumoniae in the recent past but no drug has received
that indication to date based on the agency\'s feeling that the
information out there on this drug wasn\'t adequate at that point in
time. But we\'re bringing that up again today to ask the committee
whether they think the time is ripe to address this.

We\'ve had several meetings addressing drug development for resistant
pathogens in the last year. One was almost a year ago to this very
advisory committee, and then one was more recently on November 19th and
20th this year in a workshop cosponsored by the agency, the Infectious
Disease Society of America, and PhRMA. And at that meeting, members of
industry and IDSA requested us to develop a list of resistant pathogens
for which there is a public need for drug development.

Now, the public health importance of various organisms may vary over
time based on changing epidemiology of the infections and the
availability of alternative drug therapies. For instance, in the
mid-1940s, penicillin-resistant Staphylococcus aureus was considered a
huge problem because the only drug available to treat it was penicillin.
However, with the advent of vancomycin and then methicillin after that,
one might consider penicillin-resistant Staph. aureus as not of great
importance today but replaced by methicillin-resistant Staph. aureus.

So at that meeting in November, we discussed what we would consider the
seven criteria or characteristics of a resistant organism that would
characterize it as being of public health importance from a drug
development point of view.

The first would be the incidence or prevalence of those organisms in the
disease in question.

The second would be the virulence of the organism in question.

The third would be is resistance to the drug that we\'re talking about a
drug commonly used to treat infections in the population under study.

The fourth would be are there available alternative therapies for the
disease besides the drug that we\'re talking about.

The fifth, related to that, is are the organisms resistant to multiple
drug classes, and that\'s a little separate than that in that sometimes
we\'ll talk about, say, resistance of Strep. pneumo to chloramphenicol.
However, chloramphenicol really isn\'t used that often to treat
Streptococcus pneumoniae.

The sixth is something recommended to us by our colleagues at the CDC
which is, is the drug an essential component to prevent spread of the
organism in the population. Just to give you an example of what this
would mean, something like Neisseria gonorrhoeae infections where there
is no vaccine currently and the actual drug is used to prevent the
spread from person to person.

And then finally, the correlation of in vitro resistance with actual
clinical failures.

What we talked about in November was there are some very clear-cut cases
of organisms which fit these criteria such as methicillin-resistant
Staph. aureus, vancomycin-resistant enterococci, and
penicillin-resistant Streptococcus pneumoniae for which the FDA has
already granted indications to drugs out there on the market.

However, less clear-cut was macrolide-resistant Streptococcus
pneumoniae, and we asked this question directly in November and didn\'t
get a whole lot of information there. So that\'s why we\'re bringing it
up again today.

So let\'s apply these seven criteria then to macrolide-resistant
Streptococcus pneumoniae and see what we know. What, again, I would like
to do and finally get to at the end is to present both sides of this
issue so the committee can help give us some advice.

The prevalence of macrolide-resistant Streptococcus pneumoniae is
clearly increasing, and in an active surveillance study done by the CDC
from invasive isolates from eight counties and Atlanta, from 1994 to
1999 the prevalence of this organism went from 16 percent to 32 percent.
So it doubled over time.

There are two types of resistance to macrolides in Streptococcus
pneumoniae, as I\'m sure you\'ll hear more about in the Aventis
presentation. The one is the mefE mutants which is a gene that codes for
an efflux pump. The other is the ermAM resistance gene which codes for a
ribosomal methylase. In this study from Atlanta, they showed that the
level of ermAM resistance remained stable through the 1994 to 1999
period, and almost all of the increase in resistance was made up by the
mefE mutants.

However, the MICs for the mefE resistant isolates increased as well over
time, from 21 percent with an MIC greater than 8 in 1995 to 94 percent
with an MIC greater than 8 in 1999. And 63 percent of those had an MIC
greater than 16 micrograms per milliliter. So we\'re also seeing, even
amongst those mefE\'s, the MICs went up over time.

In a more recent study here, the epidemiology of MRSP from over 1,500
isolates in 33 medical centers across the U.S., so giving us a broader
look at this, in a more recent time period from 1999 to 2000, showed
that the MIC50 for these organisms was around .06 micrograms per
milliliter. The MIC90 was 8, with a range that went all the way up to
64. .5 percent of those were considered intermediately susceptible to
erythromycin based on the current National Committee for Clinical
Laboratory Standards breakpoints. 25.7 percent of those isolates were
considered highly resistant to erythromycin. But they did find that the
rate of resistance, much like penicillin-resistant Streptococcus
pneumoniae, was highly variable depending upon geography, ranging
anywhere from 4 to 44 percent of the isolates.

So this raises very two related questions. The first is if we\'re going
to call something susceptible resistance, how is this resistance defined
in vitro. And the second question then is related. Is the population
with invasive disease, such as that studied in the Atlanta study, the
same population that would be treated with oral antimicrobials on an
outpatient basis?

There\'s been some controversy over the breakpoints for macrolides, and
I probably shouldn\'t say controversy except to say that they\'ve been
changing and sometimes most recently. Before 1996, the NCCLS breakpoints
for erythromycin were between 1 and 4 for intermediate strains and
greater than 4 for resistant strains. After 1996 based on this paper by
Jorgensen, the NCCLS changed the breakpoints to .5 for intermediate
strains and greater than 1 for resistant strains, to bring them more
into line with what was seen for clarithromycin at the same time.

However, some authors in the literature have argued that the breakpoints
should be higher than this or the breakpoints should be lower than this.
Some of the arguments that have been raised for raising the breakpoints
have included that, in this study by Gerardo, 31 percent of isolates,
when compared by E test versus broth dilution, had different MICs by
sometimes up to eight-fold. An incubation of the organisms in ambient
environments as compared to 5 percent CO2 lowered the MICs by one or two
dilutions, making it look like an organism that had an MIC of 8, really
had an MIC of 4 when incubated in air instead of CO2.

An older study done in 1988 showed that mixing 50 percent human sera in
the media lowered the tube dilution sometimes again by up to 8-fold. So,
again, an organism which may look like it had an MIC that was 8
sometimes came out to look like it was 2.

Also other studies, which we\'ll talk about in a little more detail,
show that the pharmacokinetics of macrolides which concentrate the drugs
in the white blood cells and the endothelial lining fluid really deliver
more of the drug than what we see in the serum. Therefore, the
breakpoints based on just serum levels alone would not be appropriate.

On the other side of this argument, however, other authors have claimed
that the pharmacodynamic parameters of these drugs from animal studies
show that the breakpoint should be as low as .5 to determine resistant
organisms.

The second question then is, is the population that harbors these
resistant organisms really the one that would be getting these
antibiotics? And guidelines recommend oral outpatient therapy for
patients with mild disease, less than the age of 60, and no
comorbidities. According to the Pneumonia Outcome Research Trials, or
PORT studies, these are people who fall into class 1 or class 2 of the
pneumonia severity index as defined by those studies.

However, the risk factors for macrolide resistance in adults in this one
study from Spain show that age of greater than 65 years and multiple
comorbidities were the major risk factors for harboring a
macrolide-resistant organism, which would put a person in class 3 or
above based on those things.

Other studies, however, show that age less than 5 years, isolates from
the middle ear or the respiratory tract, prior antimicrobials, and also
nosocomial acquisition are also risks. So although we see these
organisms in patients greater than 65 with multiple comorbidities, they
also occur in patients on the outpatient side who are less than 5 and
get these bugs in their respiratory tract.

The second issue is the virulence of the organism. Streptococcus
pneumoniae is clearly a virulent organism and can cause very serious
invasive disease. However, to look at this another way, several studies
show an inverse relationship of invasive disease with antimicrobial
resistance. In other words, the resistant organisms are less likely to
cause blood stream or CSF infections.

Also, outpatient mortality from community-acquired pneumonia is low,
with the class 1 patients having a .1 percent mortality and the class 2
patients having a .6 percent mortality.

And several other studies show that the major risk factors for dying
from community-acquired pneumonia have more to do with age and
comorbidities than they do with the actual resistance pattern of the
organism.

Are macrolides commonly used to treat these kinds of infections? Well,
they certainly are. Macrolides are used to treat mild to moderately
severe community-acquired pneumonia, and in one study that was based on
the PORT data, 62 percent of outpatients who had no comorbidities and
were less than the age of 60 received a macrolide as their sole therapy
for community-acquired pneumonia.

However, on the flip side of this, macrolides are rarely used as sole
therapy in severe community-acquired pneumonia. In this study from
Spain, although 62 percent of hospitalized patients received a
macrolide, all of them got it in conjunction with a cephalosporin and
none of them received the macrolide alone.

Other studies showed that only 2.5 percent of inpatients in this country
received a macrolide as sole therapy for their community-acquired
pneumonia if they were hospitalized.

And also macrolides are not used to treat severe disease associated with
community-acquired pneumonia such as meningitis.

Are there alternative therapies for macrolide-resistant organisms? Well,
some macrolide-resistant organisms are also resistant to other drug
classes used to treat pneumonia. 15 percent of macrolide-resistant
Streptococcus pneumoniae are highly resistant to penicillin, and this is
an interesting question. It depends upon how you look at it and what you
start with. If you look at penicillin-resistant organisms, the majority
of those are macrolide-resistant, but at least by this study from Gay
done through the CDC, only 15 percent of macrolide organisms are
penicillin-resistant, looking at it the other way. And another 19
percent of these macrolide-resistant organisms are intermediately
susceptible to penicillin.

The question, though, remains based on data looking at penicillin and
cephalosporin treatment of these patients, that the data imply that
third generation cephalosporins and high-dose penicillin may still be
effective for many of these penicillin-resistant organisms even with
MICs up to or greater than or equal to 4.

So the question then comes up of are there actual data to indicate that
patients will fail therapy more often with macrolides for
macrolide-resistant Streptococcus pneumoniae, and we\'ll get to that in
a little bit.

Continuing on with cross resistance to other drugs, for more recent data
from the Doern study, for PRSP organisms, 77.8 percent of them are
macrolide-resistant as well, and penicillin resistance also predicts
resistance to clindamycin in a quarter of those patients, tetracyclines
in almost half, and 94 percent of those PRSP isolates are also resistant
to trimethaprim-sulfamethoxazole.

On the flip side of this, this Doern study doesn\'t present starting off
with MRSP and them looking at PRSP. So going back to the Gay study,
remember that only 15 percent of MRSPs are PRSPs as well.

So the real question here is, are we even calling these drugs the
correct thing? Are penicillin-resistant Streptococcus pneumoniae really
more accurately called drug-resistant Streptococcus pneumoniae? And the
question here comes up similar to vancomycin-resistant enterococci.
Those organisms are almost all resistant to ampicillin and high doses of
gentamicin as well, and yet we call them vancomycin-resistant
enterococci, and yet, to date we haven\'t granted separate indications
of vancomycin-resistant enterococcus, ampicillin-resistant enterococcus,
and gentamicin-resistant enterococci. So does drug activity against PRSP
accurately predict activity against MRSP and other forms of resistance
as well based on this high rate of cross reactivity?

Then do we need drugs to control pneumococcal disease in the population.
Well, the answer here is probably an easy one. It\'s probably not
because 87 percent of PRSP isolates are serotypes included in the 23
valent pneumococcal vaccine according to this data by Gay, and 66
percent of those isolates are serotypes included in the 7 valent vaccine
as well. And it\'s predicted that these vaccines may result in a
decrease in invasive disease.

Remember, however, that the resistant isolates are less likely to cause
invasive disease. So the question remains, will the vaccine have a
bigger impact on decreasing susceptible disease and less of an impact on
decreasing resistant disease, given that these organisms cause less
invasive disease?

Finally, we get to really where the money is, and that is, what is the
correlation of in vitro results with clinical outcomes in patients who
have macrolide-resistant Streptococcus pneumoniae infections? And this
is the part that gets very humbling when you start looking through the
data and trying to find information on this. There\'s really a paucity
of data out there looking at this question.

There are almost no data on diseases other than community-acquired
pneumonia. So that\'s where I\'ll concentrate the majority of my
comments.

There are no reports on how patients do with acute bacterial sinusitis
when they harbor resistant versus susceptible organisms.

There were few reports on patients with acute bacterial exacerbations of
chronic bronchitis that show no increased failures in patients who
harbor macrolide-resistant organisms. However, this is very complicated
by the fact that the actual role of bacteria in acute exacerbations of
chronic bronchitis still remains debatable, and even the impact of
antimicrobial therapy versus no therapy is still a subject of debate as
we talked about in November.

One study of group A beta-hemolytic streptococcal pharyngitis showed
lower bacterial eradication rates with macrolide-resistant Streptococcus
pneumoniae, 60 percent with resistant organisms versus 80 with
susceptible, but no difference in clinical failures, with a 1.6 percent
clinical failure rate in resistant organisms and 1.5 percent in the
susceptible. Again, very complicated by the fact that it\'s unclear
whether any antibiotic alters the course of your sore throat in group A
strep pharyngitis. So these people might have gotten better anyway even
though the drugs didn\'t work very well to eradicate the organisms. So
the clinical outcome here doesn\'t really help us very much in this
particular type of disease that has a very high spontaneous cure rate in
any case.

So there are case reports or case-controlled reports on failures of
patients treated with macrolides who are infected with
macrolide-resistant Streptococcus pneumoniae.

This one study by Kays included 32-year-old man who was receiving
azithromycin and had a breakthrough bacteremia.

The study by Kelley includes 4 patients out of 41 in their hospital who
received macrolides prior to coming into the hospital and then had
breakthrough bacteremias.

The study by Lonks that was published last year in Clinical Infectious
Diseases is a case-controlled study that looks at 18 patients who
received macrolides prior who had macrolide-resistant Streptococcus
pneumoniae. They had a larger number of cases. I think it was 86 all
told. However, the problem here again gets to be that people who get
admitted to the hospital don\'t often get macrolides as sole therapy. So
trying to pick out people who got macrolides who then failed is
sometimes difficult even when you find people who have
macrolide-resistant Streptococcus pneumoniae because they may be
receiving concomitant cephalosporins or other drugs that may affect the
outcome.

However, on the other side of this equation, there are case reports of
successes of patients treated with macrolides who are infected with
macrolide-resistant Streptococcus pneumoniae.

This study published a couple of years ago by Moreno and colleagues
showed that 4 of 6 patients who were infected with macrolide-resistant
Streptococcus pneumoniae, 3 of whom were bacteremic, were cures.

A study by Vergis on IVA azithromycin compared to cefuroxime plus
erythromycin showed that 1 patient who was infected with a
macrolide-resistant organism with an azithromycin MIC of 8 was a
clinical cure.

And this study by Gotfried in the Journal of Antimicrobial Chemotherapy
showed a similar survival rate in patients with macrolide-resistant
Streptococcus pneumoniae, of which there were 27 patients. 95 percent of
them were cured. The macrolide-susceptible Streptococcus pneumoniae
patients, of whom there were 41, 82 percent of these were cured.
However, the information on what drugs these people received was not
available in a large number of those cases.

So there are challenges in interpreting this data either way when
looking at both the successes and the failures of patients who have
macrolide-resistant Streptococcus pneumoniae infections. As you can see
on that previous slide, there are usually very small numbers of cases.
They\'re usually retrospective, uncontrolled, or case-controlled data.
When you look through some of these cases, when the information is
supplied, some of these patients probably weren\'t appropriate for oral
therapy in any case. For instance, in the Kelley study of those 4
patients, one of them was a 75-year-old man with renal failure and liver
failure. That\'s probably not the kind of person you would have put on
oral macrolide as an outpatient in any case.

The other thing that gets very complicating is, can the natural history
of the disease or other factors explain these failures? We know from
data from Robert Austrian back in the 1960s from the University of
Pennsylvania that no drug has any effect on the course of pneumococcal
pneumonia in the first 5 days of treatment. So if someone gets a drug
and on day 2 they fail, is that because they had such severe disease
they were going to fail any drug, or is it because that is a failure of
that particular antibiotic?

And it\'s also very complicated by the inherent differences in patients
harboring resistant organisms. So when we compare patients who have
macrolide-susceptible organisms to macrolide resistance, there are
inherent differences, namely based on age and comorbidities, between the
patients who have those. So it\'s unusual to be able to compare
22-year-old healthy people with macrolide-resistant organisms versus
22-year-old people with macrolide-susceptible organisms.

So what can these cases tell us? They tell us that failures do occur.
But the more relevant question that remains unanswered is, are the
failures more likely to occur in patients who receive macrolides for
macrolide-resistant pneumococcal disease versus macrolide-susceptible
pneumococcal disease?

Well, why would anyone even suppose that patients who have MRSP may
still be clinical cures when treated with macrolides? And there\'s some
information out there in the literature that tries to explain this.

The first is the concentrations in endothelial lining fluid and white
blood cells may exceed the serum concentrations for macrolides. And at
least for the mefE mutants, this may exceed the MIC of these organisms.
However, for the ermAM mutants this still may not be able to exceed the
MIC.

Also, the contribution of the host immune system in younger patients
with no comorbidities may help them get better despite whatever
antibiotic they have or the resistance pattern of the drug.

According to some authors, the clinically relevant breakpoints for
macrolides may be higher than the current NCCLS standards, as we already
discussed.

Why would one expect clinical failures in patients with
macrolide-resistant Streptococcus pneumoniae infections when treated
with macrolides? Well, even though those concentrations in the white
blood cells and the endothelial lining fluid are high, they still may
not be high enough for some of the isolates, especially the ermAM
mutants. The other question this doesn\'t answer is, although this may
be adequate for intracellular pathogens, how does this impact on
extracellular pathogens, of which the pneumococcus is one?

Also, several reports show poor lung tissue levels of azalides in health
volunteers despite the high endothelial lining fluid concentrations.
Others would argue that these are in healthy volunteers and once the
people are infected and the inflammatory component kicks in, the white
cells then mobilize into the lung and carry this high level of drug with
them. So the question remains what\'s the important parameter to look at
here. Is it lung tissue levels? Is it white blood cell levels? Is it
endothelial lining fluid concentrations?

Some studies in immunocompromised animals show failure of bacterial
eradication with macrolide-resistant Streptococcus pneumoniae organisms
treated with macrolides. However, other studies in immunocompetent
animals show a better eradication rate, although still lower than that
with macrolide-susceptible organisms.

And finally, the breakpoint for macrolides based on pharmacodynamic
parameters may actually be lower than the current NCCLS standards based
on some authors.

So finally, what do we have here in the end result? Is this organism
significant or not at this point in time? And there are arguments on
either side, and this is why we\'d like the committee\'s advice on this
today.

On the pro side of saying yes, this organism is of clinical significance
at this time is the fact that the rising MICs, even for the mefE
mutants, are occurring at this point in time in the U.S. Macrolides are
commonly used for community-acquired pneumonia, and macrolide-resistant
Streptococcus pneumoniae may be resistant to other drug classes as well.
And there are case reports of clinical failures in the literature with
macrolide-resistant Streptococcus pneumoniae.

On the other side of the equation saying no, this organism is not of
clinical significance at this point in time, is that the mefE mutants
are the most prominent, about two-thirds in the U.S. today, of all the
macrolide-resistant Streptococcus pneumoniaes, and some authors would
argue that you can dose these drugs for cure based on the increased
concentrations in the endothelial lining fluid and the white blood cells
which exceed the MIC for some of these mefE isolates.

Also, if we look at the Gay data, if we just look at macrolide-resistant
Streptococcus pneumoniae, only 15 percent of them are resistant to
penicillin. So are there alternative therapies available for most of the
MRSPs? If we look at it the other way of around, however, most of the
penicillin-resistant organisms are macrolide-resistant.

And finally, there are no studies directly evaluating the impact of
macrolide-resistant Streptococcus pneumoniae on outcome. However, can we
reasonably expect to ever get this data based on the fact that
macrolides are not used as sole therapy in severely ill patients, and in
most clinical settings, one doesn\'t get the sputum culture or blood
cultures on a young, healthy outpatient with no comorbidities who may
happen to then get community-acquired pneumonia.

So in conclusion then, what we\'d like to ask you today is, does the
current body of information on macrolide-resistant Streptococcus
pneumoniae support granting indications for any drug for this organism
at this point in time?

Also, should this vary depending upon the indication based on the fact
that most of the information that we know is about community-acquired
pneumonia? We have very little on sinusitis at all. And there\'s the
question of what impact even of antibacterial therapy for anything is in
acute exacerbations of chronic bronchitis.

Would granting claims for macrolide-resistant Streptococcus pneumoniae
at this time affect physicians\' prescribing patterns? So, in other
words, if the FDA approves a drug for macrolide-resistant Streptococcus
pneumoniae, will physicians then assume that this is important and start
changing their prescribing patterns?

Given that there may be other treatment options for macrolide-resistant
Streptococcus pneumoniae, is it appropriate for physicians to be
changing their prescribing patterns at this point in time for
macrolide-resistant organisms?

And then given the overlap between penicillin-resistant Streptococcus
pneumoniae and macrolide-resistant organisms, does granting an
indication for penicillin-resistant pneumococcus imply that the drug
must be effective for macrolide-resistant Streptococcus pneumoniae as
well? And this goes back to the question that I raised earlier for
vancomycin-resistant enterococcus, we don\'t grant separate indications
for all the other drugs to which it is resistant, and one could make the
same case for methicillin-resistant Staph. aureus, that although we
label it as methicillin-resistant, that organism is also resistant to a
number of other drugs, but we don\'t grant separate indications for each
one of those.

So I\'ll stop at this point in time.

DR. LEGGETT: Thank you, Dr. Powers.

Are there any questions? Yes.

DR. PATTERSON: When you\'re using the term \"PRSP,\" particularly with
regard to calling it drug resistant Strep. pneumo, are you referring to
nonsusceptible; i.e., MIC greater than .1 or fully ‑‑

DR. POWERS: No. Everything I said today I used as MICs of 2 or above,
given the fact that it doesn\'t appear that people with intermediately
susceptible Strep. pneumo have any difference in outcome. So I confined
it to only the highly resistant ones.

DR. MAXWELL: Under the virulence, the studies that showed the inverse
relationship to invasive disease with antimicrobial resistance, was it
primarily in patients with no comorbidities or was it across the board?

DR. POWERS: They don\'t actually comment on whether they have
comorbidities or not. Some of those are in hospitalized patients as
well.

There\'s a debate about that as well. Even though you look at that, some
people would claim that the organisms which then mutate and become
resistant are less fit and are less virulent. However, when you look at
the people who actually get invasive disease, their mortality is no
different, and sometimes higher, if they have a resistant isolate than
if they have a susceptible.

So there are two ways of looking at that. Even though it looks overall
that it\'s less invasive, once you get an invasive isolate with a
resistant pneumococcus, it\'s not like you\'re less likely to die.

DR. LEGGETT: Dr. Bell.

DR. BELL: John, that was an excellent summary.

I also was interested in that statement you made about that the
drug-resistant infections were less invasive. What I do know is that
rates of drug resistance are higher in respiratory isolates than in
invasive isolates. That\'s very clear.

Whether the converse can be said, I\'m trying to think about that. The
invasive isolates resistance patterns are determined in ‑‑ at least in
the CDC study, these are population-based active surveillance in large
populations. The studies of resistance in respiratory isolates to my
knowledge tend to be sentinel sites, not population-based, sometimes
research projects. And I just wonder if we know enough to make the flat
statement that resistant isolates are less invasive.

DR. POWERS: Yes. I think the way to look at this is there are two ways
of looking at it. There\'s looking at it from a population-based point
of view. Those studies are mostly from Spain where they take people that
had an invasive disease and they look back at their risk factors. And
then they say, in the people who had invasive disease, they were less
likely to have a resistant pathogen, but in the individual patient, if
you are infected, if you have a blood culture positive, you\'re not less
likely to die just because the organism is resistant versus susceptible.

DR. LEGGETT: Dr. Cross.

DR. CROSS: John, excellent presentation.

I have a technical question. What is endothelial lining fluid and how is
it obtained?

DR. POWERS: What they do is they obtain by bronchoalveolar lavage. They
actually go down there and wash out the lungs and then back-calculate
for the dilutional factor of, I think it\'s, 100 ccs that they put into
the lung, and then also normalize that based on the person\'s blood urea
nitrogen concentration to come up with this. So this is what\'s actually
lining the lung. That doesn\'t tell you what the concentration of the
drug in the actual lung tissue is. So it\'s sort of lining the alveoli,
but not in the spaces itself.

DR. CROSS: But it\'s not intravascular.

DR. POWERS: No.

DR. CROSS: I mean, the endothelium is on the inside of the ‑‑

DR. POWERS: No, not at all. So you\'ve got really three things to look
at here. You\'ve got serum concentrations of the drug. Four things. I\'m
sorry. Serum concentrations of the drug, the actual tissue levels of the
drug, the white blood cell concentrations of the drug, which may be very
high compared to serum concentrations depending upon which macrolide or
azalide you\'re looking at, and then the endothelial lining fluid
concentrations. Which of those is the most important in determining
outcome really remains to be seen.

DR. LEGGETT: Yes, Dr. Brown.

DR. BROWN: I agree this was a wonderful presentation. I was hoping,
however, that it would be a little more instructional than rhetorical.
And I wonder if you would answer your own question for us.

(Laughter.)

DR. POWERS: Okay. No, I won\'t answer them. If I could, I wouldn\'t be
asking it up here then.

DR. BROWN: I had several questions. I would like you to answer. You must
have some final opinion, and I would like to hear what that is.

DR. POWERS: I never have opinions.

DR. BROWN: Secondly, I had a question about the value that you attribute
to the case-controlled and single-case data that you reviewed for us.

And thirdly, on your last slide, would granting claims for MRSP affect
prescribing patterns, my question is, is that the charge to the FDA? And
I\'m asking this as a sincere historical question. My impression is that
your division is asked to make one single decision. For the claims which
the manufacturer wants to present, have they made their case the drug is
effective and safe, not whether they\'re going to alter or try to
control prescribing patterns for physicians.

DR. POWERS: You\'re absolutely correct. That is not our job. Our job is
not to regulate the practice of medicine. However, I think that\'s
something important for you on the committee as practitioners to
consider when you\'re thinking about this.

Mike Scheld asked me at this November workshop about one of the ways we
could determine how important an organism was, of public health
importance, was look at what drugs physicians are using for those. I
asked him the question, isn\'t that kind of circular reasoning in that
once a drug gets approved, aren\'t physicians going to think it\'s
therefore an important organism and start changing their prescribing
patterns. Which is the one that really drives what\'s going on? And I
think that\'s an unclear question.

You\'re absolutely right. It\'s not a question for us to answer, but I
still think it\'s one for you to answer as clinicians. But you\'re
right. The level of evidence that we\'re looking at is does the drug
work for that particular type of organism in that particular type of
infection.

DR. LEGGETT: One final question. Dr. Rupp.

DR. RUPP: Kind of a follow-up to the question that Dr. Patterson asked.
With regard to macrolide resistance, particularly in the case studies
that you looked at in the case-controlled trial, did they break it down
with regard to any level of in vitro susceptibility or with regard to
mechanisms of resistance, mef versus erm?

DR. POWERS: I\'m sorry. As far as which studies?

DR. RUPP: Any of the outcomes data.

DR. LEGGETT: The CID.

DR. POWERS: The case failures?

DR. RUPP: The case failures and the case ‑‑

DR. POWERS: Actually for macrolide resistance, it\'s really not that
helpful to break it down into intermediate versus highly susceptible
because almost all of them fall into the highly susceptible. At least in
the U.S. today, only .5 percent of them are intermediately susceptible
to macrolides. So it\'s almost not worth talking about. In fact, the
difference was 25.7 versus 26.1 or something when you look at that. So
for macrolide resistance, unlike penicillin resistance where it\'s
almost split down the middle, it doesn\'t make a whole lot of difference
to split that up.

When you do look at the resistance, depending upon where those cases
come from, the majority of the U.S. failures have mefE resistance
patterns. Some of the ones from Spain have ermAM resistance patterns. If
I total up all of the clinical failures, most of them are mefE, though,
because most of them come from the U.S. So I think what you\'re going to
see depends upon where you are since two-thirds of the isolates in the
U.S. right now, regardless of whether you succeed or fail, are mefE
resistance mutants.

DR. LEGGETT: Thank you, Dr. Powers.

I think we should move on now to the sponsor presentation, and the
introduction will be made by Dr. Steve Caffe.

DR. CAFFE: Mr. Chairman, members of the advisory committee, members of
FDA, ladies and gentlemen, good morning. My name is Steve Caffe and I\'m
from the U.S. Regulatory Affairs Department at Aventis. It is my
pleasure to introduce the sponsor\'s presentation on Ketek, generic name
telithromycin.

Ketek is a ketolide antibiotic derived from the macrolides.

The indications we are seeking are for the treatment of
community-acquired pneumonia, acute exacerbation of chronic bronchitis,
and acute sinusitis.

As just Dr. Soreth just reviewed, Ketek was presented to this committee
in April 2001, which led to the recommendation that additional safety
and efficacy data would be needed, including efficacy on resistant
strains of S. pneumoniae and safety in a greater number of patients,
particularly the elderly and those with comorbid conditions.

In June 2001, an approvable letter was received for Ketek for the
treatment of CAP, AECB, and AS.

We are very pleased to be here today to share with you the results of a
large additional clinical program which was successfully designed in
collaboration with the Division of Anti-Infectives and which has
addressed all the concerns that have been raised. As presented earlier
also, this program included pharmacokinetic studies in special
populations, additional efficacy trials in CAP and AECB and a 24,000
patient safety study comparing telithromycin to amoxicillin-clavulanic
acid in a usual care setting. This study, focusing on the detection of
hepatic, cardiac, and visual and vasculitic adverse events, showed that
the safety of telithromycin is comparable to that of
amoxicillin-clavulanic acid.

Ketek was approved in the European Union in 2001, and post-marketing
data is available from the countries where it has been launched, mostly
coming from France and Germany. As of December last year, more than 1.5
million exposures were seen, and these data, taken together, show that
all the issues have been addressed and that the safety and efficacy of
Ketek have now been confirmed with this very large experience. The
presentation today will show that Ketek is an important new treatment
option for respiratory tract infections in the community setting.

The presentation will go as follows.

Dr. Iannini, who was the principal investigator for the large usual care
study, will discuss the medical need for a new anti-infective for the
treatment of respiratory tract infections.

Dr. Jenkins will review the microbiology of telithromycin.

Dr. Leroy will present the clinical efficacy data, including the
additional data on resistant strains of S. pneumoniae.

Dr. Bhargava will review the human pharmacology of telithromycin with
emphasis on special populations, as per the FDA\'s request.

And Dr. Lagarenne will present the clinical safety data to address the
questions that have been raised at the last Ketek advisory committee
meeting.

Dr. Iannini will then return to conclude.

In addition, several experts are here with us today who can assist the
committee with questions and deliberations. Their expertise covers all
the areas to be discussed. Full details of their titles and affiliations
have been provided to the committee.

I will now turn the podium over to Dr. Iannini.

DR. IANNINI: Well, good morning, ladies and gentlemen.

I\'ll be presenting the medical need for a new anti-infective agent for
community-acquired respiratory tract infections really from a
clinician\'s point of view.

Clinicians want agents available that have a targeted spectrum of
activity against the most common respiratory pathogens. These pathogens
include common bacteria, atypical organisms, and now strains that have
acquired antimicrobial resistance. And complete confidence in the
spectrum of activity is important because the vast majority of
ambulatory patients receive empiric therapy without the benefit of
microbiological guidance.

High potency against Streptococcus pneumoniae therefore is very
important. Rapid microbial killing is also desirable, as are therapeutic
choices that include concentration-dependent killing agents which allow
for shorter durations of therapy.

Clinicians are concerned with the effects of broader than necessary
therapy on the development of resistance in pathogens in other areas.

And safety is always a high priority for clinicians, as is acceptable
patient tolerance.

In selecting empiric therapy for community-acquired pneumonia, the
greatest concern is that the two pathogens with the highest risk of
mortality, Streptococcus pneumoniae and Legionella, are reliably
treated. The increasing level of resistance of Streptococcus pneumoniae
makes this an important issue.

Additionally, clinicians want reliable efficacy in patients with risk
factors such as clinically unsuspected bacteremia, advanced age, and
comorbid conditions. Treating AECB also requires reliable clinical
efficacy, as failure of initial therapy may result in the need for
hospitalization.

The clinician\'s concern in selecting treatment for patients with acute
sinusitis is to ensure that the organism associated with the highest
frequency of serious secondary complications, Streptococcus pneumoniae,
is well covered.

Patient convenience and compliance are also important for optimal
outcomes and are more probable with a short duration of therapy.

This diagram depicts the currently available agents. As you can see,
virtually all, telithromycin, macrolides, amoxicillin-clavulanate, and
the fluoroquinolones, have appreciable activity against the common
pathogens, Streptococcus pneumoniae, H. flu, and Moraxella cattarhalis.
Amoxicillin-clavulanic acid lacks activity against the atypical and
intracellular pathogens. Telithromycin and the fluoroquinolones have
activity against erythromycin and penicillin-resistant strains of
Streptococcus pneumoniae, while the macrolides have some activity
against penicillin-resistant strains of Strep. pneumo, and
amoxicillin-clavulanic acid has some activity against strains that are
resistant to the macrolides.

In terms of activity in other pathogens, telithromycin and the
macrolides have some modest activity against non-respiratory
Gram-negative rods, whereas there\'s appreciable activity of
amoxicillin-clavulanate and the fluoroquinolones which does raise the
concern of resistance development in this group of pathogens by some
clinicians.

Now, the current status of antimicrobial resistance in Streptococcus
pneumoniae is difficult to determine and that\'s because survey data may
overestimate rates of resistance. What is consistent and clear, however,
is that there\'s a growing trend towards resistance to penicillin-like
drugs and the macrolides. Resistance levels to fluoroquinolones are
currently low overall but do have an upward trend. And local outbreaks
of fluoroquinolone-resistant Streptococcus pneumoniae have occurred and
may be associated with high local rates of resistance. Resistance to
multiple drugs is now reported in approximately 10 percent of survey
isolates. This trend suggests the useful life of some older agents may
be diminishing.

What are the implications of increasing resistance? The higher MICs of
the more resistant isolates of Streptococcus pneumoniae have resulted in
the inability of some currently available and commonly employed agents
to achieve drug concentrations or time above the MIC that are predictive
of optimal clinical outcomes. This is a particular concern for isolates
with MICs of 8 micrograms per ml or greater to amoxicillin, 16 or
greater for the macrolides, and 4 or greater for fluoroquinolones.
Reports of clinical failures are being published and reported with these
commonly prescribed agents.

Despite the absence of controlled study data linking microbial
resistance to clinical failure, clinicians are asking the question, do
the available agents meet all of our clinical needs? Treating patients
with respiratory tract infections with antimicrobial agents that the
pathogen is likely to be reported as resistant to is at best
uncomfortable for practitioners.

The clinical implications of resistance are under considerable debate,
as you\'ve early this morning. Some current publications suggest there
is an increase in mortality and an increase in the incidence of
suppurative complications such as empyema. When isolates of
Streptococcus pneumoniae exhibit high level penicillin resistance.
Controlled studies of outcomes in patients receiving concordant versus
discordant therapy for highly resistant Streptococcus pneumoniae in
community-acquired pneumonia are sparse, and they\'re also limited by
the inclusion of small numbers of highly resistant strains. To date they
fail to show increased mortality related to resistance to beta-lactams.

Other outcomes such as length of hospitalization and secondary
complications have not been extensively studied.

Similarly with macrolides, recent papers show a high likelihood of
failure to prevent breakthrough bacteremia when macrolide therapy is
used to macrolide-resistant Streptococcus pneumoniae when it causes
community-acquired pneumonia even when the mechanism of resistance is
efflux, and many of these failures were patients who were started on
macrolides in the community and then presented on day 3 to 5 with
bacteremia.

Clinical failures with macrolides in non-bacteremic cases have also been
reported.

Fluoroquinolone failures in subjects infected with strains that are
either initially resistant or that acquire resistance mutations during
therapy have also been reported. There is concern on the part of some
clinicians of an increasing incidence of resistance mutations in
isolates that are reported in the susceptible range because additional
mutations on therapy could increase the risk of clinical failure. This
concern is greater for the older, pre-8-methoxy-fluoroquinolones.

Clinicians want to be able to choose agents that have potent activity
against the pathogens including those that are resistant to current
drugs. They want rapid bactericidal agents and they want activity at the
site they\'re treating and not elsewhere. They want reliable therapy for
unsuspected bacteremia in the ambulatory setting. They want to be able
to prescribe therapy that is most likely to be the greatest potential
benefit to their patients. All of these factors create the need for a
new antimicrobial agent for respiratory tract infections.

I\'d like now to introduce Dr. Stephen Jenkins who will discuss the
microbiological aspects of telithromycin.

DR. JENKINS: Good morning, ladies and gentlemen.

I\'ll be spending a few minutes today discussing several of the salient
features of the microbiology of telithromycin. First I\'d like to
briefly describe the issues that I\'ll be discussing over the next
approximate 10 minutes.

Telithromycin is the first of the new ketolide class of antibacterial
agents. It\'s differentiated from the macrolides, from which it was
actually derived, based on its dual binding mechanism. This enhanced
binding to the bacterial ribosome has endowed the compound with a very
focused spectrum of activity that encompasses all of the common
community-acquired respiratory tract pathogens and does so without
disrupting, to any significant degree, the usual enteric or anaerobic
gastrointestinal flora.

Specifically, the drug demonstrates very good activity against
Haemophilus influenzae, irrespective of beta-lactamase production;
Moraxella cattarhalis, irrespective of beta-lactamase production;
methicillin-susceptible strains of Staphylococcus aureus; Streptococcus
pyogenes; and the atypical and intracellular pathogens, including
chlamydophila, or as we used to say, Chlamydia pneumoniae, Mycoplasma
pneumoniae and Legionella pneumophila.

Telithromycin is especially active against strains of Streptococcus
pneumoniae, including the increasingly common macrolide-, penicillin-,
and multi-drug-resistant strains, and unlike the macrolides demonstrates
rapid, concentration-dependent bactericidal activity.

First, I will address the novel mechanism of action of this compound
that clearly differentiates it from the macrolides. Telithromycin
inhibits protein synthesis by binding to two specific sites on the
bacterial ribosome, thereby interfering with elongation of the nascent
polypeptide chains. Like all MLS class antibiotics, it interacts with
domain V on the 23S ribosomal RNA at position A2058. But unlike the
macrolides or clindamycin, it also binds strongly to domain II at
position A752.

As a function of this dual binding, telithromycin is active against the
vast majority of macrolide-resistant strains of Streptococcus
pneumoniae. In fact, in the ongoing U.S. PROTEKT surveillance study, the
MIC99 was 1 microgram per ml against macrolide-resistant strains of
Streptococcus pneumoniae. This means that less than 1 in 100 clinical
isolates exceed the proposed susceptibility testing breakpoint for
macrolide-resistant pneumococci.

On this slide, we\'ve attempted to depict the novel binding of
telithromycin diagrammatically. If the position A2058 is blocked either
by methylation or is changed due to a mutation, it renders the
macrolides and clindamycin, in effect, inactive against strains of
Streptococcus pneumoniae. By comparison with telithromycin, because it
has a binding site both at A2058 and at A752, methylation at that site
or mutation at that site does not render the compound inactive, and in
fact the drug remains active against these strains.

On this next slide, the current United States antimicrobial resistance
data from the PROTEKT program are depicted geographically. PROTEKT is a
very well-controlled surveillance program with both national and
international arms. It identifies at the molecular level the genes that
are responsible for antimicrobial resistance among strains of
Streptococcus pneumoniae. High-level penicillin resistance is now
demonstrable in every part of the United States, as is macrolide
resistance, the orange bars. And although somewhat variable
geographically, approximately 10 percent of all strains of Streptococcus
pneumoniae in the United States are now multiply drug-resistant, defined
as resistance to penicillin, the macrolides, the tetracyclines, and
trimethoprim-sulfamethoxazole.

On this slide, the overall current antibiotic resistance rates for very
well characterized strains of Streptococcus pneumoniae are presented.
Among over 10,000 isolates that were recovered in the United States in
the 2000-2001 respiratory tract season and tested in the central
laboratory, approximately a quarter were fully resistant to penicillin
with MICs greater than or equal to 2 micrograms per ml. Of real concern,
approximately one-third were cross-resistant to all of the macrolide
class antimicrobial agents, 13 percent were resistant to clindamycin, 31
percent to trimethoprim-sulfa, and 22 percent to the tetracyclines, all
compounds frequently used for treatment of respiratory tract infections
in the outpatient setting.

Now, although admittedly higher than the rates that are observed among
the isolates that were recovered during the past 5-plus years in the
clinical trials performed by Aventis, if you take a look at the 3,700
blood culture isolates recovered in 2000-2001 in this surveillance
program, 21 percent of those blood culture isolates were fully resistant
to penicillin and 25 percent were fully resistant to the macrolides.
This is consistent with the susceptibility results observed in the
overall PROTEKT program.

Although still relatively low at 0.9 percent, resistance to the
fluoroquinolones was observed in more than 80 isolates in this study,
including 14 recovered from blood cultures. And telithromycin was active
against every one of those isolates.

On this next slide, the in vitro activity of telithromycin against the
common bacterial pathogens associated with community-acquired
respiratory tract infection are presented. The compound is clearly
highly active against Streptococcus pneumoniae with an MIC50 of only
0.015 micrograms per ml ‑‑ this is the concentration that would be
expected to inhibit at least half of all clinical strains ‑‑ and an
MIC90 of 0.5 micrograms per ml.

Telithromycin also has very good activity against Haemophilus
influenzae, irrespective of beta-lactamase production; Moraxella
cattarhalis, again irrespective of beta-lactamase production;
Staphylococcus aureus for methicillin-susceptible strains. Telithromycin
has very limited activity against methicillin-resistant strains of
Staph. aureus. And finally, Streptococcus pyogenes, an organism that we
see not infrequently in acute bacterial sinusitis, likewise the compound
demonstrates excellent activity.

For Haemophilus influenzae, another important point to raise is the fact
that this compound does demonstrate concentration-dependent bactericidal
activity unlike the macrolides such as azithromycin that demonstrate
time-dependent bactericidal activity. In addition, as will be discussed
by Dr. Bhargava in his presentation, the levels of telithromycin that
are demonstrable in the epithelial lining fluid of subjects with
respiratory tract infections, approximately 15 micrograms per ml, 2 to 3
hours after a standard 800 milligram dose, significantly exceed the
MIC50 of 1 microgram per ml and the MIC90 of 2 micrograms per ml for
Haemophilus influenzae. And likewise, the drug is significantly
concentrated by the alveolar macrophages that are recruited to the site
of the infection, with levels exceeding 300 micrograms per ml 10 to 12
hours after standard dosing.

As demonstrated on this slide, telithromycin also exhibits excellent
activity against the atypical and the intracellular pathogens that are
typically refractory to the beta-lactams in vitro and is particularly
strong against strains of Legionella pneumophila. In addition, the MIC90
and the MCC90, which is the minimum chlamydicidal concentration, are
identical for chlamydophila pneumoniae at 0.25 micrograms per ml.

Without dwelling on the actual MICs in any great detail, as is presented
on this slide, telithromycin maintains its activity against
macrolide-resistant strains of Streptococcus pneumoniae, right here,
whether it be due to methylation of the ribosome, the ermB strains, or
efflux, the mefA strains. It is also active against strains that harbor
both mechanisms of resistance, methylation and efflux. The compound is
also active against essentially all penicillin-resistant pneumococci,
fluoroquinolone-resistant pneumococci, and multi-drug-resistant
pneumococci.

The distribution of MICs, as depicted on this slide, clearly shows that
telithromycin retains activity against macrolide-resistant pneumococci,
with MICs typically ranging from less than .015 micrograms per ml up to
around 1 microgram per ml. By comparison, the MICs for all of the
macrolides has shifted far to the right, with MICs frequently greater
than 16 micrograms per ml. In fact, in this program when they went back
and retested these isolates with MICs greater than 16, the majority of
them actually had MICs in the range of 256 micrograms per ml, clearly
far higher than the achievable levels for these compounds.

Importantly, approximately 59 percent of the isolates that were
resistant due to the efflux mechanism were, in fact, highly resistant
with MICs of 16 micrograms per ml or greater, and 69 percent of all of
the blood culture isolates in this program that were resistant because
of efflux likewise had MICs of greater than 16 micrograms per ml, levels
clearly non-achievable with the macrolides.

Similarly, unlike the Gay study in Atlanta where 15 percent of so of the
macrolide-resistant strains were penicillin-resistant, 67 percent of the
macrolide-resistant strains due to efflux in the PROTEKT program were
also resistant to penicillin.

The bactericidal activity of telithromycin, even against strains of
pneumococci that are resistant to the macrolides because of efflux or
methylation of the ribosome, is demonstrated on this slide. Although
strain-to-strain differences were sometimes seen, bactericidal activity
was almost uniformly observed.

Finally, as described on this slide, telithromycin has been shown to
have a low propensity to select for antibiotic-resistant mutants. In
vitro telithromycin fails to induce MLSB resistance amongst the common
respiratory tract pathogens, and in serial passage experiments has been
shown to be less likely to select antiobotic-resistant mutants of
Streptococcus pneumoniae than other MLS class compounds.

Telithromycin also demonstrated a lower propensity to select for mutants
resistant to itself amongst the normal oropharyngeal flora, the viridans
group streptococci, than was clarithromycin in a controlled clinical
trial. This is important since it\'s been shown that the resistance
genes in Streptococcus pneumoniae have actually been picked up,
including the mosaic penicillin resistance genes, through the process of
transformation from these oropharyngeal viridans group streptococci.

In summary, telithromycin is the first of the new ketolide class of
antibiotics.

Unlike the macrolides or clindamycin, it binds tightly to two different
sites on the 23S ribosomal RNA.

It has a very focused spectrum of activity against the
community-acquired respiratory tract pathogens and, unlike compounds
such as the fluoroquinolones, does not significantly alter the normal
Gram-negative or anaerobic gastrointestinal flora.

Telithromycin appears to select for resistant mutants at a very low
frequency, has done so in animal models and in controlled clinical trial
situations.

And finally, telithromycin is especially active against Streptococcus
pneumoniae, the most common cause of infection in all of the indications
being requested regardless of the organism\'s susceptibility or
resistance to other antimicrobial agents.

Thank you for your attention, and I\'d like to now turn the podium over
to Dr. Leroy for his presentation on the clinical efficacy of the
compound.

DR. LEROY: Good morning. We will now review the clinical efficacy data.

14 clinical efficacy studies were performed with telithromycin in three
indications: community-acquired pneumonia with a duration of treatment
of 7 to 10 days except in a recent study where a 5-day treatment
duration was investigated, acute exacerbation of chronic bronchitis with
a treatment duration of 5 days, and acute sinusitis with a treatment
duration of 5 or 10 days.

Elements of the study design were standardized across all indications in
all studies, and the test of cure was performed between day 17 and day
21 at the same time after the study start in all groups. And this
approach is very stringent since it allows the capture of early relapses
in the test of cure, which is the main analysis. And this approach is
also recommended by the FDA.

In studies with 5-day treatment duration of telithromycin, a placebo
period of 5 days was added in order to maintain the blind.

In western countries, four double-blind comparative studies were
performed in the indication of pneumonia, with a total of 1,583 subjects
treated, 881 subjects treated with telithromycin 800 milligrams once
daily for 5 to 10 days. Comparators included amoxicillin high doses of 1
gram given three times daily for 10 days, clarithromycin 500 milligrams
given twice daily for 10 days in two studies, and trovafloxacin 200
milligrams given once daily for 7 to 10 days.

In addition, 1,408 subjects were treated in four non-comparative
studies, three of these referred as to enriched studies since the
inclusion criteria were modified in order to increase the number of
Streptococcus pneumoniae at inclusion and in order to increase the
number of strains resistant to the macrolides or to penicillin G.

Data will also be presented on resistant S. pneumoniae from two studies
from Japan, with a treatment duration of 7 days and a dosage of 800 or
600 milligrams once daily. And these include one dose comparison study
and one comparative study versus levofloxacin given for 7 days.

In total, more than 2,500 subjects were treated with telithromycin in
pneumonia in phase III studies, and we will see later that the clinical
experience with strains of S. pneumoniae resistant to the macrolides has
almost doubled to a total of 50 strains in this presentation.

On this slide, the bars represent the cure rates with telithromycin in
blue and the comparators in gray, and at the bottom of the bars are the
study numbers and the comparator used. At the top of the bars are the
cure rates and the 95 percent of the difference in cure rates between
the two treatment groups.

The per-protocol clinical population was the population used for the
primary analysis and will be used throughout the presentation. And
results obtained in the modified intent-to-treat analysis, which
excluded subjects with a clear misdiagnosis, were always consistent with
the per-protocol data and are displayed in the briefing document.

Cure rates obtained with telithromycin showed that telithromycin was
equivalent to high-dose amoxicillin and to clarithromycin in two
studies, with telithromycin cure rates ranging between 88 and 95
percent, and a lower bound of the 95 percent confidence interval well
within plan limits. Equivalence was also shown in the modified
intent-to-treat analysis with a stringent delta of 10 percent.

Of note, in a recent study 4003, equivalence was also demonstrated
between telithromycin given for 5 days and clarithromycin given for 10
days.

Study 3009 with trovafloxacin was stopped before the planned sample size
was reached when the FDA restricted the use of trovafloxacin, but these
results show an efficacy rate of 90 percent of telithromycin and also
supports the efficacy of this drug in this indication.

In the telithromycin group, the clinical cure rate by pathogens for the
targeted organism observed in our patients varied between 88 and 95
percent, with the highest cure rates observed for Streptococcus
pneumoniae. Excellent efficacy was also shown for Haemophilus influenzae
in this indication, and this was based on a large number of patients,
over 200 patients.

For atypical pneumonia, stringent serologic criteria were used and no
common pathogens were to be present in order for the patient to qualify
for this diagnosis. The cure rates were over 90 percent for all atypical
pathogens, and interestingly 13 subjects were diagnosed with Legionella
infections for which early effective treatment is needed to avoid severe
complications, and all those 13 subjects were cured.

On the next two slides, I\'d like to show you the efficacy against the
two main pathogens of the indication, Streptococcus pneumoniae and
Haemophilus influenzae, according to telithromycin MIC.

Let\'s begin first with Streptococcus pneumoniae, the most important
organism to consider in this indication. What we can see, as already
stated by Dr. Jenkins, is that telithromycin is highly effective with
outstanding in vitro activity against the strains of S. pneumoniae since
the majority is below 0.016 microgram per ml, and for the strains with
an MIC over 0.25 microgram per ml, the clinical efficacy was excellent.

Now, when we look at Haemophilus influenzae, the key point I\'d like to
make here is that high bacterial eradication and clinical efficacy was
observed up to an MIC of 8 microgram per ml.

Let us now examine the outcome in patients with resistant isolates of
Streptococcus pneumoniae treated with telithromycin, and the results
obtained in western countries and in Japan are presented on this slide.

We can see here that the efficacy rates are high both for
penicillin-resistant strains and macrolide-resistant strains, over 85
percent, and the number of strains isolated in this program is high,
with macrolide-resistant strains of Streptococcus pneumoniae with 50
isolates. With these 50 strains, this enables us now to evaluate the
efficacy of telithromycin according to the genotype of resistance, and
the main point here is that the efficacy appears similar in patients
with an ermB, that is to say, MLSB mechanism of resistance, or with mefA
strains, that is to say, efflux mechanism of resistance.

And of note, most of the strains with an MLSB mechanism of resistance
displayed a very high level of resistance to erythromycin, as expected,
with MIC to erythromycin greater or equal to 32 micrograms per ml and
telithromycin was very effective against those strains.

As said earlier by Dr. Iannini, one critical attribute of an antibiotic
to be used in the community setting in patients with pneumonia is the
activity in subjects with pneumococcal bacteremia. And the numbers
obtained in this clinical development program are now very substantial
given that these were outpatients treated with an antibiotic given
orally. Telithromycin was shown to be highly effective in the 82
subjects microbiologically evaluable, exhibiting an efficacy rate of 90
percent. And if we look at the subset of patients with resistant
Streptococcus pneumoniae, five out of seven strains resistant to
penicillin G were cured, and 8 of the 10 subjects with Streptococcus
pneumoniae resistant to the macrolides were cured.

It should be noted that among the two failures that are displayed in
this row, they are the same patients. One patient did have eradication
of S. pneumoniae resistant to penicillin G and erythromycin A with
sterile blood culture and clear clinical improvement, but this subject
was classified as a failure because of a secondary infection due to
Staphylococcus aureus.

In addition, 4 other subjects had a sputum positive with
macrolide-resistant strains of S. pneumoniae and a Binax antigen soluble
urinary test for S. pneumoniae positive. And all those 4 subjects were
cured. This is important because for some authors it has been considered
as a surrogate of a systemic infection in subjects with a negative blood
culture.

Given the expected low rates of resolutions and the risk of
complications and even death in patients with untreated pneumococcal
bacteremia, these results clearly strengthen the proof of efficacy of
telithromycin against strains of Streptococcus pneumoniae resistant to
the macrolides.

What is important to consider in the outpatient setting is the
population of subjects with underlying diseases or criteria of severity
which are more prone to develop severe complications. And telithromycin
was shown to be highly effective in the elderly in subjects with
pneumococcal bacteremia and in subjects with a Fine score greater or
equal to 3. This is based now on a substantial number of subjects when
we pooled all the data from the pneumonia studies.

In summary, telithromycin given 800 milligrams once daily for 7 to 10
days was highly effective in community-acquired pneumonia. High cure
rates were obtained for the key pathogens isolated in outpatients, both
common pathogens, including also ERSP and PRSP, and atypicals including
Legionella pneumophila. And efficacy was also shown in the most
vulnerable patients, that is to say, elderly and patients with
pneumococcal bacteremia.

I will now present the results obtained in the acute exacerbation of
chronic bronchitis. Three randomized, double-blind, controlled
comparative studies were performed, including over 1,200 subjects
treated, 612 treated with telithromycin 800 milligrams given once daily
for 5 days. And the comparators were amoxicillin-clavulanic acid 500
milligrams given three times daily for 10 days, cefuroxime axetil 500
milligrams given twice daily for 10 days, and clarithromycin 500
milligrams given also twice daily for 10 days.

Patients enrolled in this study had a history of chronic bronchitis as
per IDSA guideline definitions, and in study 3003 versus
amoxicillin-clavulanic acid, all subjects were to have a documented
bronchial obstruction at entry.

In addition, patients were enrolled with at least two or three criteria
of exacerbation which are the most established Anthoniesen criteria used
to identify patients who benefit from antibiotic treatments.

In the per-protocol clinical population, the clinical cure rate after
the short 5-day treatment with telithromycin was equivalent to the
longer 10-day treatment with the comparators used:
amoxicillin-clavulanic acid, cefuroxime axetil, or clarithromycin, all
given for 10 days two to three times daily. Noninferiority was also
demonstrated with a delta of 10 percent in all those three studies in
the modified intent-to-treat analysis, which is also displayed in the
briefing document.

In this indication in which the outcome is highly related to the
underlying condition, the cure rate for the key pathogens ranged from 73
to 93 percent for clarithromycin and 79 to 85 percent for the comparator
groups. For telithromycin, the cure rates were slightly better for
Streptococcus pneumoniae and Moraxella cattarhalis, but also
telithromycin exhibited a 90 percent cure rate in patients diagnosed
with Chlamydia pneumophila infections which seems to play a role in the
progression of the obstruction in this indication.

We\'ve also verified that telithromycin was effective in the outpatients
most likely to develop complications in this indication and cure rates
were around 80 percent and similar to the active comparators in elderly
in subjects with morbidity risk factors and in subjects with a
significant bronchial obstruction.

To summarize, telithromycin 800 milligrams once daily for 5 days is
effective in the treatment of acute exacerbation of chronic bronchitis
in patients requiring antibiotic treatment, that is to say, patients
with two Anthoniesen criteria of exacerbation and with a spectrum
targeted to common respiratory pathogens, including also Chlamydia
pneumoniae. Efficacy was demonstrated also in the outpatients most
likely to develop complication, in particular the elderly and patients
with a significant bronchial obstruction.

Let us now turn to the efficacy data obtained in acute sinusitis. Three
randomized, double-blind studies were performed to support this claim,
comparing telithromycin 5 days with telithromycin 10 days, each given
800 milligrams once daily, and this study was performed in patients with
total opacity or air fluid level in their sinus x-ray and all subjects
had a sinus puncture for bacterial documentation at entry. 5 and 10 days
telithromycin with 10 days treatment with amoxicillin-clavulanic acid
given 500 milligrams three times daily for 10 days, and 5 days
telithromycin with cefuroxime axetil 200 milligrams given twice daily
for 10 days. And this study also included bacterial documentation at
entry in outpatients.

In the comparative studies, equivalence was demonstrated between
telithromycin given for 5 days and the two standard treatments in this
indication, amoxicillin-clavulanic acid and cefuroxime axetil, each
given for 10 days. And cure rates after the 5- or the 10-day
telithromycin evaluated in two studies were also shown to be equivalent.

Clinical cure rates for all targeted pathogens were high and comparable
for the 5-day treatment, 10-day treatment with telithromycin, with rates
over 85 percent for Streptococcus pneumoniae, Haemophilus influenzae,
and Moraxella catarrhalis, as well as Staphylococcus aureus, in fact,
frequently isolated in this indication.

Looking now at the experience obtained with Streptococcus pneumoniae
resistant strains in the sinusitis trial, the first point I would like
to make is that the macrolide-resistant strains were at a higher rate,
above 30 percent, in the sinusitis clinical trial in the U.S. centers.

And I will focus first on the population of patients pooled from the 5-
and 10-day treatment duration treated with erythromycin, which are
displayed on the right of the table. 11 out of 13 strains
penicillin-resistant were cured and 18 out of 21 cases with strains
resistant to the macrolides were cured. Effectiveness was also shown in
the 5-day group with rates over 85 percent in patients with
macrolide-resistant strains.

Looking now at key subgroups in this indication, we note that in
subjects with 7 days of symptoms or more or in subjects with a pathogen
isolated at entry, the efficacy of telithromycin was above 80 percent,
and for subjects with signs of severe illness at entry or total opacity
on their sinus x-ray at entry, the efficacy is also above 80 percent.
And in all the subgroups, telithromycin had comparable efficacy versus
the comparator treatments.

To summarize, telithromycin 800 milligrams once daily for 5 days is
effective in the treatment of acute sinusitis and comparable to widely
used standard comparators in this indication. Telithromycin also proved
to be highly effective against the four main pathogens encountered in
this indication, Streptococcus pneumoniae, Haemophilus influenzae,
Moraxella catarrhalis, and Staphylococcus aureus, but also emerging
strains of Streptococcus pneumoniae.

In conclusion, telithromycin was consistently shown to be effective in
14 clinical efficacy studies in treatment of three respiratory tract
indications: in acute exacerbation or acute sinusitis with a treatment
duration of 5 days, which was equivalent to a 10-day treatment regimen
of a standard antibiotic given two to three times daily, and will favor
a better compliance; in community-acquired pneumonia with a treatment
regimen of 7 to 10 days. And a large experience has been obtained in
patients most likely to develop complications in all three indications.

Finally, as mentioned earlier, one of the main differentiating features
of telithromycin is its very focused, targeted spectrum to respiratory
tract pathogens, and high efficacy was demonstrated against both common
and atypical pathogens in this indication, as well as against
Streptococcus pneumoniae resistant to penicillin G or to the macrolides.

I would like to thank you for your attention, and I will now turn it
over to Dr. Bhargava who will present the key clinical pharmacology
results obtained with telithromycin.

DR. BHARGAVA: Good morning. Today I\'m pleased to present the clinical
pharmacology characteristics of telithromycin which primarily address
two key pharmacokinetic issues raised by the FDA: first, the variability
in the pharmacokinetics of telithromycin, specifically in the
multiple-impaired population, and second the drug-drug interaction
potential of this drug.

To address these topics, we have extensively examined the
pharmacokinetics of telithromycin, and I will cover three important
aspects.

First, I will present the key plasma and tissue pharmacokinetic
characteristics of telithromycin supporting the once-a-day dose regimen
and high and sustained tissue levels for the duration of the dosing
interval.

Second, I will present the multiple elimination pathways of
telithromycin which limits the increase of its exposure when elimination
pathways are blocked.

And third, we will look at the drug interaction potential of
telithromycin to impact levels of other drugs that are metabolized by
the CYP3A4 pathway. Data will support that this effect is similar to
that observed with widely used drugs such as clarithromycin.

The pharmacokinetic data shown on this slide has been confirmed in
several other studies. In summary, a few important points about the
plasma pharmacokinetics. Absorption is rapid, as shown by the short
Tmax. Maximum plasma concentration of over 2 micrograms per ml are
achieved. Steady state was rapidly achieved after the second or third
dose with a terminal half-life of 7 to 10 hours.

Next, let\'s look at the tissue concentrations of telithromycin after a
800-milligram once daily dose to steady state. We see that in both
tissues, the epithelial lining fluid as an example of extracellular
tissue and alveolar macrophage for intracellular tissue, concentrations
are rapidly achieved and maintained for 24 hours, the dosing interval.
Note that levels in epithelial lining fluid, as high as 14.9 micrograms
per ml were achieved. Levels in the tissues are well above the targeted
MICs.

There are multiple pathways of telithromycin elimination. As mentioned
before by Dr. Jenkins, there is structural similarity of telithromycin
to macrolides. I will present data to show that the disposition and
exposure profile of telithromycin is similar to that seen with
macrolides such as clarithromycin. The disposition profile shows that
the absorption is good, over 90 percent, after oral absorption. 33
percent undergoes first-pass metabolism, resulting in an absolute
bioavailability of about 60 percent.

Once in the systemic circulation, it has several routes of elimination.
It can be excreted as unchanged drug in the feces with the biliary
excretion or as unchanged drug in urine with a renal excretion, and it
is further metabolized into several metabolites. Total metabolism is
about 70 percent.

Three important points about the metabolism of telithromycin. One, about
a third of the dose is mediated by non-cytochrome P450 which which are
rarely associated with clinically relevant drug interactions. Another
third is mediated by the CYP P450 isozyme. Data will shown that due to
the limited involvement of the CYP3A4, the potential for increased
exposure in situations when this pathway is blocked is minimal. In
addition, the well-known polymorphic isozyme 2D6 is not involved in the
metabolism of telithromycin.

In collaboration with the FDA, we examined the exposure of telithromycin
under conditions of impairment. The hepatic and renal study looked at
the effect of mild, moderate, and severe impairment on telithromycin
exposure compared with a healthy controlled population. The effects of
3A4 impairment were examined using a crossover design where
telithromycin levels were measured in healthy subjects when they were
either receiving or not receiving the potent 3A4 inhibitor ketoconazole.

Additionally, we stressed the system and looked at telithromycin
exposure when both the metabolic and renal pathways were impaired. We
did this by administering telithromycin to subjects who were greater
than 60 years of age with renal impaired function and to whom we also
administered ketoconazole to block their CYP3A4 pathway. A
clarithromycin arm was also used in this study to compare the exposure
seen with telithromycin in this population.

Let\'s examine the results from each of these studies.

First, the hepatic impairment study. The data in the mild, moderate, and
severe groups were not different and hence are presented as combined
data. In all stages of renal impairment, there were no changes seen in
either Cmax or AUC. Please note the increase in renal clearance for
subjects with hepatic impairment compared to the sex- and age-matched
healthy controls. These results indicate that renal elimination is a
compensatory pathway in situations where the liver is impaired. These
findings for telithromycin are similar to what has been well documented
for clarithromycin.

Let us now look at the data related to renal impairment. The study
compared a control group of subjects with greater than 80 mls per minute
to subjects with different degrees of renal impairment, mild, moderate,
and severe. The mild and moderate groups showed small increases in Cmax
and AUC, and in the severe renal group, the increase was limited to
1.5-fold and 2-fold in Cmax and AUC, respectively.

Here we see the effects of blocking the CYP3A4 pathway by the
administration of ketoconazole. We see that with a strong inhibitor,
there is a 1.5-fold change in Cmax and about a 2-fold change in AUC.
With other inhibitors such as itraconazole, a lesser interaction was
observed, and with grapefruit juice no interaction was observed.

At the request of the agency, we looked at the additive effect on
exposure when both the renal as well as the metabolic pathways were
impaired. In these patients with multiple impairment, the Cmax and AUC
seen here are only modestly above those seen previously when only the
CYP3A4 pathway alone was blocked. Thus, the added effect of renal
impairment on top of the 3A4 pathway being impaired is minimal.

While the intent of the study was to recruit individuals whose
creatinine clearance was between 30 and 80, we had two individuals in
the telithromycin group who had creatinine clearance less than 30 mls
per minute. Data for both these individuals is shown here, and higher
exposures are seen as compared to those with creatinine clearance
greater than 30 mls per minute. We will put these levels into
perspective in a few moments.

As mentioned previously, a clarithromycin arm was used in this study to
look at the exposure of this drug in a similar population. The Cmax and
AUC of clarithromycin are shown here. Let\'s put these exposures seen
for both drugs in the multiple impaired population in context.

These are the exposure data for telithromycin and clarithromycin that we
have just seen in the multiple impaired population. Cmax data are shown
on the left panel and AUC on the right panel. We now add the comparative
healthy population for these two drugs. The healthy population for
telithromycin is from an Aventis study, and the healthy population for
clarithromycin is from the literature. We can see that the increase in
Cmax and AUC for telithromycin is comparable to that seen for
clarithromycin in this population. These data demonstrate that in this
population, where multiple pathways are blocked, the increase in
exposure of telithromycin is limited and comparable to that observed
with clarithromycin.

In addition, the electrocardiograms obtained in this study were analyzed
for prolongation of the QT interval using well-defined outlier criteria.
That is, QT corrected outlier criteria of QTc, that is, QT corrected for
heart rate which is greater than 450 milliseconds for males and greater
than 470 milliseconds for females or a change of greater than 60
milliseconds measured at multiple time points throughout the dosing
interval following drug ingestion. These outlier criteria were not met
by any subject in the telithromycin treated group during the entire
dosing interval.

So let\'s summarize the data that we have just seen.

The data shown here are the fold increase in telithromycin exposure in
special populations when compared to healthy controlled data. All data
shown here are at the 800 milligram dose under steady state conditions.
Two important points from this slide.

First, we see that under various conditions of impairment, hepatic
impairment, renal impairment with mild, moderate, or severe, CYP3A4
inhibition with a potent inhibitor ketoconazole and milder with
itraconazole, and including in the multiple impaired population when
creatinine clearance is greater than 30 mls per minute, the
telithromycin levels, as measured by Cmax and AUC, show no significant
increase in exposure. The only exception is the situation with multiple
impairment where creatinine clearance is less than 30 mls per minute. A
dose adjustment is recommended in this population.

Second, in studies where we had a control population as part of the same
study, the variability estimates are shown. We see that the variability
is limited and that the upper end is well defined.

In the last few slides, we have looked at the effect of impairment on
telithromycin levels. We now change gears and look at the potential of
telithromycin to impact the levels of drugs that are metabolized by the
3A4 route.

Simvastatin is a drug with high first pass effect and low
bioavailability. Due to this, it is known to interact with several
inhibitors of the CYP3A4 isozyme. When telithromycin and simvastatin are
given together, we see that there is an increase in both the levels of
simvastatin and simvastatin acid.

To put this level of interaction in context, we see the effect of
several other CYP3A4 inhibitors on the levels of simvastatin. We see
that the interaction with clarithromycin is similar to that seen with
telithromycin. And a larger interaction on simvastatin is seen with
grapefruit juice and itraconazole.

Telithromycin is administered once a day, and knowing the kinetics of
CYP3A4 inhibition, we conducted a study to evaluate the
telithromycin-simvastatin interaction when the drugs are administered
together or administered separately. The data showed that we see a more
than 50 percent reduction in the level of interaction for both
simvastatin and simvastatin acid under these dosing conditions.

Before we move on, I\'d like to point out that as mentioned in the
sponsor\'s briefing book, data analysis for the
clarithromycin-simvastatin interaction shown on the previous slide and
the telithromycin-simvastatin interaction shown on this slide have been
recently completed and submitted to the agency.

As stated before, simvastatin is sensitive to the inhibition of 3A4. Two
other 3A4 substrates were also investigated, midazolam and cisapride.
Comparison of interaction between telithromycin and clarithromycin on
these 3A4 substrates are shown here. We see that the level of
interaction for telithromycin is similar to that observed for
clarithromycin for both of these 3A4 substrates. Thus, the CYP3A4
inhibition potential of telithromycin is similar to or less than that
observed with clarithromycin.

In summary, telithromycin pharmacokinetics have been extensively
investigated under stressed conditions. Its pharmacokinetics are
reproducible and variability is limited.

Telithromycin rapidly achieved plasma and respiratory tissue
concentrations above the MICs of the relevant pathogens.

Telithromycin has multiple pathways of elimination and its metabolism by
the CYP3A4 isozyme is limited. It is also metabolized by non-CYP3A4 P450
pathways and these properties limit its potential for increased exposure
when multiple pathways are blocked. The potential for telithromycin to
increase the exposure of other drugs that are metabolized by the CYP3A4
pathway is comparable to clarithromycin and significantly less than
potent inhibitors such as ketoconazole.

In addition, telithromycin is dosed once daily and for a limited
duration in patients with respiratory tract infections, further
lessening the potential for drug interactions.

I thank you for your attention and would like to ask Dr. Lagarenne to
present the safety data on telithromycin.

DR. LAGARENNE: Thank you and good morning.

Today I\'m pleased to present our extensive safety experience with
telithromycin with data available from three key sources.

Phase III studies enrolled nearly 4,500 telithromycin-treated subjects,
with nearly 3,000 of these in controlled clinical trials.

Study 3014, our large usual care study, enrolled more than 24,000
patients, including more than 12,000 subjects treated with
telithromycin, making this the largest randomized comparative clinical
trial ever performed for an anti-infective agent. This unique study,
designed in collaboration with the FDA to address concerns raised at the
last advisory committee, utilized a variety of methods to increase
exposure in more diverse risk populations and to enhance safety
monitoring.

And finally, telithromycin has been approved and marketed in Europe and
other countries for over 15 months, providing more than 1.5 million
exposures to help us confirm the overall safety profile of
telithromycin.

Phase III studies provided an initial assessment of the overall safety
profile of telithromycin, and I will focus on the controlled clinical
trials.

This slide displays the most frequent adverse events reported in phase
III controlled clinical trials irrespective of investigator causality.
The pooled comparators in these studies included penicillins,
beta-lactams, macrolide, and quinolone antibiotics. The frequency of
subjects with adverse events was balanced between treatment groups, with
the most common adverse events reported in both treatment groups being
gastrointestinal in nature.

In controlled phase III studies, adverse events leading to
discontinuation of study treatment, serious adverse events, serious
adverse events considered possibly related to study drug and deaths were
all uncommon and balanced between the treatment groups.

The most common events leading to drug discontinuation were
gastrointestinal in nature. Most of the serious events ‑‑ as you can see
here, there are very few that were considered treatment related ‑‑ were
infectious or respiratory events related to underlying illnesses rather
than to the study drug, and none of the deaths in these studies were
considered related to study drug by the investigator.

Blurred vision was an uncommon event of note that occurred more
frequently in the telithromycin-treated subjects in phase III studies.
However, the incidence was very low, occurring in 0.6 percent of
telithromycin-treated subjects. Further, this event was generally mild,
of limited duration, fully reversible, and with no sequelae. There were
no serious reports and only one subject in controlled trials required
discontinuation due to this event.

This visual effect was further characterized in two phase I studies and
potential mechanisms were also investigated. Healthy volunteers were
administered supratherapeutic doses of up to 2,400 milligrams and a
number of ophthalmic examinations were performed. Blurred vision was
most frequently described as a delay in focusing from near to far vision
and occurred almost exclusively in subjects under the age of 50. Onset
was generally within a few hours of dosing which corresponds to the Tmax
observed in the clinical pharmacology studies, with rapid and full
recovery noted within 2 to 3 hours. Although described as blurred
vision, actual decreases in visual acuity were not noted. More
importantly, thorough evaluation ruled out etiologies associated with
potential irreversible vision loss such as angle closure-glaucoma and
retinopathy. Altogether these findings suggest a mechanism consistent
with a slight delay in focusing.

Phase III studies also included detailed cardiac evaluation designed to
determine the relevance of data obtained from preclinical studies
revealing activity at the IKr channel comparable to those observed with
currently marketed macrolide antibiotics. ECGs were performed pretherapy
and on therapy in nearly 2,500 subjects. These ECGs revealed a minimal
mean change of 1.5 milliseconds in QTc, that is, the QT corrected
according to Bazett\'s formula for heart rate, with no differences noted
in the rare QTc outliers such as on-therapy increases in QTc greater
than 30 or 60 milliseconds or QTc\'s over 500 milliseconds, and this was
versus both macrolide and non-macrolide comparators.

We know that noncardiac drugs with QT effects of concern, that this
effect is generally a concentration-dependent effect. So we have
performed an assessment of drug concentration and QT interval in
subjects from the phase III studies.

As can be seen here, plasma drug levels were drawn 2 to 3 hours after
drug administration and matched with QTc intervals that were obtained
within an hour of the plasma sample. More than 1,500 matched data points
were analyzed over a wide variety of concentrations. A linear best fit
concentration versus QTc relationship revealed a shallow slope of 0.88
milliseconds per microgram per milliliter. But more importantly, a very
low correlation is manifested by the minute r squared value of .0025
which, translated in laymen\'s terms, essentially means that teli
concentrations explained less than 3 one-thousandths of the QTc interval
variability observed in these subjects.

Additionally, as noted by the data highlighted in the rectangle and in
this box here on this slide, this observation is supported by the
absence of any meaningful QTc increases in those patients with the
highest plasma concentrations. For instance, we see here no QTc over 450
for men or 470 milliseconds for females.

In addition to the visual and cardiac evaluations, detailed hepatic
evaluations were also included in the phase III studies. As seen here,
ALT elevations greater than 3 times upper limit of normal were similar
between treatment groups, as was the overall proportion of subjects
experiencing hepatic events.

As noticed in the briefing document from the FDA and Aventis, our
previous NDA submission reported a single case of clinical hepatitis.
The subject in question had a preexisting, ill-defined baseline hepatic
abnormality as evidenced by ALT values approximately 2 times the upper
limit of normal. Plus, he had baseline eosinophilia, consistent with his
underlying asthma condition. Four days after completing a 10-day course
of therapy for pneumonia, the patient experienced a gastroenteritis-like
illness shared by several other family members. Six days following this,
symptomatic transaminase elevations without hyperbilirubinemia were
noted.

A liver biopsy during this episode has been reviewed by our pathology
expert, Dr. Rubin, who is here today and who would like to review these
slides later, if possible, during the Q&A. His review demonstrated focal
accumulation of macrophages with moderate liver cell dropout.
Eosinophils observed on biopsy were entirely consistent with the
background eosinophilia due to asthma.

The patient recovered within 6 weeks with no further intervention.

Nine months later and with no further exposure to telithromycin, the
patient experienced an asymptomatic increase in transaminase levels. A
second liver biopsy exhibited chronic active lymphoplasmacytic
infiltrate, some fibrosis and nodule formation suggesting early
cirrhosis, consistent with progression of autoimmune hepatitis.

In view of the preexisting baseline ALT elevations noted before the
first episode and in view of the second biopsy findings with the
additional presence of positive autoantibody noted during that second
episode, the initial biopsy retrospectively is consistent with an early
autoimmune hepatitis following a pattern of exacerbations and
remissions.

Following the second episode, the patient has been followed closely with
regular lab monitoring every 6 months for the past 4 years. ALT
elevations have remained similar to his baseline values of approximately
2 times the upper limit of normal and the patient has been asymptomatic.

This case has been extensively reviewed and discussed with our hepatic
expert consultants who are also here available today to discuss the case
further if needed. However, as far as we are aware, there are no
published case reports and no drugs known to induce an indolent, chronic
hepatic injury following a single short course of therapy. Given these
facts, a telithromycin-related etiology for this patient\'s underlying
hepatic disorder appears highly unlikely. Nevertheless, we have
conducted an extensive assessment of clinical hepatic events in our
large usual care study and we have closely evaluated all post-marketing
reports of hepatic events, as will be described shortly.

I will now focus on study 3014, our large comparative clinical endpoint
study performed in a usual care setting and designed in collaboration
with the FDA.

Permit me to outline the key features of this trial which was designed
specifically to address the concerns raised at the previous advisory
committee by capturing major clinical outcomes in a usual care setting.
Study 3014 was a randomized, open-label comparative study. More than
24,000 subjects were enrolled and treated with either telithromycin or
amoxicillin-clavulanic acid. Several approaches were undertaken to
enrich the population with potentially at-risk individuals and thereby
enhance safety signal detection.

First, the study was performed with minimal exclusion criteria to
simulate real-world experience. Specifically, we enrolled large numbers
of patients who exhibited relevant comorbidities and who were taking a
variety of concomitant medications.

Second, in response to the FDA\'s recommendations, we increased the
treatment duration for acute exacerbation of chronic bronchitis from the
5-day course used in the phase III trials to 7- to 10-day course used in
this study.

Third, enrollment targeted older subjects, and 46 percent of subjects in
this study were age 50 or older.

And lastly, 40 percent of the subjects in this study had either
community-acquired pneumonia or acute exacerbation of chronic bronchitis
as opposed to the sinusitis indication.

Safety data collection was designed to capture prespecified adverse
events of special interest, or AESIs, in the usual care setting. These
AESIs consisted of cardiac, hepatic, visual, and vasculitic events.
Office visits were planned at the pretherapy visit, that is, day 1, and
at a post-therapy visit between days 17 and 22. Contact at a third late
post-therapy visit either by phone or office visit was planned for days
30 to 35. However, it\'s once again important to note that all subjects
with adverse events of special interest or serious adverse events were
asked to return to the office for this late post-therapy assessment.

Additionally, it\'s also important to note that hepatic lab testing was
systematically obtained at pre-therapy and the post-therapy visit. The
investigators were instructed to review and report all adverse events
occurring during the 35-day window of observation, focusing particularly
on identifying all AESIs.

The four AESIs are defined on this slide. Hepatic AESIs included all
reports of hepatitis, jaundice, or any worsening of a preexisting
hepatic condition, but in addition, all cases of ALT greater than or
equal to 3 times the upper limit of normal were systematically
designated as AESIs whether symptomatic or not.

Cardiac AESIs included torsades de pointes or other ventricular
arrhythmias, syncope which was defined as a complete loss of
consciousness, cardiac arrest, and all unwitnessed or unexplained
deaths. Additionally any death occurring during the period of
observation, that is, through day 35, was designed as a cardiac AESI.

Visual AESIs included all cases of blurred vision and associated
complaints.

And lastly, vasculitic AESIs included purpura or other clinical signs of
vasculitis.

Additionally, any other events so designated by the investigator were
considered AESIs.

These definitions were intentionally defined very broadly to cast a wide
net and screen for all potential clinical endpoint cases.

All adverse events ‑‑ that\'s not just AESIs, but rather all adverse
events ‑‑ and all lab values were reviewed daily by the sponsor and the
CRO to ensure complete identification, collection, and follow-up of all
AESIs.

All AESIs were then investigated using detailed questionnaires designed
to maximize and standardize the available information for each AESI. The
questionnaire included such items as symptoms, diagnostic workup,
information that might exclude other causes for the event, and details
on the temporal relationship of the event to study drug administration.

In addition, hepatic lab tests were systematically performed at the
pre-therapy and post-therapy visits to ensure the capture of all
potential hepatic endpoint cases. For all ALT levels greater than or
equal to 3 times or more of the upper limit of normal, a specific
algorithm was followed by obtaining an additional standardized lab
evaluation which included total and direct bilirubin, serum
transaminases, alkaline phosphatase, complete blood count with
differential, prothrombin time, and hepatitis serologies. Any additional
labs or diagnostic evaluations were to be obtained and reported per
investigator clinical discretion.

Each AESI was to be followed to clinical resolution.

It is important to note that AESIs are not study endpoints in this study
but instead represent potential endpoints. Rather, the blinded,
independent expert clinical event committees, or CECs, were provided
complete information packages for all AESIs as described above. These
packages were then reviewed and adjudicated by the CEC to identify
predefined clinical safety endpoints. Additional information was
provided as requested by the CEC. The study endpoints will be presented
shortly.

Follow-up was actively pursued in all subjects enrolled in this study.
Only 2 telithromycin-treated subjects and 1 AMC subject were treated but
had no post-baseline assessment. Thus, virtually all of the treated
population had an assessment after starting study drug and constitute
the safety-evaluable population.

99.5 percent of telithromycin subjects and 99.2 percent of AMC subjects
had detailed adverse event information available on day 28 or later,
that is, detailed AE status information. We obtained vital status, that
is, additional information or other information whether the subject was
alive or dead, in an additional 0.5 percent of subjects, resulting in an
overall 99.8 percent out of these 24,000 subjects with follow-up
information obtained at day 28 or later.

I will now review the study results.

The adverse event profile, including total subjects with adverse events,
discontinuations due to adverse events, and serious adverse events, were
similar and balanced between treatment groups. As noted in the phase III
studies, gastrointestinal events were again the most commonly reported
events in both treatment groups.

Discontinuation rates were low and comparable between treatment groups.
As in phase III, the most common events leading to discontinuation were
gastrointestinal in nature.

Serious adverse events were also uncommon, occurring in approximately 1
percent of subjects, and again as noted in phase III, these serious
events were primarily unrelated and due to underlying conditions.

As noted on this slide, the size of study 3014 allowed us to assess
safety in significant numbers of subjects exhibiting comorbid conditions
and taking a variety of concomitant medications of interest such as
those metabolized by the cytochrome P450 system. The overall frequency
of adverse events in these subgroups was balanced between treatment
groups. Of particular note, 1,420 telithromycin-treated subjects were
also taking HMG CoA reductase inhibitors metabolized by the CYP3A4
pathway, that is, simvastatin, atorvastatin, or lovastatin. However, no
reports of rhabdomyolysis or significant myopathy were seen in any of
these subjects.

I will now discuss the key analyses for this study.

Analysis of the hepatic AESIs revealed that they were uncommon and
balanced between treatment groups occurring in approximately 1 percent
of subjects. Most of these represented asymptomatic ALT elevations noted
during the routine lab monitoring rather than clinically manifest
illnesses. With the exception of 1 AMC subject who refused to give any
further clinical information to the investigator, all hepatic AESIs were
followed to clinical and/or lab resolution. There were no reports of
chronic or immune-mediated hepatic injury, and most importantly, there
were no occurrences of drug-related hepatic failure, liver transplant,
or death from primary hepatic causes in either treatment group in this
study.

The predefined clinical hepatic endpoint in this study was possibly
drug-related clinically significant hepatic injury. Predefined guidance
for the adjudication of the hepatic endpoints included the presence of
clinical signs or symptoms, a meaningful increase in ALT of at least 3
times the upper limit of normal, the exclusion of other common causes
such as cholelithiasis or viral hepatitis, and the new onset of symptoms
at day 5 or later so as to differentiate drug-related symptoms from
those associated with the underlying infection. However, it\'s important
to note that all final endpoint determinations were ultimately made
according to the blinded CEC\'s expert clinical judgment and discretion.

Positively adjudicated endpoints, as can be seen here, were observed in
3 telithromycin and 2 AMC subjects with considerable overlap of the 95
percent confidence intervals. Of note, the five endpoints events were
mild or moderate in intensity, and recovery was documented in all cases
but the 1 AMC subject who previously was mentioned and refused
follow-up.

One endpoint subject had a liver biopsy performed during the study. This
case has been reported in the FDA\'s and the sponsor\'s briefing
documents and is discussed here. This telithromycin-treated subject with
documented cholelithiasis demonstrated elevations in ALT, alkaline
phosphatase, and bilirubin on day 23 following a 10-day treatment for
pneumonia. There was no eosinophilia noted. Due to the cholestatic
presentation and increasing alkaline phosphatase levels, the subject had
an abdominal ultrasound performed on day 30 revealing cholelithiasis and
thickening of the wall of the gallbladder. On day 36, the patient
underwent laparascopic cholecystectomy. Gallbladder pathology was
consistent with cholelithiasis and cholecystitis, and simultaneous liver
biopsy supported this diagnosis with cholestasis, mild fibrosis, minimal
inflammation, and no eosinophils noted. The patient fully recovered.

As mentioned previously, one of the main aims of the study was the
detection of clinically evident drug-related hepatic adverse events. A
review of hepatic lab measurements, performed primarily as part of our
thorough case ascertainment in this study, is presented here, focusing
on criteria that have been proposed to attempt to predict untoward
hepatic-related clinical outcomes.

This slide presents the frequency of noteworthy hepatic lab values for
subjects with both normal and abnormal values at baseline. ALT
elevations greater than or equal to 3 times the upper limit of normal
were comparable and balanced between treatment groups, occurring in
approximately 1 percent of subjects. The incidence of ALT elevations
greater than 8 times the upper limit of normal, or approximately 250
units per liter, was uncommon but tended to be numerically higher in the
telithromycin group. These events were predominantly asymptomatic lab
abnormalities of a moderate level, in the range of 300 to 500 units per
liter, that were reversible.

Recently greater emphasis has been placed on assessing combined
elevations of ALT and bilirubin. Here we see the combined elevations of
ALT greater than or equal to 3 times the upper limit of normal with a
bilirubin greater than or equal to 1.5 times the upper limit of normal
were also uncommon but, on the other hand, tended to be more frequent in
the AMC group.

And lastly, 1 patient in the AMC group exhibited a pattern of elevated
ALT with clinical jaundice, that is, a bilirubin greater than or equal
to 3 milligrams per deciliter, and I believe this patient\'s bilirubin
was close to the 5.1 or 5.2 level and with no elevation in alkaline
phosphatase. And this was also considered a clinical endpoint.

This sort of value here is considered the most, perhaps, interesting of
these lab analytes because according to the famous or infamous Hy\'s
Rule, patients who exhibit these kinds of findings have a greater
tendency to have significant sequelae to their hepatic event. However,
it should be noted that all of these patients recovered and there were
no similar cases of hepatocellular jaundice seen with telithromycin.

Overall, when looking at these different analyses, it\'s important to
remember that the sensitivity, specificity, and predictive value of
these have not been firmly established and remain largely unknown.

I would now like to focus on the second AESI, cardiac events. The focus
of this investigation was clinical cardiac events reflecting possible
ventricular arrhythmic events. ECGs were obtained only as needed
according to the investigator\'s clinical judgment. Cardiac AESIs were
uncommon and balanced between treatment groups, occurring in 0.3 percent
of subjects in both treatment groups. As mentioned previously, all
deaths occurring up to day 35 were considered cardiac AESIs. These
deaths were also similar and balanced between treatment groups, and none
of these deaths were considered treatment-related as assessed by the
investigator.

The cardiac CEC also performed a blinded review of all deaths to
determine those that were presumed arrhythmic in origin. Please note
that all cases identified in the telithromycin group occurred 7 days or
later after study treatment, thereby mitigating against any causal
relationship.

This slide presents the cardiac AESIs noted for the large number of
subjects enrolled in study 3014 with important baseline cardiac risk
factors. Enrollment of these at-risk subjects and more importantly the
proportion of these subjects experiencing cardiac AESIs was balanced
between treatment groups. I think these numbers are also a little bit
unprecedented in terms of phase III studies in terms of just the numbers
of patients that you see here in these groups.

The cardiac endpoint in study 3014 was any event likely to represent
malignant ventricular arrhythmia and that had a reasonable temporal
relationship to study drug administration. No cardiac endpoint was
identified for telithromycin. A single cardiac endpoint, sudden death in
a subject treated with amoxicillin-clavulanic acid, was identified by
the CEC. Thus, the CEC identified no increased risk for malignant
ventricular arrhythmic events for telithromycin in this study.

Next I would like to focus on the third AESI in this study, visual
events. The visual endpoint was drug-related blurred vision. Positively
adjudicated endpoints were identified in 0.6 percent of telithromycin
subjects and 0.4 percent of AMC subjects. Overall, the characteristics
of this event were similar to those seen in phase I and phase III, with
the reported median onset within 1 hour after dosing, with a median
duration of 2 hours, and the majority of cases were of mild to moderate
intensity with infrequent severe blurred vision reported in only .04
percent of telithromycin-treated subjects.

Discontinuation of therapy due to blurred vision was uncommon, noted in
0.2 percent of telithromycin subjects, and some impact on activity
occurred in approximately 0.3 percent of teli subjects, most frequently
described as difficulty reading.

It should be noted that no telithromycin subject with blurred vision
reported any accidental injury and, moreover, that all of these cases
were fully reversible.

Finally, before moving to the next slide, I would like to mention that
for the fourth AESI, vasculitic events, only four combined AESIs were
identified in the entire study with three reported for telithromycin and
one for AMC. However, there were no positively adjudicated endpoints of
drug-related vasculitis in either treatment group.

I would now like to address the extensive post-marketing experience that
we have accumulated with telithromycin thus far. These data help us
confirm product safety in a real-world setting and also to assess the
clinical relevance of any unanswered safety concerns remaining from
earlier experience.

Telithromycin is marketed in many countries, including Germany, France,
Belgium, Italy, Spain, Mexico, and Brazil, and over 1.5 million courses
of therapy have been administered since marketing began in October of
2001 with France and Germany accounting for nearly 1 million exposures.
It should be noted that both of these countries have well developed and
sophisticated post-marketing safety surveillance and reporting systems.

Of note, our marketing data indicates that approximately 10 percent of
prescriptions represent re-exposure, which adds a useful new dimension
for safety assessment that\'s generally absent from phase III studies.
In addition, Aventis has intensively followed up adverse event reports
and has utilized standardized questionnaires to guide follow-up on
reports of adverse events of special interest. To date, the
post-marketing safety profile of telithromycin confirms the safety
profile seen in clinical trials, with no new or unexpected safety
signals identified.

This post-marketing review that I will present includes updated data
through the end of December 2002. As seen in the clinical trials, the
most commonly reported adverse events were gastrointestinal in nature,
with dizziness, headache, and blurred vision also noted. Therefore, I
will focus the post-marketing review on the visual, cardiac, and hepatic
AESIs discussed in detail in study 3014.

The majority of visual events seen in post-marketing reports are similar
in character to those identified in the clinical trials. As in clinical
trials, most commonly reported events remain blurred vision, abnormal
focusing, and visual abnormality. 78 percent of these events occurred in
patients less than 50 years of age, again consistent with an effect on
focusing. The visual events are generally of limited duration, with full
recovery noted.

While specifically noted in the FDA briefing package, although isolated
reports of \"loss of vision\" have been received, in each instance where
follow-up has been completed ‑‑ and this represents actually the
majority of these reports ‑‑ they have, in fact, revealed varying
degrees of blurred vision and not true vision loss.

Most importantly, no evidence of sequelae was noted in any case report,
and to date we have received no reports of accidental injury in patients
either with or without blurred vision after more than 1.5 million
exposures for telithromycin.

With respect to cardiac events, post-marketing findings are again
consistent with the experience in the clinical trials setting. There
have been no reports of sudden or unexplained deaths and no confirmed
cases of torsades de pointes. Two questionable reports have been
received.

The first case reported as a torsades de pointes was a report
demonstrating fatal ventricular fibrillation but with a QT interval
noted to be normal less than 30 minutes prior to the fatal arrhythmia.
Polymorphic ventricular tachycardia characteristic of torsades was not
identified upon expert review of this case. Moreover, this subject had
multiple risk factors for sudden death and began having syncopal
episodes 3 days prior to administration of telithromycin. For these
reasons, we do not believe that this case represents either torsades de
pointes or a drug-related event.

For the second report, a complete and thorough follow-up investigation
failed to identify an actual patient or event. The original reporter did
not treat the patient for the event but initially reported a specific
physician and hospital where the event allegedly occurred. However, the
specified physician was contacted at the hospital and denied any
knowledge of such patient, and following an extensive search of the
hospital emergency and cardiac units, including all possible related
services on or around the specified dates, he in fact determined that no
patient had been treated for the same or similar diagnosis.

Additionally, it\'s interesting to note that there have been no other
reports of any ventricular arrhythmias from post-marketing surveillance.
Thus, we believe that the available post-marketing data in over 1.5
million patients exposed worldwide support no increase for cardiac risk
associated with telithromycin therapy.

With respect to post-marketing hepatic adverse events, reports were
uncommon, with 64 events reported in 28 patients. No reports of
drug-related hepatocellular jaundice have been received. There have been
four reports of cholestatic jaundice received. However, one of these
patients had a well-documented acute mononucleosis, and all of these
patients recovered fully.

There have also been no reports of chronic or immune-mediated hepatic
injury received from the post-marketing experience.

Additionally, there have been no reports of drug-related hepatic
failure, liver transplant or death. We have received recently a single
report of a fatal acute hepatitis A with hepatic failure in an elderly
gentleman with a documented hard nodular liver and who has undergone
expert review with our consultants. This report is not considered
drug-related by either our experts or the reporting physician.

This 75-year-old patient experienced serum transaminase and bilirubin
increases and marginal alkaline phosphatase elevation 1 day after
completing a 5-day course of telithromycin for a febrile illness
diagnosed as acute exacerbation of chronic bronchitis. The patient also
had received doses in excess of 4 grams per day of acetaminophen for 4
to 5 days prior to the event. One day after admission, the patient
underwent emergency laparotomy due to worsening clinical status presumed
secondary to acute cholecystitis, as suggested by the physical
examination and abdominal ultrasound, but this was not confirmed on
surgery. However, during the laparotomy, a hard nodular liver was noted,
strongly suggestive of significant preexisting chronic hepatic disorder.
Liver biopsy was not performed due to bleeding complications during the
surgery.

Lab evaluation, which had been initiated on admission and returned 1 day
following the surgery, revealed documented acute hepatitis A with
unequivocal high elevated IgM antibody and additional documentation of a
recent acute Q fever. The patient experienced post-surgical
complications, including disseminated intravascular coagulation and
multi-organ failure and died on day 11.

This patient\'s clinical course is consistent with an underlying chronic
hepatic disorder as evidenced by the hard nodular liver noted at surgery
with superimposed acute hepatitis A, a well-documented cause of acute
liver failure.

Additionally, we have reviewed this case in the context of FDA Freedom
of Information post-marketing surveillance data and determined that the
occurrence of one such case in over 1.5 million exposures in an
infectious disease population is consistent with the background rate
noted with other marketed antibiotics.

In summary, extensive experience with telithromycin in diverse
populations and high risk subgroups has demonstrated the safety of
telithromycin. This experience includes more than 16,000 subjects
treated with telithromycin in phase III clinical trials and more than
1.5 million exposures in the post-marketing setting.

Overall, telithromycin has displayed a safety profile comparable to
marketed antibiotics. It is well tolerated with the most commonly
reported adverse events in the gastrointestinal system and with low
rates of discontinuation of therapy.

Blurred vision was uncommon, generally mild to moderate in intensity, of
limited duration. The mechanism appears consistent with a delay in
focusing as supported by the age distribution of the event and the
symptom description. Importantly, detailed ophthalmic examinations in
phase I have excluded potentially serious or irreversible etiologies,
and both clinical trial and post-marketing reports have revealed no
sequelae or associated injuries.

An extensive cardiac evaluation has also been performed with
telithromycin. No increase in ventricular arrhythmic events or cardiac
deaths was noted in the phase III studies or the 24,000-subject usual
care study 3014. Notably, these combined studies enrolled significant
numbers of older subjects, subjects with significant cardiovascular
disease, and subjects taking a variety of concomitant antiarrhythmic
drugs and drugs with known potential to prolonged QT interval.
Similarly, the post-marketing experience reveals no evidence of excess
risk and no confirmed cases of torsades de pointes after more than 1.5
million exposures.

And lastly, following extensive hepatic evaluation, no hepatic safety
signal has been confirmed. Clinical hepatic events occurred at rates
comparable to currently marketed antibiotics in both study 3014 and in
the post-marketing arena. Moreover, there have been no cases of
drug-induced hepatocellular jaundice, no cases of chronic or
immune-mediated hepatic injury, and no cases of drug-related hepatic
failure, liver transplant, or hepatic deaths observed.

Thus, telithromycin\'s safety profile has been carefully evaluated and
demonstrated in over 16,000 clinical trial patients and over 1.5 million
patients treated in the real-world setting.

I would now like to call upon Dr. Iannini to put this large clinical
experience into perspective and to present the final conclusions. Thank
you.

DR. IANNINI: In brief summary, optimal therapy for community-acquired
respiratory tract infections requires that all likely pathogens be well
covered by an agent with a targeted spectrum that includes both common
and atypical pathogens.

The rate of resistance of respiratory pathogens to commonly used
therapeutic agents is currently high and increasing and may shorten
their useful life.

Current antimicrobial agents have limitations that result in an unmet
medical need. Beta-lactam antibiotics are limited by poor activity
against atypical organisms, penicillin-resistant pneumococci, and in
some cases beta-lactamase positive Haemophilus influenzae.

The macrolides are limited by appreciable pneumococcal resistance.

And fluoroquinolones have a broad spectrum that is not targeted to
respiratory pathogens. Resistance development to fluoroquinolones by
enteric and other Gram-negative rods is a clinical concern.
Additionally, fluoroquinolone resistance mutations are present in
Streptococcus pneumoniae and may limit the use of older agents in this
drug class.

Telithromycin is as highly effective as comparators in the treatment of
community-acquired pneumonia, acute exacerbations of chronic bronchitis,
and acute sinusitis. It has the additional benefits of having a second
site of ribosomal binding, concentration-dependent rapid killing, a
targeted spectrum of activity that\'s well-suited for respiratory tract
infections, and is active against resistant strains of Streptococcus
pneumoniae.

Telithromycin is effective when given for short treatment durations, a
feature that may promote better patient compliance and limits exposure
time for drug-drug interactions.

Telithromycin has been shown to be a safe drug.

In addition to the phase III data presented here today, more than 1.5
million patients have been treated with telithromycin since its approval
in European countries. No toxicity signals have emerged.
Telithromycin\'s safety profile is comparable to widely prescribed
antimicrobial agents even in a large 24,000-patient trial in usual usage
situations.

The most common intolerances are gastrointestinal and most are mild to
moderate. Visual events are uncommon, mild, and reversible with no
sequelae. There\'s no evidence of increased cardiac risk when compared
to other agents. No increased risk of clinically appreciable hepatic
injury has been detected. Drug-drug interactions are limited because of
multiple routes of elimination and short exposure times. Specific
drug-drug interactions related to cytochrome P450 isoenzymes have been
studied in detail and no major issues have been identified.

Telithromycin fulfills an unmet medical need for reliable empiric
therapy for community-acquired respiratory tract infections. It brings
the additional benefits of a second site of ribosomal binding,
concentration-dependent and rapid killing, a targeted spectrum of
activity unaffected by current common resistance mechanisms, and
requires short durations of treatment.

Telithromycin has a comparable safety profile to other marketed
antimicrobial agents.

In conclusion, telithromycin would be a valuable option for clinicians
and patients in the treatment of community-acquired respiratory tract
infections.

That concludes our presentation. On behalf of the sponsor, I\'d like to
thank you all for your attention.

DR. LEGGETT: I think what we should probably do now is address some
questions about this part of the study so that then we can all take a
short break. We\'re running behind. So why don\'t we address questions
to all the presenters from Aventis at this point. Don.

DR. PORETZ: Yes. I\'d like to ask a question about Staph. aureus. You
presented data on sinusitis, and I think there were 15 or 17 patients
who had Staph. aureus sinusitis and they were all cured. But then you
also presented data with the MICs on Staph. aureus, some of which were
quite high. There were no patients, as I could tell, who had Staph.
aureus pneumonia or acute exacerbations of chronic bronchitis due to
Staph. aureus. I\'d just like to know some more information about Staph.
aureus and telithromycin and how telithromycin compares with macrolides
against Staph. aureus.

DR. LEROY: I will first answer the question regarding Staphylococcus
aureus and sinusitis. First, we applied the rule of 10 to the 4th to
qualify the patient with a Staphylococcus aureus. They were all
susceptible to telithromycin in the acute sinusitis indication and just
very few patients were erythromycin-resistant but susceptible to
telithromycin, which we can see in non-constitutive strains.

But your question was larger and asked also about the overall efficacy
of telithromycin. So I\'ll ask Dr. Jenkins, our microbiologist, to
answer the question.

DR. JENKINS: Telithromycin is interesting in that it is very active
against strains of Staph. aureus that have an inducible mechanism of
resistance. In other words, they have inducible methylation of the
ribosome. Those strains that have a constitutive production of the
methylase enzyme, telithromycin is typically inactive.

And if you take a look at strains of staph that are either susceptible
or resistant to methicillin, most of the methicillin-susceptible strains
either are macrolide-susceptible in general or they have the inducible
methylation mechanism. By comparison, the methicillin-resistant strains
are almost uniformly constitutively producing the methylase enzyme.

DR. LEGGETT: Dr. Elashoff?

DR. ELASHOFF: Yes. I have three related questions. One is with respect
to slide 34 in which you compare clinical cure by pathogen, but the
comparator sample sizes seem to be very much smaller than the others.
You didn\'t do those for most of the comparators, or it\'s simply not
reported here, or what? That\'s question one.

DR. LEROY: The answer is that the telithromycin group includes the
non-comparative trials which were meant to gather a lot of Streptococcus
pneumoniae strains, and therefore we\'ve gathered all information
concerning telithromycin in comparative and non-comparative trials in
this table.

DR. ELASHOFF: Okay.

The second question has to do with slides 37 and 38 which show clinical
cure for resistant isolates for telithromycin, but don\'t show that same
information for comparators. Presumably there are some cases that could
be shown for comparators.

DR. LEROY: There were only a few cases because most of the experience
was obtained in non-comparative studies for Streptococcus pneumoniae
resistant for two reasons. One is that it\'s difficult to use a
comparator which is not active on S. pneumoniae when there is a high
rate of resistance. Ethics committees generally discard those drugs as
potential drugs to be used in a double-blind trial, and that clearly
causes a real problem. Therefore, we would need to go to countries with
lower rates of resistance, and in this case the number of strains
isolated in the comparator group is small.

I will summarize that the most experience that we have is with
clarithromycin, and I will show you two things. First, 4 or 5 cases of
erythromycin resistance were cured with telithromycin, but 1 of the 4
had a late relapse. So in fact 3 out of 5 cases were cured with
clarithromycin.

But I would like to show you the failure cases observed with
telithromycin. It\'s the patients for the 4003 study. Slide on.

So that\'s an interesting case because it relates to the former
presentation. There is a 51-year-old female with a Fine score which is
not elevated, Fine score 2. Chest x-ray shows pneumonia. Pneumococcus
shows a strain with a genotype ermB, and an MIC of 64 in the blood as
well as in the sputum. And these strains were susceptible to
telithromycin, but resistant to clarithromycin. Additionally, these
patients had Moraxella catarrhalis isolated from the sputum.

On day 6, this pneumonia worsened with development of aseptic arthritis,
and this S. pneumoniae was isolated from the pus of the septic
arthritis. Chest x-ray was unchanged. The patient was switched to an IV
antibiotic and the patient was secondarily cured with several IV
antibiotic use subsequently adjusting to the results obtained in this
patient in the pus of the septic arthritis of this patient.

So despite the fact that we cannot study on a large scale efficacy in
comparators to a patient, this is very informative of what exactly is
the fear described by Dr. Iannini when taking care of such patients with
possibility of resistant strains.

DR. ELASHOFF: And the third question is since apparently the strain
wasn\'t determined in most of the cases in the comparative trials and if
clarithromycin has a 31 percent resistance rate, you would expect in
comparisons like slide 33 that clarithromycin might look a little worse
than telithromycin if resistance is an important factor. And in fact,
that doesn\'t seem to be the case.

DR. LEROY: We did not observe a rate of 30 percent in those pneumonia
studies. They were performed, as Dr. Jenkins explained. The development
started 5 years ago, so the recent trend overall in the pneumonia
studies was around 10 percent. That does not allow us to show, in a
study design for equivalence, any superiority. We would require a much
larger number of patients, in the range of the thousands, 2,000 or
3,000, per treatment group, to show that versus the same comparator.

DR. LEGGETT: Dr. Rupp.

DR. RUPP: Yes, just a few questions. In follow-up to the first question
with regard to Staph. aureus, one of the failures in your
community-acquired pneumonia trial was a patient who developed a Staph.
aureus superinfection. Can you elaborate on any details on that? Where
was the site and what was the susceptibility of that Staph. aureus
isolate?

DR. LEROY: The site was urine in fact, which is uncommon. But it was the
reason why the patient was treated with an additional antibiotic.

And the susceptibility. If I can have this patient. I have a loss of
memory here. I\'ll get back to you with the susceptibility for this
patient. But telithromycin is not meant to treat Staphylococcus aureus
in urine in any case.

DR. LEGGETT: And if you have difficulty finding slides, we can address
that after lunch to move this along.

Dr. O\'Fallon.

DR. O\'FALLON: I also had a question about the numbers, but before I say
that, I would like to say I was very impressed by the number of studies
you managed to get done in that period of time. It was impressive to me.

But I did have a problem with the numbers, and this comes from your
original packet when I was looking at that before we came into the
meeting. And in your original packet on page 71, I notice this in all
the studies. Basically there\'s an interesting differential in the loss
of patients that were in your studies, and I wondered why this happened.

Table 6-5 in CAP, which would be a big one. It showed that, for example,
in the per-protocol group, 84 percent of the telithromycin were there to
be analyzed but only 77 percent of the comparators. And when we got down
to the biological ‑‑ well, BMITT ‑‑ there were 46 percent of the
telithromycin but only 35 percent of the comparators. And I was
wondering why there was this differential loss. I saw that in all the
studies, but this is the earliest one. Can you explain why you seemed to
lose more from the comparators than from the telithromycin?

DR. LEROY: You\'re saying that the number of patients lost in the
telithromycin group ‑‑ the test of cure or ‑‑

DR. O\'FALLON: No, no. The telithromycin, you were doing a good job. Why
were you losing them in the comparators? Because remember, you are
comparing, so this would affect the comparisons to my way of thinking.

DR. LEROY: I understand your question. I\'m not sure I have the precise
table to look at. Are you speaking of the table where we pooled
non-comparative and comparative, or are you speaking of a table where
comparative trials were presented at the same time? Because that may
explain the difference.

DR. O\'FALLON: Well, it uses randomized. I didn\'t go through and check
that out, but the first line on this is randomized. So I assume it\'s
not the pre-marketing or anything like that. Post-marketing I mean or
the enrichment studies. It says randomized, not registered, but
randomized. Now, maybe it was a mistake. Maybe that\'s misleading, but
if it\'s indeed the randomized, then ‑‑

DR. ALEXANDER: If I may. The particular ‑‑

DR. LEROY: I\'m sorry.

DR. ALEXANDER: I\'m sorry. The particular table that you are looking at
does include patients from comparator trials as well as from open-label
studies.

DR. O\'FALLON: Okay.

DR. LEROY: It may have explained this difference in this case.

DR. O\'FALLON: Okay, thank you.

DR. LEGGETT: Dr. Maxwell.

DR. MAXWELL: I have three quick questions. On slide 31, when you\'re
looking at the community-acquired pneumonia phase III studies, the
western studies, of the 881 treated with telithromycin, what\'s the
racial diversity? Do you have that data?

DR. LEROY: The ratio?

DR. MAXWELL: Racial diversity.

DR. LEROY: Racial diversity?

DR. MAXWELL: Yes.

DR. LEROY: We have these data in the briefing document, but I would say
generally caucasian would be 82. I\'ll get back with a more precise ‑‑
but 82. Black would be 12 to 15 and Asian would be less than 5 percent.
It would be an overall ball park. I can come back. I have it here. Slide
on. So it was just lower for caucasian and approximately that, yes. And
other includes in fact Hispanic.

DR. MAXWELL: My second question was looking at slides 58, 59, and 68,
just in summary, I just wondered if there was any comparator or
comparing to protease inhibitors or nucleoside, reverse transcriptase
inhibitors, or if any of that was done but not reported just for my
knowledge.

DR. LEROY: No, it was not done. Ketoconazole was thought to be the
highest blocker, and therefore we did not repeat with a protease
inhibitor.

DR. MAXWELL: Okay.

And my last question has to do with slides 97 and 100 looking at the
visual adverse events or potential. I know that in study 1059 the plasma
concentration of telithromycin was slightly higher in older patients and
was slightly lower in the tears. And I couldn\'t understand why that
would be. Yet, in study 1064 where you looked at 24 healthy subjects,
you looked at the plasma concentration and reported that data, but there
was no data about the concentration of the drug in tears. And I just
wondered what that was, if you had that data.

DR. LEROY: I will ask the person who conducted the trial to help me with
this question. Dr. Vashrom and Dr. Harding. Professor Harding was the
investigator of the 1064, and I will ask Professor Vashrom also about
the concentration seen in the tears.

DR. HARDING: The measurements in tears were not made on the 1064 study,
only on the 1059. The subjects were undergoing a fairly rigorous program
which involved 2 hours of visual testing, so there\'s a limit to what
could be done.

DR. MAXWELL: Thank you.

DR. LEGGETT: Dr. Patterson.

DR. PATTERSON: I had a question also. I guess these are for Dr.
Lagarenne regarding slides 97 and 100. In the study 3014, the rate of
visual effects was noted to be .6 percent. And was there a difference in
the rate between women and men, and if so, what was the difference?

DR. LEROY: Yes, Dr. Lagarenne.

DR. LAGARENNE: The effect was seen a little bit more frequently in
females, I think approximately 60 percent of the reports being in
females.

DR. PATTERSON: And then on slide 100 in the post-marketing experience,
you mentioned that the visual effects were of limited duration. I just
wondered if you could be a little more specific about that. Was it
hours, days?

DR. LAGARENNE: In post-marketing, it\'s hard to pinpoint because it\'s
not a trial situation. It\'s patients often reporting to their
physicians afterwards.

DR. PATTERSON: Or in the other studies, if you could comment.

DR. LAGARENNE: In the studies it was very consistent that generally it
would occur within a few hours of dosing and would resolve generally
within 2 to 3 hours, I would say, on average. There were some outliers
outside of that, but for the most part it was consistent.

In the post-marketing, where we have specific information, I would say
it ranges sometimes up to a day, sometimes 12 hours. It\'s hard to get a
pinpointed number.

DR. PATTERSON: Thank you.

DR. LEGGETT: Dr. Wald.

DR. WALD: Could I ask for them to clarify exactly how was the
surveillance done in the post-marketing patients? What was the mechanism
by which adverse events were reported? Was it passive reporting? Was
there some active mechanism?

DR. LAGARENNE: This is passive spontaneous reporting from each country.
Germany and France being the two countries where most of our exposure
has been have very developed pharmacovigilance reporting systems, and
typically the reporting rates there are comparable to what you would see
in the United States.

DR. WALD: And a follow-up question maybe someone from FDA could answer.
How many doses of trovafloxacin were administered before the
hepatotoxicity was observed?

DR. GOLDBERGER: It varied considerably, but I believe there were cases
that were as few as just a couple of doses.

DR. WALD: I\'m asking the total volume of ‑‑

DR. LEGGETT: How many millions.

DR. GOLDBERGER: Before hepatotoxicity.

DR. WALD: We\'re talking about a million-and-a- half patients now.

DR. GOLDBERGER: We started to see some definite cases I think around the
time that there were a million or so patients who had been exposed to
product. There was some lag in terms of when events occurred and when
they were reported, but I seem to recall we had at least one case, if
not more, within a couple months after exposure, but that was so
confounded, it\'s hard to understand really what happened. But in terms
of starting to get a definite signal, there were at least a million
exposures, and by the time regulatory action was taken, as I recall, it
probably was closer to double that.

DR. WALD: And then a question about the number of patients who underwent
sinus aspiration and the number that had a positive culture.

DR. LEGGETT: Did you understand? In your sinus studies, how many were
positive out of the denominator of punctures?

DR. LEROY: Around 50 percent. We had two studies. One was higher than
the other, but it was in the ball park of 50 percent of patients.

DR. WALD: And then the last question I\'d like to ask is Haemophilus
influenzae is about 200 times less susceptible than S. pneumoniae to
this drug. And I understand that the endothelial lining fluid has a high
concentration of macrophages. What would be the suspected fluid that
would have sufficient antimicrobial activity in patients with sinusitis?
I think about sinus fluid levels, and then I\'d ask the question were
there any sinus fluid measured levels of telithromycin measured because
I imagine that the level in the sinus fluid is yet less than the serum
level.

DR. LEROY: There has been a study performed, which has not been
submitted because it was completed recently. It was performed in France.
The peak concentration in sinus tissue is around 6 micrograms per gram
of tissue.

What we have also, which could answer partially your question, is that
in the development that we\'re conducting in pediatrics, we see that the
diffusion in middle ear fluid shows some degree of accumulation in this
closed environment, and it\'s very consistent with this level of
approximately 6. But it is still a related answer. It\'s not exactly a
sinus fluid level.

DR. LEGGETT: Dr. Elashoff.

DR. ELASHOFF: For slides 33, 42, and 47, I would like to see the average
or the distribution of the day on which the test of cure was made since
there is a several-day window and I want to be assured that the days on
which that happens are comparable for the drug and for the comparators.

DR. LEROY: For this question, we\'ll need to get back to you. It
requires manipulation.

DR. LEGGETT: Yes, thank you.

Dr. Cross.

DR. CROSS: With regard to slide 47, I was struck by the fact that the
three studies reported, while each comparator and telithromycin are in
the same ball park, there\'s quite a striking difference in terms of the
efficacy, going from 91 percent in one study down to 75 percent in the
other. And this is quite different from the similar slides on 42 and 33
for CAP and chronic bronchitis.

So my question is, was there any difference in terms of the endpoints or
clinical design of these three studies which would explain the rather
large inter-study difference? For example, was there a difference in the
aspirations which were used as endpoints or any other differences to
account for this?

DR. LEROY: No, there was no difference in design in all three studies.
Slight differences in the patient population enrolled because when you
perform a sinus puncture, generally it drives to a certain type of
investigator, and the types of patients enrolled are slightly different.
In addition, some ethics committees, for example, would not accept sinus
puncture, in terms of mucosal thickening only, and therefore, one of the
studies, the one with the highest cure rate, in fact, was done with only
air fluid level or total opacity in order to increase the yield.

One way to answer your question is to say we\'ve looked at everything,
any kind of factor that could explain the difference between the results
in those studies, and the only thing that we\'ve seen is that possibly
in the 3005 study we have ‑‑ it was in a broader type of investigation,
and there were more mucosal thickening only patients and sort of acute
exacerbation of a subchronic state.

One important point here is that compared to the trial that you are
seeing several years ago, the test of cure now is at 17 to 21 days. So,
in fact, the results that you are seeing at over 85 percent, which were
all often at the end of treatment, in these types of studies are more
likely to be in the upper 70\'s or 80. Clearly when it was bacteremic ‑‑
that\'s why I showed this slide on the patients with the bacteremia, the
sinus culture positive with the bacteria ‑‑ the cure rates were higher.

DR. LEGGETT: Dr. Lee.

DR. LEE: Yes. I have two questions.

First, could the sponsor address study 3009? There was a patient here on
page 171, a 36-year-old woman with HIV who died rapidly after a course
of therapy. Obviously, there are other complicating issues here, but I
just wondered, first of all, do you have any more information on that
case, and second, what\'s the experience, just anecdotally, in patients
who might be HIV- positive? Would there be any likelihood to think there
would be an interaction with the heart drugs?

DR. LEROY: For this patient, first concerning the liver abnormalities,
they were higher at entry than they were during the course of the study.
So this patient came with a level of 2,000 transaminase at entry and was
really a sick person.

The difficulty that we have is that we cannot perform HIV serology at
entry and screen those patients. This is very legitimate. So sometimes
in studies we have patients that have, in fact, a high degree of
immunodepression that we cannot identify at the start of the study. And
this patient had, in fact, an advanced HIV status that should have been
treated with an antibiotic given intravenously, obviously.

DR. LEE: Sure.

DR. LEROY: And regarding your question about HIV patients, we have a
very small experience in 3014 where we asked patients that were known to
be HIV-positive. We didn\'t show any striking difference versus
Augmentin. So it\'s very little experience in fact.

DR. LEE: So the first patient did have preexisting very high enzyme
levels before receiving the drug.

DR. LEROY: Yes, absolutely.

DR. LEE: The second question was on your post-marketing experience, they
said there were four cholestatic cases, and we didn\'t hear any detail.
Do you have more details on the four cases of so-called cholestatic
hepatitis in the post-marketing experience?

DR. LEROY: Yes. We can review those details. I will ask Dr. Lewis to
review those cases. He reviewed the cases and he\'ll be able to speak to
it.

DR. LEWIS: Good morning. Jim Lewis from Georgetown University.

Actually I don\'t want to steal too much thunder from the FDA\'s
presentation. They have this in their packet as well, and I think they
were going to go over some of these cases. They selected five that were
of significant interest.

One you\'ve already heard about which was the French case which was
hepatocellular with acute hepatitis A in a patient who probably had
cirrhosis and was elderly.

The other cases that we have are from Germany that were cholestatic, and
just briefly, one was a 61-year-old woman with underlying endocarditis
who was treated. We have it up on the board. You can read the
description. There were no liver enzyme values actually provided in this
case, but she did have a biopsy which is shown there. And this is the
description from the reporting physician: focal fatty degeneration with
moderate intrahepatic cholestasis, mild infiltrates, no eosinophils. And
it was interpreted in their parlance as nutritive toxic origin, and it
was included as a possible relation to telithromycin, but the reporting
physician did not feel that it was actually suggestive of drug injury.
It was sort of a nonspecific biopsy showing some cholestasis, and the
patient recovered. But there\'s not any additional information provided
with this one. So as with many other post-marketing reports, it\'s quite
difficult to interpret completely.

The second case is a 70-year-old man from Germany with an underlying
COPD, and you can read the rest of his history. A past history of
hepatitis A, on several medications including steroids, treated for
bronchitis. The enzyme pattern that was found here on the next slide,
he\'s admitted on day 50, which is many days after the telithromycin was
done, with, quote/unquote, a cholestatic hepatitis and jaundice. Again,
we would probably not consider this cholestatic. This would be
hepatocellular. Bilirubin went as high as 25 milligrams.

But the most important part of this history, which was left out in the
materials provided by the FDA, was that this man, after he had received
telithromycin because of failure of that drug apparently to work,
received a course of Augmentin. He had that for a couple of weeks we
believe and it\'s well within the time frame when he\'s readmitted with
this jaundice episode and a biopsy is done and is consistent with
cholestatic hepatitis. So that\'s one case which is probably not related
to the drug at all, and it would be much more likely to relate that to
the course of Augmentin that he had.

The next case is a 33-year-old woman from Germany. Again, no significant
history. She\'s on birth control pills for 3 years. Two days after she
starts telithromycin, which she took for just a few days, for sinusitis
and bronchitis, a 5-day course, she develops symptoms of abdominal pain,
nausea, vomiting, fever, sweats, a form of collapse of some type. And
her enzymes, again not cholestatic per se. These were mostly
hepatocellular. Her ALT peaks at 823. Her bilirubin level is never
appreciably high. There\'s no eosinophilia. There are no pretreatment
values to look at in comparison. This happened just right after she
started telithromycin.

So this one is listed as hepatocellular in nature, possibly related, but
again it\'s an unusual presentation of drug injury. It doesn\'t really
conform very well to several other cases that are in the data set which
are often asymptomatic and delayed after the drug has been received for
several days. So this one again is ‑‑ who knows. It can be called
possibly related. There was no biopsy here and no additional
information. She recovered, as did the majority of these patients.

And then the final one which is in fact cholestatic. A 44-year-old woman
again from Germany presented 2 to 3 days after she starts a 1-week
course of therapy with tiredness and right upper quadrant pain. It was
originally reported she may have been jaundiced, but that was later
retracted. In fact, her bilirubin was never elevated. It was always
normal. She had an alkaline phosphatase, when they originally tested,
that is 760. So that\'s quite high with an elevated GGT. There are no
baseline values that were available to review. She had mild elevations
in transaminases, no eosinophilia. So this is another one where she
recovered several days later. It was assessed as possibly an
idiosyncratic reaction by the reporting physician. It resolved. Again,
whether it was truly drug-related or not I\'m not sure we can tell.

But those were the cases that the FDA had selected, and you\'ll hear
more about them. If they have any additional information, we can discuss
them then. But again, this is a fairly small number of cases, not all of
which we have sufficient information to really make a call as to whether
it\'s truly drug-related. One clearly wasn\'t, the hepatitis A case, but
the other cholestatic ones are reversible, relatively mild to moderate
in intensity, and no sequelae.

DR. LEGGETT: Dr. O\'Fallon.

DR. O\'FALLON: Obviously, the ascertainment of adverse events does
depend upon the diligence with which the data are collected. And the
protocol apparently asked for them to be submitted real-time, on-line,
and all that. But there was some suggestion in the FDA packet that in
fact many of these adverse events were actually submitted in batch at
the end of the study. Is that true? And if so, what kind of percentage
of the adverse events were reported in batch instead of in real time?

DR. LEROY: The objective of the adjudication was to ‑‑ the process
included first contact with the investigators by physicians from Aventis
to make sure that all the algorithm possible was implemented at the
source of the data. The clinical event committee was not here to guide
the clinical evaluation of the case. It would have been impossible. And
this is not how the clinical event committees are operating. So, on the
contrary, all the information on the cases was gathered and all the
information that was generated by the algorithm that was discussed with
the CEC before the study that listed a certain number of questions to
ask and examinations to perform was gathered and submitted to the
clinical event committees with clean data. And that\'s why they were
submitted in batches.

So the speed was used here to go to the site and make sure that the
patient had the appropriate examinations, and that\'s where we were
making sure that all information was collected. Then all the packet was
completed and provided complete to the clinical event committee.

DR. O\'FALLON: So then basically you\'re saying that the adverse events
were known to the company in real time but were reported to the CEC in
batches, mostly.

DR. LEROY: They were to be reported in batches as predetermined in the
protocol.

DR. O\'FALLON: To the CEC.

DR. LEROY: To the CEC.

DR. O\'FALLON: But to the company ‑‑

DR. LEROY: And to us it was on an on-line basis, yes.

DR. O\'FALLON: Okay.

DR. LEGGETT: Sort of looking at the time, I\'ll ask Dr. Brown to give a
quick question, and then I would like to ask a quick question, and then
we\'re going to take a break.

DR. BROWN: We\'ve heard nothing about anaerobes this morning, and so I
need to ask. Non-first cases of sinusitis are frequently associated with
anaerobes, and anaerobes are obviously important in the stool. So I\'d
like to hear something about the effect of this drug on stool anaerobes
and sinus anaerobes.

DR. LEROY: I will ask Dr. Jenkins to answer this question.

DR. JENKINS: The activity of telithromycin against anaerobes is mixed.
If you take a look at the range of MICs, generally we see that
telithromycin is less active against the gut anaerobes, the Bacteroides
fragilis group. This looks at ranges of MICs, but the MIC 50 for B. frag
is in the range of 2 to 4 micrograms per ml. Whereas, if you take a look
at the activity against the oropharyngeal anaerobes, the
Peptostreptococci, the Prevotella species, and so forth, typically the
MICs for these organisms in fact are quite low. The ranges don\'t really
do it justice, but the MIC50 for Peptostrep is in the range of around
.25 micrograms per ml and the MIC50 for the Prevotella species likewise
is in the range of .25 to .5 micrograms per ml. So the short of it is it
has better activity against oropharyngeal anaerobes than it does against
gastrointestinal anaerobes.

DR. LEGGETT: I have a couple of questions for Dr. Jenkins or any of your
experts. I would like to get some clarification about the establishment
of the breakpoints. The company, I believe, is calling for a breakpoint
of 1, whereas the FDA in the briefing document had a lower breakpoint.
That would obviously have some impact in regards to your slides 18 and
22, as well as Dr. Leroy\'s slides of 35 and 36.

DR. LEROY: I think that we\'ve clarified with the FDA that it was the
breakpoints of the previous document and that will be discussed at the
NCCLS, given the fact that all the strains above 0.25 were cured.

DR. JENKINS: We will be making our presentation to the NCCLS for
antimicrobial susceptibility testing breakpoints on Tuesday, and the
breakpoints that we\'ve used in these discussions are consistent with
those that we will be requesting based on population distributions of
organisms, pharmacokinetic data, PK data, PD data, and also the clinical
cure rates for the more serious indications.

DR. LEGGETT: And finally, for Dr. Bhargava, can you tell us some
information about how endothelial lining fluid levels correlate with
clinical cure? I mean, we\'re given numbers, and he made the statement
that it was correlated with extracellular fluid, but that\'s not quite
the case. Interstitial fluid should be in equilibrium with serum. So
I\'m a little confused about that.

DR. LEROY: I don\'t think that we have data showing correlation and I
don\'t think that any other sponsors have done this exercise in these
type of studies. What we have here is that the studies were performed in
a laboratory that is used to doing those studies, Honeybone and Weiss,
that has done those studies in fact for azithromycin and clarithromycin,
allowing a comparison.

What we have with this compound is a very good balance between the serum
levels that are between 2 and 3, the epithelial lining fluid level,
according to the methodology of Weiss with a peak at 14, and the
macrophage levels that are over 100.

To answer your question, back to your question, we didn\'t perform a
correlation between the ELF and ‑‑

DR. LEGGETT: So it\'s still a hypothesis basically.

DR. LEROY: It\'s still a hypothesis, yes.

DR. LEGGETT: Thank you.

Now, I would like for us to take maybe a 10-minute break.

For the committee members, I\'m trying to get the FDA\'s thing done this
morning, so that our lunch could be shorter if we all agree to eat at
the buffet. So, let me know during the break. And we\'ll come back in 10
minutes. Thank you.

(Recess.)

DR. LEGGETT: Hello again. I would like us to get started since we\'re
only an hour and 10 minutes late.

This next portion will be the FDA presentation. I would like to get
through this and questioning before we take a break for lunch. We\'ll
start off with John Alexander who is going to give us a presentation
about the efficacy of telithromycin.

DR. ALEXANDER: Good morning. Unfortunately, I\'m not going to be able to
make up an hour and 10 minutes\' worth of time, but I\'m going to try
and go through this as quickly as I can.

My outline is that I\'ll go through the presentation of efficacy for
each of the separate indications, and what I\'ve done is highlight the
original NDA submission and the results that you\'ve seen previously in
the April 2001 advisory committee meeting in blue, and then any new
information that we received is highlighted in yellow in studies that
were in the resubmission. I\'m going to try and go through those quickly
so that we can get to talking about drug resistant Strep. pneumoniae,
especially those patients with community-acquired pneumonia due to DRSP.

So the three indications for which the sponsor is seeking approval in
this resubmission are acute exacerbation of chronic bronchitis, acute
sinusitis, and community-acquired pneumonia. The studies of
tonsillopharyngitis were done as part of the original submission. That
information is part of the FDA\'s briefing package, the appendix the you
received as a briefing package back in April, but we\'re not going to
discuss those today.

For acute exacerbation of chronic bronchitis, there were a total of
three studies done. Two were provided within the original NDA
submission, studies 3003 and 3007, and there was one additional study
provided for the resubmission. All of those three studies were fairly
similar in design.

The results of clinical outcome of the test-of-cure visit for the
per-protocol population and the MITT population are shown here. These
results are basically consistent with the results seen by the sponsor.

One note here is that for study 3003 the FDA used a 97.5 percent
confidence interval as a statistical adjustment for an interim analysis
that was done in the study.

Looking at clinical outcomes by pathogen for acute exacerbation of
chronic bronchitis, these are the two studies that were in the original
submission, study 3003 and 3007. One note to make here was with the
telithromycin clinical cure rates for patients with H. influenzae which
was part of the concern that the FDA had and why within our approvable
letter we asked for submission of an additional study of acute
exacerbation of chronic bronchitis.

These are the results for that study 3013 of clinical outcome by
pathogen. What you see in this study is a clinical outcome for
Haemophilus influenzae of 77.1 percent with a greater number of isolates
here.

Moving on to acute sinusitis, there were three studies that were
presented within the first review cycle, and there were no new studies
in the resubmission. Study 3002 was a study that compared 5 days to 10
days of telithromycin and was otherwise uncontrolled. This was a study
that included microbiology. Study 3005 compared telithromycin to
amoxicillin-clavulanate in a study that was based on clinical diagnosis
and only had microbiology obtained in a small group of patients.

Study 3001 compared telithromycin to cefuroxime axetil and this study
had a microbiology obtained by sinus puncture within the United States
and obtained by endoscopy within other countries. So each of these
studies is slightly different from one another.

When we look at the results that are shown here, this is the clinical
outcome at the test-of-cure visit for the clinical per-protocol
population, the bacteriologic per-protocol population, and the overall
MITT population.

In answer to Dr. Cross\' question earlier, part of the reason that you
might see a higher cure rate in the per-protocol clinical population for
study 3002 is because that comparator that\'s listed there is 10 days of
telithromycin. So no matter which arm of the trial that you were in,
people knew that patients were receiving telithromycin so there might be
some bias towards reporting a higher outcome rate.

With the other study, study 3005, where the rates are lower, there we
don\'t really have an explanation as far as the reason for lower
outcomes, but this was based on a clinical diagnosis and not based on
bacteriologic diagnosis in most of those patients.

Moving on to the by-pathogen cure rates, these are the three main
pathogens for acute sinusitis. These are the clinical outcomes that were
seen at the test-of-cure visit for patients who had these pathogens
isolated at baseline by sinus puncture and separately are shown the
telithromycin 5-day, 10-day, and then the two comparators.

Moving on then to community-acquired pneumonia, within the original NDA
submission there were three comparative studies that were done and three
open-label studies. One note here, the study 3009 that used the
comparator of trovafloxacin was stopped early, as noted previously by
the sponsor.

These results here show the clinical outcome at the test-of-cure visit
for the per-protocol clinical population and the MITT population. Again,
these results are consistent with those shown by the sponsor earlier.

Looking at the specific pathogens identified at baseline, these are the
clinical outcomes at the test-of-cure visit by the particular pathogen.
This includes all Strep. pneumoniae.

Also shown here separately are those patients with atypical pathogens,
Chlamydia, Mycoplasma, and Legionella. I would note here with the
Legionella pneumophila that the patients, for the most part, were
diagnosed serologically. There were 4 patients out of this group that
had a diagnosis that was by urinary antigen.

So for new studies in the resubmission, there were three new studies
that were provided. Study 4003 is a comparative study done in western
countries. Study 3012 was an open-label study of telithromycin given for
7 days, and then there was a separate submission of a Japanese study of
telithromycin. I\'m going to talk about the Japanese studies separately
from the presentation that I make about the western studies because the
designs of these studies really are a bit different from the designs of
the western studies. So I present the information that\'s obtained from
DRSP separately.

Now, since the goal of the resubmission was to address questions of the
activity of the drug for drug-resistant Streptococcus pneumoniae,
that\'s what the rest of my presentation focuses on.

So clinical cases of patients with drug-resistant Strep. pneumoniae were
collected for patients for both CAP and sinusitis, and these were the
definitions that were used for penicillin resistance and erythromycin
resistance.

One thing that I wanted to note before we get into the actual clinical
outcomes are the results of in vitro studies, and what I\'ve done here
is taken the patients who had community-acquired pneumonia that were the
per-protocol population and separated the patients who had either
erythromycin-sensitive or intermediate strains from those who had
erythromycin-resistant Streptococcus pneumoniae. What I show is the
telithromycin MIC. Now, what you see is a slight shift upward in terms
of the telithromycin MIC for those patients who have
erythromycin-resistant versus erythromycin-sensitive strains, but we
don\'t necessarily know what, if any, clinical significance this has.

So moving on to community-acquired pneumonia due to drug-resistant
Strep. pneumoniae. There were a total of 49 cases of CAP due to DRSP
from the western studies. I\'ll also get into briefly the subset of
bacteremic cases and the additional cases from the Japanese trial.

Now, what the sponsor had focused on previously was what the
bacteriologic per-protocol population was and the outcome that\'s there.
I want to focus a little bit on the MITT population and talk about the
difference between the evaluable and the subjects that were
non-evaluable.

Among the non-evaluable patients, there were 5 patients who were
categorized by the investigator as success, 2 who were categorized as
failures, and 5 that were indeterminates. Now, among these patients,
none of these patients in my estimation had a misdiagnosis of
community-acquired pneumonia. They all had clinical and radiologic
criteria that met that. Some of the reasons for non-evaluability related
to whether the sputum specimen was qualified as adequate by a Gram stain
or not, but in most of those cases I did think that Strep. pneumoniae
was still the likely pathogen within the cases.

With the 5 indeterminate patients, there was 1 patient who was withdrawn
for an elevated BUN and creatinine. That was his baseline BUN and
creatinine was elevated, and that was part of the exclusion criteria,
but the patient didn\'t follow up again until day 6 and at that patient
seemed to be doing well and was switched off therapy to something else.
And I would categorize that as a patient who truly had an indeterminate
outcome.

For the other 5 patients who were categorized as indeterminate, there
was 1 patient who had bronchitis that was diagnosed at the test-of-cure
visit and started on other antibiotic therapy.

There was 1 patient who was on therapy and had a sudden increase in
labored respirations, transferred to the ICU, was felt by the
investigator to have a suspected aspiration, and ended up dying on day 5
of therapy.

There was another patient who was started on new antibiotics on day 3,
citing a baseline blood culture that was positive for Streptococcus
pneumoniae, but the patient was also experiencing some adverse events as
well.

The final patient was a withdrawal for personal reasons. This patient
completed his entire course of telithromycin, came to the end-of-therapy
visit, seemed to be doing well, 2 days later withdrew from the study due
to personal reasons, but then 4 days after that, there\'s an AE form
that\'s filled out that indicates that the patient had a recurrence of
pneumonia. So that\'s within the test-of-cure visit window, and the
patient actually ended up dying 2 days later.

So from my standpoint, for all PRSP ‑‑ so this is those patients who
have either PRSP with or without macrolide resistance ‑‑ the outcomes
that were seen as far as clinical cure at the test-of-cure visit is a
rate of 70.4 percent, and then for all ERSP, regardless of the
penicillin resistance, it\'s 78.4 percent.

For comparator patients within the controlled studies, there were 7
comparator patients who had drug-resistant Strep. pneumoniae. Two
isolates were susceptible to the comparator agent. So there was 1 PRSP
that was treated with clarithromycin that was erythromycin-sensitive,
and 1 erythromycin-resistant but penicillin-sensitive strain that was
treated with amoxicillin.

Interestingly, there were 5 patients who were treated with
clarithromycin within the controlled studies that had erythromycin
resistance, and the outcome in those is 3 out of 5 clinical successes.

This looks at the subset of patients who had bacteremia and shows again
what the per-protocol population and the MITT population results were.

And these results come from Japanese studies. Again, I decided to
present these separately in part because of the fact that the study
designs are somewhat different, as well as the fact that you\'re talking
about a different dose, 600 milligrams, in most of these patients. Some
did receive 800 milligrams and the Japanese formulation that was used.
These are the results that were seen. There weren\'t any bacteremic
cases among these because bacteremia wasn\'t assessed within those
trials.

And then finally for acute sinusitis, there were a total of 29 cases of
acute sinusitis due to drug-resistant Strep. pneumoniae. These include
both patients that had a 5-day duration and a 10-day duration of
telithromycin treatment, and all these cases are from studies within the
original NDA.

Again, what I\'m showing here is the clinical outcome at the
test-of-cure visit for those patients who had a baseline pathogen,
separating out those patients who had just PRSP, those who had just
ERSP, and then those isolates that were both penicillin- and
erythromycin-resistant.

That\'s my presentation.

DR. LEGGETT: I think we\'ll probably take questions at the very end.

The next speaker will be Dr. Charles Cooper about telithromycin, an
integrated summary of safety.

DR. COOPER: Thank you.

I\'ll start with my outline. First, we\'ll start with a description of
the safety database for phase III clinical trials. Then I\'ll give an
overview of the safety-related events and then spend some time with
specific adverse events of special interest, namely cardiac, hepatic,
and visual, and then end with a summary slide.

Interest in the cardiac and hepatic risk profile was generated from data
from preclinical and phase I studies, and interest in the visual risk
profile arose from data from phase I and phase III studies.

This is an overview of the phase III safety database. This excludes the
large safety trial, 3014. That\'s the 24,000-patient safety trial. That
is excluded and will be discussed later in detail by Dr. Rochester.

As you can see, there are 1,207 new telithromycin-treated patients.
Those come from three different trials and results in a total of 4,472
telithromycin-treated patients.

The treatment groups were balanced for age, sex, race, and weight. There
were slightly more patients in the comparator arm who were over age 65,
and there were 59 patients who were treated with telithromycin who were
under age 18.

This table shows the deaths overall and by indication and by controlled
versus uncontrolled, and they\'re similar between telithromycin-treated
patients and comparator. None of these deaths were thought by the
investigator to be related to study medication.

This table shows nonfatal serious adverse events in controlled phase III
trials. As you can see, they are relatively similar, slightly higher in
comparator, but otherwise relatively similar between the two and mostly
related to underlying disease.

This table shows adverse events in controlled phase III trials and shows
that the most common adverse events in telithromycin-treated patients
were gastrointestinal, and telithromycin-treated patients seemed to have
a slightly higher rate than comparator-treated patients of
gastrointestinal adverse events, as well as dizziness, although
generally fairly similar.

I\'d also like to point out at the bottom for blurred vision, for
controlled studies there were 17 patients versus 2 in comparator.

With regard to adverse events resulting in discontinuation in controlled
phase III trials, the rates were similar between the two treatment arms
or between telithromycin and comparator, slightly higher rates for
gastrointestinal adverse events resulting in discontinuation, but
overall very similar.

With regard to the cardiac risk profile, preclinical and phase I studies
showed that telithromycin blocks IKr and prolongs action potentials in
isolated fibers, also prolongs QT and increases heart rate in dogs.
Also, there was shown to be a concentration-dependent increase in QTc in
phase I studies. As well, as was described earlier, there is an
increased exposure with patients with severe renal impairment with or
without concomitant CYP3A4 inhibitors.

With regard to cardiac adverse events in controlled phase III studies,
the rates are similar between telithromycin-treated patients and
comparator-treated patients, a slightly higher percentage of patients
with palpitations in the comparator-treated arm, but otherwise very
similar.

On the right of the slide, you will see a list of all the causes of the
serious cardiac adverse events in telithromycin-treated patients. On the
left, we see it broken down according to controlled versus uncontrolled
studies. And below that, we see the rate for comparator. Roughly
similar, and none of these were thought to be related to study drug by
the investigator.

ECG data from phase III clinical trials includes additional data from
one of the new studies, which was 3013. The two other new studies
didn\'t consistently collect ECG data and therefore wasn\'t incorporated
into the original data. The incorporation of the new data from 3013 did
not result in a significant change in what was concluded from before.
There was a mean on-therapy change in QT increase of 1.5 milliseconds.
And when compared to telithromycin in those controlled studies in which
clarithromycin was used as a comparator, we see an increase of 3.8
milliseconds for telithromycin and 3.3 milliseconds for clarithromycin,
but there was quite a wide interval there. Roughly similar.

With regard to hepatic risk profile, preclinical studies demonstrated
hepatotoxicity in rats, dogs, and monkeys, increased transaminases, and
hepatic necrosis in a 4-week rat study, also hepatocellular hypertrophy
and multi-nucleated hepatocytes were seen. Hepatic effects of
telithromycin were assessed to be greater than that of clarithromycin in
animals.

Hepatic toxicity seen in study 1030, one of the phase I studies, was
shown in 8 elderly subjects who received doses of 1,200, 1,600, and
2,000 milligrams of telithromycin or placebo. Three of the subjects
experienced increases in transaminases in the 100 to 300 range, and if
you look at the subjects, you\'ll note that there is a 7-day, a 17-day,
and a 14-day delay in the onset of these increases in transaminases
suggesting a possible latency period.

This table shows the hepatic adverse events in controlled phase III
studies. Roughly similar between telithromycin and comparator for the
different adverse events that were reported.

There were 4 patients with serious hepatic adverse events, 3 in the
telithromycin arm, 1 in comparator. Drug effect was unlikely in one of
the telithromycin patients and in the comparator patient. Drug effect
was thought to be plausible in 2 of the telithromycin patients. One was
a 76-year-old woman who was also on pravastatin. The patient was
asymptomatic and had an increased transaminase on telithromycin, but
recovered without sequelae.

The second patient is a 53-year-old male with eosinophilic hepatitis
that you heard about earlier, and I\'m going to go into a little bit
further detail about this patient in the following slides.

The patient is a 53-year-old male with asthma and diabetes. The
medications are listed here. The patient was treated with a 10-day
course of telithromycin for CAP and received six doses of acetaminophen
beginning approximately around day 13. On day 14, the patient
experienced fever, vomiting, and diarrhea. You can see the table shows
the laboratories during the course of the adverse event. The patient
began with an elevated ALT of 81 and then after treatment with Ketek, or
during the course, developed an increase in transaminase with the ALT
peaking at 1529. Eosinophils were also elevated at baseline and also
increased over the course.

On day 23, this patient was hospitalized for hepatitis and serologies
for viral etiologies were negative. A liver biopsy was done on day 29
which revealed centrilobular necrosis and eosinophilic infiltration. By
day 94 LFTs were virtually normal.

At follow-up on routine testing, the patient was asymptomatic, but 9
months after the event was found to have ALT that was increased to 1331
and a total bili that was also increased. Again, serologies for viral
etiology were negative and an anti-smooth muscle antibody was positive
at 1 to 1,000. There was no eosinophilia.

A second liver biopsy was done and revealed zone 3 and portal fibrosis,
piecemeal necrosis, a plasma cell infiltrate, consistent with autoimmune
hepatitis.

This slide shows changes from a normal baseline for patients in
controlled CAP studies who began with a normal ALT and tracks the number
of patients who then developed increases in ALTs according to severity.
As you can see, there\'s a slight increase in the telithromycin arm for
increases in ALT below 5 times the upper limit of normal. This pattern
was seen in the original submission, and when the new data from the new
study was incorporated, the pattern persisted.

And now for information on the visual risk profile, blurred vision in
phase III studies was seen in 20 out of 4,472 telithromycin-treated
patients versus 2 in the comparator-treated patients. In controlled
studies, there was a rate of 0.6 percent versus 0.1 percent for
comparators. You can see for females the rate was 0.9 percent, whereas
for males it was 0.4 percent, thus suggesting an increased rate in
women.

We looked at whether the presence of a 3A4 inhibitor affected the rate
of blurred vision in phase III studies. I want to stress, before talking
about these numbers, that this is an exploratory analysis. Patients were
not randomized according to 3A4 inhibitor intake, and therefore
conclusions may not be able to be drawn and much care needs to be taken
in looking at this data.

When we look at patients who received a CYP3A4 inhibitor, 1.9 percent of
patients who received telithromycin had blurred vision versus 0.4
percent for patients who did not receive a CYP3A4 inhibitor. 15 of the
patients had mild blurring, 4 with moderate blurring, and 1 with severe
blurring. The median duration was 2 days and the median onset was on the
second day. The range of duration was between 1 and 10 days, and the
range of onset was on day 1 up to day 6. Most of these patients remained
on study drug.

There were 5 discontinuations due to visual adverse events, 4 of which
were in controlled studies and appear to be related to this mechanism of
blurred vision.

There were two phase I studies, 1059 and 1064, that looked at
telithromycin-associated visual blurring. There was an incidence of 13
to 50 percent in subjects who received 2,400 milligrams of
telithromycin, and the incidence seemed to be higher in younger
subjects. The median onset was 3 hours with a range of 1 to 5 hours, and
the median duration was 2.8 hours with a range of .9 to 20.3. It
appeared that the blurred vision was at least in part likely due to
interference with accommodation.

There was one serious visual adverse event in a patient in study 3005.
It\'s a 42-year-old female who had a serious adverse event of unable to
accommodate. The adverse event was determined to be significantly
disabling and began 2 hours after study drug administration. The patient
was seen by an ophthalmologist who gave a diagnosis of unable
accommodate. The adverse event was initially assessed as related to
study drug. Telithromycin was discontinued, and the adverse event
resolved. Later the causality of the adverse event was changed to not
related to study medication.

In summary, overall the most common adverse events for telithromycin are
gastrointestinal in nature.

Phase I and preclinical studies show a concentration-dependent QT, and
there were no drug-related serious cardiac adverse events.

Hepatotoxicity was seen in preclinical studies, and there was a cluster
of patients with increased transaminases in phase III. There was also a
slightly increased incidence in low-level ALT elevations in phase III.
There was 1 patient with eosinophilic hepatitis in phase III.

The incidence of blurred vision was found to be 0.6 percent in
controlled studies and appeared to be higher in females. This adverse
event is thought to be possibly, at least in part, due to interference
with accommodation.

And that\'s the end of my talk.

DR. LEGGETT: Thank you. Again, we\'ll take questions at the end.

The next speaker will be Dr. George Rochester who\'s going to talk about
study 3014.

DR. ROCHESTER: Today I would like to present some of the basic findings
and discuss some of the design issues related to the large comparative
safety trial conducted in a usual care setting. Of course, sometimes
when we think about planning these large, so-called simple trials, they
sound simple but in trying to execute them, certainly there are many
issues that do come into play. So I will address some of those issues as
I go along.

Study 3014 was a randomized, comparative, open-label trial, and it would
appear that the randomization scheme was carried out properly. Both
treatment arms were similar in terms of any subgroup characteristics
that one could look at.

It was designed to look at safety in community-acquired respiratory
tract infection patients, which is not the same as just safety in
healthy patients. This cohort consisted of three groups: patients with
community-acquired pneumonia, AECB, or acute sinusitis.

And certainly when we use the term \"24,000 patients,\" what we really
mean is we\'ve got 12,000 patients in each treatment arm. So essentially
there were 12,000 patients on telithromycin.

Telithromycin was given for 5 days for the treatment of sinusitis and 7
to 10 days for CAP or AECB, and we\'ve heard that although a claim is
requested for treatment of AECB of 5 days, in this study 7 to 10 days
therapy was used in order to gain further safety information on the
longer duration of therapy given that at the time of planning the study
we had a smaller database of 3,265 from the previous submissions, and
there appeared to have been an increased number of adverse events seen
in CAP which was the group that received the longer therapy.

And our comparator here is amox-clav, which was given for 10 days for
all three indications.

The usual care setting. What that means is we\'ve got very relaxed
inclusion and exclusion criteria, so we could get then a very
heterogeneous, more real-to-life sort of population that we hoped would
reflect the population to which the drug would be given, should it be
approved.

In terms of how these indications were distributed, we had a target set
up to get about 40 percent of subjects with CAP or AECB, and the study
exceeds that. I think we had about 46 percent.

Also, we wanted at least 35 percent of the subjects should be above age
50, with a goal of getting more information in the elderly, particularly
those over 65. Again, the study exceeded that number. We had probably
about 25 percent of the subjects over 65, and almost 1,000 in each
treatment arm were over 75 years of age.

We also wanted subjects with concomitant illnesses. So we included
subjects with cardiovascular disease for obvious reasons, renal or
hepatic impairment ‑‑ there is probably about 1 percent, maybe 100 or
more subjects in each group with these conditions ‑‑ and with
significant concomitant drug use, such as subjects taking drugs that
inhibit or are metabolized by the CYP3A4 or CYP2D6. Again, we had, in
terms of concomitant drug use, about 1,500 subjects that were taking a
CYP3A4 inhibitor.

The study was designed with four adverse events of special interest in
mind. The hepatic which was defined as a clinically overt presentation
of significant hepatic injury, an ALT of greater than 3, a total
bilirubin of greater than 1.5, and worsening of a preexisting hepatic
condition. So the patient had a baseline hepatic problem, but on therapy
or during the study period, if that worsened in intensity or, for
example, required a prolongation of hospitalization or produced
hospitalization, that would have been considered an adverse experience.

And then there were three others: cardiac, visual, and vasculitic.

Now, in trying to size the study, we basically thought there was about 1
case in almost 4,000 patients, and so we accepted 12,000 patients as a
good effort. The study was not powered in the sense of being able to
simultaneously rule out all four adverse events of special interest. So
most of the data then was driven by the hepatic situation.

What do these overall adverse event rates ‑‑ how reassuring did these
kind of make you feel? In the phase III trials, generally we were seeing
about a 50 percent adverse events rate. In study 3014, there were many
subjects with comorbidities such as diabetes, renal impairment, and so
on, which was quite enriched in terms of at-risk subpopulations, many of
them on concomitant drugs. In this study what we saw is an overall
adverse experience of about 23 percent which is just about half of what
we\'ve seen before, which in my mind is a little bit surprising. I
can\'t tell you exactly what number to expect in that. I just know that
when you look at a mixture of patients in this kind of cohort, one would
expect the adverse events rates to be slightly more similar to what
we\'ve seen before.

Again, in this study only 10 percent of the subjects did have CAP, and
we understand that there could have been more heterogeneity in terms of
the population that was studied here versus what we\'ve seen in previous
trials.

The adverse events rates, when you look at the various subgroups ‑‑ and
all these subgroups are subgroups that we anticipated when the study was
designed. What we\'ve seen is an overall, again, 23 percent in both
arms. We\'ve seen that if you look at age greater than 65 years, hepatic
impairment, generally cardiovascular disease as a group, and CYP3A4
substrates or HMG CoA inhibitors, basically you\'re seeing rates similar
to comparators.

If one looks at severe renal impairment, it will look different from the
sponsor\'s numbers in the sense that this group is not just all patients
considered to have had some renal impairment, but these were the ones
documented with less than 30 mls per minute of creatinine clearance.
There were 23 patients that were in that group. 5 of them had an adverse
event. In the comparator group, 17 such patients, and there were no
adverse events reported there.

If you look under cardiovascular disease, particularly the ones who had
a history of congestive heart failure, there were 277 patients and an
adverse events rate of about 30 percent. If you look at the comparator
group, a similar number of patients, about 270, and that rate was about
24 percent, which is similar to the overall rate that we\'ve seen in the
population.

The way in which these hepatic events were supposed to be investigated.
Visit 1 on day 1, which is the start of study medication. All subjects
were going to have basically a panel of hepatic labs. And all subjects
were to report to a clinic visit on day 17 to 22 for their follow-up,
and at that point they were also going to have a repeat lab.

Now, any subjects who had, for example, a 3 times the upper limit of
normal change from baseline in their ALT values were flagged as
potential hepatic adverse events of special interest, and these subjects
were to be followed carefully and followed obviously to resolution. That
group consisted of about 209 patients, 110 in one group and 98 in the
other.

Follow-up was to be up until return to baseline or sufficient decline.
Sufficient decline is basically defined as return to about 1.5 times the
upper limit of normal if you started with a normal baseline and 2 times
the upper limit of normal if you started at an abnormal baseline. Most
of the subjects in this study, at least in this group, were followed up
for 6 months, which I think was quite impressive in the sense that of
209 subjects, we had essentially complete follow-up information on all
but 13. Three patients had died not from a hepatic-related event, but
they had died. Therefore, we had partial information on those. And 9
subjects out of the other 10 were in the telithromycin arm, and they
refused follow-up. Essentially they said they have no symptoms, they\'re
fine, and they didn\'t want to continue in the study.

Now, one way that this study could have significantly been improved ‑‑
during the design of the study, we talked about implementing some
management algorithms that would guide investigators with respect to the
minimum expectation for follow-up of adverse events of special interest.
This could have minimized obviously missing critical data and improved
completeness of case documentation during the conduct of the study. In
other words, we recognize that in any trial we\'ve got quite wide
variability in terms of follow-up of subjects by investigators. Some are
very diligent; others may not be so diligent. Investigators have
different medical specialties and interests and therefore they may
follow patients differently. And that\'s to be expected in the usual
care setting, and in that setting we understand that.

However, there\'s a difference between just the usual care setting
practice and a clinical trial. A clinical trial still needs to have a
little bit more structure. So this was something that we did emphasize.
In the actual carry-out of the trial, this was certainly not a major
thing that was emphasized.

Of course, that does pose some limitations in terms of asking questions
like, how long did it take the patients to achieve maximum change in
LFT, the time course of the subjects? You follow them over time and you
want to find out how long it took them to resolve or to return to their
baseline status. And because that data is not collected in a systematic
way, it poses very difficult issues in terms of analysis and/or
interpretation.

Adjudication was explained before. It should be done blindedly, and it
was done by the CECs. They were planned to be at regular intervals,
about biweekly intervals. It was largely done in batch at the end of the
trial.

Hepatic AEs were followed to resolution. Of the 209 subjects that were
in this group, most of them had lab recovery. All of them, except just
about 9 or 10, did not have complete follow-up information, and I
explained that before.

What are the changes like among subjects who had normal baseline ALT
values? In this version of our PowerPoint, we get donuts, but actually
these mean greater than.

(Laughter.)

DR. ROCHESTER: I suppose you become greater than if you eat donuts.

(Laughter.)

DR. ROCHESTER: So here we\'ve got subjects who are less than or equal to
1 time the upper limit of normal. So they retain their baseline status.
Essentially the majority, over 90 percent, of these subjects are in that
group. You\'ll find that telithromycin looks fairly similar up until you
get to about greater than 2 times. Greater than 2 times, you begin to
see numbers, about 35 compared to 22, 12 to 8, and as you get above 8,
you begin to see numbers like 7 to 2. Again, these are very small
numbers. However, you\'re seeing this trend always that on the one arm
that always exceeds the other, it\'s the telithromycin arm.

If you look at the late post-therapy, these are subjects who were
followed up greater than 35 days. Again, here you\'ll see fairly similar
up until about 3 times. When you get above, say, 5 times the upper limit
of normal, there\'s 4 compared to none, 8 compared to 3. So slightly
more patients in that group. Again, not large numbers of patients.

Changes in AST. It was a similar picture. Somewhere between 5 and 8,
there were 5 in teli, 1 on Augmentin. If you looked at greater than 8, 5
in teli, 1 on Augmentin. They\'re smaller numbers, but you just
consistently see on the telithromycin arm that there were more patients
there.

Changes in hepatic analytes at any post-therapy time point. Greater than
3 times ALT I\'ve already mentioned. Greater than 8 times, at any time
point, again you saw about 19 subjects here, twice as many, 10 in the
other arm, that you would see on Augmentin. Here, of course, we\'ve got
subjects with an ALT greater than 3 and a total bili of greater than
1.5. There were only 3 here on telithromycin, and of course, there were
6 on Augmentin.

Combined ALT and bilirubin changes at any post-therapy time point.
Again, the numbers showed for telithromycin here they were a little bit
better in the sense that for ALT greater than 3, total bili 3 to 6.
Patients were having those same changes but without increase in alk
phos, 1 on telithromycin, 4 on Augmentin. And there were no cases on
telithromycin that had transaminase elevation; in addition, jaundice
without an increase in alk phos.

If you look at 10 days versus 5 days of therapy ‑‑ and these numbers to
me were quite similar, 7 to 5. Greater than 8, there were 5 to 2.
Essentially I didn\'t see anything major here in terms of 5 days versus
7 to 10 days of telithromycin.

Subjects who met a hepatic endpoint definition. Essentially the cases
that were adjudicated, we have the same numbers. There were 3 here.
There were 2 in the other arm. Yes, there\'s overlap in these confidence
intervals. You\'d probably expect around 7 cases in 10,000 exposures to
meet an endpoint definition such as was used in this study on the
telithromycin arm.

A couple of cases that I just wanted to go through quickly. One case was
a 60-year-old female treated for 7 to 10 days telithromycin for AECB.
The patient had a past medical history that included recurrent cystitis
and asthma. Medications included Bactrim. The patient remained
asymptomatic. Baseline LFTs were normal on day 1, day 17. On day 25,
reported an ALT 3 times the upper limit of normal and AST 2.5 times. On
day 29, ALT continued to be up to 7 times the upper limit, which reached
a maximum value of 10 times the upper limit on day 36. AST also reached
max of 5 times the upper limit. Serologies were negative, and ANA and
smooth muscle antigens and so on were all negative. There was some
eosinophilia seen in this case. This was again at about day 36, and ANA
was positive at that time point, 1 in 160 dilution.

The patient was then treated with prednisone. This was a case of a
patient who, I guess, was determined to go on vacation and convinced her
physician to give her some treatment rather than further biopsy or any
other thing. This patient went on to have prednisone treatment, was
adjudicated as clinically well and possibly related to study drug. This
was by the committee.

Another case, 3440-001, a 75-year-old white female treated for acute
sinusitis, received 5 days. A history of cholecystectomy, coronary
artery disease, hypertension, and some degenerative joint disease. No
history of anything concerning liver disease, and negative for alcohol
intake.

The patient did have in her concomitant meds Tylenol, which she took
p.r.n. Four hours after her last dose, she had a Tylenol level of 2 and
an upper limit for a toxic range would have been greater than 150.

Day 18 she presented with severe epigastric pain, right upper quadrant
tenderness, fever of 101 degrees Fahrenheit, jaundice, and fatigue. She
had a CT scan which was negative for gallstones, negative to duct
dilatation. On day 18, she had her maximum change between 8 to 15 times
the upper limit of normal in ALT. AST was 21 to 37 times the upper limit
of normal, a doubling in her alkaline phosphatase, and a total bili of
about 1.8. By day 29, all these labs were resolved after a 4-day
hospital course.

It was considered a clinically serious event by the investigator and
ruled as probably drug-related but passage of a stone cannot be ruled
out by the CEC adjudication.

And the last case I\'d like to talk about is a 72-year-old male treated
for 7 to 10 days of teli for CAP. The patient had an underlying history
including diabetes mellitus, hypertension, coronary artery disease.
Negative for liver disease or for alcohol intake. The medications, did
use Tylenol p.r.n.

Symptoms on day 30, presented with jaundice. This patient was also
treated with Levaquin. On day 1, had normal baseline status. Day 23, ALT
8 times the upper limit of normal. Alk phos 5 times and t. bili about 5
times the upper limit of normal. On day 29, those repeat labs were ALT 5
times, AST 3 times, alkaline phos 4 times. Total bili was reduced from 5
to about 4. Direct bili was 6.5 times. Eosinophils were within normal
limits and all the serologies were negative. A CT scan showed a
gallbladder with low density calculi and sludge. I think this patient
also had an ERCP which did show sludge.

This case was one that went on to liver biopsy, had a cholecystectomy
done, and that will be discussed later by our guest consultant.

By day 58, the patient appeared to be clinically resolved, and the
adjudication committee thought this was possibly drug-related. Passage
of a stone probably cannot be ruled out in this patient as well.

So in summary, regarding the hepatic adverse events of special interest,
yes, they were uncommon, occurring in just about 1 percent of subjects
being treated in both arms.

Telithromycin appeared to be similar to Augmentin with elevations in
hepatic analytes, specifically ALT, up to about 3 times the upper limit
of normal. More extreme elevations, such as greater than 8 times the
upper limit of normal, were slightly more common among
telithromycin-treated subjects and consistently so.

A minority of subjects were symptomatic in both treatment arms.

There were no cases of liver failure or deaths among hepatic cases.

And at the 6-month follow-up time point, no subjects were reported with
known sequelae. One telithromycin subject had persistent right upper
quadrant tenderness on examination even at the 6-month time point
follow-up.

That concludes my presentation.

DR. LEGGETT: Thank you.

The next speaker will be Dr. David Kleiner who will give us a discussion
of the hepatic pathology.

DR. KLEINER: This is me. I\'m from the Laboratory of Pathology at the
NCI. I\'ve been their hepatic pathologist and the sole hepatic
pathologist for the last decade, and I\'m also Section Chief of the
Postmortem Section.

So what I\'m going to do is show you some of the pathology from the 2
patients who have had liver biopsies in suspected cases of telithromycin
hepatic injury. The purpose of the pathologist in this is twofold. One
is to characterize the pattern of injury that we see to put it in
categories so that we can form differential diagnoses, and the second is
to formulate an opinion as to what the etiology might be.

So the first patient I\'m going to talk about is the one that was
presented in 1999 and had two biopsies. You\'ve already seen some of
this data presented. This is just to sort of remind you of the time
course of events and where the biopsy came in relationship to the
therapy period and the profile of aminotransferases. The biopsy came
about day 26 or 27, already on the down slope of the ALT peak.

What we saw ‑‑ or what I saw ‑‑ was primarily what I would consider zone
3 necrosis and inflammation. What you see here in this sort of moderate
power shot are two central veins surrounded by a zone of hepatocyte
necrosis and inflammatory cell infiltration.

If we come up closer, you can see the residual central vein here in the
middle, a mixed inflammatory infiltrate composed of eosinophils ‑‑ and
they\'re fairly prominent and scattered all the way through ‑‑ pigmented
macrophages and lymphocytes and plasma cells.

Here\'s just another shot showing a particularly large cluster of
eosinophils.

Although the degree of portal inflammation was very mild, there was some
portal inflammation in many of the portal areas, along with a little bit
of disruption of the interface.

There was no Masson\'s stain supplied with the case, but there was
another connective tissue stain, a van Gieson\'s stain, which stains
collagen this pink color and kind of gives a sort of a yellowish color
to the hepatocytes. So this is a central vein here showing infiltration
of the vein wall by inflammatory cells and destruction of hepatocytes
around it, but you see no increase in collagen other than what we would
expect normally, so there\'s no central fibrosis at this point.

Nor was there any discernible periportal fibrosis. Here\'s a portal
area, again the collagens in pink. So this is what one would normally
expect. There is inflammation at the interface which is expanding the
portal area that way, but no fibrosis yet.

So in terms of the pattern of injury, I would characterize this as a
zone 3 centrilobular necrosis pattern with a mixed infiltrate of
eosinophils and plasma cells, lymphocytes, and macrophages. There was
moderate interface hepatitis and no significant periportal or sinusoidal
fibrosis and no cholestasis.

The differential diagnosis for zone 3 necrosis is actually much longer
than this, but these are usually the major players that we think about
just in general terms. Hypoxic/ischemic insults, veno-occlusive disease,
and drug or toxic injury is in the list. And the mixed infiltrate with
prominence of eosinophils and plasma cells is strongly suggestive of
hypersensitivity reaction, either one that given the patient\'s history,
there could have been something there before that was very mild that was
exacerbated. But in general I would not characterize zone 3 necrosis as
the typical part of acute autoimmune hepatitis.

The patient then recovered from this acute episode and was followed up
some months later with a random ALT value that showed elevated
transaminases again and received a second biopsy. At that time although
the biopsy was done in December, there were results from tests that were
done in November. ALT was up around 1300. Total bilirubin was only
slightly elevated. Immunoglobulins were increased. At this time an
anti-SMA was measured, but ANA and AMA were negative, and the viral
serologies were negative.

What was seen at this point in this liver biopsy was a pattern of
chronic hepatitis. This is again a low power shot. You can see now some
distortion of architecture with early regeneration. There\'s a fibrotic
bridge actually that wraps around here, really tracking along central
veins. There\'s a normal portal area off to the side here.

In this case this shows a portal area and a much more typical pattern
for chronic hepatitis, lots of interface hepatitis, plasma cells, and
other inflammatory cells in evidence, not so many eosinophils at this
point.

This is a central vein, showing that there was persistent inflammation
around the central vein, also kind of causing an interface hepatitis, if
you will, where the fibrotic edge met the liver cells. But each central
vein was surrounded by a large cuff of collagen.

There was also spotty necrosis out in the lobules, also consistent with
the pattern of chronic hepatitis. In this case there was a Masson\'s
stain, so one can see that there was bridging fibrosis present. This is
a central vein up here and a portal area down here and a fibrotic bridge
in between. There was expansion of other portal areas that were not
caught up in bridges, but most of the central veins were involved in
bridging fibrosis.

This is just a higher magnification around one such central vein showing
the relatively thick cuff of collagen.

So the diagnosis for this biopsy, chronic hepatitis, infiltrate again,
suggestive of an autoimmune etiology because of the predominance of
plasma cells, marked inflammatory activity ‑‑ many of the edges were
involved by interface hepatitis ‑‑ and bridging fibrosis. And the
fibrosis pattern is consistent with scarring that matches the injury
that was seen in the prior biopsy. Most of the injury in the first
biopsy was central and that\'s where we saw most of the fibrosis.

And then the second patient with a biopsy this year was just presented
and again had elevations of transaminases and bilirubin following
treatment with telithromycin and received workup and then biopsy and
cholecystectomy at this point. As was mentioned, the gallbladder did
contain stones and sludge, which of course complicates the
interpretation of all of this.

But what was seen here was a bit of a different pattern from what we saw
before. Here you don\'t see much from low power at all. There\'s a
little bit of an infiltrate in this portal area, maybe a suggestion of
something going around this central vein here, but very mild overall.
Portal areas did not show much in the way of inflammatory cell
infiltrate and little or no interface hepatitis. Many of the portal ares
were completely devoid of inflammatory cells.

But once you started focusing on the central veins, what you saw was a
pattern of spotty necrosis and bilirubin in canaliculi and in
hepatocytes. It\'s a little bit hard to show on photo mics, but there\'s
bilirubin right in that cell there and there and there and there. So you
can see this little bit of brown color.

I do have a higher magnification. And there there\'s bilirubin. So
there\'s the cholestasis, and there were also little pockets of
inflammation and occasional apoptotic hepatocytes.

There was fibrosis present as well. It was, generally speaking,
sinusoidal fibrosis and it was present around central veins and
expanding out of portal areas.

So I would characterize this pattern as a combined cholestatic and
hepatocellular injury, albeit it mild, as well as sinusoidal and
periportal fibrosis. And this I think is old and predates any treatment
by this drug but goes along with the history of diabetes mellitus.

Etiologic differential diagnosis of combined cholestasis and hepatitis
can include sepsis, acute large duct obstruction early in this patient,
as well as drug and toxic injury. In fact, in terms of patterns, since
we don\'t usually biopsy the liver to diagnose acute large duct
obstruction, this comes up much more often in this differential but you
have to keep these other things in mind.

Now, in deciding whether or not an injury is caused by a drug, what we
teach our residents and what\'s taught in the AFIP liver course is
methodology by Irey which considers temporal eligibility, exclusion of
other drugs, toxins, and diseases, a known potential for injury by the
agent, a precedent for the injury pattern, whether there was
dechallenge, which means you take the patient off the drug and then
rechallenge, and any toxicologic analysis that might have been done.

Now, when you\'re dealing with drugs in clinical trials, as I frequently
do at the NIH, a lot of this information is missing. You don\'t have a
precedent. There might have been preclinical studies that you don\'t
have available to you. So a lot depends on what the pattern of injury is
and how much you can exclude for other causes.

You try and categorize that toxicity into these categories. Causative,
where it\'s confirmed and absolute. We very rarely get this. Probable,
where there\'s good circumstantial evidence without other conflicting
evidence. A possible association, where it\'s consistent but other
factors cannot be ruled out. Coincidental where you\'re pretty sure
it\'s really just coincidence and the drug can be ruled out. And
negative is you\'re absolutely certain that there was no association.

So the way that I would categorize these ‑‑ it\'s my opinion ‑‑ for the
first patient, that this first episode was probable drug toxicity and
that\'s based on the pattern of injury of centrilobular necrosis and the
unusual and atypical appearance if one were to try to explain this as
just a flare of acute autoimmune hepatitis. Now, later on maybe
persistent drug toxicity, but it\'s more likely I think that there might
have been an underlying acute autoimmune hepatitis that was mild.

Then in the second patient, this is possible, but it\'s really hard to
rule out that coincidental early acute large duct obstruction which just
made it look like drug toxicity. But I think that the evidence for these
things is equal and that this is certainly a possibility.

Thank you.

DR. LEGGETT: Thank you very much.

The final speaker in this session will be Dr. Charles Cooper with
post-marketing information.

DR. COOPER: Thank you. I guess I\'d like to start by just pointing out
that when we review new drugs, it\'s not often that we have a large
post-marketing safety database to look at. So we viewed this
post-marketing data for telithromycin with great interest and viewed it
as being very important.

All data has strengths and weaknesses. Post-marketing data is certainly
no different. Its strengths can be in numbers, large numbers, but there
are many weaknesses. Typically post-marketing data is accrued through
passive reporting which can lead to under-reporting or reporting or
recall biases. The numerator and denominator are often and usually
uncertain. And information is frequently incomplete, and the lack of
detailed and complete information often confounds assessment of
causality and association.

I\'d like to just take a second and just tell you the data that we have
and how we came about it. When the NDA was resubmitted in July, the
sponsor submitted summary tables that gave summations of the numbers of
each different adverse event and also gave line listings with some
amount of information. However, from that information, we were unable to
really come to an understanding of specific cases. So we requested that
the company submit the actual Medwatch adverse event report forms, but
in the interest of time constraints, what the company was able to do was
to extract the narratives from all the Medwatch forms and submit them to
us for our review.

The narratives are sometimes incomplete, sometimes contain conflicting
information, sometimes are very difficult to understand, and this goes
back to the point of incomplete information and difficulty in
understanding the data.

One thing I would like to point out that I think is important to note,
when looking at these post-marketing events, is what the reporting
physician or treating physician thought about the possibility of the
adverse event being related to Ketek. I don\'t mean to imply that the
opinion of the treating physician is definite or definitive in any way,
but presumably the treating physician has a much clearer, more detailed,
and more comprehensive understanding of these individual cases,
certainly more so than what we can glean from reading these oftentimes
inadequate or difficult to understand narratives.

First, I\'d like to just point out that Ketek was approved in 2001 in
July by the European Union. It\'s been marketed in several countries,
including Germany, France, Spain, Italy, Brazil, and Mexico, and has
been approved for indications as listed.

The FDA received safety data up until October 1st, 2002, and that
includes approximately in the low 900,000 prescription range, roughly a
million prescriptions. There is one ongoing post-marketing safety survey
being conducted in Germany as well.

The data that we received from the company ‑‑ we also received a SAS
transport file that contained data listings ‑‑ had data for 406 patients
with post-marketing adverse events. 347 of the patients were reported
through spontaneous reporting. 30 were through the post-marketing safety
survey, and 29 of the patients were actually part of sponsored surveys.
For the purposes of this presentation, those patients and adverse events
from those patients have been excluded.

When looking at the adverse events by country, the majority come from
Germany, 218 patients. Next is Brazil with 99 and then Spain and France.

The distribution of prescriptions by country is that the majority were
actually in Germany and Italy. By this point, when taking into account
November and December, the majority are actually in Germany and France.
But for our database, it\'s Germany and Italy.

When looking at the post-marketing cardiac adverse events, there were a
total of 37 reported adverse events from 24 patients. This table lists
those adverse events. Patients may have had more than one adverse event.
This table also lists the number of serious adverse events.

At the bottom we see that reported case of torsades. I\'d also like to
present one additional case of torsades that just came to our attention
in the last week or two, and that case was not actually part of the
reporting period leading up to October 1st. It actually occurred after
October 1st.

That patient was a 44-year-old male with no history of cardiac disorder
who was treated with Ketek for bronchitis beginning on October 2nd. The
patient developed malaise and, on the way to a rheumatology visit on
October 12th, developed symptoms and was evaluated. The information in
this report is not very detailed. The patient was reported to be
discovered in torsades. Countermeasures were reported to have been
taken, and the patient supposedly recovered. The reporter considered the
causation as highly probable.

The company apparently has attempted to contact the general practitioner
who reported this case, and I understand that the general practitioner
has not been cooperative and may have even retracted this adverse event
for unclear reasons.

The second case of torsades that was actually shown on that table is a
spontaneous report by a general practitioner via a company
representative. The patient was a 59-year-old male, and he had a history
of coronary heart disease, status post PTCA with stent implantation
after an angina attack the previous year, a history of hypertension, a
history of paraplegia, as well as hypercholesterolemia.

The concomitant medications are listed here.

The patient started treatment on either the 22nd or 23rd with Ketek for
sinusitis and tracheobronchitis, and either on the 23rd or 28th, he
experienced an episode of confusion which was retrospectively considered
to be an equivalent of syncope. An EKG was done at that time and was
reported to be normal, as was blood pressure. Ketek was discontinued. So
Ketek was discontinued either on the 23rd or 28th. It\'s a little
unclear. There was a follow-up report that states that this event
occurred on the 23rd rather than the 28th, and that follow-up report
also states that treatment started on the 22nd rather than the 23rd.

On May 30th, while driving his car, the patient had some sort of episode
and lost control of his car and found himself in the middle of a corn
field. He was hospitalized and the EKG showed no abnormalities.

According to the patient\'s wife, Ketek was readministered during the
time of the hospitalization and the patient was without symptoms until
the next afternoon when the patient\'s telemetry monitor revealed what
was reported in the adverse event narrative as classic torsades,
persisting, finally changing to ventricular fibrillation that results in
a 0 line.

There\'s also some mention of a premature beat that may have occurred.

This is the entirety of the electrocardiographic data that we have for
evaluation of this patient. The strips were not in order, and the proper
order is strip number 1 and then 4 and then 3 and then 2, and I\'m going
to present them in that order.

Strip number 1. There\'s some artifact and what looks like sinus rhythm
at 14:52 on May 31st.

Strip number 4 at 14:57 shows what looks like sinus rhythm.

And 27 minutes later, this is what the rhythm shows. Now, there is a
27-minute gap during which time we\'re not sure exactly what happened.
We\'re not able to draw any conclusions about what happened during that
time.

This is the next strip, and that\'s that case.

This is the report of the echo, for the most part normal.

The patient had elevated CK but CKMB was percentage-wise very low.
Potassium was 3.6 and other values were reported to be within normal
ranges.

With regard to hepatic adverse events, there were 42 reported adverse
events from 18 patients. All of these are from Germany. This table shows
the numbers of adverse events according to MEDRA Preferred Term.

There were no deaths in hepatic-related post-marketing adverse events.
There were two liver biopsies. Many of the reports again lacked detailed
information which is, like we discussed, not unusual for post-marketing
adverse events.

Case number 1 was a 61-year-old female who, according to the narrative
we had, had a history of infective endocarditis who was on long-term
prophylaxis. The exact drug that the patient had been on for prophylaxis
at the time of this event was not stated in the narrative.

The patient was treated for 2 weeks with Ketek for sinusitis and
tonsillitis. After treatment, the patient continued with fever and a
work-up was negative except for increased liver function tests.

The admitting hospital physician suspected liver reaction as caused by
Ketek. The patient underwent a liver biopsy. The date of the liver
biopsy in relation to Ketek administration was not reported in the
narrative that we have.

There was no information on alcohol use or ultrasound results, but the
biopsy results are listed here. This is verbatim: \"a focal fatty
degeneration of hepatic tissue with moderate intrahepatic cholestasis,
as well as mild inflammatory mesenchymal activity. No signs of
malignancy or specificity. No typical histologic aspects of chronic
viral hepatitis. The findings could indicate a nutritive-toxic
genesis.\"

Case number 2 involves a 70-year-old with a history of COPD, diabetes,
and status post Bilroth surgery. No history of liver disease or
alcoholism was reported.

The patient was admitted on December 13th with flu-like symptoms,
productive cough and hemoptysis, and was started on treatment with Ketek
for what was presumed to be COPD exacerbation. The patient completed
Ketek on the 15th and was discharged on prednisolone.

The patient was readmitted on January 28th with cholestatic hepatosis,
likely drug-induced by telithromycin. This is a verbatim report out of
the narrative for the adverse event.

The results of the ultrasound are listed here.

The patient underwent liver biopsy on February 2nd, and this is the
verbatim report in the narrative that we have for the results of that
liver biopsy. \"A marked cholestatic hepatopathy with mononuclear
inflammatory infiltration in the periportal triangle with singular cell
necrosis and surrounding granulocytic reaction. Morphol picture
compatible with a cholestatic drug-toxic hepatitis as can occur after
antibiotics.\"

I suppose I understand from what was said earlier that this patient
received Augmentin. However, that information was not in the narrative
that we have. The words amoxicillin and clavulanate are listed almost as
a non sequitur in the narrative, but there are no dates associated with
that. So it\'s unclear to us when he received that, but I understand
from follow-ups, as stated earlier, that he may have received Augmentin.

Case of interest number 3. Well, first let me say we have, with these
two biopsies and previous biopsies, what appear to be varying patterns,
and we can discuss later what exactly this might mean with regard to the
likelihood of drug-related hepatotoxicity as possibly mediated by
telithromycin exposure.

Case of interest number 3 is a 33-year-old female with a history of
pyeloplasty on oral contraceptives with no other past medical history.
She was treated with Ketek from March 10th to March 14th, 2002 for
sinusitis and bronchitis. On the third day of treatment, she developed
nausea, vomiting, fever, sweats, right upper quadrant pain and was found
to have an increased ALT to 823 and total bili of 33 micromolar per
liter. Viral serologies were negative and ultrasound was reported as
unremarkable.

Enzymes normalized after 5 weeks and the narrative does not report
anti-smooth muscle antibody.

The first set of labs that were done in this patient reported increased
eosinophils by a percentage of 7 percent. Repeated eosinophil counts
were not reported. It\'s probably more accurate to say maybe they were
repeated but we didn\'t see it in our narrative.

The physician who reported this case reported the causation as probable.

Case of interest number 4 is a 44-year-old female with a history of COPD
on a beta-stimulant, budesonide, and corticosteroids. The patient was
treated with Ketek for 6 to 7 days for a febrile infection. After 2 to 3
days of treatment she developed severe tiredness, right upper quadrant
pain, fever, and icterus.

A follow-up report on March 26th of 2002 clarified no icterus, and the
reporter listed with no doubt the diagnosis as \"allergic hepatopathy\"
and Ketek causation as highly probable.

The disorder lasted from February 13th to February 25th of 2002 and
resolved 15 days after withdrawal of Ketek.

Transaminases were in the 200 to 300 range. AMA, ANA, and ANCA were
reported as negative. We did not see a report of eosinophil count or
anti-smooth muscle antibody in our narrative.

The patient was hospitalized from February 13th to February 16th.
Serologies for viral etiology were negative, as was for Epstein-Barr.
Sonography showed that \"there was no congested bile ducts, and the
liver was morphological without findings.\"

A follow-up report the next month in April, April 3rd, the reporting
physician changed the cause to idiopathic.

This case of interest number 5 is the final hepatic case that we just
learned about last week, and I\'d like to point out that this also is
another adverse event that occurred after the reporting period, but
since the patient had a fatal adverse event or a fatal course, I should
say, we felt it was important to present the case. Obviously, there was
a lot going on with this patient. It\'s quite an unusual case and many
confounders exist.

The patient is a 75-year-old male with a history of chronic bronchitis
and chronic stable respiratory insufficiency. No history of alcoholism
or family history of hepatitis. Concomitant medications include
acetaminophen.

Liver function tests were reported as normal 6 months prior to the
event. On November 27th, the patient was treated with Ketek for 5 days
for AECB exacerbation. He was also treated with prednisolone and
increased doses of paracetamol of the maximum dose, 4 grams per day. The
patient was also treated with formoterol.

On December 3rd, 2002, the patient experienced fatigue, jaundice, and
fever. Lab tests revealed ALT elevation to 2,810 and a total bilirubin
of 133. Ultrasound revealed liver normal for size and for contour with
homogenous echostructure. No dilatation of intrahepatic or extrahepatic
biliary ducts. There was at least one stone in the gallbladder.

During the night of admission, the patient developed a coma and was
transferred to the ICU where he was intubated. On December 4th, the next
day, the ALT dropped to 595. The patient underwent exploratory
laparotomy which did not confirm cholecystis but did show a hard and
nodular liver. Postoperatively the patient experienced hemorrhage and
multi-organ failure and metabolic acidosis. Total bilirubin increased
significantly. Hepatitis A IgM was strongly positive. The patient was
also found to have a positive acute serology for Coxiella burnetti.

Measurement of paracetamol 2 days after the admission was low.

The patient died on December 8th. No postmortem was performed as the
family refused.

Now I would like to turn to the visual post-marketing adverse events.
There were 168 reported visual adverse events from 124 different
patients. The most common were vision blurred, visual disturbance,
accommodation disorder, and at the bottom you\'ll see that 36 were
reported as serious, 24 not reported with regard to whether they were
serious or not, and 108 were reported as not serious.

In the category of visual disturbance, just a sampling of some of the
adverse events that were reported are listed on this slide.

Now, I\'ve selected some narratives to present, and these are verbatim
narratives that we received. This first one actually also occurred after
the reporting period, but I thought it was important to present. There
may be a follow-up on this. The company can let us know about that, but
I think thought it was important to present because according to the
narrative that we have, the patient had a partial recovery of vision at
the time of this report.

It\'s a 39-year-old woman who received therapy with Ketek from October
25th to 26th for the treatment of sinusitis. There was no mention of
relevant history or concomitant medications. On October 25th, the
patient experienced vision loss. She had partial recovery of vision by
October 29th. The events are ongoing at the time of this report. The
reporter assessed the events as highly probably and medically important
and serious.

This report came from an internal medicine physician, a report of severe
visual disturbance. A 36-year-old female. No information on medical
history or concomitant medications was provided. The patient was treated
with Ketek orally. The first intake was on October 1st. One hour later
the patient developed severe visual disturbance so that she had to rely
on her husband\'s help. The event resolved after 9 hours and the
physician assessed the causal relationship between Ketek and the adverse
event as highly probable and considered to be serious.

This report is of a 33-year-old male. It\'s a spontaneous report. The
patient was treated with Ketek from January 13th to January 15th for
sinusitis and tracheitis. There\'s no information on further
medications. The patient had no medical history of visual disorders, and
on January 15th the patient developed a visual disturbance which was
blurred vision affecting near and far sight. He was considerably
impaired in his activities. The symptoms started increasingly within
hours after intake of Ketek and resolved hours after stop of treatment
of Ketek. The end of the event was January 16th.

The patient was not seen by a specialist. According to the physician,
there was no alternative explanation for the event. He assessed the
causal relationship between the event and Ketek as highly probable and
serious.

This case involves a 27-year-old female with the adverse event reported
as visual disorder, visual loss. It\'s a spontaneous report from a
physician. The patient received therapy of telithromycin from May 31st
until June 2nd. Relevant medical history includes hypothyroidism and
dysrhythmia. Concomitant medications include salbutamol, betamethasone,
and thyroxine. On June 2nd, the patient experienced visual disorder with
visual loss.

She discontinued treatment with telithromycin and underwent a CT scan
and visual field studies. Both were reported to be normal. I just want
to point out that this is the narrative, so we don\'t know when the CT
scan and the visual field studies were done with relationship to the
actual symptoms.

The patient experienced a complete recovery after discontinuation of the
drug. The physician assessed the event as highly probable and serious.

This last case also occurred after the reporting period. These are
verbatim excerpts from the narrative.

The adverse event was reported as visual disorder, visual loss. The
patient is a 17-year-old female who received Ketek 800 milligrams orally
on November 11th of 2002 for the treatment of lung infection. The
patient experienced blurred vision 30 minutes after intake of Ketek. The
visual loss was a severe blurred vision. It was severe enough to make
the patient unable to distinguish her face in a mirror, walk, or eat by
herself. It was presumed that the problem was an accommodation problem.

The patient was alone when the event started. The patient\'s mother
arrived 5 hours later and found the patient in bed due to the event.

The patient has no history of visual abnormalities. She complained of
blurred vision in both distance and near vision. The event lasted 12
hours after the Ketek dose was received. The patient was not only unable
to read but was also unable to walk due to the visual abnormality. She
had to remain in bed and needed assistance with eating.

And that\'s the end. Thank you.

DR. LEGGETT: Thank you. I think in the interest of time and hunger,
we\'ll take our lunch now. Would the committee members please remember
their questions for when we come back? I think we can do the open public
hearing. If there is no one to speak, we will then tie in Dr. Rubin\'s
discussion of the pathology and sort of lead on from there and go into
the discussion. It\'s now 1:30. Can we come back here at 2:15?

(Whereupon, at 1:37 p.m., the committee was recessed, to reconvene at
2:15 p.m.)

AFTERNOON SESSION

(2:25 p.m.)

DR. LEGGETT: Hello again. I\'d like to reconvene.

Hopefully the way things will go this afternoon, we will have a brief
question and answer period for the panel and the FDA, followed by the
open public hearing session, followed by Dr. Rubin from Aventis
reviewing the liver slides, and then the company talking about those
same toxicity data in the post-marketing studies that we talked about,
and then hopefully segue from that into the discussion session. And
we\'ll be out of here by tomorrow I\'m sure.

(Laughter.)

DR. LEGGETT: Does anyone have any questions for the FDA discussion?
Dave?

DR. BELL: Yes. I\'m relatively new on the committee, and I would
appreciate it if somebody from the FDA could provide some perspective
here, as far as they could, in terms of previous decisions when drugs
were submitted for approval and had this amount of information and this
amount of toxicity information. What has the FDA decided? What have
previous committees decided?

I mean, I can form my impression here as to what I think, but I don\'t
know the questions you\'re asking us, should this be, should it not be.
Is there some perspective?

DR. LEGGETT: Mark or Janice, could you give us a little bit of
institutional memory?

DR. SORETH: I can try. In terms of previous advisory committee meetings
that have discussed this amount of data that you refer to, I think the
experience we have here is unique in that I can\'t recall the last time
we had an application pending where there was a million or a
million-and-a-half exposures elsewhere. Can you, Mark? This is a first
for me in that sense, in the amount of data.

DR. GOLDBERGER: Yes, I would agree. Certainly the things over the years
that I\'ve been involved in, we have not had this degree of
post-marketing data. I\'m thinking about one of the fluoroquinolones we
may have had some post-marketing data but not at the level, for
instance, of this.

In fact, we will occasionally have larger sets of data in certain
circumstances from treatment INDs that have been in place, most notably
I think for some products for HIV while they\'re in the late stages of
development, and that can amount, again, to some thousands of patients.
That, of course, can give you a broader picture of safety, but in the
setting a drug for HIV, when one is thinking about the potential
benefits versus the safety, there is a different calculus than a drug
for the type of indications for which Aventis is currently seeking
approval.

So I think there is some level, at least certainly in the anti-infective
world, of uniqueness here. I don\'t know how much of a problem that
should really pose. I think it\'s always hard when you see this amount
of post-marketing data to then understand, well, what do these events
mean. You can get an idea, for instance, of the extreme level, for
instance, potentially of the visual events. I think it\'s quite clear
they have the potential to be very serious. It doesn\'t mean, however,
that they\'re necessarily that common. We can\'t really make any
estimate.

All we know is that somewhere on the order of a million people got the
drug, maybe a little more. Although when the cutoff was for reporting
and how much drug actually had been administered may not be entirely
clear, the drug was administered in a number of countries whose
reporting of adverse events may be very different. You notice, for
instance, that all the hepatic events came from Germany, even though, my
understanding is, maybe half or less of all the exposures were in
Germany, giving you some idea of some of these differences. So we have
no sense of what the frequency is. All we know, I think, for the visual
is perhaps what the more severe end may look like. The hepatic I think
is quite tricky.

As you know, we have two consultants here, one of whom has already
presented, the other is Dr. William Lee. The company has their own
experts as well. I was sort of hoping that, as part of afternoon
session, we could ask the consultants from both the FDA and from the
firm to try to synthesize the information we have about the liver. I.e.,
we have some information in the animals in preclinical data. We have
some small studies in older people with some abnormal liver functions.
We have the data you\'ve heard presented from the phase III trials. We
have the data from the large safety study, and finally we have the data
from post-marketing.

I mean, realistically although you can, obviously, think of each piece
as an individual component, if you were thinking about it from a model
of clinical medicine and were dealing with a difficult case, one of the
things you\'d be trying to do would be to synthesize all this and
seeing, well, what kind of conclusion at this moment in time can you
reasonably draw and how can you then link it to the kind of indications
the company is seeking. So that\'s one of the things that I think may
potentially be helpful.

As far as the cardiac, there has been a lot of discussion. There have
been a couple of cases which are not easy to really come to a conclusion
because they have various confounding factors. I can tell you when
we\'ve gone through these same issues with the fluoroquinolones and when
we looked at post-marketing data, when you get a million,
million-and-a-half people in, you will get a few cases that clearly look
like they might be an issue, but most of them are not clear enough that
you can say absolutely. So we don\'t have a real estimate here of the
frequency as well.

The experience in general ‑‑ and I want to speak very generally ‑‑ with
noncardiac drugs for issues related to torsades is the products that can
be somewhat problematic potentially may have an effect of their own on
QT and then they have the drug interactions usually due to one of the
cytochrome systems that magnify their levels, et cetera. We can probably
have some more discussion from the people here who are more skilled in
clinical pharmacology to get a little better handle maybe on the levels
of those. But you can see there\'s perhaps a couple of events, again in
a post-marketing period, that reasonably can be thought of probably in
the hundreds of thousands of cases, giving you some only vague idea of
what the frequency is.

But that\'s the best we can do. And you guys are sort of stuck, which is
why we use advisory committees, with trying to take that and trying to
link it as best you can to the indications that are being sought and
recognizing that it will be a while before, for instance, some of these
things are clarified. Truthfully only after substantial additional
numbers of patients either in this country and/or abroad are exposed to
the drug will things perhaps start to become clearer.

The liver, in particular, is very challenging and that\'s why we\'re
sort of hoping we have the opportunity to have a little discussion and a
little attempt at synthesis because one of the things that\'s always
troubling about liver is, in general, there\'s no really good way to
predict who is going to get it and not a whole lot you can put in
product labeling.

With the eye, it may be possible, for instance, to warn people. This is
possible. At least don\'t do anything like driving or anything that
requires a lot of visual attention after at least you take your first
dose or so to see what happens.

There seems to be potentially the slightest suggestion of an
exposure-response relationship. You might be able to say something about
that for people with renal-hepatic disease or on certain other drugs.

The cardiac, at least, you could presumably put in some boiler plate
statements about certain drugs that might be contraindicated, et cetera,
or if you have certain types of cardiac disease, not that in practice
that\'s always that useful since often the person prescribing the drug
doesn\'t have all that information. But it\'s a start.

The liver is kind of out there a little more and I think that that\'s
the kind of thing we sort of need the maximum amount of advice that we
can get, and we have no hesitation, in addition to using our own
consultants, about getting the best possible opinion from the
consultants that the company has brought.

So that\'s about the best we can do as sort of a starting point. Whether
later on we can come back and revisit this, when we\'ve heard more
information, that\'s certainly a possibility.

DR. LEGGETT: Thank you.

Go ahead.

DR. ELASHOFF: Yes. This question has to do with guidance on the issue of
concluding efficacy based solely on equivalence studies with an active
comparator. You clearly need a very clear endpoint in these, and to me
the definition of clinical cure is a little vague.

Secondly, you need a small enough equivalence level that not only do you
exclude possibly important differences, but you establish that it
couldn\'t possibly be as close as the difference between the comparator
and placebo.

And then thirdly, you need solid historical evidence of the efficacy of
the comparator because it\'s very easy to prove that two different
things, neither one of which works, are equivalent. Especially this is
relevant to me because, of course, I don\'t have the experience on this
committee, but also Dr. Powers made some comments about the bronchitis
situation and that perhaps there would be a high proportion of
spontaneous recoveries in that group. So as far as I\'m concerned, the
data that are presented don\'t have that last piece, which is to
establish and to demonstrate that the comparators are, in fact,
effective.

DR. LEGGETT: You summed up nicely the last three or four of our
meetings.

(Laughter.)

DR. LEGGETT: Dr. Wald.

DR. WALD: Sort of along the same lines, I think one of the reasons that
the FDA sent Aventis back was because of the relative paucity of
resistant pneumococci. The hope was that we would have more cases. When
it comes right down to it, the number of cases is still relatively
small, and when you look at the resistant organisms that cause
bacteremia, it gets exceedingly small, and actually very little is added
to our original database.

So I would bring up the same question about the comparators. So what we
see is that in this situation we get 5 of 7 cases cured or 8 of 10 cases
cured when we\'re looking at resistant organisms that cause bacteremia.
I think in this case clarithromycin is not the right comparator. I\'m
wondering how well an excellent drug would do that had a lot of activity
against resistant pneumococci. Are there data, say, from the
fluoroquinolone submission of bacteremic S. pneumoniae that were highly
resistant? What\'s the best we can expect under these circumstances?

DR. GOLDBERGER: Well, the data, if I can recall it now, from
levofloxacin ‑‑

DR. LEGGETT: I can give you numbers.

DR. GOLDBERGER: You remember the numbers?

DR. LEGGETT: Community-acquired pneumonia, there were 245 out of 250,
for 98 percent efficacy; 15 of 15, 100 percent for penicillin-resistant
pneumococcus, of which there were only 6 bacteremias, of which 5 were
severe. And it was on that basis that they got the FDA approval for
penicillin-resistant pneumococcus. So the numbers here are actually
bigger.

DR. GOLDBERGER: I think our underlying approach was the following with
Levaquin, and so it would be our approach I think with any drug. The
first step is, particularly if you\'re dealing with an out-of-class
resistance, as we were with Levaquin for penicillin resistance, and we
would, for instance, be with this drug for penicillin resistance, first
establish that the drug is effective in pneumococcal infection. And we
did that with levofloxacin by having like 250 cases or so with close to
a 100 percent cure.

Then establish that the drug is effective in severe pneumococcal
disease. I think there was a total of something like 55 bacteremic
pneumococcal cases with again levofloxacin a 100 percent cure.

Then establish that the drug is effective in the resistant cases. Again,
one of the reasons to do that is in theory you need 0 resistant cases
because it\'s out of class. But practically speaking, we have always
been concerned that patients who have infections with PRSP, for
instance, may be different in other ways, and it would be prudent to
establish efficacy in those patients in case they are sicker or
otherwise have other comorbidities, et cetera. So we had 15 patients,
and again all were cured. And finally, as Dr. Leggett said, a total of 6
bacteremias all were cured.

So that\'s kind of the approach that we\'ve, overall, used. What we
found most comforting, for instance, with regards to levofloxacin was
the large body in pneumococcal infections, including serious disease,
and the very high cure rate. So that\'s kind of the approach that we\'ve
sort of used from then on.

DR. LEGGETT: Yes. Go ahead, Dave.

DR. BELL: Since we\'re on the subject of resistance, I had a comment
that I wanted ‑‑ actually two ‑‑

DR. LEGGETT: We\'re not in discussion yet. We\'re in questions for the
FDA.

DR. RUPP: I have two questions, one directed to Dr. Rochester. On page 9
of your handout you showed a nice graph of transaminase elevation for
both telithromycin and the comparator drug, broken down into levels
above the upper limits of normal. Did you do any statistical analysis on
that data? Is there a statistically significant trend towards greater
transaminase elevation, or is there a statistically significant increase
at any of the specific levels?

DR. LEGGETT: He\'s referring to slide 9.

DR. RUPP: Slide 9. So it\'s kind of a brief answer. No, if there
wasn\'t. You made the comment that at each level there were increased
numbers of patients with elevated transaminases in the telithromycin
group compared to the comparators, but I didn\'t hear of any statistical
analysis of that I guess is what I\'m asking for. And I\'m not a
mathematician, so I\'m not sure what would be the most appropriate test.
I would leave that up to your discretion.

DR. ROCHESTER: One could have looked at this and done small sample
statistics, exact kind of methods looking at chi-squared approaches, for
example, which I think I did at some point in terms of exploratory work.
It did not show significance, and I didn\'t expect it to be significant.

DR. RUPP: Okay, thank you.

Then I guess my second question would be to Dr. Alexander or perhaps to
the sponsor. Both your analysis of the data as well as the sponsor\'s
seem to indicate about 1 percent of pneumococci are resistant to
telithromycin. Do we know anything about those resistance mechanisms?

DR. ALEXANDER: Yes. Actually the sponsor had also provided data on the
genotype of the patients, and there was actually a mixture of those who
had mef resistance and erm resistance, but I don\'t have on the top of
my head exactly how that breakdown falls out.

DR. RUPP: I guess my question is, are they feeling that there is
ribosomal alteration at that second binding site or is there a presumed
telithromycin pump? Something different than erm and mef that we already
know about.

DR. ALEXANDER: No, I don\'t think so. The way that the patients, in
terms of the drug-resistant Strep. pneumoniae, were categorized were
based on, okay, this is the erythromycin resistance and then they did
genotyping of those erythromycin-resistant isolates. I\'m not sure if
there\'s any more work that\'s been done microbiologically in terms of
looking at telithromycin resistance itself and the mechanisms ‑‑

DR. LEGGETT: I\'ll ask the company to tell us that because they\'re
going to go into that later.

DR. RUPP: I don\'t think it impacts immediately upon efficacy or safety,
but obviously down the road it would be something that\'s very
important.

DR. LEGGETT: Any other questions? Barth?

DR. RELLER: Dr. Cooper, both from your safety presentation and
post-marketing, when I listened to your presentation and contrasted it
with what was presented earlier by the sponsor, it seemed to me it\'s
almost as if I were hearing two different presentations. So my question
is ‑‑ and this has to do with both cardiac events, possible probable
liver toxicity, as well as visual disturbances ‑‑ is it because you are
presenting data that are different, because of newer information or
additional information, from what the sponsor presented, or is it a
difference in interpretation of the same data?

And coming to the direct question, are you in substantial agreement with
their conclusions or in substantive disagreement with their conclusions
regarding the relative ‑‑ whatever it means is another issue, but the
relative risk in these three areas?

DR. COOPER: Well, I think the data that I presented is actually
extracted from data that the sponsor submitted and contained in summary
tables at the end of their ISS, at the end of their report. So I don\'t
think our numbers are necessarily different.

With regard to trying to draw conclusions with regard to the relative
toxicity of this drug in the various areas of special interest, that\'s
more difficult to do and I think part of the reason why we\'re
presenting this to you. Of course, with each individual indication,
there will be a different risk-benefit analysis based on this data and
different conclusions may be drawn from the same safety data but for
different indications.

So I don\'t think our numbers are specifically different. Whether or not
our conclusions will be different after this discussion or into the
future is hard for me to say at this point.

DR. RELLER: For example, in listening to the visual issues, they were
short-lived, not very serious, not such a big problem in listening to
the sponsor. But then when you look at the numbers, .2 percent of
patients had discontinuation owing to visual events. There are clearly
differences between comparators and the agent, and if you start looking
at even the post-marketing, there were only minimal additional
exposures, with the largest post-marketing database that we\'ve ever
been presented, or something of that ball park. And yet, if you do some
quick calculations, you come up with you should have had 3,000 people
that discontinued. Even if you take the severe events in .04 percent,
you\'re talking about 1,200 patients with severe visual problems, but
yet we don\'t see it. So it makes me wonder, no matter how big the
post-marketing, if things are not getting through ‑‑ something is
missing here for me.

DR. COOPER: Well, I would sort of reiterate one of the main problems or
a potentially big problem with this sort of passive reporting in the
post-marketing safety data in that it is well recognized that there is a
significant amount of under-reporting that occurs.

There are other things that I can\'t really explain to you about this
post-marketing data. For instance, for the reporting period that we
have, which is until October 1st, the country that had the second most
prescriptions was Italy, and maybe the company can clarify this. We
didn\'t really have any reports coming out of Italy. I don\'t know why
exactly that is. I assume that there are differences between different
countries in terms of their infrastructure or their accuracy or ability
to detect and report post-marketing adverse events.

I don\'t know if that helps. Maybe the sponsor could ‑‑

DR. LEGGETT: They can address that with all the other things they\'re
going to address I think.

Dr. Maxwell.

DR. MAXWELL: Following on the theme of the visual disturbances, if my
memory serves me correctly, most of these were seen in women. What I
want to know from the agency perspective, have you seen anything like
this before reported in any other antibiotic? And if you have, was the
presumption that it was probably due to something related to estrogen or
not? Just as a reason why women would be more adversely affected than
not.

DR. CHAMBERS: Good afternoon. I\'m Wiley Chambers. I\'m an
ophthalmologist. I\'m the Deputy Director for the Division of
Anti-Inflammatory, Analgesic, and Ophthalmologic Drug Products at the
FDA.

Let\'s talk a couple minutes about some of the visual things. I\'ll try
and put some of this stuff in perspective.

The visual disturbances have, at best, been identified or talked about
as being a problem with accommodation and it\'s not just your ability to
accommodate, it\'s the ability to release accommodation, and was
probably best seen in one of the focused studies. That means if you\'re
trying to do a task such look at me, look down to your paper, look back
at me, when you first do that initial change, you\'re not going to be
able to either read your paper or you\'re not going to be able to tell
it\'s me. That will last a few seconds for the most part. That\'s
generally what we\'ve seen.

That, if it\'s never happened to you before, can be very scary and gets
reported by different people in different ways. Some people say, oh, I
can\'t see anymore. Some people say, I\'ve lost vision. Some people say,
it\'s blurring.

Not only do you require being able to focus at different points back and
forth, but your eyes have to move together. In fact, as you go and read
something, you expect your eyes to converge. So there\'s some muscle
balance that goes along with that. And if that gets to be impaired and
there is some evidence that that may be also going on ‑‑ it may be some
of the reason for some of the diplopia reports. Again, you can\'t see
things quite the way you would expect to, and so you get a wide variety
of different reports.

For better or worse, we tend to get more reports from women as far as
visual events than we do for men for all drugs. You pick it. I don\'t
know of any particular cases where we\'ve had more for men than women
with the possible exception of Viagra.

(Laughter.)

DR. CHAMBERS: You knew I had to throw that in somewhere.

(Laughter.)

DR. CHAMBERS: If you take a look at the comparator rates for the
anti-infectives, you will see more reports from the women in the
comparator rates than you do from the men. It\'s just a general
phenomenon that we tend to see. So it\'s not particularly unusual to see
more reports coming from women than men.

Whether there\'s also a factor as far as body weight and body mass,
along there, I don\'t know, but I don\'t have any reason to believe in
anything that\'s going on that it\'s related to estrogen or any kind of
hormonal factors.

As far as whether I\'ve seen a particular event in any product so far to
date, I have not. I have not seen something. We certainly have plenty of
products that affect accommodation, but not as quickly, a quick change
in accommodation, just slowing the accommodation or slowing the release,
I\'m not aware of products go and do that.

DR. MAXWELL: Just to follow up on that, Wiley, the Institute of Medicine
report released ‑‑ I don\'t know ‑‑ maybe about a year ago that sex does
matter in the way women absorb or maybe metabolize drugs and things like
that is part of the reason why I\'m asking because if this is seen
almost exclusively from the data that\'s presented in women, it just
makes me wonder, well, is it just perception or there\'s actually
something else that\'s different. I don\'t know the answer. I wondered.

DR. CHAMBERS: The cases for the drug in question are not all women. They
are mixed, men and women, but there are more women than men. There are
plenty of products that I think alter vision and alter things within the
visual system that are different between men and women. I don\'t see any
evidence of that occurring here. I am aware of what you\'re referring
to.

DR. LEGGETT: I\'d really like to stay away from discussion. I really
want questions.

DR. O\'FALLON: But they were all so young. I thought that was an
interesting thing that the visual disturbances were reported primarily
in the young, and I was wondering why.

DR. CHAMBERS: We do know from the higher doses and looking at it, that
there\'s definitely an effect on ability to accommodate and your ability
to release accommodation. For better or worse, everybody in this room
starts losing their ability to accommodate at birth. We start with a
great deal of reserve. For most people that means they need reading
glasses to help with that accommodation at about the age of 40, but
you\'re losing it all the way through along, and those people who are
younger have much more accommodation, much more ability to quickly go
and look at different things. So any drug that\'s going to affect that
is going to have a much more pronounced effect in the younger than
older.

DR. LEGGETT: Barth.

DR. RELLER: Question. Are there other drugs that have a similar
magnitude of effect, and if so, some examples so that we have some
comparative information of, well, you see this degree of difficulty with
accommodation with drug A, B, or C, or you see it with A, but this is an
order of magnitude 5 times, 10 times as frequently as that, to get some
balance in this?

DR. CHAMBERS: Probably the biggest class of products that affect
accommodation are the cholinergics, and things that affect the
cholinergic system will affect accommodation. We clearly have products
that do much more in magnitude of accommodative retardation than this
does. Those products, while they have a bigger magnitude, are not an
on-off kind of phenomenon. They\'re not a slowing. They impair
accommodation. They don\'t slow your ability to do things. I\'m not
aware of other products that do exactly this type of thing where they
just slow it and/or slow the release. That I\'m not aware of other
products.

DR. RELLER: So this is real. It\'s different, and what we have to
grapple with is simply the magnitude of the problem relative to the
benefits? Would that be a fair summary?

DR. CHAMBERS: Yes. I think it\'s real. I think it\'s dose-related which
is why in the higher doses you see it. The focused trials on it used
2,400 milligrams and were able to elicit it in up to 50 percent of the
people, approximately a third or so, but enough to clearly study it.
That\'s clearly not consistent with the normal reporting, but there is
clear reporting. There\'s a clear difference between comparator groups
and this drug. So I don\'t think there\'s any question it\'s the real
phenomenon.

The difficulty you have is that different people report things different
ways and you get these magnitudes. You know, I completely lost vision to
just a mild blurring. And some of those events may be the same events.
You\'re just getting the filter of how people report them.

The difficult issue I think is people are going to have problems if they
have to change focus. If you\'re trying to drive and you\'re trying to
look at the speedometer and look in the distance, you can\'t go back and
forth and do that quickly. So there are going to clearly be people that
are going to be affected in doing that and other tasks that are there.
And you need to evaluate how much those kind of activities weigh.

In many cases we have labeled those kinds of products. We\'ve permitted
them on the market and labeled them. That is entirely possible to be
done with this particular product based on what we know. Whether that\'s
enough is a judgment we\'re asking you.

DR. LEGGETT: Thank you.

Janice?

DR. SORETH: To try to answer a specific question that Dr. Maxwell raised
which was do we see this with other antibiotics, I think to date we have
not with other antibiotics that I\'m aware of. However, recent
experience with fluoroconazole led to labeling that anti-fungal for
patients with candidiasis, candidemia ‑‑ Aspergillus, I\'m sorry ‑‑
because up to 30 percent of patients reported visual problems. Now
that\'s in a setting of a parenteral drug where patients by and large
are hospitalized and have a serious infection, life-threatening in
cases.

So I think you have to temper what you see, take it in balance with the
formulation of the drug, in this case oral, treating outpatients with
respiratory diseases that span a spectrum from pneumonia to sinusitis to
bronchitis who will not be hospitalized, who will be, by and large, out
and about and take into account how a visual disturbance that might last
minutes or can be reported to last hours spans the spectrum, how that
might affect their day-to-day activities.

I think one thing that looks different from the clinical trial reports,
AE reports, versus what we have post-marketing seems to be differences
of degree. We didn\'t get the more alarming kind of reports reported by
patients in terms of I couldn\'t see my face in a mirror, had to lie in
bed until the mother came home. That sort of thing wasn\'t seen in the
clinical trial database, but post-marketing, we have seen those kinds of
reports.

Again, numerator and denominator. I don\'t have a good handle on that. I
don\'t know the precise number of cases, for example, coming from
Germany with regard to reports of visual adverse events and the
exposures there which are not a million but maybe, as of October,
500,000.

DR. LEGGETT: As a follow-up to that, Dr. Cooper, in your slide number 24
where you talked about phase III trials with 50 percent of AEs and then
3014 with 23 percent and you sort of shrugged your shoulders, is that
because you really have no idea or does this happen a lot from one study
to the next? Or actually that\'s Dr. Rochester. Sorry.

DR. ROCHESTER: I\'m surprised that I did shrug my shoulders.

(Laughter.)

DR. ROCHESTER: But no. The thing is when you look at safety data in its
complexity and entirety, one has some general expectation for adverse
events rates overall, and from drug to drug and study to study and so
on, there\'s always going to be some variability.

But if we look at, say, telithromycin studies ‑‑ there were probably 17
or so phase III trials ‑‑ within those trials you would see a certain
rate, variable but within the 40 percent, let\'s say, 50 percent range
of adverse events and some of them certainly without causality being
attributed to drug. We\'re just saying this is what we see.

And then if you enrich a specific safety study in which you enriched the
population in terms of comorbid conditions and improve their numbers of
subjects that are exposed to concomitant drugs and you\'re studying the
same sort of infections, even though to enroll in the trial you didn\'t
have that strict criteria that we use in the efficacy, but we\'re
trusting that if a physician says you have pneumonia or you have
sinusitis, that\'s what you have basically, and if you get into that
trial and you have this mixture of things that would say up and above
your regular situation, you should enrich for more AEs, then I would
expect the AEs to be somewhat closer to the trials.

What I\'m seeing is about half as many, and then trying to think as to
possibly why ‑‑ I realize in the original studies half the patients were
CAP patients. They seemed to have had more such events. And in designing
this new trial our goal was to certainly see more of the safety profile
in CAP patients. But we set a target of 40 percent CAP or AECB. Well, it
turned out we do have our 40 percent, but the composition of that 40
percent is 10 percent CAP and 30 percent of AECB.

Then I also thought it could be related to just probably a fairly much
healthier population. That\'s possible, but I still don\'t feel very
reassured in the sense that the comorbid conditions were there. The
concomitant drug use was there. Several other factors actually made both
arms look quite similar in every subgroup that I looked at. So I would
have expected more. Exactly how much I would have expected I don\'t
know, but if I saw something like 35-40 percent, I would have felt
better about the vigilance probably in which these adverse events were
collected.

DR. LEGGETT: Thank you.

Dr. Goldberger.

DR. GOLDBERGER: Just to follow up on that in terms of a potential
explanation, over the years in different settings, we have used
sometimes in the treatment IND format, sometimes without a formal
treatment IND, large open-label studies far along in development
programs while the product is being reviewed, et cetera. And there is
data collection with regards to safety, but one of the observations
realistically is that the quality of the follow-up, the quality of data
collection in these studies is just not at the level that it is in
randomized trials, even if these big studies are in fact randomized.
It\'s just not the same level. So one of the things we\'ve observed is
in these studies adverse event rates tend often to be lower.

But what you do get, however, is by enhancing your denominator
substantially, you do get the opportunity to see some patients who may
have these concomitant factors where a rare or unusual adverse event
will show up, which can be quite helpful in rounding out the safety
profile. So you get the more common events clearly defined in a
randomized trial. Sometimes you get the less common events, you get a
clue to them by these larger trials, and then you sort of have to put
the whole thing together.

It\'s one of the reasons on occasion we will discourage sponsors who
like to take all the studies together, these large studies and their
controlled clinical trials, average out the adverse event rates and then
put a single number in the label. Often it\'s better to provide the
information separately since it gives a better picture.

DR. ROCHESTER: Shall I just add one sentence here too?

DR. LEGGETT: If it\'s only one sentence.

DR. ROCHESTER: Sure. In addition, though, the only difference or
reassurance in here was that the types of adverse events, if you look at
the system organ classes, gastrointestinal, nervous system, whatever,
remain consistent with the phase III trials.

DR. LEGGETT: Okay.

Dr. Wald.

DR. WALD: Dr. Cooper, you presented five cases of interest in terms of
the hepatic toxicity. Did you make a best estimate for each of those
cases as to whether or not there was an association with the drug?
Because you didn\'t tell us that.

DR. COOPER: Well, I think because of incomplete information, it\'s
difficult necessarily for me to draw a conclusion based on those cases.
I think the cases where there\'s a liver biopsy provide us with an
opportunity to explore a possible connection in more depth and maybe
perhaps more accurately. I can\'t say for sure. I think that there\'s
information missing from all of those studies. That makes it difficult,
but I think that the biopsy cases might be helpful.

DR. LEGGETT: I think, Ellen, we\'re going to ask the four consultants to
give us their views.

Since there are no more questions, I won\'t recognize any more
questions.

(Laughter.)

DR. LEGGETT: Why don\'t we pass on to the open public hearing. We did
not get any requests. Are there any requests from people here? Seeing
none, I would like to pass on to ‑‑ oh, is there one? I can\'t see an
arm. Yes, go ahead. State your name and also please disclose any
financial potential conflicts of interest.

DR. BROOK: No financial conflicts. I\'m Itzhak Brook from Georgetown.

Just a short comment, since nobody mentioned it, that there is a
situation where resistance to a macrolide may clinically be important
and that is in the penicillin-allergic patients where there\'s no other
choice.

DR. LEGGETT: Thank you.

Could we have Dr. Rubin come and give us your hepatic pathology
interpretation?

DR. RUBIN: Good afternoon. I\'m Emanuel Rubin. I\'m Chairman of the
Department of Pathology at Thomas Jefferson University Medical School in
Philadelphia. Just briefly, I have had a longstanding interest in liver
disease and I have been examining liver biopsies for some 40 years,
going into the many thousands.

I had the opportunity to look at the slides of the patient from Finland
who had two biopsies that was shown here previously and also the
gentleman who had a gallbladder condition and who also had some
cholestasis.

After I looked at the glass slides through the microscope, they were
also examined by other members of the liver panel here who I think by
any standards are nationally recognized experts in liver disease: Drs.
Maddrey, Sorrell, Young, Watkins. And what I\'m going to indicate to you
is really a unanimous opinion and our consensus.

When you look at slides, it\'s like looking at a photograph of, say, a
face and, say, two women, presented with the same photograph of a man\'s
face, one might say he\'s very handsome; the other would say, well,
he\'s interesting.

(Laughter.)

DR. RUBIN: So I want to congratulate Dr. Kleiner for a scholarly
discussion, and actually I think we\'re in agreement on most aspects. I,
together with the other members of the panel, would differ perhaps on
some emphasis, but he has a sharp pathologic eye.

So let\'s go to LB-3. This is the 72-year-old man who was treated with
the drug and who had chronic cholecystitis, among other things, and
cholelithiasis. As you can see, there is some change at this low power
view. It doesn\'t tell you all that much.

Now, LB-7 please. Now, here what you can see here, this is a hemotox.
It\'s not connective tissue. But here\'s a scar and this is fibrosis.
Here\'s a portal tract going the entire width of the biopsy here, and
then another spur of fibrous tissue here going this way. It\'s like a Y.
And this is old fibrosis. There are very few inflammatory cells here.
The collagen is clearly old. What this tells us is that there has been
some chronic condition here, perhaps repeated episodes of cholangitis.
This is a gentleman who had stones and I believe was probably passing
stones, perhaps some silent. He did have some abdominal pain, some were
symptomatic. In any event, when a stone enters the common duct, it is
very common to get an ascending infection, ascending cholangitis.

Now, LB-4 please. Now, we can see that this man does, indeed, have
changes consistent with an ascending cholangitis because this is a
portal tract and you see that the portal tract is infiltrated not only
by chronic inflammatory cells but by a few acute inflammatory cells. So
this is a mild ascending cholangitis which reflects the passage of
gallstones down the common bile duct.

Now, let\'s have number LB-5. Now, here is a high power of the liver.
You see most of the liver is actually bland. There\'s very little going
on here and you can see one brownish area there. That really is the
extent of cholestasis. Occasionally you see these small bile passages
that contain dried or inspissated bile. So he does have a cholestasis
which is consistent with stones and an ascending cholangitis and other
evidence, clinical and structural evidence, that all of this reflects
chronic cholecystitis and cholelithiasis.

Now, Dr. Kleiner did mention that this was certainly a strong
possibility, and I agree with him. My emphasis would be that this is the
diagnosis.

Now, we then come to the other case which has elicited a great deal of
interest and was discussed previously, that of the man who had two
biopsies and autoimmune hepatitis. I\'d like to go through the second
biopsy first just because we\'re quite clear as to what that biopsy
reveals.

Let\'s have LB-16. Here\'s a connective tissue stain of a biopsy. This
is a needle core biopsy. The one thing you can see, as Dr. Kleiner
pointed out, there\'s a lot of collagen, a lot of scarring ‑‑ collagen
means scars ‑‑ a lot of scarring in this liver which is in almost every
lobule and actually beginning to surround nodules of liver tissue. Now,
we call that, when it completely surrounds nodules of liver tissue,
cirrhosis. This is not a full-blown cirrhosis but it\'s on the way. This
is an early cirrhosis.

Now, LB-17 please. Now, if we look at a higher power in the liver, we
see there are inflammatory cells all over the place and they look like
so-called lymphoplasmahistiocytic, which means there are chronic
inflammatory here, lymphocytes, plasma cells. There\'s dropout of liver
cells here. This is a classic appearance of autoimmune hepatitis.

And if we\'ll go to LB-18 please. Here under higher power you can see
what these cells look like. There are certainly no eosinophils. There is
not a true zonal distribution. They are scattered throughout the
parenchyma, and the interface between the collagen and the parenchyma of
the liver is an irregular, so-called piecemeal necrosis. This is the
classic appearance of autoimmune hepatitis with early cirrhosis. So
it\'s been going on for some time. You cannot get this appearance in a
day or a week or a month. This is a chronic process that\'s been going
on for some time.

And Dr. Kleiner again I believe favored autoimmune hepatitis. Dr.
Goodman from the Armed Forces Institute of Pathology favored autoimmune
hepatitis, and considering the fact that he had anti-smooth muscle
antibodies in very high titer, which is an autoimmune phenomenon, I
think we can safely diagnose this as chronic autoimmune hepatitis with
early cirrhosis.

But now that we know all of this, we know this man\'s chronic course and
what the underlying disease is, we can now go back, because we now have
more information, to the first biopsy and take a look at what that is.

The first biopsy, if you\'ll remember, was in a man who had elevated
transaminase before he received the drug, before he received the
antibiotic, which tells us that he has a preexisting and continuing
liver disease before he ever got the drug. He also had a peripheral
eosinophilia which is characteristic of many types of allergic asthma.
He also had an episode of some gastrointestinal infection which
apparently was in the family. We don\'t know the nature of it, but
remember that the products of infection in the gastrointestinal tract go
into the portal vein and are then carried throughout the liver. So a
reactive hepatitis ‑‑ we don\'t ordinarily biopsy for that, but a
reactive hepatitis to gastrointestinal infections is actually very
common in biopsies that are taken incidentally for other purposes.

In any event, let\'s look at LB-9. We don\'t see much. This is a low
power.

And go to LB-10. Here we see a little bit of fat. That has no meaning.
This man is a diabetic. A little bit of fat in the liver in a diabetic
doesn\'t really tell us much.

And let\'s go to higher power right away, LB-11. Now, here we see a
liver which is certainly distorted by the presence of numerous
inflammatory cells. Here Dr. Kleiner and I and our panel would differ in
the emphasis. There is definitely some accumulation of inflammatory
cells around central veins, but they also can be seen in the vicinity of
portal tracts. There are two small bile ducts over here. There\'s one
there. That\'s a small bile duct, and the other one doesn\'t show up
well. And there are some eosinophils in here.

Now, the presence of eosinophils in a person with peripheral
eosinophilia and who is hyper-reactive for eosinophils, as allergic
asthma is, such people will get eosinophils in virtually any
inflammatory reaction in the body. The liver is not an exception and the
eosinophils in this case simply are a background phenomenon. The
important cells here are the lymphocytes and the plasma cells, of which
there are many.

Next please, and here under higher power you can see that there is liver
cell dropout. There is not what we call true zonal necrosis. We call it
coagulative necrosis or eosinophilic necrosis. Most of these cells are
actually ‑‑ the background cells are macrophages here and those
macrophages have been there for some time. They\'re the cells that come
late in the inflammatory reaction, tend to mop things up, are not
characteristic of drugs, but are characteristic of longstanding chronic
inflammation in the liver.

The next is LB-14.

DR. LEGGETT: How many more of these are we going to go through? This is
almost discussion. I\'d rather save this.

DR. RUBIN: All right. That\'s enough.

So what we have basically is a liver that has many macrophages, these
late-appearing cells, with a background of eosinophils which is
accounted for by the allergic asthma and the reactivity, the peripheral
eosinophilia. And knowing now what the underlying disease is, this most
likely represents a flare of autoimmune hepatitis, which again Dr.
Kleiner alluded to as a possibility. I would put that certainly as the
most likely diagnosis here.

DR. LEGGETT: Thank you.

Dr. Caffe, could we go on to the responses that we carried over from
this morning real quickly? Or Dr. Leroy, whoever.

DR. LEROY: Yes. So one of the questions was were CPK drawn in patients
taking statins, and the answer is no in this usual care setting. But Dr.
Lagarenne emphasized that there was no myositis in those patients.

The second question was did we try to see, in patients who had blurred
vision, if they were taking this drug before bedtime, they would
experience the blurred vision. We did not perform such a study, but as
explained also by Dr. Lagarenne, when we\'ve been able to measure
accurately the duration of the symptoms, it was with a median time of 2
hours. The long duration is more because of the collection of the
adverse event in phase III that are reported in an adverse event form.
But when we\'ve been able to precisely investigate the duration, it\'s
largely within 12 hours. So it could be one other possibility.

DR. LEGGETT: I was also referring to, though, you were going to collect
some data from the leftover questions from this morning.

DR. LEROY: Yes. Those data have been provided, if I can have those data.

DR. ELASHOFF: Do you want me to just provide it?

DR. LEGGETT: Yes.

DR. ELASHOFF: Basically they gave me mean date on which cure was
evaluated and the standard deviation, and the range for each of the CAP
studies and the bronchitis studies and the sinusitis studies. The means
appear generally to be very close. If there\'s any difference at all,
the comparator is slightly larger by .1 of a day. The ranges are
sometimes extremely large, as in one case where the range of the day on
which cure was established was 4 to 35. In one or two cases, it\'s
really as low as 17 to 23 as advertised, but there isn\'t any real
evidence of systematic difference.

DR. LEGGETT: Was there any other question left over from this morning?
Does anybody remember that they had a question?

DR. PATTERSON: I think someone asked about the susceptibility of the
Staph. aureus superinfection.

DR. LEROY: I think it was answered. In sinusitis, they were all
susceptible to telithromycin, and Dr. Jenkins provided an answer
regarding the susceptibility depending on the susceptibility to
erythromycin.

DR. PATTERSON: No. The superinfection that occurred. Somebody asked
about the Staph. aureus superinfection that occurred.

DR. LEGGETT: The one in the urine.

DR. LEROY: In urine, yes. No, we do not have the MIC to this
Staphylococcus aureus. But this is the narrative of the patient. I think
that we need to go quickly through this patient because we\'ve already
discussed this patient.

The patient had Streptococcus pneumoniae resistant to erythromycin with
the genotype ermB and MIC to telithromycin at 0.03, had an initial
improvement, sterilization of blood culture at day 12 and secondary ‑‑
no, in fact on therapy, and at day 12 of therapy, he had a recurrence of
dyspnea and fever and a secondary UTI infection, Staph. aureus, which
was treated with intravenous antibiotic.

DR. LEGGETT: Thank you very much.

DR. LEROY: Thank you.

DR. LEGGETT: I think I\'d like to pass on to the discussion. Unless
there are any other questions or any other problems, what I would like
to do is perhaps talk through the safety issues so we get everybody\'s
opinion or discuss those, go to the efficacy issues, and then pass on to
the answering of the questions.

DR. LEROY: Would it be just possible to provide some clarification
regarding the case reported as torsades de pointes, or will we have time
to clarify just this case and the ECG reading of this case?

DR. LEGGETT: Can we do that later as it comes up in the safety issues?

DR. LEROY: Fine.

DR. LEGGETT: David.

DR. BELL: Well, my comments about the public health issues don\'t fit
neatly into either efficacy or safety. So do you want me to hold them?

DR. LEGGETT: Yes. That will go with that discussion, after the safety,
go to the efficacy. That will be part of that.

We have heard varying discussions about the etiology of the hepatic
injuries on the side of Aventis and of the presenter, Dr. Kleiner. Dr.
Goldberger, you said there was another expert?

DR. GOLDBERGER: Yes. We would like Dr. William Lee, who we invited here.

DR. LEGGETT: Okay. I didn\'t know if that was someone in addition to Dr.
Lee.

DR. GOLDBERGER: No. There\'s Dr. Lee and actually perhaps if you might
ask Dr. Kleiner to respond to some of the comments that were just made
by one of the Aventis experts, we\'d be very interested in hearing that
as well.

DR. LEGGETT: That would be great. And then what I would like to have Dr.
Lee start off with is his take on this as well. Dr. Kleiner, do you want
to go first?

DR. KLEINER: Sure. I agree, as Dr. Rubin said, with many of the things
that he said. I think I would still stand by my own interpretation of
the features that I saw. I do think that there was more definite
evidence of injury in zone 3 in the first biopsy, and I think of the
three, that\'s certainly the most suspicious for involvement of drug. I
think it\'s entirely reasonable that the patient may have had an
underlying autoimmune hepatitis the whole time, but that doesn\'t mean
that you can\'t have a superimposed injury by something else. Patients
have two diseases all of the time. So I do think that that\'s possible.
It may have exacerbated an underlying condition, but I think that there
is evidence for separate injury.

As to the other case, it could go either way. I think there is so much
overlap in the potential patterns of injury from a drug and from acute
large duct obstruction that I interpreted the fibrosis as possibly
related to the patient\'s diabetes. Diabetics are known to get
sinusoidal fibrosis. That can be present without any of the other
features of standard hepatitis.

I think we\'re in substantial agreement on what was seen. It\'s our
interpretations that vary a bit.

DR. LEGGETT: Dr. Lee.

DR. LEE: Yes. I think this is quite a unique situation for consideration
of hepatotoxicity in part because this is a drug that would be used
widely and would be used for short periods of time, 5 to 10 days, and
for the most part, I guess 5 days in duration. Now, while that, on the
one hand, gives you less exposure and we know that drug reactions often
take more than 5 days and certainly more than 10 or 20 days in many
instances, so the good side would be that the shorter exposure means you
probably will have less toxicity. The other side of it is that you may
have toxicity that shows up after the drug has been discontinued.
Indeed, that appears to what has been seen in a couple of cases.

Now, I think there are probably some signals for hepatotoxicity here
that are real. I think there were certainly signals in the animal data.
There were signals in the high dose data in the elderly in the phase I.
Even if you throw out a good percentage of the cases, which are always
confounding in the clinical studies and certainly in the post-marketing
studies, there\'s probably still a few real cases in here.

Again, I think the issues for us as the committee would be to consider
whether people are going to use this drug outside packaged labeling. And
certainly this has been partially addressed by the sponsor. There will
be people who will be taking repeated courses of medication in the
future. Now, I would take it that there would not be too many instances
where one would be likely to take prolonged courses like, say, 3 or 4
weeks, of medication.

I think it\'s unlikely that there\'s zero toxicity with this drug. I
think the antibiotics as a class are right up there with the
nonsteroidals as likely drugs to have hepatotoxicity.

I think the amount of data that we\'ve been shown has been very
exciting. It\'s really a new benchmark for other companies coming to FDA
to have 12,000 patients exposed in this most recent study and to have
this much post-marketing data as well. And we haven\'t seen a case of
acute liver failure although, as we know, post-marketing data is
notoriously unreliable in this country, so I doubt that it\'s any better
over there. I think the point about the Italians not having any cases
show up is simply they didn\'t show up. At least it appears not.

Now, as far as this one case that everyone has beaten to death, the poor
Finnish man, I still would interpret it differently than Dr. Rubin and
the expert panel and say that this looked like a drug hepatotoxicity
case. I reviewed the slides at lunchtime. I don\'t know what else to
say. It\'s loaded with eosinophils. I don\'t see why they can\'t be
there due to a drug reaction, but I take the point about the possibility
that he certainly was an allergic person to begin with.

The time delay to having hepatotoxicity looked very good. He didn\'t
have cirrhosis at that time, and then a year or a year-and-a-half later,
whenever he had the second biopsy, he\'s evolved to something. And I
still would posit that it\'s theoretically possible that the drug
triggers something that becomes an autoimmune hepatitis. There wasn\'t a
lot of evidence for autoimmune hepatitis on the first biopsy. But again,
we can differ over that one.

I think the second case, the 72-year-old, was a cholecystitis case and
we should just drop that. I don\'t think it\'s very likely. I think the
amount of damage was very minimal although the biopsy was quite late.

So to sum up, I think there\'s really been a lot of data presented. I
think again there\'s been no bigger study than the 3014 study that I\'m
aware of. However, the data suggests that there may be some people who
have LFT abnormalities that are seen late in a very small percentage.
Although, again, if they\'re only going to use it for 5 days, it\'s not
going to appear.

But I guess the question that we still don\'t have an answer to is
whether a year or two later, when they get the second course, they would
have an accelerated reaction. The model for that, of course, is
halothane where it was multiple exposures associated with eosinophilia,
associated with fever, with shorter latency with each secondary
exposure. Now, I don\'t know that this is anything like that. I\'m not
saying that, but I\'m saying at least that model is there.

The other model, of course, for length of treatment would be the analogy
to bromfenac where again the agency said this was for limited use, only
10 days, but since it was a pain reliever, it was used for longer
periods of time and the toxicity first appeared in patients who had been
taking it more than 30 days. Again, I don\'t think that really applies
here either because I think it\'s only going to be used for 5 days
presumably or maybe 10.

So I think overall I think the sponsor said it right. The toxicity is
going to be there and it\'s going be in the range of other antibiotics.
I don\'t think it\'s zero and I don\'t think it\'s in the range of
isoniazid. I think it\'s likely to only be fully measured once the drug
is approved.

DR. LEGGETT: Thank you.

Alan, did you want to have a question?

DR. CROSS: I wonder if I could ask the hepatic pathologists a general
question. I was struck by the inconsistent patterns from patient to
patient here, and is it reasonable to suggest that before we associate a
specific drug with hepatic toxicity, are we looking for similar types of
injury patterns? Or are we just simply trying to differentiate between
chronic and acute damage? Or is there a whole panoply of changes which
can be associated with antibiotics that have come to be associated with
hepatotoxicity?

DR. KLEINER: Well, first of all, drugs have been able to mimic
everything in liver disease that\'s not caused by a drug. So you can get
any pattern of injury from a drug that you can get from something else.

The problem with cases like this is that we\'re really sort of operating
in an information vacuum. We don\'t know what pattern of injury to look
for because there really isn\'t any precedent with this drug. All we
have are the three liver biopsies that we have, and they all show
different things. So you have to sort it out in other ways. If, as it
turns out, one is just acute large duct obstruction, has no relationship
to a drug, and the second biopsy on the Finnish patient turns out to be
a chronic thing that\'s related or unrelated to the initial episode, you
might only have one pattern. Or if one makes the argument that none of
these are related to drug, well, then you haven\'t got any pattern yet
at all, and all you have are the other evidences of hepatotoxicity that
are based on clinical laboratory values and follow-up and things like
that.

DR. CROSS: But based on a drug, for example, like INH, where we tend to
see a highly repetitive, similar pattern in that instance where we\'ve
already made the association between INH and hepatotoxicity, would we
see a similar biopsy pattern?

DR. KLEINER: Yes, in general, although some drugs do have more than one
injury pattern. Generally speaking, the same drug will result in a
similar ‑‑ but it can still have a broad spectrum just like chronic
hepatitis C can be very mild or very severe.

DR. LEGGETT: Any other questions about hepatic toxicity? Barth.

DR. RELLER: Dr. Kleiner, you said there may be few, maybe no pattern
associated. Is there any help? I was noticing the earlier information
not presented today when this drug was discussed before, the statement
that hepatotoxicity was seen in all species tested. These were dogs,
rats, and monkeys. So were there any patterns there or does drug
toxicity in animals look totally different from drug toxicity in humans?
I mean, are we totally without any leads is what I\'m asking.

DR. KLEINER: Sometimes you can get some information, but animals can be
very different from humans as well. I didn\'t see those slides, so I
wouldn\'t have been able to compare them anyway. It\'s, I think, helpful
if you understand what the mechanism of injury is and to know how
related it is to the species. And if you saw the same injury pattern
across many, many species, then that\'s probably good evidence.

Somebody has something to say.

DR. LEGGETT: Please enlighten us.

DR. PETERS: I\'m Terry Peters. I was the original reviewer for this
product, and I\'m an acting team leader in the Division of
Anti-Infective Drug Products.

The things that I can tell you about this drug from an animal
perspective is that the liver function tests in these animals were quite
markedly increased. I can tell you that phospholipidosis, which is a not
uncommon finding with some of the macrolide antimicrobials, indeed was
significant with this product. I can tell you that we had some increases
in bilirubins in basically all species. We had more significant liver
effects in rats than in dogs with necrosis and fairly significant
effects. Can I give you comparators? I can tell you that the signal was
fairly strong which is why all the emphasis, when we got into the
clinical trials, to evaluate the hepatic effects.

DR. LEGGETT: Jan.

DR. PATTERSON: Would we expect this hepatotoxicity to be more common in
people with underlying liver disease, or is it totally idiosyncratic?

DR. LEE: Most times there\'s not a good correlation between presence of
underlying liver disease and increased susceptibility. Now, there may be
some in certain instances like veno-occlusive disease, but for the most
part, as I think the data showed, there didn\'t seem to be any tie-in to
increased toxicity in people who had preexisting liver disease. Now, you
might not want to get two diseases at once, but there doesn\'t seem to
be increased susceptibility.

DR. LEGGETT: Dr. Lee, a comment. We in infectious diseases are really
used to seeing hepatotoxicity with antibiotics, and I think it\'s seen a
lot more. What\'s your gestalt on the hepatotoxicity with telithromycin?
Is it in the ball park of several others, or is this 2 standard
deviations above or what?

DR. LEE: You\'re saying clarithromycin versus ‑‑

DR. LEGGETT: Yes, or Augmentin or erythromycin estolate or rifampin.

DR. LEE: Yes, I think this is in the ball park probably of Augmentin or
erythromycin perhaps. Now, Augmentin is more cholestatic, but again,
it\'s often used for longer periods of time as well.

DR. LEGGETT: I\'m just waiting for this drug to be used for 4 months for
disseminated Mycobacterium and then we\'ll really know.

(Laughter.)

DR. LEGGETT: We\'ve beaten hepatotoxicity to death I think.

Why don\'t we pass on to visual since we still, hopefully, have our
ophthalmologist here. Any questions or further debate on the part of the
members here about the visual toxicity question?

(No response.)

DR. LEGGETT: Okay, everybody wants to go.

How about the final one on the cardiotoxicity issue? Dr. Leroy, if you
or someone could ‑‑

DR. LEROY: Yes, thank you. I would like to call on Dr. Pratt to comment
on this case that was reported as a torsades de pointes.

DR. PRATT: Good afternoon. You\'ve had a little bit of a tough time
today. You have multiple, different issues to consider and I know that
torsades de pointes VT isn\'t on the tip of all of your tongues.

I\'m Craig Pratt. I\'m a professor of medicine at Baylor College of
Medicine. I\'ve been former chairman and long-time member of the
Cardio-Renal Advisory Board that we affectionately call CRAB.

(Laughter.)

DR. PRATT: My research interest is in arrhythmias, sudden cardiac death,
torsades. I\'ve had the opportunity to chair the cardiac events
committee of 3014 which even in cardio-renal we\'d be pretty proud of in
terms of the size and the substance the study.

My overall view of teli in the big spectrum of noncardiac drugs causing
torsades is that the risk is very low, and I\'d be happy to tell you in
a couple of sentences, but let me, since I was asked to talk about this
report, talk about it first.

Now, those of us that have worked on advisory boards like cardio-renal
really take these reports seriously, just like the agency does. But
while we take them seriously, I think that a previous President said it
best. He said, trust yet verify. So why don\'t we verify what we know
about the case, if you could project CK-26 up there.

First of all, if we look at the risk of sudden cardiac death in general,
this would have been a posterman for the issue. He was a middle-aged,
white male who was quite heavy who had heart failure, angina, previous
angioplasties, multiple risk factors for cardiac disease, and most
members of his previous family had already dropped dead. So it\'s a
little bit of a shame he didn\'t have a real workup in a real medical
center.

CK-27 please. If we look 3 days prior to any treatment with the present
subject telithromycin, he had a syncopal episode. So whatever was going
on with him was already going on. At a time that he was evaluated after
a motor vehicle accident 3 days ago for another syncopal episode, he had
a normal QT interval.

Then on the day of his death, we actually have some rhythm strips which
Dr. Cooper has shown you, and I would like to review. CK-28.

To do this, what I\'d like to do is just remind you that from a
cardiologist perspective, especially those in arrhythmias like myself,
torsades means something very specific. It\'s pause-dependent,
polymorphic VT with QT prolongation. And I think that Dr. Soreth started
the day, a long time ago now, with a quote from Jeremy Ruskin who was
one of my co-people on the CEC of this project, saying that it\'s really
the drugs that not only prolong QT a little bit, but that with a
combination of comorbidities and co-therapies can lead to great
accumulation and rapid and great increases in QTc interval. So let\'s
reflect on that when we look at this patient.

This is a patient who has a normal QT interval. There it is right there.
It\'s about even corrected, about 420 milliseconds. This is some noise
over here. Dr. Cooper presented one other strip that I didn\'t have, but
it would have been great one for my cardiology fellows because it was
full of artifact. CK-29 then shows us what happens. Within 30 minutes of
having a totally normal QT interval, this is just, of course,
ventricular fibrillation, exactly the kind of arrhythmia that occurs in
obese patients with a family history of everybody dropping dead,
coronary artery disease, status post-myocardial infarction.

And CK-30 is simply a more agonal rhythm 9 minutes later.

So if we take pause dependence, we take polymorphic VT with a torsades
look, and QT prolongation, the three components of torsades, we have
none of them. The reason we are so specific is if we identify something
that\'s pause-dependent with polymorphic VT and QT prolongation, it
almost invariably really is drug-related. So this case doesn\'t meet
that criteria.

If I just take one more minute, I\'d just like to make a couple of
points of why I think that on the spectrum of noncardiac drugs, this is
a relatively low risk drug. And to do that, I\'m going to shorten what I
told my group, so I\'ll drive them totally crazy and go directly to
CK-12. We made CK \"cardiac kit.\" That\'s quite cute. So, CK-12. If you
put that up there.

You saw this before, but from the standpoint of clinical cardiology, I
think this is very important. Remember we said the outliers that have
comorbidities like heart failure and might be female and might be
elderly, all high risk for torsades, who were on CYP 450 drugs and all
sorts of other things, would have high plasma concentrations. These are
the plasma concentrations that exceed the normal for teli by 3- to
7-fold I guess. And if we look at the EKGs within 30 minutes of those
numbers, we have no QT even reaching 440. So this tells me that when we
talked about the slope ‑‑ and you were already given the formula for how
this was figured out ‑‑ that\'s a lot of fancy talk, but the bottom line
is that even high blood concentrations did not lead to a QT interval
that was near what we get concerned about for the risk of torsades which
is a cutoff that has proven through history to be pretty good, 500
milliseconds.

And if I could just go to one other thing, number 13. If we look at
this, I just want to point out that we have a lot more information here
because in addition to QT, which can drive you crazy if you just keep
listening to it, we have a lot of information about comorbidities and
co-therapies. And to just remind you, 16. CK-16 up please.

We had 5,000 patients over the age of 65. A lot of them were females who
could have a 2- to 4-fold increased risk of torsades. A lot of patients
even above the age of 75, and on CK-17, if I could have it up please,
not only did we have 4,500 patients on CYP 450 3A4 inhibitors, but over
11,000 on CYP 450 substrates. So this is a big database with no signal,
and I think if we look at the preponderance of the evidence with this
drug, we would conclude that the risk is very low for torsades.

Thank you.

DR. LEGGETT: Thank you.

David, could you talk to us a little bit about the public health thing?
Because in terms of toxicity data, to me the question of vasculitis or
not vasculitis is such a rare event. It\'s probably the same
idiosyncratic thing as we have with other antibiotics. Unless somebody
has something different, another thought about that. I mentioned the
vasculitis because it was on one of the first slides this morning.

DR. BELL: Thanks. I wanted to make a couple of comments on the public
health issues. These are stimulated in part by the discussion that John
Powers so nicely had this morning about public health impacts of
macrolide-resistant Strep. pneumoniae.

The public health impact of drug-resistant infections can be difficult
to define, particularly when the infections are not life-threatening and
other drugs are available to treat them. Even when they are
life-threatening, there are often comorbidities. So to do the necessary
studies to really define the impacts can be resource intensive. Those
resources have to be devoted from other public health priorities, and
sometimes there\'s a delay in getting that done.

Partly for that reason, we are sensitive to other parameters, including
upward trends in resistance rates and anecdotal reports of treatment
failures that accompany these upward trends. We frequently use this
information to identify a public health hazard and to take action partly
because of the difficulties involved in defining the impact, but also if
we wait until there is a conclusive public health impact, the chances
are that resistance has reached such a high level that it\'s too late to
save the drug so that any preventive interventions at that point are too
late.

When I talk about saving the drug here, I\'m talking about saving
macrolides, prolonging the effects of the respiratory agents,
macrolides, fluoroquinolones, beta-lactams for that matter. To prolong
the useful lifetimes of these drugs, we need multiple drug choices for
respiratory infections. The more choices, the better.

Now, here we\'re talking about a new class of drug. I think the
manufacturer is to be complimented for persistence in bringing forward a
new class of drug. We certainly haven\'t had many of them, and that\'s
very much what we need to stay ahead of the problem of drug resistance.
We know manufacturers are dropping out of antibiotic production. If we
set the approval barriers too high, we just won\'t have any more
antibiotics in the pipeline. We can talk forever about appropriate drug
use and all that, but if we don\'t have the new drugs in the pipeline,
we\'re never going to get ahead of the problem.

Now, obviously efficacy and safety are the two most important
considerations that have to be evaluated in an application for drug
approval. But I think my feeling is that if there\'s some doubt, it
would be helpful, particularly with a new class of drug, if it were
possible to justify approval with some precautionary labeling. That
would be very nice rather than disapproval.

DR. LEGGETT: Any comments around the table in general about the efficacy
of this drug for the three indications? Anything different than the last
time we went through this. Dr. O\'Fallon.

DR. O\'FALLON: One of the things that we haven\'t said that was sort of
at the back of my head when I was reading through the data was remember
when we looked at this, sinusitis business, we\'ve seen the Pollyanna
effect and this one was not double-tapped and that type of thing, the
equivalent thereof.

So I was sort of looking to see if the cure rates, these clinical cures,
are more than what you would have expected from just using something as
sloppy as clinical cure as an endpoint. It seemed to me the data really
were higher than you would expect, the 70-ish percentage that we were
talking about. These pretty much across the board seem to be higher.
They were mostly 80 percent and up in the different subsets. And it
seemed to me that spoke of a real effect. So throughout all this
questioning, I thought that there really is pretty sound data of
efficacy.

DR. LEGGETT: Yes, Dr. Elashoff.

DR. ELASHOFF: Well, I think the data establish that a lot of people were
classified as having gotten better. I think they establish that the
proportion who were so classified is no more than 10 to 15 percent less
with this drug than with the comparators. But without data in front of
us establishing the efficacy of the comparators, the data in front of us
does not establish efficacy of this new drug.

DR. LEGGETT: Yes, Dr. Poretz.

DR. PORETZ: First of all, I\'d like to thank Dr. Powers. That discussion
was really helpful this morning. It really was.

From a practical point of view, I think telithromycin is at least as
efficacious as any of the other drugs on the market, the comparators
that they demonstrated for pneumonia, bronchitis, and sinusitis. And for
that reason, I think it\'s going to be just as valid using that drug as
anything else.

My hope would be that some of the drugs at the present time are
obviously being overused. The macrolides are being tremendously overused
in my area of practice in northern Virginia right over here. Everyone
and their brother is being put on a macrolide or a quinolone, and I\'m
very, very concerned about it because even in my local hospital I\'ve
been watching the resistance rate go higher and higher and higher. I
think that\'s really dangerous.

My only concern, a simple concern perhaps, is the visual problem because
I think practically that could be a problem because as mentioned by the
ophthalmology people a while ago, suppose someone wants to drive a car
and they\'re trying to accommodate from looking forward and closer and
so on. That could be a real problem and if someone got in an auto
accident, crashed their car because of that, because of inattention
because they couldn\'t accommodate, that could be a social phenomenon,
if you will, that could cause legal repercussions and a whole bunch of
other things. And I think even though the incidence is less than 1
percent, 0.4 percent of whatever it is, I think it needs to be noted
with significance, if you will, in the package insert or the PDR or
whatever.

I\'m not that concerned about QT prolongation. I think the discussion
today showed it was no worse than anything else.

And the hepatotoxicity doesn\'t look like it\'s any worse than any other
antimicrobial. My goodness, cephalosporins can raise liver enzymes in
themselves.

So I\'m particularly concerned about the visual aspect, and I think that
needs to be somehow noted significantly in the package insert.

DR. LEGGETT: Given the way they drive in Italy, that might be the reason
that none of it was reported.

(Laughter.)

DR. LEGGETT: It\'s okay. My wife is Italian.

Any further general statements before we pass on to the votes?

(No response.)

DR. LEGGETT: This is always the fun part. I think the voters are from
here down to the end of the table, not including Dr. Brown.

The first question is, do the safety and effectiveness data presented
support the use of Ketek for the following indications? A,
community-acquired pneumonia. And why don\'t we go around and everybody
sort of puts in their 2 cents. Do you want to start, Jan?

DR. PATTERSON: I would say yes for those three indications. I think that
the caveats that should be included in the label include the warning
about rare instances of hepatotoxicity that\'s idiosyncratic and also
the blurred vision which is more common in those less than 40 years old
and more common in women. That should be specified in the label and
perhaps some specific directions about not driving and doing other
things that require clear vision the first 12 to 24 hours after the
first dose.

And I think in consideration of the safety and efficacy, along the lines
expressed by Dr. Bell, we need new agents and this one has a targeted
respiratory spectrum that doesn\'t increase our concerns for
Gram-negative resistance, and that enters into my decision.

DR. LEGGETT: I would echo that.

In addition, I would perhaps think about mentioning in the label
something about limitation of the duration of the medication, to be on
the safe side.

Then in terms of the visual effects, it was my understanding from today
that the data had come in so late that the FDA had not yet analyzed
that. So I think there\'s probably still some more work to be done I
think. At least in the packet that we got, there were several things
that hadn\'t been analyzed yet, and today I thought that one of the
statements was about the visual effects.

DR. SORETH: I think that one study or a set of studies that we haven\'t
been able to analyze yet were those submitted December 31st which had to
do with simvastatin and telithromycin pharmacokinetic information.

Secondly, with regard to post-marketing safety data, I think we need to
get a more complete handle, since we have excerpts from Medwatch forms.
I don\'t know that we have everything as yet in house because it\'s a
dynamic thing. Reports come in on a regular basis, et cetera. At some
point you have to lock the database, lock what time you say you\'re
going to give things to the FDA, et cetera. So we need to get a better
handle I think on the full scope of post-marketing reports, et cetera.

DR. LEGGETT: Thanks.

Oh, I forgot you, Bill.

DR. LEE: Yes. I would vote all three for yes, but I would certainly put
on the package insert a comment about increased ALTs and possible
hepatotoxicity. I think your point about the duration is important as
well.

DR. LEGGETT: Do you want to do B and C while we\'re doing this on number
1?

DR. PATTERSON: I would say yes for those also.

DR. LEGGETT: That\'s three yeses.

Dr. O\'Fallon.

DR. O\'FALLON: I agree with what\'s been said so far.

For, Janet, Dr. Elashoff, this committee has seen data in the past that
has tended to make us believe that these comparators are better than
placebo, but I\'ve seen some meta-analysis data at times that they\'ve
given us in other studies. But it wasn\'t presented here. Dr. Elashoff
is absolutely correct. When you\'re comparing two different active drugs
and saying are they different, that\'s great, but both of them could be
terrible. Something has to show that at least one of them is generally
active and better than a placebo, and we didn\'t have that data. She\'s
correct about that, but we have seen something like that in other cases.

DR. LEGGETT: Barth.

DR. RELLER: I\'d say yes for community-acquired pneumonia, no for acute
exacerbations of chronic bronchitis, and yes for acute sinusitis.

My reservations about acute exacerbations of chronic bronchitis are
twofold. One is it didn\'t make it in my view for Haemophilus
influenzae, which was the most common of the documented causes. The
overall database is smaller than with any of the other indications. We
voted 0 to 10 18 months ago, and I don\'t see a substantive improvement
in the database for acute exacerbations of chronic bronchitis. And
lastly, of all of these indications where the drug is apt to be used
repeatedly it would be for this indication. That\'s my reasoning.

DR. LEGGETT: A clarification. One of the reasons we were 0 for 10 is we
didn\'t have the safety data as well. Do you want to address that
aspect? Is your no for the AECB based on the efficacy part and not the
safety efficacy ‑‑

DR. RELLER: That\'s why I had my additional comments. My no is
principally based on efficacy with that being driven largely by the
results with Haemophilus influenzae, the overall relatively small
numbers compared with the other indications, and a sprinkling of concern
about safety given how often patients take drugs repeatedly for acute
exacerbations of chronic bronchitis.

DR. LEGGETT: Thank you.

Dr. Maxwell.

DR. MAXWELL: Yes. I vote yes on community-acquired pneumonia. I vote yes
on acute exacerbation of chronic bronchitis and acute sinusitis.

However, I have some concerns and believe that the labeling should be
clear as to the adverse events that we mentioned and that there should
be some more evaluation of the visual involvement in these patients and
to look primarily at women to see if women present a different
population, and there should be some kind of adjustment made based on
that.

DR. LEGGETT: David.

DR. BELL: I vote yes for all three of them, pneumonia, chronic
bronchitis, sinusitis, with the precautionary labeling dealing with the
visual, cardiac, and hepatic manifestations that has been alluded to.

DR. LEGGETT: Alan?

DR. CROSS: I vote yes for community-acquired pneumonia. I share Dr.
Reller\'s concern both about the data and other aspects that he
mentioned in terms of chronic bronchitis. So I would vote no for that,
but I would vote yes for the acute sinusitis. And I also agree that the
labeling ought to highlight the visual aspects and the potential for
hepatotoxicity, especially among those who already start with a baseline
of a high ALT.

DR. LEGGETT: Dr. Wald.

DR. WALD: I vote yes for CAP and no for bronchitis and yes for sinusitis
and agree with the recommendations about labeling specifically with
regard to the visual toxicity.

DR. LEGGETT: Dr. Rupp.

DR. RUPP: I vote yes for all three indications. I think the
precautionary labeling should reflect what\'s already been discussed
with regard to vision, prolonged dosing, perhaps some caveat on the
frequency of repeated dosing, and the precautionary labeling with regard
to hepatotoxicity and cardiac toxicity should be similar to the
comparative agents.

DR. LEGGETT: Dr. Elashoff.

DR. ELASHOFF: I vote no on efficacy of all three since the data at hand
do not establish the efficacy of the comparators. I would like to see if
it is, in fact, approved the kinds of caveats that people have
previously mentioned with regard to safety.

DR. LEGGETT: Don.

DR. PORETZ: I vote yes for community-acquired pneumonia. Although I have
some reservations about chronic bronchitis, I think those are very, very
difficult studies to do and compare, but it seems like it\'s just as
efficacious as the other drugs that it was compared against. So I vote
yes for that, and I vote yes for acute sinusitis with the same caveats
that everyone else has said.

DR. LEGGETT: One thing that came to mind, when you were talking about
the low numbers, Barth, you were talking about the bacteriologic numbers
or were you talking about the clinical cure rates? Because people
alluded to that same problem all this time. We have the same clinical
cure problem in all respiratory tract infections except for bacteremic
pneumonia. Did you have specifically in mind the low clinical cure for
Haemophilus or were you talking specifically about our low numbers of
bacteriologic per-protocol numbers?

DR. RELLER: The data presented by the sponsor ‑‑ I mean, there were big
differences between efficacy for Haemophilus influenzae, and it\'s a
leading cause, not the only, but a leading cause among the big three for
acute exacerbations of chronic bronchitis that one might expect to
respond to antimicrobial therapy. I realize it\'s a complex clinical
gemisch, but if there would be any benefit to antibiotics, it\'s for
these organisms and a major one is found wanting.

DR. LEGGETT: Let me pursue this a second. I\'m trying to fish it out for
them. Should the H. flu in pneumonia be different from the H. flu in
chronic bronchitis? Is there something that you\'re alluding to, or is
it that we just can\'t look at it as much?

DR. RELLER: Well, I mean, on theoretical grounds, why would it possibly
work in one? I mean, I\'m only going by the data that we have before us.
I\'m not speculating. I think the charge is based on the data presented,
what do you think, and I told you what I thought.

DR. LEGGETT: I\'m not trying to put you on the spot. I\'m just trying to
flesh it out.

Number 2, and Don, we\'ll start with you. Do the safety and
effectiveness data presented support the use of Ketek for the treatment
of penicillin-resistant Streptococcus pneumoniae for the following
indications: community-acquired pneumonia and acute sinusitis? If yes,
are there any special caveats on the label? If no, what other
information would be required?

DR. PORETZ: I vote yes in favor of both. I do think we need drugs in our
armamentarium, especially on an outpatient basis, to put patients on.
Again, I\'m very concerned about overusage of quinolones, and I\'m
concerned about the other macrolides being used. I think this is another
drug that can be used safely to keep someone out of the hospital to
treat them with an oral medication. So I vote yes for both.

DR. LEGGETT: And the label would be the same?

DR. PORETZ: Yes.

DR. LEGGETT: Dr. Elashoff.

DR. ELASHOFF: No.

DR. LEGGETT: Presumably for the same reasons?

DR. ELASHOFF: Yes.

DR. LEGGETT: Dr. Rupp.

DR. RUPP: I vote yes for both those indications for penicillin-resistant
Strep. pneumo.

In addition, I guess I would add a caveat that I didn\'t mention before,
that for community-acquired pneumonia, it should be for mild to moderate
disease.

DR. LEGGETT: Dr. Wald.

DR. WALD: I feel a little bit worried about the overall reported
activity against resistant cases. We have an overall cure rate of 70
percent for all comers with resistant pneumococci and that\'s not
different from the preliminary data a couple of years ago. And for the
bacteremic, well, we just have so few. So I would not recommend it for
resistant cases.

DR. LEGGETT: And that goes for both of them. Ellen, that\'s for both?
Yes.

DR. WALD: Yes.

DR. LEGGETT: Dr. Cross.

DR. CROSS: I would vote yes for both.

DR. LEGGETT: Dr. Bell.

DR. BELL: I would vote yes for both and would agree that it\'s for mild
to moderate pneumonia.

DR. LEGGETT: Dr. Maxwell.

DR. MAXWELL: I would also vote yes for both and agree to the indication
for mild to moderate.

I would have liked to have seen, though, if it were possible, because I
believe this is the kind of drug that would be used in patients that are
HIV positive, some comparison on patients that are taking either
protease inhibitors or something like that to see if there is a
difference.

DR. LEGGETT: Barth.

DR. RELLER: I vote no, and the reason is not because I don\'t think that
it works. I feel actually more strongly about this than I did about the
other issues, and that is because I believe that separating these out
specifically is not necessary.

DR. LEGGETT: Separating what?

DR. RELLER: This has to do with the labeling.

DR. LEGGETT: Okay.

DR. RELLER: That is, denoting that these are efficacious is not
necessary nor in my view are the data sufficient to do that. My
reasoning is this, that the way I would label this compound, which I do
believe works for community-acquired pneumonia, is that it would be
approved for susceptible pneumococci, and if 98 percent of pneumococci
are susceptible, even though some of those that are susceptible may be
resistant to penicillin or resistant to erythromycin by this mechanism
or that, so be it. But to designate it separately gives the impression
to me that there\'s something special about this drug that makes it
really super, and I don\'t think we have the comparative data. That is,
special for those resistant strains. I don\'t think we have the
comparative data for that, that is, the direct comparison.

And moreover, based on the compounds that have got that designation
before, though it\'s not a direct comparison, the success rates are far
better for every indication than what the data are here.

So I think to single out this as being the implication that it has
special utility against resistant organisms, as opposed to saying it
works for telithromycin-susceptible organisms, would be the wrong thing
to do.

DR. LEGGETT: Dr. O\'Fallon.

DR. O\'FALLON: I agree with what Dr. Reller has said, but my reasons are
a little bit different.

First of all, you know that I wasn\'t very happy when we approved those
other ones. The sample sizes were pitiful, and these are better. They
really are better. So, again, great. That\'s a lot of improvement but it
isn\'t very good. These numbers are not very big.

And the thing that really bothered me was that presentation this morning
in which there was a question as to whether the sensitive and resistant
and so on organisms result in different outcomes of disease. Given that,
the underlying real uncertainty about the usefulness of this designation
to begin with, I don\'t think we should go there yet. If it proves to be
important, then we can come back and deal with it, but right now I
don\'t think there\'s enough information and there is a real question as
to how important that difference is in the real world.

So I vote no. I agree with what Dr. Reller said.

DR. LEGGETT: My vote is no for the following reasons. This drug is going
to be used empirically before we know whether the bugs are resistant or
not, so it makes no sense clinically. The pneumococci are multiply
resistant more than they are, so does the next company come back and
say, well, we warrant something for TMP sulfur-resistant pneumococci? It
doesn\'t make a lot of sense.

And we have seen emergence of resistance over time. We\'ve seen MIC
creep for amoxicillin and penicillin. We are in the process of seeing
MIC creep, or at least efflux creep, for the macrolides, and we\'re now
seeing the emergence of resistance of fluoroquinolones.

So I think for me the proper way to approach this would either be to
just say for penicillin-susceptible pneumococci. But to me the better
way would just be to say Streptococcus pneumoniae and not specify the
susceptibility.

Dr. Patterson.

DR. PATTERSON: I would vote yes for mild to moderate community-acquired
pneumonia and yes for sinusitis. Entering into my decision would be that
although the therapy is indeed empiric most of the time, our decision
making in empiric therapy is based on people\'s risk factors for
drug-resistant Streptococcus pneumoniae which are becoming more and more
clear.

Also, in terms of a special caveat that should be included on the label,
I think it would be worth saying that it may not be active against
strains that are both penicillin-resistant and macrolide-resistant, and
that\'s based on the data on pages 25 and 26 of the FDA briefing
package.

DR. LEGGETT: You did such a good job with that one. Do you want to jump
right to 3?

Oh, I forgot him again. There\'s a blank space there, and so I stop.
Sorry.

DR. LEE: I would vote yes for both indications. I think we\'re going to
see more resistance in future years, and I think the in vitro data is
supportive that this works, although I take the point of the ID
specialists who know more about this than I do, that the real problem is
simply facing up to Strep. pneumoniae.

DR. LEGGETT: Do you want to start off number 3, Bill? This is the
macrolide part.

DR. LEE: I would say yes for both of those as well.

DR. LEGGETT: Jan.

DR. PATTERSON: I would say yes for both. I would also add, based on the
discussion that we had earlier about the influence of resistance on
virulence and outcome, I\'m not convinced that resistant organisms are
any less virulent than susceptible ones, and so they\'re still quite
significant.

And the special caveat would be parallel to what I just said for PRSP in
that strains that are macrolide-resistant and penicillin-resistant ‑‑ it
may be less effective against those strains, again based on that same
data.

DR. LEGGETT: To catch up for both of you, what would you say about a
public health impact of having an additional new class of drug in terms
of macrolide resistance, sort of what David was referring to earlier?

DR. LEE: I would just support what David said. I don\'t have any other
additional comment.

DR. LEGGETT: And you, Jan?

DR. PATTERSON: I think that antibiotic heterogeneity and the use of
different classes of agents is probably an important factor in trying to
decrease the emergence of resistance.

DR. LEGGETT: My comments for number 3 really are about the same as they
are for number 2.

A little worry that I had, until we can sort out this NCCLS sort of
thing, was the sort of higher MIC creep on the erythromycin-resistant
pneumococci as opposed to the erythromycin-susceptible that was shown in
the slide this morning. I\'m worried about what the implications of that
are, but for how this drug is going to be used, I don\'t think we need
the label of erythromycin-resistant use.

Dr. O\'Fallon.

DR. O\'FALLON: My concerns about the previous are the same for this, and
so yes, I vote no.

DR. LEGGETT: Dr. Reller.

DR. RELLER: No. I would prefer that local antibiograms that guide
empirical therapy, consensus statements, guidelines similarly, and
marketing prowess would point out where this drug might work for
patients whose organism, if it were recovered, may be resistant to
existing macrolides. But to point this out specifically I would not do.

Moreover, I am like Dr. Leggett wary of the creep associated with the
macrolides, and I\'m skeptical of how robust a statement like this may
be with widespread use.

DR. LEGGETT: Dr. Maxwell.

DR. MAXWELL: I vote yes for both of them. However, I would encourage the
labeling to be such that widespread use or indiscriminate use is, as
best as possible, avoided and the other concerns that I had for the
toxicities be addressed.

DR. LEGGETT: Dr. Bell.

DR. BELL: I vote yes for both of them somewhat reluctantly because, A, I
wish we had more cases, but of course, that\'s what we have. And we do
have the in vitro data and some pharmacokinetic data. So I think that\'s
okay.

I\'m somewhat uncomfortable with this creep, you know, a formal
indication for yet another drug that it becomes resistant to. On the
other hand, that bridge was crossed with levofloxacin, and I don\'t know
exactly how to go back now. So I vote yes.

DR. LEGGETT: Just an aside. We\'ve burned bridges in past wars too.

(Laughter.)

DR. LEGGETT: Dr. Cross.

DR. CROSS: I vote yes for both. I too would like to see more data but
we\'re not going to have that. It\'s nice to have data on individual
patients, but I agree with Jan and you, Jim, that this will be used
empirically. And I think it\'s helpful data to know that if in your
community or in your hospital there are macrolide-resistant Strep.
pneumoniae, that this will be useful for that. So for that reason I
would say yes for both.

DR. LEGGETT: Before we go on, Alan, in the label I guess the question
is, is there a possibility to say that this drug has shown efficacy in
limited numbers of patients with penicillin and erythromycin resistance?
Is that something that can be put in without putting a label of
\"approved for\"?

DR. SORETH: Well, I think basically if you have statements in the label
that there is experience with it, it\'s basically something that can be
advertised. We\'ve tended in recent years to shy away from limited
experience, less than 10 isolates, et cetera. So it\'s either in or out
basically.

DR. LEGGETT: Yes. Well, you guys are writing the label, not us.

DR. SORETH: That\'s why they pay us the big bucks.

(Laughter.)

DR. LEGGETT: Dr. Wald.

DR. WALD: Will the label contain the information that for all PRSP,
there was a 70.4 percent cure?

DR. SORETH: Labels can contain clinical study sections in which a fair
amount of detail is given.

DR. WALD: I would advise that the label include that statement, and I
would again vote no for both.

DR. LEGGETT: Dr. Rupp.

DR. RUPP: I vote yes for both. I think that antibiotic-resistant
pathogens are clearly clinically significant. They\'re going to
increase. We need additional choices, and I agree with many of the
comments that my colleagues have made here with regard to the labeling.
To me it\'s to a large degree a matter of semantics. Either you say
it\'s indicated for susceptible organisms ‑‑ I think that would be the
best way of doing it, but the precedent has been set. So other products
are labeled as indicated for penicillin-resistant pneumococcus, and so I
think we follow suit. And I would say yes for both of these.

DR. LEGGETT: Dr. Elashoff.

DR. ELASHOFF: No for both for previously stated reasons.

DR. LEGGETT: Last but not least.

DR. PORETZ: I vote yes for both because again I keep seeing more
resistance in my area, more quinolone use. I\'m still scared of
quinolone use empirically for everything, and I think this gives
practicing doctors and nurse practitioners, whomever an added sense of
security that perhaps they are at least playing the odds that the
organism is going to be sensitive.

DR. LEGGETT: So you\'re using Dr. Bell\'s public health thing, the more
options you have, so you don\'t just have to use fluoroquinolones?

DR. PORETZ: I think the practicing prescribing physician needs some
added protection, at least odds-wise, as far as active against the
Strep. pneumoniae.

DR. LEGGETT: Since we, as usual, were unanimously probably split down
the middle, I think that is another option that the FDA could consider
in whether they label it or not, the implications of having another
class of drugs besides fluoroquinolones that would have a label such as
that. And you can weigh the pros and cons of something like that.

DR. LEE: Are you ready to start on the next thing? Because I have to
leave.

DR. LEGGETT: Go to number 4? Sure.

DR. LEE: My only suggestion for additional studies would be kind of
following on from my comments and Dr. Reller\'s comments that it might
be well to track these multi-use cases and particularly maybe focus on
the AECB cases for tracking evolution of liver toxicity and possibly
also looking at if there\'s a reason to treat HIV patients to use this
drug ‑‑ I\'m not sure there is right now, but if there were instances of
use in HIV, that would be the other at-risk population I think.

DR. LEGGETT: Jan.

DR. PATTERSON: As Celia mentioned, I think studies of the visual
effects, the mechanism of that and, in particular, why this previously
unseen effect of accommodation or lack of is more common in women, and
to track those who get repeated dosing of this agent, and also, as Celia
mentioned as well, to look at it with protease inhibitors, particularly
those that we know are liver toxic.

DR. LEGGETT: My comment about HIV is that I\'m not going to be using it
anytime soon on my patients with protease inhibitors until I let
everybody else figure out if it\'s toxic.

Dr. O\'Fallon.

DR. O\'FALLON: No.

DR. LEGGETT: Nothing for Dr. O\'Fallon.

Dr. Reller.

DR. RELLER: Among the toxicities, the one that I\'m most cautious about
is the visual disturbances. One of the things that I think through some
mechanism needs to be sorted out as to whether, if it\'s going to occur,
it occurs after the first dose or whether there is any cumulative or
it\'s unpredictable because if one is going to have any caveats in the
label, it would be helpful to be able to spell them out more precisely.
That is, this unusual event or rare event or whatever the frequency is
may be seen after the first dose and it lasts this long so that you can
put some reasonable boundaries. I mean, if one is taking the drug for 5
days or 5 to 10 days, does that mean that one needs to be cautious about
it, and does it come on without any warning? Does it start out that you
have a little bit of trouble accommodating and then more trouble
accommodating?

And I don\'t want to blow this out of proportion in terms of how
frequent it is, but the implications with drugs that are used in the
millions, not necessarily would this one be, though that\'s every
sponsor\'s dream in terms of market share, but in the aggregate there
are tens of millions of prescriptions for the indications that are
given.

I think if it\'s transient, if it happens, it either happens or it
doesn\'t happen right away, and it lasts no more than 12 hours, then it
puts some common sense into the labeling as opposed to it could happen
anytime during the course and it may last days. You get the idea.

DR. LEGGETT: Dr. Maxwell.

DR. MAXWELL: I underscore the comments of my colleagues. I would like to
add particular emphasis, though, on the fact that I think this seems to
preferentially impact on women somewhat differently and no one has been
able to give me a clear explanation as to why. So I think that studies
that look at women more closely going forward would be something that
would be important.

DR. LEGGETT: Dr. Bell.

DR. BELL: Yes. I think particularly since this is going to be mostly
used as an outpatient, the studies that Dr. Reller and Maxwell have
alluded to are particularly important, risk factors for the toxicity.
It\'s young women. Can anything else be said besides that about who is
at risk and then a better description, as Barth has pointed out, of the
timing and so on.

DR. LEGGETT: Dr. Cross.

DR. CROSS: I would agree with the need for more visual studies on the
lines that have already been mentioned by my colleagues.

DR. LEGGETT: Ellen.

DR. WALD: I agree.

DR. LEGGETT: Mark.

DR. RUPP: I would encourage the sponsor to continue a robust
surveillance network. I\'m concerned that already we\'re talking about 1
percent pneumococci being resistant to this compound. I think it\'s very
important to track that. I would also say if there\'s any way ‑‑ I
don\'t know if it\'s logistically possible, but to track patients who
have had repeated courses of telithromycin to see if it amplifies any of
the possible toxicities would be suggested.

DR. LEGGETT: Or amplifies resistance.

DR. RUPP: That as well.

DR. LEGGETT: Dr. Elashoff.

DR. ELASHOFF: I would support the previous committee members\'
suggestions about additional studies.

DR. LEGGETT: Don.

DR. PORETZ: The only thing I would add would be ongoing surveillance for
drug interactions. In the package insert in Europe in our briefing book,
they talked about actually stopping statins while people are taking the
drug. A lot of people on statins in the United States, a lot of people
on lots of drugs, a lot of transplants in this country. I think drug
interactions is a major, major problem that needs to be watched.

DR. LEGGETT: Yes, I would assume that the label is going to talk about
cyclosporine A and those sort of things.

Do you want to give us a tally?

DR. TURNER: The tallies for the questions are as follows.

For question number 1, we had 8 votes of yes for all three indications;
3 votes of yes for all except chronic bronchitis; and 1 vote of no for
all three indications.

For question number 2, we had 7 yes votes for both indications and 5 no
votes for both indications.

For question number 3, we had 7 yes votes for both indications and 5 no
votes.

DR. LEGGETT: Dr. Soreth, what would you have us do at this point?

(Laughter.)

DR. SORETH: Go back to your hotel room and relax.

(Laughter.)

DR. LEGGETT: Thank you.

(Whereupon, at 4:35 p.m., the committee was recessed, to reconvene at
9:00 a.m., Thursday, January 9, 2003.)