UNITED STATES OF AMERICA

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

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PULMONARY ALLERGY DRUGS ADVISORY COMMITTEE MEETING

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Tuesday,

September 6, 2002

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The meeting was called to order at 7:32 a.m., in the Main Ballroom of
the Gaithersburg Holiday Inn, Two Montgomery Village Avenue,
Gaithersburg, Maryland, by Dr. Mark Dykewicz, Committee Chairman,
presiding.

PRESENT:

DR. MARK S. DYKEWICZ, Chairman

DR. ANDREA J. APTER, Member

DR. T. PRESCOTT ATKINSON Member

DR. VERNON CHINCHILLI, Member

DR. JESSE JOAD, Member

DR. PETER E. MORRIS, Member

DR. POLLY E. PARSONS, Member

DR. ERIK R. SWENSON, Member

DR. JAMES K. STOLLER, Voting Consultant

DR. DONALD PATRICK, Voting Consultant

WILLIAM J. KENNEDY, Industry Representative

MS. KIMBERLY LITTLETON TOPPER, Executive Secretary

SPONSOR REPRESENTATIVES AND CONSULTANTS:

DR. BURKHARD BLANK

DR. BERND DISSE

DR. JAMES DONOHUE

DR. PAUL JONES

DR. STEVEN KESTEN

DR. DONALD MAHLER

DR. SHAHENDRA MENJOGE

DR. ERIC PRYSTOWSKY

DR. THEODORE WITEK

FDA REPRESENTATIVES:

DR. BADRUL CHOWDHURY, FDA Representative

DR. LISA A. KAMMERMAN, FDA Representative

DR. ROBERT J. MEYER, FDA Representative

DR. EUGENE SULLIVAN, FDA Representative

C-O-N-T-E-N-T-S

[PAGE]{.underline}

Introductions

Opening Remarks/Conflict of Interest Statement

Boehringer Ingelheim Presentation

FDA Presentation

Open Public Hearing

Discussion of Questions

Adjournment

P-R-O-C-E-E-D-I-N-G-S

(7:32 a.m.)

CHAIRMAN DYKEWICZ: Good morning. Let\'s convene our meeting of the
Pulmonary-Allergy Drugs Advisory Committee. I am Mark Dykewicz, Chair,
and I am a Professor of Internal Medicine, and Director of the Training
Program of Allergy and Immunology at St. Louis University School of
Medicine.

And let\'s begin the meeting with introductions by each of us, starting
with Dr. Kennedy. For each of you on the committee, when you do want to
speak, push down on the microphone button, and then when you are done
speaking, push it off so that you are not going to broadcast your
comments all over.

DR. KENNEDY: Good morning. I am bill Kennedy, and I am the Industry
Representative, and consultant to the pharmaseutical industry, and I was
formerly vice president of regulatory affairs for it.

DR. SCHATZ: I am Michael Schatz, and I am Chief of the Department of
Allergy at Kaiser-Permanente Medical Center in San Diego, and a clinical
professor at UCSD, and I am a guest speaker today.

DR. PARSONS: I am Polly Parsons, and I am a Professor of Medicine at the
University of Vermont, and Chief of Pulmonary Critical Care at Fletcher
Allen Health Care, and Chief of Critical Care Services there.

MR. MORRIS: I am Pete Morris, and I am an Assistant Professor in the
Division of Pulmonary and Critical Care Medicine at Wake Forest, North
Carolina.

DR. JOAD: I am Jesse Joad, and I am a Professor of Pediatric Pulmonary
and Allergy at the University of California at Davis.

DR. STOLLER: I am Jamie Stoller, and I am a Professor of Medicine with
the Cleveland Clinic, and Vice Chairman of the Medicine and Associate
Chief of Staff.

DR. SWENSON: I am Erik Swenson, and I am a Professor of Medicine at the
University of Washington in Pulmonary and Critical Care Medicine.

DR. APTER: I am Andrea Apter, Associate Professor, Allergy and
Immunology, Division of Pulmonary Allergy and Critical Care Medicine,
University of Pennsylvania.

DR. CHINCHILLI: I am Vern Chinchilli, and I am a Professor of
Biostatistics at the Penn State Hersey Medical Center.

MS. SCHELL: I am Karen Schell, and I am a respiratory therapist in rural
Kansas, and I manage a respiratory care department.

DR. KAMMERMAN: I am Lisa Kammerman, and I am a biometrics team leader in
the Center for Drugs.

DR. CHOWDHURY: I am Badrul Chowdhury, Acting Director, Division of
Pulmonary and Allergy Drug Products, FDA.

DR. SULLIVAN: My name is Gene Sullivan, and I am a Medical Officer in
the Division of Pulmonary and Allergy Drug Products.

DR. MEYER: I am Bob Meyer, and I am the Director of the Drug Evaluation
II in CDER.

CHAIRMAN DYKEWICZ: Thank you. We will now receive the conflict of
interest statements by Ms. Kimberly Topper.

MS. TOPPER: The following announcement addresses a 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 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 exception.

Dr. Andrea Apter has been granted waivers under 18 U.S.C. 208(b)(3), and
505(n)(4) of the FDA Modernization Act for her spouse\'s interest in
Pfizer, a co-marketer of Spiriva, and a competitor to Spiriva.

The stock value is between \$50,000 and a hundred-thousand dollars.
These waivers permit Dr. Apter to participate in the committee\'s
deliberations and votes concerning Spiriva. A copy of this waiver
statement may be obtained by submitting a written request to the Freedom
of Information Office, Room 12A30, of the Parklawn Building.

With respect to invited guests, Dr. Michael Schatz, we would like to
report that he is a researcher for Aventis, Giaxo, and Astra, on inhaled
corticosteroids. He also receives speaker fees from Astra for his talks
concerning asthma and pregnancy.

In addition, we would like to disclose that Dr. William J. Kennedy is
the non-voting guest industry representative. He is not a government
employee, and hence we do not screen him for conflict of interests and
we can make no comments on his actual or perceived conflicts of
interests.

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participate has a financial
interest, these participants are aware of the need to exclude themselves
from such involvement, and their exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose products they wish to comment upon. Thank you.

CHAIRMAN DYKEWICZ: Thank you. Dr. Patrick, would you like to introduce
yourself, please.

DR. PATRICK: I am Donald Patrick, and I am a Professor of Health
Services and an Outcome Research Specialist from the University of
Washington in Seattle.

CHAIRMAN DYKEWICZ: Thank you. We will now begin with introductory
comments by the FDA, starting with Dr. Robert Meyer.

DR. MEYER: Thank you. I want to leave the more formal introductory
comments to Dr. Chowdhury, but I did want to make special note of the
choice of having the meeting today. At sundown tonight, an important
holiday for many of us in the FDA side, and on the committee, and I am
sure in the audience, as well as in the company, begins.

And it was not by first choice by any means that we had the meeting
today, but because of not wanting to hold the meeting in conjunction
with September 11^th^, where travel would be necessary over that
anniversary, and because of wanting to constitute the most full and
expert committee possible, this was the only feasible day.

So I certainly offer apologies for the choice of the day, but again we
felt that we did not have a choice in having it today, and due in
difference to the holiday beginning this evening, we did start the
meeting early, which explains why we are all here at 7:30, and we will
try to wrap up in a timely fashion to get folks home.

And now I will turn it over to Dr. Chowdhury for more formal
introductory comments.

DR. CHOWDHURY: Good morning, Honorable Chairman, and Members of the
Pulmonary and Allergy Drug Advisory Committee, I welcome you to this
meeting, and thank you for your participation this morning.

This meeting is to discuss the new drug application of tiotripium
bromide inhalation powder inhalation powder from Boehringer Ingelheim
Pharmaseuticals. The materials to be discussed in this meeting, and
opinions that we are seeking from you, are solely related to clinical
issues of tiotripium.

Please bear in mind that the regulatory decision-making process to
determine approvability of the drug product, the agency takes into
consideration various factors, in addition to clinical issues, such as
chemistry, manufacturing, and controls for drug product, and
pre-clinical considerations.

These are not being discussed in this meeting. This meeting is solely to
discuss the clinical issues of tiotropium. Boehringer Ingelheim is
seeking an approval for tiotropium bromide inhalation powder for the
treatment of bronchospasm, and dyspnea, associated with COPD.

While all clinical issues related to tiotropium are open for discussion,
we are asking for a deterred deliberation on the dyspenea claim because
the specific indication of dyspenea is unique amongst all drugs that are
currently approved in the United States for COPD.

As you can see in the agenda, Boehringer Ingelheim will first present an
overview of the clinical data, following by the Agency\'s presentation.
As you hear through the presentation, I would request for you to keep in
mind the questions that are in the FDA briefing book, and also attached
to the agenda, since you will discuss and deliberate on these questions
later in the day.

We look forward to an interesting meeting and again thank you for your
time, effort, and commitment in this important public service. I turn it
back to you, Mr. Chairman.

CHAIRMAN DYKEWICZ: Thank you, Dr. Chowdhury. We will now proceed with
the presentation from the product sponsor, Boehringer Ingelheim,
beginning with Dr. Burkhard Blank.

DR. BLANK: Good morning, Mr. Chairman, and Committee Members, and
Members of the FDA, Ladies and Gentlemen, my name is Burkhard Blank, and
on behalf of Boehringer Ingelheim, I want to thank you for the
opportunity to discuss with you today Spiriva NDA in COPD.

COPD is a growing health problem worldwide. In the United States, it is
the fourth leading cause of death, and further increases in its
prevalence and mortality of being predicted. The disease is
characterized by an increasing limitation of air flow, partly the result
of bronchospasm present in many patients.

Typically after many years of smoking, patients first develop chronic
cough and increased mucous production. It is not, however, until they
develop shortness of breath or dyspnea that most patients seek medical
care.

This dyspnea is chronic and it gets worse, and eventually it limits the
abilities of the patients to perform every day activities, and in
unfortunate patients it may be present at rest. So far the only
intervention that has been shown to change the course of the disease is
smoking cessation.

Therapeutically, bronchodilators, primarily inhaled anticolonegics, and
beta aganists (phonetic) are widely used for the relief of bronchospasm.
Spiriva is an inhaled, long-acting, once-daily anticholinergic, and we
have developed it for the treatment of patients with COPD.

The NDA contains data of over 4,000 subjects. In Phrase III, we enrolled
more than 2,600 patients, roughly half of them receiving Spiriva. We
performed six long term trials, which were conducted as three replicate
pairs.

Three, one year trials, comparing Spiriva against placebo done in the
United States, two ipratropium one-year controlled trials in Belgium and
The Netherlands, and somewhat later in the Phrase III, two, six-month
trials with both a placebo and a salmeterol control group.

The objectives of Phase III were first to confirm that Spiriva, when
inhaled once daily, provides to the patients reliable 24-hours of
bronchodilation. For that purpose, and in line with the outcome of the
phase and end of Phase II meeting with the agency, we selected the
trough FEV1 response; i.e., the extent of bronchodilation present at the
end of a 24-hour dosing interval as primary end point in all six trials.

The four, one year trials, as I indicated earlier, were performed first,
and they included the measurement of dyspnea as a secondary end point in
all treatment arms.

We found the results for Spiriva so encouraging that we decided to
confirm these findings in two pivotal trials. After consulting with the
agency about our intentions, we amended the study protocols of the two
six month trials to include as a co-primary end point the assessment of
improvement of dyspnea when comparing the Spiriva group with the placebo
group.

This amendment was made at a time when both trials were clinically
complete. However, when the study blind how remained intact. Finally,
the six long term trials allowed us to evaluate the safety of Spiriva in
a broad patient population in COPD receiving long term treatment.

We are here today because the agency seeks your advice on a number of
questions which all fall in these areas. First, does Spiriva really show
24 hours of bronchodilation, and secondly, are the observed improvements
in dyspnea supported by measurements of a validated instrument and is
the observed improvement of dyspnea meaningful.

Specifically, the agency asks the question was the responder definition
that we choose clinically meaningful and is the difference in response
rates between tiotropium and placebo important.

Finally, as in regards to the safety, was the safety of Spiriva
adequately assessed, and is the safety profile appropriate for the
intended use. The agency makes specific reference to subtle indications
that the use of Spiriva may be associated with cardiac events,
especially in the category of heart rate and rhythm disorders.

In our presentation, we will present to you all data that we feel are
helpful for answering these questions. First, we will show you the
trough FEV1 primary end point across all six studies, and go through the
consistency of the findings, and then show you the secondary spirometric
and the secondary nonspirometric findings.

Following that, we will explain the BDI/TDI instrument, and argue to you
what it is an appropriate tool to measure dyspnea. We will then show you
the data on dyspenea from both the pivotal trials and from the four, one
year trials. Finally, we will share with you the safety profile as it
was observed in the Phase III, and the total of 2, 600 patients, half of
them on Spiriva.

This safety profile, not unexpectedly, reflects the pharmacology as an
antichologenic compound in a very similar way to what we have seen from
atrovent, which has been widely used over many years. Most importantly,
we see no association with Spiriva and life-threatening events.

In reviewing today with you the clinical results of Spiriva, we hope
that you will find the data convincing and in support of the proposed
indication statement outlined on this slide. Dyspnea is the most
disabling symptom for patients with COPD, and we will present to you
data from two pivotal trials confirming an improvement of dyspnea by
Spiriva.

These data, together with consistent supportive data from the four, one
year trials, provide the basis to include the improvement of dyspnea in
the products label, and we propose the indications and usage sections as
the most appropriate place for this. Following me, my colleague, Dr.
Bernd Disse, will show you bronchodilation data. Then Dr. Jones will
explain the instrument.

My colleague, Dr. Theodore Witek, will show you the data on dyspnea, and
the safety profile will be provided by Dr. Kesten. Dr. Jim Donohue will
share with you his perceptions as a treating physician on where he sees
the place for Spiriva, and what does Spiriva offer to the patients with
COPD, and I will come back with concluding remarks.

Since our presentation is built on each other, we believe that it is
most appropriate for the objective of the meeting if we can answer
questions at the end of our presentation. We are honored today to have
not only Dr. Donohue and Dr. Jones with us today in the audience, but
also Dr. Mahler, who developed the BDI/TDI instrument; and Dr.
Prystowsky, who gave us his independent assessment of the cardiac safety
of Spiriva.

Unfortunately, for reasons which Dr. Mahler addressed in his
introduction, Dr. Prystowsky has to leave after the lunch break, and we
would ask you that if you have questions that you want to direct
directly to Dr. Prystowsky, please do so before the lunch break. I would
now like to hand this over to Dr. Disse.

DR. DISSE: Thank you, Dr. Blank. Good morning, ladies and gentlemen. I
am Bernd Disse from Boehringer Ingelheim, and it will be my pleasure to
introduce basic and bronchodilator efficacy results to tiotropium, and
here is the overview of my presentation, and I will mainly focus on the
Phase III spirometry results.

Basic cholinergic tone, as well as a major proportion of bronchospasm in
COPD is mediated by isocolon (phonetic) and mass kirenreceptus
(phonetic), or cholinergic receptus as they are often called in clinical
medicine. And the standard bronchodilator used in obstructive lung
diseases is ipratropium bromide, used 3 to 4 times a day, and the
obvious room for improvement is duration of action.

Now, the new anti-mascorinic (phonetic) tiotropium is firstly more
potent at about an affinity constant of 10 picomolar, which is very
potent, but the most important quality of tiotropium is its long
duration of action, and this is most likely brought about by slow, very
slow, disassociation from M3 receptors, and M3 is the receptor subtype
responsible for smooth muscle constriction.

Tiotropium was first investigated in single dose studies in COPD,
covering a dose range from 10 to 160 micrograms, and these studies
established the pharmacodynamic duration of action to exceed 24 hours. A
multiple dose study of four weeks treatment duration covered a range
from 4.5 to 36 micrograms end placebo, and allowed us to select the dose
for Phase III.

And this selection was based on the fact that the 18 microgram dose was
approaching the pharmacodynamic plateau for FEV1, trough, average
effects; and on the other hand, that the net dose, the 36 microgram
dose, already had a slight tendency for increase in dry mouth, which is
the most sensitive systemic side effect of anticholinergic treatment.

Tiotropium is a typical N-quaternary anticholinergic, and it shares all
the positive properties of that compound class. For instance, it does
not pass the blood-brain barrier. Now, from the nominal dose of 18
micrograms, and up to an 8 to 10 microgram dose is delivered through the
mouth piece, and the fine particle fraction of about 20 percent can be
deposited in the lungs and eventually absorbed.

The coarse participles, the major proportion, deposits in the
oropharynx, and is swallowed, and the remaining portion is cleared. As
for absorption from the oral part, there is very low absorption, and
this contributes minimally to the overall systemic load.

Now, to balance this, 3.6 micrograms reach the lungs, and distributes in
the lungs, and gives rise to high tissue concentrations. Then absorbed
systemically, it is 3.6 micrograms in the system which is diluted
throughout the body, and gives rise to low tissue concentrations.

Here the overall as to pharmacokinetics. I mentioned already that the
bioavailability by inhalation is about 20 percent, which gives rise to
very low plasma concentrations. The molecule is metabolized by about 25
percent by P450 enzymes in the liver, and to some extent
nonenzymatically, but the major route of excretion is unchanged
compound, 75 percent, via the kidneys.

The renal clearance is high, and exceeds even the creatinine clearance,
and as may be expected for most renal excreted drugs in patients with
moderate to severe degrees of renal impairment, we have seen increases
in the plasma levels, but they never exceed more than doubling of plasma
concentrations, and the consequences of this in older aged patients with
renal impairment, we have seen some increase in the side-effect of dry
mouth.

The half-life of this drug is about 5 to 6 days, and this is a
pharmacokinetic half-life, leading to steady state in about 2 to 4
weeks, but the pharmacodynamic half-life, which depends on lung
concentrations, is reached much faster, in about one week.

I will now focus on the long-term Phase III studies. Our proposed
indication is tiotropium indicated for long-term, once daily,
maintenance treatment of bronchospasm, and dyspenea, in COPD, and my
focus will be long-term, once-daily, bronchospasm and to provide the
substantial evidence needed for this.

We conducted six major studies organized in sets of three repetitive
studies, and all of these were randomized, double-blind, double dummy,
if applicable, of course, parallel group comparisons, and the treatment,
the active treatment was 18 micrograms of tiotropium by dry powder
inhaler.

In the first set of studies, we had one year treatment duration and
comparator placebo. In the second year, in the second set of studies,
again one year treatment duration, and comparison to ipratropium by MDI,
four times a day. And in the third set of studies, we compared the
placebo and salmeterol two times a day.

Here is our patient selection. The selection was based on a clinical
diagnosis of COPD, and we excluded patients with asthma, allergic
rhinitis, or atropy, and everyone was required to be 65 percent of
predicted normal, or less than 70 percent of the force vital capacity of
these patients.

The age was higher than 40 years, and they had to have a smoking load of
more than 10 pack years. The exclusion criteria were defined as follows.
We excluded unstable patients not able to participate in a long term
study as judged by the investigator. Patients with a recent respiratory
tract infection were included.

Further, patients with a recent history of myocardial infarction,
cardiac arrhythmia, requiring treatment, or hospitalization for heart
failure, were excluded; and anticholinergic class contraindications,
narrow-angle glaucoma, bladder neck obstruction, or prostatic
hypertrophy, were excluded.

These inclusions and exclusion criteria allowed us to recruit a COPD
population with a broad range of significant and stable co-morbidities
typical for the age group, and this is further outlined in the next
slide.

Concomitant diagnosis of cardiovascular diseases was in about 50 percent
of these patients, and among these the most prominent were hypertension,
with about 20 percent, but also cases of coronary artery disease,
cardiac arrhythmias, myocardial infarctions in patients\' histories,
ranging from 2 to 12 percent.

Neurologic and psychiatric diagnosis were quite common, too, and most
prominent, the class of depression, with about 21 percent. Patients with
prostatic hypertrophy and micturation disorders ranged from 2 to 11
percent in this patient population, and the ranges do not really reflect
differences in the populations, and I think that is more differences in
the diagnostic habits in the countries involved.

Now, here is the demographics of our study population, and I should
first mention that it was balanced between the treatment groups within
the studies, and comparable in the sets of repetitive studies.

The included patients were mainly male, mostly Caucasian, and some
African-Americans included, and there is a separate program ran in Japan
to include the Asian population, not part of this in any way.

The mean FEV1 and percent predicted normally characterizes the severity
and in the one year placebo control studies, it was moderate to severe,
slightly more moderate in the ipratropium control study, and in the six
month studies in between. So the range of patients covered is from very
severe, at about .3 liters, which is really very severe, to mild
patients, at about 2.5 liters of FEV1.

Here is the overview of our primary end points. We have chosen Trough
FEV1 as the primary end point in the one year studies, measured at 13
weeks, and at 24 weeks in the six month studies. In addition, we
measured dyspnea as a co-primary end point in the six month studies at
the end of the study, and this will be covered by my colleague, Dr.
Witek.

Now, trough FEV1, and that is the mean of the pulmonary function
breathings at 1 hour and 5 minutes before the next drug administration,
and this reflects the maintained drug activity at the end of the dosing
interval, and so this is why we made this choice.

As secondary end points, we measured the time course of FEV1, in clinic
measured forced vital capacity, to support pulmonary function
measurements, and home-measured peak flows. The shuttle walking test was
included in the six month studies. This test has not been shown to
separate drug treatment effects in the literature, and we also have not
been able to show the separate effects of tiotropium, spirometry, or
placebo, with this test.

However, symptoms and exacerbations of COPD in patient recorded outcomes
may lend support of overall and consistent patient benefit. Now, here is
the key spirometry results. In the next few diagrams, I will always use
the same scheme. The FEV1 is on the y-axis, and please note that it has
depicted changes higher than one liter, and the x-axis is at the time
after administration, and it is not entirely to scale.

Now, this is the first dose effect of the placebo adjusted for a common
base line, and you do see an appreciable bronchodilator response. After
eight days of treatment, we reached a steady state, and now patients
wake up at an elevated daily base line, versus a study base line, and
they present in clinic already with a better lung function value.

So this represents sustained activity for 24 hours, and 90 days of
treatment brings us to our primary end point, and the trough FEV1 value
versus placebo was significantly elevated, and we high significancies
throughout the day, and so peak, average and trough, and that all time
points were significant at a p-value of 0.0001.

Now, here is the value at the end of the study, and again lung function
measured for three hours, and you do see that the lung function profile
is unchanged over time, and that means that we have maintained efficacy
over the one year treatment period, and there is no indication of
tolerance whatsoever.

To be mentioned, we conducted two studies of this kind, and Number 115
is really absolutely comparable, and I don\'t need to present these data
as they have been outlined in the briefing documentation. Now, as to the
comparisons in ipratropium, the active comparator, the day one and day
eight response, and again you see on the first day that ipratropium, the
green, and tiotropium, the yellow, is in the beginning comparable, but
then tiotropium is more long acting.

On day eight, patients wake up with their improved lung function
(inaudible) base line, and so the trough value is elevated, and our next
dose again shows an increase in FEV1, which is substantial, and the end
of study shows that you only followed for three hours, and the end of
study shows the lung function profile is unchanged for both drugs. So
this has maintained efficacy over the one year period.

Here are the results of the comparison study to placebo and salmeterol
and the interesting feature here is that we measured lung function over
the date, and that means the 12 hours. You do see the profile on
Thursday, and a substantial increase over the 12 hour period, and
unrepeated dosing reaching a steady state, and we have the elevated
draft effect.

And again an increase over the day, and the efficacy is sustained over
the 24 hour period, and maintained over the one year treatment period,
or over the half-year treatment period. I\'m sorry. And here is a
comparison to salmeterol, and the profile on day one, on day 15, and on
day 169.

Here is the replicant sister study, and only measured lung function for
three hours, and so this was done somewhat simplier, but the lung
function profile was essentially the same, and so you do see the first
dose effect, and the trough effect elevated over baseline, and
maintained over the half-year period, and again in comparison to
salmeterol, day 1, day 15, and day 169.

And I would like to summarize the magnitude of spirometric improvements.
Tiotropium elicited an appreciable magnitude of response, and this table
is compiling the mean response reached in comparison to placebo at the
end of the treatment intervals. The mean response reached 190 to 250
milliliters at peak, and this is about 17 to 24 percent improvement from
baseline compared to placebo.

And even in trough, an improvement of about 13 percent of baseline
versus placebo is reached, and this is a lot considering that the trough
reflects the minimum effectiveness reached and sustained over the entire
24 hour period, and the interesting feature is that tiotropium reaches a
trough to peak rate ratio of 53 to 72 percent, and this sets the
standard for 24 hour effectiveness.

The values for salmeterol are explained on the right-hand side of the
stable, and they are numerically lower at peak than trough in both
studies. We conducted subgroup analysis, and it was analyzed in the
combined replicate studies for an influence of age, gender, smoking
status, severity of disease, previous atrovent use, and most important,
concomitant medications, and it can be stated that tiotropium was
similarly effective in all subgroups analyzed here.

Now I would like to report the supportive information obtained from the
secondary end points. The vital capacity was assessed in all the
studies, and as an example, I show the peak and trough force vital
capacity response of a one year treatment period for the combined
studies, comparing the placebo for one year.

And, of course, the statistical evaluation was based on the individual
studies and it can be stated that the results were significantly with
P-values less than 0.0001, and at all time points after reaching steady
state.

As you can see, tiotropium treatment provides maintained improvement of
the fourth vital capacity over the year, and that the trough reaches
values of 290 milliliters, and at peak it reaches values of 440
milliliters, always in comparison to placebo. This effect can be
interpreted as improvement of air flow limitation and reduction of
hyperinflation, leading to reduced breathing, and should be associated
with an appreciable symptomatic improvement in these patients.

Also, home measured peak flow rates were assessed in weekly intervals
and weekly means, and as can be seen here, the morning peak flow was
increased by 10 to 30 liters, and the evening peak flow was increased by
15 to 40 liters, and these results were significant at most time point,
again evaluated in the two individual studies.

As a secondary end point, we assessed exacerbations of COPD, and they
were defined either as an exacerbation diagnosed by the physician, or as
a complex COPD related symptoms, cough, wheeze, dyspnea, sputum
production, two of these, lasting at least three days, and reported as
an adverse event.

Now, when analyzing our four, one year studies for this secondary end
point, we saw encouraging trends and occasionally nominal P-values of
less than 0.05 in the individual studies. For this reason, we conducted
retrospective exploratory analyses in the combined replicate twin
studies, and pre-specified it as combined analysis in the six month
studies, which were conducted somewhat later.

And we would like to share these interesting scientific results with
you. A common way to analyze exacerbations is by Kaplan-Meier analysis,
and the probability of no exacerbation is depicted here, versus the days
on treatment in the placebo-controlled one year study, and you do see an
appreciable improvement of tiotropium of the placebo, and the
appropriate way of statistical analysis is the time to first
exacerbation, and a nominal p-value of less than 0.05 could be assigned.

And in a similar graph here, the comparison to the active comparator,
ipratropium, and again an appreciable advantage of tiotropium in the
probability of non exacerbation, versus ipratropium and the time to
first exacerbation has a nominal p-value of less than 0.05, and the same
for the six month comparison of tiotropium versus placebo again, and the
time to first exacerbation has a nominal p-value of less than 0.05.

With this, I would like to outline the results we obtained with the COPD
specific health status assessment with the St. George\'s Respiratory
Questionnaire and the instrument assesses patient\'s health status in
symptoms, activity, and impacts, and gives the total score, and a
decreasing score indicates improvement, and the score change of more
than four points is suggested to be clinically meaningful.

And here as an example for all, the results from our one year study, and
in Study 114, you do see an improvement of the score, which increases
over time, and becomes significant after a year, and it is approaching
at the end of the year a threshold that is suggested to be clinically
meaningful.

And in the second study, it is a similar picture, and so improvement
over time, and at the end of the study the clinical meaningfulness is
reached. The findings with the St. George\'s Questionnaire support the
impression of overall benefit achieved with tiotropium.

In summary, tiotropium, once daily, provides clinically meaningful
improvement of spirometric measures sustained for 24 hours, and the
improvements were maintained over one year with no evidence of
tachyphylaxis.

The analysis of secondary end points, as well as exploratory analyses
show improvements of related lung function measures, such as the force,
vital capacity, and peak flows. Exacerbations of COPD appear to be
reduced, and improvements in health status as measured by the St.
George\'s Questionnaire meet or approach the threshold of clinically
meaningful change with prolonged treatment.

Thank you for the attention, and I would like to hand over the podium to
Professor Jones, who will introduce the assessment of dyspnea.

DR. JONES: Thank you, Dr. Disse. I am Paul Jones, and I am a
pulmonologist, but I have developed health status instruments in the
past, and I have also worked in the field of dyspnea measurement,
although I was not involved in either the development or the validation
of the BDI and the TDI that we are discussing here.

This presentation will be in three parts; the measurement of
breathlessness, the validation of the instruments that we are
discussing, and the identification of a clinically significant
threshold.

Dyspnea is a principal symptom of COPD, and there are multiple causes
for it. Expiratory airflow limitation, increasing static lung volume,
and the dynamic hyperinflation that occurs at exercise onset. Recent
studies have shown that these two components are more important
predictors of dyspnea than expiratory airflow limitation, but they are
complex measurements.

And in fact there is no simple physiological measure, whether complex or
simple, that can be measured as a surrogate for dyspnea. So dyspnea
should be measured directly. Dyspnea is a sensation, and for that reason
it should be related to a known level of stimulus.

In the laboratory, that is easy. We can measure breathlessness, and
relate it to a known level of work rate, minute ventilation, or oxygen
consumption. But the requirements of laboratory exercise tests are far
too complex to be included in large multicenter Phase III clinical
trials.

For that reason, breathlessness is related to reference points in daily
life. For example, being breathless when getting washed or dressed, or
walking up hills, and in fact these reference points were used as the
basis of the MRC and the American Thoracic Society grading systems for
dyspnea.

You will appreciate that what we have here is a ranking of activities
based on metabolic demand. It is important to understand this, because
you then realize that the breathlessness measurements are grounded in
physiology. Thus, in contrast to functional disability, or health status
measurements, there is more grounded in patient\'s perceptions.

There is a multifactorial relationship between dyspenea and activity.
There are activities that cause dyspenea, and activities that become
more difficult because of dyspnea, and activities prevented by dyspnea.
And it was an understanding of this that led the developers of the BDI
and TDI to develop this particular construction.

It has three components; functional impairment, magnitude of task, and
magnitude of effort. There is also a focal or total score. The two
questionnaires are related, but have different properties. The BDI is
cross-sectional, used for distinguishing levels of dyspnea between
patients so that it is discriminative.

The TDI is grounded on the BDI, but it is longitudinal, used within
patients to evaluate changes. We now look at the psycometric properties
of the BDI, and we find that it has good internal consistency, good
inter-rater reliability, and test-retest reliability. The panel should
understand that a questionnaire with poor psycometric properties will
tend to underestimate the true effect of a change that is reparent.

Perhaps more importantly the question is do these instruments measure
dyspnea, Unfortunately, it is not possible to address this question in
one step. We have to set up a number of hypotheses, and then test with
the questionnaires related to physiological impairment, other measures
of dyspnea, and health status.

The next few slides summarize the evidence for this. First, we find that
there is in fact to my view a relatively surprisingly good correlation
between FEV1 and the BDI. That is, the expected level of correlation
with exercise performance and with other measures, with established
measures of dyspnea; the ATS questionnaire, the Oxygen Cost Diagram, and
the more recent Shortness of Breath Questionnaire developed at UCSD.

The BDI correlates with disease specific health status, measured using
the CRQ and the SGRQ, and generic health status measured with the SF-36
and the QWB. If we turn now to the TDI, we find that it has good
inter-rate reliability, and in terms of its responsiveness to change, we
find that following pulmonary rehabilitation the TDI score correlates
with change in the CRQ dyspnea score, and following recovery from a COPD
exacerbation, again there is a very good correlation with change in the
CRQ dyspnea score, and really quite a surprisingly good correlation with
change in FEV1.

If we now turn to the issue of clinical significance. There are a number
of different ways in which this can be assessed, but historically the
first and perhaps the most widely used is the humanistic approach, and
perhaps best described in the seminal paper from Dr. Guyatt\'s group in
1989, in which he defined the minimum clinically important difference
was that difference in score which patients see as beneficial, and would
mandate in the absence of troublesome side effects and excessive costs a
change in the patient\'s management.

I should also point out that this approach was used for the development
of the threshold for the Juniper Asthma Quality of Life Questionnaire,
which I believe is now accepted by the agency. If we turn to the TDI,
and look at one of the components, the magnitude of task, we see that
there are three grades of deterioration, and three for improvement.

Let us concentrate on the smallest degree of improvement and look at an
example. Here we have a patient who was dyspneic when walking on the
level, or perhaps even when washing, and now has become dyspneic only
when walking up a gradual hill or carrying a light load on the level.

To clarify this and set this into a broader setting, let us return to
the ATS Dyspnea Grade that I have simplified for the purposes of
presentation. I should just point out that COPD is a chronic and
incurable disease, and it is not possible to convert a patient who is
severely disabled, such as they are breathless when they are getting
washed and dressed, to someone who can undertake strenuous exercise.

But worthwhile improvements can be achieved, and to illustrate that,
what a change of one unit in the TDI can mean, we may have a patient who
is still breathless on walking up hills, but is now no longer breathless
when walking at a normal pace on the level.

Another example would be a patient who is breathless when they are
walking slowly on the level, but they are now no longer breathless when
washing or dressing. These changes I would contend are not trivial, and
they more than exceed the criteria for minimally important improvement
as defined by Dr. Guyatt.

So in summary the BDI and TDI have reliable measurement properties.
Their scores are valid measures of dyspnea, and we can attach clinical
significance to them. I would like to thank you for your attention, and
pass over to Dr. Witek, who will present the results from the tiotropium
studies.

DR. WITEK: Thank you, Dr. Jones, and good morning, ladies and gentlemen.
My name is Ted Witek from Boehringer Ingelheim, and as my colleagues
have mentioned, dyspnea is a unique claim in our proposed indication,
and I would like to spend the next 15 minutes describing the data and
the application of the instrument in the program to help us in our
deliberations today.

I will briefly review the assessment of dyspnea in clinical trials, and
how we applied the BDI and TDI in our program, and then I will review
the response of the TDI and the related measures to tiotropium. Now, in
the assessment of dyspnea in clinical trials there are several things
that we needed to consider.

Particularly with tiotropium, where we have a long term maintenance
treatment, it is important that we evaluate and find an instrument that
can assess the effects of dyspnea over time, and in fact, knowing that
the TDI have been previously used in a two year perspective study, where
we saw the drop in TDI of about .7 units over two years, indicating the
natural decrement in dyspnea, this was one of the elements in our
selecting the BDI and TDI.

Also, the instruments need to be practical for a multi-center, and in
our case, in multi-national programs, where the instructions for the use
of the instrument are in the uniform training and investigator meetings.
Secondly, dyspnea assessments need to be in the context of a clinic
visit where there are many measurements.

However, it is important that we have supported measurements in our
assessments to both determine and help determine the validity of the
instrument in practice, as well as evaluating the consistency of related
measures.

Now, briefly, just some key protocol elements to keep in mind. The TDI
evaluations were performed at clinic visits. For example, in the six
month studies, in days 57, 113, and day 169. As noted by Dr. Jones, the
TDI assessments referenced the BDI scores, which were collected at
baseline, and the TDI is completed after the SGRQ, and prior to the
post-dose pulmonary functions.

Now, this further evaluates or illustrates the domains that Professor
Jones had mentioned; the functional impairment, the magnitude of task,
and magnitude of effort. If I just focus on the BDI for one moment, here
we have scores that range from zero to plus four, and that gives us a
focal score range of zero to plus 12 units at baseline; zero being very
severe dyspnea, and 12 being little or no dyspnea.

And if we put some real numbers to the BDI, this is the distribution of
the BDI score baseline in our population in the one year study, and here
you see the BDI focal score, and on average the patients that were
enrolled in our clinical trial have a BDI focal score of six, indicating
moderate dyspnea.

And a BDI focal score of six, for example, could be a patient who
recorded a grade of two in each of the three domains; and if that was
the case, a BDI focal score of six may be describing a patient who
abandoned at least one activity due to shortness of breath, became short
of breath with an average task, such as walking up a gradual hill, and
become short of breath with moderate effort task performing, with
occasional pauses, and requiring longer to complete than the average
person.

Now I would like to turn to show you our data. I will describe for you
the two studies where TDI was listed as the co-primary end point, and
there our specification was responder analysis, and the four studies
where TDI was a secondary end point, and in those reports we had
originally looked at the mean TDI response.

Now, in our discussions with the agency, we have discussed the advantage
and disadvantage of the two ways to evaluate or to express the data in
responder analysis or means, but what was agreed was that whatever we do
select, it should be stated in a formal protocol amendment, which we did
do and which was outlined by Dr. Blank, and that both illustrations
should be provided; i.e., responder analysis, and the means.

So I will do this for you. I will show you these TDI improvements, list
the supporting endpoints from our secondary measures, and would like to
point out the consistency across the time of the trial, as well as
cross-studies, which we do feel is a strength of our data.

Now, just a point on the responder analysis and mean response. We chose
the responder analysis, and what this is, is the proportion of patients
achieving a meaningful response, which we did define a priori as a
plus-one unit change in TDI focal score.

So this one unit change as described by Dr. Jones is inherent in the
instrument, and of course this responder analysis will then reflect the
individual patient changes from baseline. The analysis of means is also
important, because that does reflect the overall population change, and
you are able to illustrate the differences you see from the drug
relative to placebo.

And here a positively and significant delta, versus a placebo, indicates
an overall benefit. So I will show you all of the data from particularly
the placebo control studies, where a drug effect could be evaluated.

These are the data from Study 130 described by my colleagues, which was
the first of the two, six month studies. On the y-axis is the percent of
patients responding; i.e., the percent of patients that reach the plus
one unit change or greater, and the x-axis is the three study days.

Here you see the proportion of patients responding to tiotropium
relative to the placebo, and all three of the study days, particularly
day 169, which we pre-specified as the primary end point analysis. As
noted in these trials, salmeterol was included, and here you see the
proportion of patients salmeterol relative to placebo.

And in this study, the proportion of patients relative to placebo in
salmeterol was not significantly different. In Study 137, the sister
study, here we see again the proportion of patients responding to the
TDI relative to placebo, and again the consistent response across the
three time points, and importantly also in the day 169 that was
pre-specified.

The study again also included the salmeterol comparator, and in this
study, salmeterol was significantly greater than placebo in the
proportion of patients responding relative to the placebo as I
mentioned, with no difference between the tiotropium and the salmeterol.

Now, showing you the mean TDI focal score for the population, that is
what is illustrated in this slide. On the y-axis is the mean TDI focal
score, focal score units, and the x-axis is time, the same three time
points that I mentioned to you.

And here you see the effects from the improvement with tiotropium
relative to placebo across the three time points. Here at the end point,
day 169, the effect size is 1.02 units in TDI focal scores, and so that
is the mean difference between tiotropium and placebo. In the second
study, again you see the improvement with tiotropium, the significance
indicating the effect relative to the placebo mean, and the mean effect
size in the second study was 1.2 TDI focal score units.

In this study, salmeterols were included as I mentioned, and here in the
first study, you see the effects of salmeterol in the mean TDI relative
to placebo; and in the second study, as was the case with the responder
analysis, there was a significantly higher mean effect relative to
placebo for salmeterol, with again no difference between salmeterol and
placebo.

Now, I will review for you the one year studies, the one group of
studies relative to placebo, and the second group of studies relative to
tiotropium that Dr. Disse showed you for lung function.

So in the top panel is study 114, and the bottom study is 115, and the
y-axis is the proportion of patients responding, and here you see the
higher proportion of patients responding in tiotropium relative to
placebo, and in the second study, you see the same pattern, with the
asterisks indicating a nominal p-value of p-less-than-0.05.

When we go to the tiotropium controlled studies, here we see in yellow
the proportion of patients responding to tiotropium relative to
ipratropium bromide, and you see that similar pattern in both study 122a
and 122b. These asterisks are indicating a nominal p-value of p-less
than .05, even versus the active control in ipratropium bromide.

Now, to complete this, I will show you the mean TDI focal score for the
one year studies, and again the y-axis is the focal score, and x-axis is
time. So in the first placebo controlled one year, we see the
improvements with tiotropium relative to placebo, and here is the
p-value, p-less-than.05 on all test days.

And similar in study 115, the improvement with tiotropium relative to
placebo, and once again the nominal p-value significant at the level of
p less than 0.01. These are the data in the ipratropium control trials.
The same axis, and here you see a rather atypical response, but the
improvement with the tiotropium that wanes over time, and a parallel
response to the ipratropium with the difference between the two drugs,
and the mean and TTDI focal score are still evident.

And here are the nominal p-value are all but one test day of less than
0.05. And in study 122b, you see the improvement with the tiotropium
that is maintained over the one year, and in the ipratropium group, the
increase, and again these two are paralleling each other with the
differences being p-less than 0.05 on all test dates.

So these are the temporal pattern of response under two, one year
studies. Now I would like to turn to the secondary supportive end points
that one would expect to see improvement with a change in the TDI, and
this is the shortness of breath score, and to highlight the scale for
you here, this is a scale on a unit of zero through three.

And this is a simple assessment, diary assessment, where you have here
the placebo response, and the improvement in tiotropium relative to
placebo, and all nominal p-values relative to the placebo are
significant, and in the sister study, study 137, you see this
improvement with tiotropium, and on the last day the nominal p-value is
lost in this study, the last time point.

Looking in the one year studies, and this is the same pattern following,
and here is this zero through three score, and four point scale, and the
improvement with tiotropium. This delta, with this effect size, has a
nominal p-value of p-less-than-0.05 on all days, and that pattern is
also illustrated in the second one year study.

If we turn to the physician\'s global evaluations that were described,
here again this is a scale representing a range of zero through eight
scale, and here you see the improvement with tiotropium that is
maintained and that is relative to placebo.

And a similar pattern of response in the 137 study, and again we see
that drop at the end with these differences, tiotropium less than
placebo having a nominal p-value of p-less-than-0.05 on three of those
test dates.

And again the one year studies, and the improvement with tiotropium
relative to placebo in both trials, and in both of these studies,
nominal p-values were achieved. Now, the last secondary end point that I
will review for you is the supplemental albuterol use in patients who
were allowed supplemental albuterol use, and here this is expressed and
we are looking at weekly averages of the daily use.

And in study 130, we see the drop early on in the study that is
maintained over the course of the six months, and in the second study,
we see that initial reduction in albuterol use, and that initial
reduction was not maintained later on in that second study.

And in the one year studies, however, we saw the reduction in the use of
supplemental albuterol that was maintained throughout the study, and
that was also the case in the second one year study, where albuterol
reduction is illustrated.

And again all nominal p-values were p-less than 0.5 or greater. So Dr.
Disse had reviewed for you the FEV1 trough, and I briefly reviewed for
you the TDI data, both in terms of response and the TDI mean from
placebo. In all of those cases where we have listed our primary end
point, we have achieved the statistically significant level versus
placebo.

And importantly in those secondary end points that I just reviewed for
you, it was with rare exception that we did not achieve a nominal
p-value, indicating the drug effects of tiotropium in these secondary
measures. So in summary, we believe that we have selected and utilized a
validated instrument, and not only in the literature that was reviewed
for you briefly with Dr. Jones, but also in our own internal program,
where we looked at these similar correlations.

We gave pre-specified the primary end points, and the key statistical
significance in the two independent studies. The proportion with a
meaningful change that we selected as our primary analysis was supported
by the responses and the dyspnea response was reflected in the related
measures that I have just shown for you.

So given the importance of dyspnea as a COPD symptom, and given our
demonstration of dyspnea relief, we believe that dyspnea should be
included as an indication for tiotropium\'s use. So, I thank you for
your attention, and I would like to turn the podium over to my
colleague, Dr. Stephen Kesten, who will review for you our safety
analysis.

DR. KESTEN: Good morning. My name is Stephen Kesten, and I am the
medical director of the International Spiriva Program for Boehringer
Ingelheim. My task today is to summarize an extensive safety program in
a focused and concise presentation.

And in a manner that provides you with the critical information
necessary to allow you to judge the safety of tiotropium, and respond to
the questions posed by the agency. The data will demonstrate a safety
profile consistent with ipratropium bromide, an inhaled
anti-cholinergic, used in the treatment of COPD in the United States for
approximately 15 years, and approximately 25 years globally.

For background information, the anti-cholinergic effects appearing in
the most recent version of the U.S. label for ipratropium bromide are
listed in this slide. These include the more common events of dry mouth,
and less common or infrequent events seen such as tachycardia and

Superventricular tachycardia.

These events are those that you might expect to see with a drug such as
tiotropium. Our early experience in healthy volunteers indicated that we
could elicit anti-cholinergic effects with tiotropium when administered
in high doses and over multiple days.

Single dose studies of up to 282 micrograms, however, failed to show any
effect on ECGS, vital signs, pupillometry, or salivary secretions.
Multiple dose studies of 70 and 140 micrograms could show
anti-cholinergic effects, such as decrease in salivary secretions and
reports of dry mouth.

However, even at these doses, we cannot see any effects on vital signs,
ECGS, and pupillometry. The COPD experience with tiotropium in a dry
powder formulation is illustrated in this slide. There were 1,723
patients randominzed to receive tiotropium, and 414 received tiotropium
in studies of up to six weeks in duration, and 1,308 received tiotropium
in long term studies ranging from 6 to 12 months in duration.

The safety profile of tiotropium has been characterized through a
variety of measures which are depicted in this slide, and are
illustrated in your briefing document. Abnormalities that would be
expected in patients with COPD were observed.

The majority of our safety information comes from the clinical adverse
event reporting. However, with these other measures, I would like to
highlight a few aspects. A vital sign evaluation showed no effect of
tiotropium on heart rate.

Lung function testing indicated that acute inhalation of tiotropium was
well tolerated. The laboratory evaluations showed no influence of
tiotropium, a finding consistent with what we would expect from inhaled
and quatemary anti-cholinergics, and we performed several
characterization studies evaluating different attributes of tiotropium
which supported the overall safety of the compound.

The next few slides will summarize the electrocardiographic monitoring
in the tiotropium program. Twelve lead ECGs and two-minute rhythm strips
were performed as part of a four week, multi-dose, dose ranging study,
with doses up to 36 micrograms daily.

ECGs were performed before, and at 1, 3, and 5 hours after dosing, these
serial ECGs being conducted at baseline, and then at 1, 2, and 4 weeks.
There were 134 patients who received tiotropium in this evaluation,
yielding over 2,000 ECGs.

Twenty-four hour holds for monitoring was conducted before and after six
weeks of treatment in 72 patients who received tiotropium, and in the
long term studies, there were 12 lead ECGs performed at baseline, and
then at 3, 6, and 9, and 12 months in the one year studies, and in the
baseline and end of treatment in the six month studies.

ECG abnormalities in these long term studies were recorded as adverse
events if the investigator deemed them to be clinically significant, or
requiring treatment, or leading to the discontinuation of therapy.

Now, this slide summarizes the ECG findings on heart rate, rhythm, or
conduction in the four week multi-dose, dose-ranging study. The ECG
abnormalities in those categories are listed here. The numbers refer to
the number of patients who had the associated ECG abnormality at any
time while on treatment.

Now, I recognize that this is a busy slide, but what it illustrates is
that there is no pattern here suggesting an association of these
findings to any of the treatment groups. That is, this study
demonstrated that there was no findings that could be on heart rate,
rhythm, or conduction associated with tiotropium, and as expected with
an inhaled anti-cholinergic, there are no suggestions of prolongation of
QT interval.

In addition to the prospective evaluations of ECGs in the one year
studies, we retrospectively obtained the ECGs and sent them to a central
laboratory for high resolution measurement of cardiac intervals.

There were no difference between groups in the proportion of patients
who had an abnormal rhythm on any ECG. There was also no difference
between on treatment groups with a mean change in heart rate from
baseline, nor in the mean maximal change seen on any on treatment ECG.

The only finding that we observed was a 0.6 percent increase in the
number of patients, or the proportion of patients who had at any time an
ECG read as having tachycardia. Now, this constituted 12 patients in the
tiotropium group, 10 of which only had this on a single occasion, and
none of them had it on all occasions.

At the bottom of this slide, I have illustrated the heart rate ranges
for the maximum heart rate that was seen on any of these tachycardic
ECGs for these 12 and these 6 patients, which is down here at the bottom
showing that most of this was in the range of 100 to 110 beats per
minute.

All of the aforementioned ECG findings, including the Holter studies,
have been reviewed by independent external cardiology consultants and
the only suggestion of a finding has been the small imbalance in
tachycardic ECGs. The remainder of this presentation will focus on the
clinical adverse event experience.

There were eight short term studies of patients with COPD receiving the
dry powder formulation in doses of 4.5 to 72 micrograms, with most
patients receiving the intended dose of 18 micrograms daily.

Overall, there was no difference in the proportion of patients having an
adverse event, and the only event seen that was associated with
tiotropium was a dry mouth, and there was some evidence of a dose
response.

For completion, I have included a summary of the serious adverse events
and deaths, and there was no difference in the serious adverse events,
and no association with increasing dose.

Two of the deaths occurred many weeks after completion of the study, and
the last death was in a placebo treated patient. The long term trial
population consists of patients who had participated in two, or four,
one year trials, and two six month trials.

Two of these one year trials were tiotropium controlled, and two were
placebo controlled. The number of patients within a treatment arm, and
the number of patients receiving tiotropium is illustrated in this
slide.

And as described by Dr. Disse, these were mainly men, age around the
mid-60s, and who had a mean FEV1 of about 40 percent predicted, and
these patients had numerous co-morbidities.

The adverse event profile in the six month studies was similar to the
four, one year studies. I will therefore highlight the one year studies
in the initial adverse event presentation of these long term trials.

Given the demographics of the population as described, and the duration
of exposure, it is not surprising to see that approximately 90 percent
of patients are observed to have at least one adverse event during the
participation in the trial.

However, tiotropium was associated with a lower proportion of patients
who had adverse events that were characterized as serious. Tiotropium
also had a lower portion of patients who had adverse events leading to
treatment discontinuation.

Fatal events were relatively few in these trials, with similar
proportions among treatment groups. The next two slides characterize the
most common adverse events observed with tiotropium in the one year
trials.

The first two columns represent the description of the adverse event
according to WHO adverse reaction terminology, with the first column
being system/organ class, and the second column being the preferred term
listed alphabetically.

The four numeric columns represent the proportion of patients within a
treatment group showing an adverse event. The most common adverse event
associated and attributed to tiotropium, with the largest difference
between treatment groups was dry mouth.

Dry mouth often resolved during continuation of therapy, and only lead
to discontinuation of treatment of 3 of 906 patients. The remainder of
the events are shown in this slide. The most frequent adverse events
overall were COPD exacerbation, and upper respiratory tract infection.

The next three slides illustrate all serious adverse events occurring
more than once in any treatment group in the one year trials. As
previously noted, there was a lower proportion of patients with
tiotropium who had serious adverse events.

As you can see, for any individual serious adverse events, the frequency
was relatively low and the differences among treatment groups were
relatively small. As with the first slide, again the frequencies of
these serious adverse events are low, with small treatment \-- with
small differences between treatment groups.

And we did see a difference with myocardial infarction, .5, versus .3
percent; and .8 versus zero percent. However, this pattern was not seen
with coronary artery disease and angina. The more frequent adverse
events are those that you might expect in a COPD population.

The most frequent serious adverse events overall, as would be expected,
occurs with lower respiratory system disorders. There was a higher
proportion of patients in the control groups in both sets of one year
trials who had serious adverse events secondary to COPD exacerbations.

This slide illustrates all fatal adverse events in the one year trials,
and have been aggregated according to system organ class due to the
relative infrequency of any individual cause of death.

The proportion of patients again are illustrated according to the one
year trials. In order to facilitate your review in line with the
questions posed by the agency, these four system organ classes, which
encompass potential cardiovascular causes of death, are going to be
broken down into their individual preferred terms for the one year and
for the six month trials.

Here you see those identical system organ classes, and on top is the
number of patients, and please note that there is unequal randomization,
and what I am illustrating in the columns now is the absolute number of
patients unadjusted for this unequal randomization.

In this case, you are now seeing the six month trials, and there was one
death with tiotropium, five deaths with placebo, and six with
salmeterol. There were two fatal outcomes in heart rate and rhythm
disorders with tiotropium in the one year placebo-controlled trial not
seen in placebo.

However, this was not observed in the ipratropium controlled trials, and
in the six month trials, there were two with placebo and none with
tiotropium. There were also or there was also one myocardial infarction
and three myocardial infarctions here in the one year trials, not seen
in the control groups.

However, this was not observed in the six month trials. As you can see
the numbers here are overall few. Given the infrequency of several of
the relevant adverse advents, including the causes of death, we have
conducted an additional analysis by pooling all placebo-controlled data
and standardizing for patient exposure in order to permit a more precise
evaluation of adverse events and to reduce random error.

We can do this because we have similar protocols and similar
populations, as well as a similar pattern of response. For the
placebo-controlled pooled analysis, we have computed incidents rates
calculated as the number of patients with an event, divided by the
patient years of exposure.

It is going to be expressed in the following slides per 100 patients
years. The rate difference is hence the incidence rate in the tiotropium
group, minus the incidence rate in the placebo group.

A positive rate difference indicates a higher rate with tiotropium, and
a negative rate difference, a higher incidence rate with placebo.
P-values have also been calculated to take into consideration the
statistical reliability of these rate differences.

The events included in this analysis were selected on the basis of
clinical relevance to the compound; that is, anti-cholinergic effects,
or to the patient population, particularly cardiovascular and spirotory
events.

This slide illustrates the population taken for this additional
analysis, and we combined the one year placebo controlled trials, and
identical arms from the two six month trials, and standardized them for
patient exposure, and that just adding these patients gives you 952
tiotropium treated patients, and 771 in the placebo group.

The incidence rates and the rate differences for the pertinent cardiac
events are illustrated in this slide. The top row shows the patient
exposure, and note with this combined analysis, we can achieve 679
patient years of exposure to tiotropium.

The end refers to the number of patients, and the rate is the incidence
rate, and the RD is the rate difference obtained simply by subtracting
these two rate columns, and the last column is the p-value associated
with the rate difference.

Again, the p-value is there to assess the statistical reliability of
these rate differences. The rate differences and rates again are
expressed per 100 patient years.

The rate differences for all of these events are low, and you see both
positive and negative rate differences, and the p-values are all high.
As an additional step, we sought to further understand these cardiac
events by combining terms that might indicate physiologically similar
events.

This slide shows the combination of terms in a similar display, and you
see the rates, rate differences, and p-values. And when we combine a
tachycardia superventricular tarchycardia and atrial fibrillation, it
showed a positive rate difference of 1.4 per 100 patient years with a
lower p-value.

And it suggests that there may be an anti-cholinergic effect of
tiotropium on increasing heart rate. The lack of, or the relative lack
of findings in the evaluation of vital signs and thousands of ECGs is
actually consistent with this analysis, in that it indicates these
events are infrequent or rare, and are predominantly transient in
nature.

We have combined angina and angina aggravated coronary heart disease and
thrombosis coronary, and separated it from myocardial infarction as
myocardial infarction could reasonably be considered a more serious
manifestation of ischemic heart disease.

A combination of these terms shows a positive rate difference lower than
the preceding one, and a weak association to treatment. However, turning
to myocardial infarction, there is no difference between treatment
groups.

Now, as you have seen, most of these deaths that occurred in the long
term trials were from cardiovascular disease, or appear to be from
cardiovascular disease. We therefore evaluated total cardiovascular
mortality and further distinguish them into ischemic deaths and
arrhythmic deaths.

For arrhythmic deaths, we have taken the most conservative position and
any event reported as cardiac arrest, sudden death, arrhythmia or death,
we will assume it is related to arrhythmias.

When we have done this, you see that there is no difference in ischemic
deaths, arrhythmic deaths, or total cardiovascular mortality. And
finally we have looked at all that cause mortality, and this shows a
negative rate difference that is a lower rate with tiotropium.

The pooled analysis also confirms the expected pharmacological effects
of tiotropium. Anti-cholinergic effects, such as dry mouth and
constipation, and positive rate differences, and low p-values.

We also saw positive rate differences for upper airway events. However,
the most profound respiratory effects were with COPD exacerbation, with
a much higher rate in the placebo group. There was also a higher rate
difference, a higher rate with adverse events reported as dyspnea in the
placebo-treated patients.

Micturation disorders, urinary retention, and urinary tract infection
showed positive rate differences, with low p-values, suggesting an
anti-cholinergic effect on bladder contractility.

To summarize then, the core of the clinical adverse event analysis has
been based on long term studies involving over 1,300 COPD patients
participating in long term trials. The analysis of these long term
trials, in combination with the evaluation of vital signs, lung function
testing, lab testing, and thousands of ECGs, has allowed us to
characterize the safety profile of tiotropium.

Events have been observed that are consistent with anti-cholinergic
pharmacology and include superventricular tachycardic arrhythmias, dry
mouth, constipation, and urinary tract disorders.

While there appear to be some numerical imbalances between key treatment
groups, the results of our analysis show that there is no association of
tiotropium with life threatening events.

In conclusion, the safety profile of tiotropium is consistent with
establishing anti-cholinergic therapy that has been used in the
treatment of COPD. I thank you for your attention today, and I would now
like to turn over the podium to Dr. James Donohue.

DR. DONOHUE: Thank you, Steve, and good morning, Mr. Chairman, and
members of the committee, and members of the FDA, and guests. It is a
privilege to have the opportunity to speak to you again on behalf of
this medication.

My role is as a practicing pulmonologist for the last 25 years or more,
and I have been involved in clinical trials with bronchodilators since
the early 1980s. The first point that I would like to make is that as
far as our patients with COPD go, there is a huge unmet burden in the
United States and around the world.

We have a very large number of people with this condition, many of whom
are not diagnosed, and many of whom are under-treated. A couple of weeks
ago, David Mannino published in the [Morbidity and Mortality Weekly
Report]{.underline} these statistics on COPD from 1971 to 2000.

And a couple of points are very meaningful. First of all, of course, the
death rates have gone up, and the number of women affected with COPD
also has gone up. But very importantly there is a large number of
patients who have not yet been diagnosed, and of those who have COPD,
over 38 percent said that their activities were limited.

Another piece of information came from the survey confronting COPD in
America a couple of years ago, 58 percent of patients with COPD
complained of dyspnea daily, and 24 percent had dyspnea even at rest,
and 70 percent of patients who walked up a flight of stairs had
shortness of breath.

So there is really a very, very large burden of unmet needs out there in
our country today. On the other hand, we have patients who have COPD,
and who tend to be older folks, and they are often in their sixties, and
many have co-morbidities.

So we have to be very careful, of course, with medications that we used.
And at the present time our therapeutic options are somewhat limited in
taking care of patients with COPD. First, we had the methylzanthines,
and the theophyllines, and they are limited by drug interactions in
older people, and a narrow therapeutic window.

The short-acting beta agonists have been around a long time, and they
are limited because they have to be used every six hours, and not that
beta-specific, and there is some tolerance with them, and some cardiac
toxicity.

We have had oral beta agonists, which also suffer from an adverse \-- in
some cases adverse toxicity type of profile. The longer acting beta
agonists of course are an improvement, but have to be dosed every 12
hours.

We have oral systemic corticosteroids, but they suffer from really very
severe side effect profiles, and as we discussed back in January with
you, the inhale corticosteroids have still not been approved for COPDs.

So we are limited in what we have to offer our patients today with this
condition, and I would like to just focus for a moment on the well-known
Fletcher and Peto curve, describing the natural history or the life
history of a patient who suffers with COPD.

And on this axis function from a hundred percent to 25 percent, and on
this axis is as we age from 25 to 75, and there are patients who are on
the blue curve here, and on the top line would be an individual who does
not have COPD, and after our lungs are grown, we lose about 24 to 30 MLs
per year.

Our patients with COPD are on this curve here, and often come to medical
attention in their 50s and 60s when they are becoming short of breath.
And they lose, 50-60 MLs per year, and patients with alpha1-antitrypsin
as Dr. Stoller here has shown, will lose a lot more rapidly, maybe a
hundred MLs, or something like 85 to a hundred MLs per year.

But the loss of 50 MLs is very, very significant when we think about how
long the lung function is of our patient, and when we look at
bronchodilator effects, even small changes, like we see with the
bronchodilators and COPD are often highly meaningful in a patient who is
losing function at this rate.

The bronchodilator effects that we have heard today I think are to me as
a clinician, and also as an investigator are very impressive in their
magnitude. First of all, what about the bronchodilator effect. I think a
once daily dose really is important for our patients.

They don\'t have to get sick, and require dosing themselves every six
hours, and they don\'t have to \-- they can just get by with once a day
dosing, and this will I believe enhance compliance, and it certainly has
with other medications, but I think it is going to make life a little
bit easier for our patients.

Now we want to talk a little bit about the trough and what do they
numbers mean, and that is the value when you first get up in the
morning, and that is the worst time of day for patients who have COPD,
and if anybody in the audience has it and comes forward, they will tell
you that.

And that in the early morning hours, and at 5:00 and 6:00 a.m., and at
7:00, they are more symptomatic. In fact, when I was a young lung
doctor, we used to have our surgeons do thoracic surgery in the
afternoon because our patients with COPD do so poorly in the morning.

So to me, looking at a trough level of 140 mls is very, very
significant, and I think it really will help our patients, and
particularly in the early morning hours. We heard the \-- Bernd showed
the average effects. Remember that this is not asthma. This is COPD, and
so these changes of peak effects in the high 200s, and the average
effects in the 200s is really excellent for a drug that we use to treat
people with COPD.

And I guess I was very impressed by the forced vital capacity changes.
As Bernd mentions, hyperinflation is really one of the major causes of
dyspnea that our patients suffer with, and these improvements in the FVC
are very similar to what we got years ago when we were studying aerosol
solutions for patients with COPD.

So I think the magnitude of those changes to me as a doctor are pretty
impressive. They also, even though the trough effect is still 60 percent
of the maximum effect, the patient still derives extra benefit every day
by taking the next dose, and they still get an additional peak effect.

We have consistent sustained bronchodilation through the day, and I
think that will translate into patients having less symptoms over the
course of the day. And more importantly, these are long studies, one
year and six months, and there has been no evidence of any loss of
efficacy.

And you have got to look at that with the idea again that the patient
with COPD is an older individual who is losing function and going
downhill, and so I think that the fact that the drugs are still working
are very impressive. I think those big bronchodilator effects explain
what we are seeing with dyspnea.

Now, dyspnea, of course, is why our patients come to medical attention,
and this is why their activities are limited. But like everything else
in COPD, it is really a hard thing to quantitate and get a real handle
on. People know that they are short of breath, and if the drug works,
they can tell you that they are no longer short of breath, and that is
certainly very, very impressive.

But it is a highly complex subjective symptom, and this is why we have
trouble with it, and patients will alter their activity to avoid this
unpleasant sensation. They will sit down and become couch potatoes.

So a real big part of our comprehensive COPD program is to get the
patient up and moving again. So you have to take into account the
patient might not complain of this because they are not doing anything.

And so that is very important and very key when we are analyzing again
some of the instruments and what have you. Individual patients vary
considerably in their evaluation, and as you know,for many good clinical
trials, there is a substantial trial effect or placebo effect. Patients
get very good medical care and they tend to get better just because of
being in the therapeutic trial.

Also, we have the co-morbidities. Lots of our patients with COPD are
anxious and they hyperventilate, and many are either overweight or
underweight, and many are deconditioned, and may have co-morbidities,
like heart disease. So this influences greatly the evaluation of
dyspnea.

Nonetheless, what impressed me about these studies, and to be a robust
effect, we have here a multi-center, multi-national study, and we still
have consistently pretty good effects when it comes to the dyspnea
scales.

Now, again, I am no expert in the scales, but we certainly used them
widely. The Mahler Transitional Dyspnea Index is widely used in clinical
trials. Gosh, all the studies we are doing now, we have that in our
program.

We have had consistent results across these six studies at least at the
end point of a one unit improvement. When we look at some of the other
studies that we have done, we have not seen that as consistently with
other medications that we use and the bronchodilators that we use in
COPD.

When we go to other outcomes, like rescue albuterol use, and some of
these symptom scores, there is correlation. Also, one of the things that
has been helpful to me was that I was just looking the other day and
reading the paper in the [New England Journal of Medicine]{.underline}
on primary pulmonary hypertension, a disease that causes terrible
shortness of breath, and they used for a new medication the TDI and the
patients improved 1.4, just to give you a different disease perspective.

Now, what about the responder rate? Consistently we were seeing over 40
percent, and in the paper that I published, 43 percent responder rate.
And when we look at the enormous number of people who suffer with COPD,
this is a very big number to me, and I think is highly meaningful in
taking care of patients.

I think that as all of you here who are experts in clinical trials know,
the placebo responder rate, regardless of the type of study that you are
looking at, is always quite high in clinical trials.

And, of course, I would like to focus on the very impressive number of
patients who have responded to this on medication with improvement in
their dyspnea. Now, what about the safety?

Well, the anticholinergic class has been around a long time, and we have
been using them since 1987, and they really are the \-- and atrovent in
particular, and comparable drugs that we have used in a variety of
clinical situations; with outpatients, with inpatients, and in critical
care.

And they really do have a very, very strong safety record, even in the
most severely ill patients. The thing that I liked about this program,
as opposed to other clinical studies years ago, where we went six weeks,
or three months, here we went one year with four studies, and six months
with two others.

So we have a very long duration of exposure to our patients. In my view
the patients in these studies are reflective of the patients that I see
every day in my practice. They are the same age group, in their 60s, and
10 years of diagnosed COPD, and same tobacco history, and same numbers
of co-morbidity.

So I think the patients are highly reflective of what we have seen in
other clinical trials, and what we see on a daily basis when we are
taking care of patients with COPD. We had a very low incidence of
adverse effects, and as most of you know, these are the anticholinergic
effect, the dry mouth.

And usually these patients will work through that and they will continue
on taking the medication. So I was greatly reassured in this older
population that the safety data were fairly good. Boehringer Ingelheim
asked me to make a comment; where do I see this drug being used.

And I think based on the very strong bronchodilator data, as well as the
efficacy as far as dyspnea goes, I would see that as a first line
chronic maintenance therapy for patients who are symptomatic with COPD,
and really of all variance severities, from mild to severe.

Just a comment. Nationally, the government has articulated a project
called, \"Healthy People 2010,\" and a number of health goals. And there
are two goals that are relevant to COPD. One is a reduction in the
mortality rate, from 119 per hundred-thousand, to 60 by 2010.

And at this point, no medication has been shown to affect mortality. The
second goal though I think is more relevant, and that is to reduce the
number of people whose activity is limited by breathlessness, from 2.2,
to 1.7, and I am hoping that tiotropium will be an effective tool to
help us accomplish this.

On a personal level, I think there is still a lot of our patients whose
needs have not been met, and I think that the increased awareness of
dyspnea might lead to more diagnosis of COPD and a more willingness on
the part of doctors to try medication in this population.

I think at the present time that our (inaudible) is quite limited for
what we have to offer patients, and I am very optimistic that tiotropium
will provide a worthwhile addition to our (inaudible).

I want to thank you very much for the chance to express my comments, and
Dr. Blank will make the concluding remarks. Thank you.

DR. BLANK: Thank you, Dr. Donohue. In my conclusion, I want to come back
to the questions that the agency brought to this committee, and share
with you Boehringer Ingelheim\'s position on these topics.

The safety of Spiriva was studied in one of the largest programs
conducted in COPD so far. The safety profile shows anticholinergic
pharmacology for Spiriva, including an association with rare
superventricular tachyarrhythmias, and it is very similar to what has
actually been widely used for many years.

The safety profile is described in the label that we have proposed in
our submission to the agency, and most importantly there is no
association with life threatening events.

Twenty-four hour bronchodilation, after once daily inhalation of
Spiriva, has been consistently demonstrated in all six week studies, and
its effect remains fully sustained throughout chronic therapy.

The improvement of dyspenea was shown in two pivotal studies with a
validated instrument. The improvement by one unit in the TDI, which is
the definition we used for treatment response is relevant to an
individual patient and for the COPD population as a whole.

We have met the regulatory requirements for the indication of the relief
of dyspnea associated with COPD. In medical practice, most patients with
COPD seek medical care because of their dyspnea, and physicians monitor
their patients according to their symptoms.

Spiriva improves dyspnea, the key symptom of COPD, which has the
greatest impact on the patient\'s lives, and this improvement should be
described in the product\'s label. We believe that the most appropriate
place for this is the indications and usage section as outlined in my
last slide.

Thank you very much for your attention and that brings us to the end of
Boehringer Ingelheim\'s part, and we will be glad, my colleagues, and I,
to answer any questions that you may have.

CHAIRM DYKEWICZ: Thank you. Before I entertain questions, Dr. Atkinson
had joined us just before the product presentation, and if you could
introduce yourself to the group.

DR. ATKINSON: Yes. I am Prescott Atkinson, and I am
allergist/immunologist from the University of Alabama at Birmingham.

CHAIRMAN DYKEWICZ: Thank you. First of all, I would like to compliment
the BI people for staying on time. My first personal question is related
to slide 16 of Dr. Witek\'s presentation, which shows the date of \-- I
believe from the two pivotal studies relative to mean TDI focal scores,
and I wanted to make sure that I understood the data. If we could
perhaps have that projected, please.

DR. BLANK: Dr. Witek, please.

DR. WITEK: Slide 16, please. If you could supply that. Well, just to
reexplain the slide here. This is looking at the mean TDI focal score in
Study 114 and Study 115. So these are the two separate, one year
studies.

On the y-axis is the focal score and the x-axis is time. Day 50 was the
first assessment point for the TDI, and the mean TDI score in the
tiotropium group was a little bit over one unit as you see here, and the
placebo group, .2 units. So a mean improvement needs group to that
magnitude, and this is describing the TDI changes over the course of the
year, and then in this second graph we see the same pattern.

CHAIRMAN DYKEWICZ: All right. Now, it has been suggested that the
clinically meaningful difference in the TDI scores is about one, and we
will of course be discussing that as a committee later.

But looking at that, it seems to me that at least in terms of Study 114,
for the five time points, did not achieve that difference, at least
between placebo and the tiotropium. Is that correct?

DR. WITEK: That is correct.

CHAIRMAN DYKEWICZ: Okay. My other question was looking at the document
that was given to us by the FDA relative to Mahler\'s screening
instrument, the chest article from 1984, it was suggested that
inter-rate variability using that instrument would be no more than one.

Now, I presume that during these large-scale studies different raters
were rating people at different time points?

DR. WITEK: Well, in each of the clinical centers, we had a study
coordinator, and whenever possible, that study coordinator would be the
same individual. However, that wasn\'t always the case.

CHAIRMAN DYKEWICZ: Thank you. Let\'s open up the floor to questions from
the committee. Dr. Patrick.

DR. PATRICK: While we are on that, could you just explain how the TDI
was administered, and at what point it was administered after the SGRO
(sic), and I believe before some physiological measures? Were the
results of the SGRO (sic) available to the raters of the TDI, and were
the people who did the rating trained to some level of kappa agreement
prior, and similar to other clinician rating scales?

DR. WITEK: No, there was \-- you know, no inter-rater analysis in the
multi-center or large-scale studies among those coordinators. To go back
to your first question, Dr. Patrick, regarding the SGRQ. There was
actually specific instructions in the trial for the coordinator to
review the last page of the SGRQ, and this is atypical for the TDI
instrument.

However, that was done to help the coordinator and patient remind them
of their activities of daily life, which is what is listed on that last
page.

CHAIRMAN DYKEWICZ: Ms. Schell.

MS. SCHELL: I noted that you start the interviews on day 50. Were there
any pre-interviews done regarding their level of activity?

DR. WITEK: Yes. In the clinical trials described here, the long term
clinical trials, those were the first assessment points. We do have in
the one year tiotropium controlled trials, an assessment as early as day
eight, and that was relative to ipratropium bromide.

And there we did see responder rates, and mean effect size, and a rate
higher in the ipratropium relative to placebo. We have other small
studies where we have earlier measurements submitted in the NDA.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: Yes, I have a question for Dr. Kesten, which is about the
Holter monitors that were done in the one study. I know that you didn\'t
bring that up, but in our briefing packet it mentioned decreased heart
rate variability, which I understand is associated with morbidity and
mortality to heart arrythmias, and I wondered if you would care to
comment on that.

DR. KESTEN: Thank you for the opportunity to clarifying that point.
First, the issue of heart rate variability and applicability. As you
noted, there has been association in context with a clinical event.

There has been no associations of pharmacological induced changes in
heart rate variability in such events. That being said, the differences
in heart rate variability changes were extremely small and just
suggested that we could see a pharmacological event.

And I would actually like to turn this over to Dr. Prystowsky who has
reviewed the information on that as an electrophysiologist for his
opinion.

DR. PRYSTOWSKY: Thank you very much, and I appreciate the opportunity to
address the panel. I am Dr. Rick Prystowsky, and I am a clinical
electrophysiologist, or known more to my patients as the electrician of
the heart, and basically I have had an opportunity to review all of the
Holter data and actually all of the cardiovascular data from the study.

I have had a major area of interest in my own research career in
autonomics in the heart and heart rhythms, and this whole \-- and let\'s
talk first of all about the issue of the heart rate variability. This is
sort of the test du jour of some of the researchers in our field.

We have seen these patterns, as I am sure in pulmonary, go in and out at
what people like to look at research wise. There has been an association
and it actually dates back several decades of looking at heart rate
variability in a more simple matter in patient\'s post-MI, patients with
significant left ventricular disfunction.

And there appears to be a correlation of lower heart rate variability in
these patients, and in some studies there appears to be an increased
incidence of sudden death in overall cardiovascular mortality.

Sometimes the \-- and the multi \-- you know, the regression analysis,
it just barely will make it, even though it is an independent predictor.
But in a population like this, there really are no data or no data at
least that I know of that any kind of heart rate variability means much.

It has been known for decades in diabetics that as they get
parasympathetic disfunction, there is a lower heart rate variability. So
I think it is there, and it would make sense knowing the effects of the
drug.

Any anticholinergic \-- you know, man is basically a vagal animal
regarding the effects of the sinus node with autonomics. The
parasympathetic is clearly prepotent over the sympathetic, and you can
take a patient who is getting isoproferenol infusions in your lab, and
if they get a vagal effect, they can go totally asystolic for 10 or 15
seconds, even in the presence of high sympathetic tone.

So the vagas runs the heart as far as sinus rate goes, and of course
heart rate variability is clearly related to that, and if you sort of
put that all together and you say now I will give somebody an
anticholinergic, even if it is a minor anticholinergic, one would
anticipate from the pathophysiology or the physiology of the autonomics,
that you would have a slight decrease in heart rate variability.

In a trial of patients that are reviewed that are sick, and clearly we
have got probably more cardiovascular disease than came out in the
questionnaires with all of the smoking history and their ages.

We have not seen, at least from my review of the data, any increase in
cardiovascular mortality. So I think that it is an interesting point
that you raise, but I think that there is really no data to support it
that has any meaning in these patients, and it follows the physiology of
the drug.

DR. JOAD: While you are still standing there, I would like you to
comment on the fact that people who had arrhythmias, and that were on
medicines, or who have had recent Mis, were excluded from these studies.
Yet, in real practice, probably it won\'t be as rigidly prescribed.

So what do you think the effect of that exclusion criteria had on the
cardiovascular risks of this drug?

DR. PRYSTOWSKY: I think that point is very well taken. As you probably
know, I was not involved in any of this until a few moments ago when I
was asked to review the data. I am not part of the trials, and I am
obviously not a pulmonologist.

And I think that this is something all of us suffer as clinicians, too,
with any trial, is that one never sees the exclusions on any basically,
and yet in real life we have to deal with that, and I think your point
is very cogent.

I will tell you my feeling based on all the data that I have reviewed.
First of all, there is no reason to believe an anticholinergic agent
will exacerbate arrhythmia, certainly not from the ventricle.

There is no data to suggest it and in fact in my line of work I have
much more commonly stopped the sympathometic agents in patients who have
come to me, and I don\'t think I have ever stopped any of the known \--
you know, the known anticholinergic agents.

Ironically, and it doesn\'t make sense physiologically, I saw an
increased incidence in atrial fibrillation, and that doesn\'t make any
sense because the classic model to produce afib in a lab, either in man,
even the data on this, as well as animals, is vagomimetic effects.

So if you want to produce afib, a high amount of vagal tone will do it.
Why there was a little bit of discordance in the afib is hard to explain
the known effects of the agent.

So what I would anticipate as far as arrhythmias go, I would anticipate
no particular problems. I would not be worried about it at all, even
though some of these people were excluded, because clearly in the COPD
population you are going to have people with afib.

There is no reason to believe an anticholinergic should exacerbate it. I
guess the only thing which isn\'t tested here that one could argue that
there could be, could you possibly have a slightly increased ventricular
response in someone with known afib, who gets an agent that is
anticholinergic?

I guess it is conceivable. It would be unlikely because whereas the
sympathetic - whereas, the parasympathetic and sympathetic effect on the
sinus node is markedly power sympathetic, the aging node is balanced.

Sympathetic and parasympathetic in humans is pretty much a balance
situation. So the slight amount of anticholinergic effect, it may be a
few beats a minute. I don\'t think much more than that.

So I am not at all worried about any of the arrhythmia issues. The one
area of anything when I reviewed the data that I would have some
concerns, and I have expressed this to the company, would be a group
that was not looked at, and probably appropriately so.

Someone with unstable anginal could be so critical with a lesion that
even a slight increase in rate could push him into having an anginal
episode. So I think in an unstable anginal in a patient, without any
data, I would have some personal concerns about using any agent that
might increase heart rate, even a little bit.

But I am not worried about arrhythmia components. It would just be more
from an anginal standpoint. Otherwise, no, I don\'t have any real
concerns based on the known long term effects of anticholinergics in
these patients that we have seen for years.

CHAIRMAN DYKEWICZ: Thank you. Dr. Apter.

DR. APTER: I have two unrelated questions. The first question is the
TDI, and underscores Dr. Patrick\'s question. I would like to hear more
details of how it was administered and how the observers scored it in
these trials, and then I will come back to the second question.

DR. WITEK: The TDI was administered in the morning when the patients
reported to the clinic, and so after the questionnaires on adverse
events, and then the SGRQ was administered, and then the TDI was
administered.

The TDI administration, as was pointed out by Dr. Patrick, patients and
the caregiver, or the coordinator, referred to the last page of the
SGRQ, which listed activities, which was again a catalyst for the TDI
instrument, where it is an open-ended interview to look at the change
relative to the BDI.

So, additionally, the BDI is looked at, and in that open-ended
interview, the coordinator makes the rating as was described here.

CHAIRMAN DYKEWICZ: This is the last question.

DR. APTER: So the subject reports on what would be moderate activity,
and what would be strenuous activity?

DR. WITEK: Yes, that would be in an open-ended interview.

DR. APTER: So it would be different for different people, and how would
it be compared against a person, just in terms of moderate, severe?

DR. WITEK: It is within patient assessment. So it is hard to say how it
would compare at those different levels. I don\'t know if this would
address your question, Dr. Apter, but in various levels of severity,
whether it be FEV1 severity, or BDI severity as an example.

We did show the same effect of the drug in those that had mild BDI and
severe BDI.

DR. APTER: And maybe even Dr. Mahler could answer this, how the TDI has
been and the BDI has been used in other populations, and the extent of
experience.

DR. MAHLER: Thank you. My name is Don Mahler, and I am a pulmonary
physician at Dartmouth Hitchcock Medical Center. I want to comment that
these instruments were developed under the direction and mentorship of
Dr. Alvan Feinstein, and he has been instrumental in the effort to
develop instruments to provide clinical outcomes and clinical measures.

The TDI right now, again, the development \-- do you want me to describe
more of the development, or its use at this point in time?

DR. APTER: Both quickly if you could.

DR. MAHLER: Sure. These instruments were developed in a four-step
process. We first looked at the available instruments, predominantly the
MRC, and saw its limitations as Professor Jones described.

We then met with pulmonary physicians at Yale University, where we
developed as Dr. Richard Matthay, and Dr. Jacob Loke, Dr. Herbert
Reynolds, and kind of had informal discussions about how best to expand
the MRC into these other components.

We then had a pilot testing at the VA Medical Center in West Haven,
Connecticut, and that pilot involved 15 patients with COPD, and I
interviewed the patients using our BDI/TDI instruments, and we had a
pulmonary function technician doing the same thing.

We then both met with the same patient and said, well, you told me this,
and you told me this, and based on feedback from the patient, we then
put together the final BDI/TDI, and then I guess what I would describe
as the fourth step is we then applied it in these 38 patients, both at a
baseline state and then at a follow-up state, and then published that
information in 1984 in [\"Chest\"]{.underline} is kind of the first
experience validation responsiveness of these instruments.

As far as its use at the present time, it is amazing as Dr. Donohue said
that these instruments are used worldwide, and there are at least 30
publications in peer review journals using the BDI/TDI predominantly in
COPD population.

And that involves bronchodilator therapy, pulmonary rehabilitation
programs, inspiratory muscle training, and lung volume reduction
surgery. It is being used by at least 10 current companies,
pharmaseutical companies in the United States, not only in
bronchodilator therapy, but looking at, say, monoclonal antibody
treatment, and the psydokines in COPD.

It is currently being used in an investigation of interstitial pulmonary
fibrosis. So at least from the information that I have available, I
would say that it is the standard instrument that is currently being
used in the pulmonary community to measure dyspnea at baseline, and
particularly the responses to an intervention.

CHAIRMAN DYKEWICZ: Thank you. We are going \-- oh, Dr. Stoller, one last
question, and then we will have an opportunity later this morning by the
way to ask some additional questions.

DR. STOLLER: I guess my question is to Dr. Witek, and it regards the
administration of the dyspnea index, and having worked as Dr. Mahler
knows with Dr. Kleinstein, I had an appreciation of this outcome, and my
question regards whether in knowing that this is a several page
instrument, and having worked with it, and the temptation to actually
give the written form to patients to complete on their own, but
recognizing that the instrument was developed to be administered in a
questionnaire.

And my question regards whether there were any protocol violations with
regard to the forms being given to patients to complete themselves, as
opposed to interviewer-lead, and what the prevalence of that.

I imagine that it happened.

And what the prevalence of that was, and whether there was any
concordance between subsequent interviews and the self-administered, and
which instrument was recorded in the data set.

DR. WITEK: Sure. As was pointed out in your briefing document, there was
one incidence in the FDA audit where patient handwriting was noticed on
the diary, and that was subsequently responded to by the investigator.

Essentially, it does follow the SGRQ, which is a patient-administered
instrument in the sequence of case report forms. In that case the
patient had begun to fill it out. Now that was noticed, and the
coordinator corrected that with a re-interview and initialed that, and
that was formally responded to with the agency.

Given that, we did go back carefully again to check particularly all the
U.S. centers, and we checked the U.K. centers, and we did find one other
case reported by the CRA visits, which were conducted every 4 to 6 weeks
in these studies, and that was the case as I think you could appreciate,
was a new coordinator that came into the study, and that visit, the
first visit with that coordinator, the patient had completed the diary.

This was noted in our routine monitoring and that case was corrected. So
those are the two cases, and our analysis was based on the U.K. centers,
and the U.S. centers from 130, subsequent to the agency\'s comments and
the briefing document on that.

CHAIRMAN DYKEWICZ: Thank you. We will resume in 15 minutes.

(Whereupon, at 9:33 a.m., the meeting was recessed and resumed at 9:53
a.m.)

CHAIRMAN DYKEWICZ: Welcome back everyone. We will now resume the meeting
with the FDA presentation, starting with Dr. Lisa Kammerman on the
transition dyspnea index.

DR. KAMMERMAN: Good morning. I am sitting up here on this stool because
I am recovering from a broken leg. So when my colleagues told me good
luck, and don\'t break a leg, that was the wrong thing to say.

So I will be discussing the issues surrounding the use of the Transition
Dyspnea Index, and the tiotropium development program. I want you to
know that the primary statistical reviewer for this application is Dr.
Jim Gebert, and he has done the nuts and bolts for looking at all of the
data and intricacies there.

And my role really is to focus on the use of the index in these studies.
My presentation will focus on the use of the TDI in the tiotropium
clinical studies, and I am going to first give you an overview of the
baseline dyspnea index as well, and as you consider the requested
indication for the treatment of dyspnea.

It is important to keep in mind the history of TDI and how it was
actually elevated from a secondary end point to a co-primary end point
in the six month studies. This is a very important point because it has
many implications for the clinical trial design issues that I will be
discussing.

Other issues to consider include the development and the validation of
the TDI, its implementation in the 6 month studies, and the definition
of a clinically meaningful difference.

The Transition Dyspnea Index, or the TDI, is the end point that is being
used to support the indication for the treatment of dyspnea. Moreover,
the rest of my talk will be focus on the TDI. I just want to go over
again an overview of both the BDI and the TDI.

As you know, they were both developed by Dr. Mahler and his colleagues,
and they described their indicates in the 1984 paper that appeared in
[\"Chest.\"]{.underline} And copies are in your FDA background package.

Each has three components, and the focal score, which is actually the
total score, is simply the sum of the component scores. It is also
important to recognize that each component is actually a single item,
and because you heard a lot about BWI earlier this morning, I just want
to comment that two of the components in the BDI are actually highly
related.

So when you look at the distribution of BDI baseline, you see that lots
of people are at six, and it might just be reflecting some
double-counting when the source of the items are added together.

As you have heard, the indices are administered by interviewers who ask
open-ended questions. The interviewer interprets the responses and
selects the score. In order to implement the TDI, the BDI needs to be
established first at baseline, and so when the TDI is actually scored,
the interviewer and perhaps the patient, which we will get into a little
bit, needs to refer back to the BDI.

The scores for each TDI component range from minus-3 up to a positive-3,
from a major deterioration, to a major improvement. In the next set of
slides I will show you the definition of minor improvement for each of
the components.

And the reason that I will be focusing on minor improvement is that a
TDI score of at least one was used to define a responder, and as you see
on this slide, a plus-one is the same as a person with a minor
improvement.

So just to remind you, the interviewer and patient need to refer back to
baseline in order to assign a score for the TDI, and here we see the
definition for a minor improvement in change and function of impairment.

And this reads, \"Able to return to work at reduced pace, or has resumed
some customary activities with more vigor than previously due to
improvement in shortness of breath.\"

This definition illustrates an issue with recall to baseline, reduced
pace, and more vigor, and implies that either this information was
recorded at the time that the BDI was administered, or that the
information needs to be gleaned from the BDI itself, or that patients
need to be relying on their memory.

Here is the definition of minor improvement for the change in magnitude
of task that causes dyspnea, and if it has improved less than one grade
from baseline, a patient with a distinct improvement within grade, but
has not changed grades, there are two more points that I want to make
from this slide.

First, the criteria for minor improvement are very subtle, and the
second point again is the need for a recall to baseline.

Again, for a magnitude of efforts, relatively subtle improvement could
be graded as plus one; able to do things with distinctly greater effort
without shortness of breath.

For example, may be able to carry out tasks somewhat more rapidly than
previously. Again, this requires the interviewers to assess a subtle
change, and to remember what was occurring at baseline.

The total score, which is the focal score, is obtained by adding
together the scores for each item. The focal score can range from
minus-9 to positive-0, where the positive number indicates an
improvement from baseline.

So why was the TDI developed? The goal was not to address differences in
drugs using clinical trials, but its goal was more clinical in nature.
Until 1984, as you have heard, dyspnea was assessed in the clinic by
looking at the magnitude of tasks needed to induce breathlessness.

And Dr. Mahler and his colleagues believed that better clinical
measurement required assessments of the functional impairment and
magnitude of effort that causes dyspnea.

And he also wanted to obtain a measure that could be used by different
interviewers, and which could produce consistent results among
interviewers. Now, these are the four year studies.

The first two, 114 and 115, were conducted in the United States; and the
second two were conducted in Belgium, and I believe in The Netherlands.
The applicant explored the data, and saw that patients were classified
as responders, with an improvement of plus one.

And then tiotropium was statistically different from placebo. Responders
were defined as those who had a score of at least one, and when you
consider the results for the responders in the one year studies, it is
important to realize that I think around only 55 percent actually had a
TDI reported at one year.

The rest of the information has been imputed by different roles. So the
applicant came and met with FDA as you heard in July of 2000 to discuss
their intent to elevate TDI from a secondary end point to a co-primary
end point in the six month studies.

The studies had been completed, but they were still blinded. The major
change was to the study hypothesis, which in their amendment now reads,
\"The proportion of patients with a TDI focal score greater than or
equal to one unit is different than those treated with tiotropium,
compared to those treated with placebo.

So what went on at that meeting, the FDA and the applicant agreed that
TDI could be promoted to a co-primary end point. However, the following
conditions needed to be met, and the applicant needed to justify the
clinical significance, but when it needed change in the TDI, both for
the comparison of the mean scores, and for the comparison of the
responders.

Again, the responder was a one unit change, and so he wanted to see
validation data for this one unit change as being clinically meaningful,
and this would include showing the TDI correlates to the clinical
improvement of subjects.

It is important to note, however, that we did not agree that the Studies
130 and 137, the six month studies were adequate to support an
indication, and that would be a review issue.

So now that we agreed that TDI could be a co-primary end-point, our next
step on the FDA\'s part was to review the NDA, and to set the context
for the rest of my presentation, I just want to give you a very, very
brief overview of some of the issues that I look at, and that my
colleagues look at when we review an NDA.

The first thing that I look at are the study protocols. I read them and
assess their clarity, their completeness, and scientific merit, and then
I look at the conduct and the analysis of the studies. And I will
compare what was actually done in the studies with what was stated in
the protocols.

And I also assess the quality of the conduct and look at the issues
related to patient discontinuations. So in terms of many of these
issues, as I discussed TDI as it was used in these clinical studies
submitted to the NDA.

So these are going to be the five major areas that I am going to focus
on and that we identified in a review as being of concern to us, and
they include the clinical trial design, and the development of the
instrument, and the validation of the instrument, and the implementation
of the instrument.

And the definition of a clinically meaningful difference, and I am going
to discuss these first in general, and then I am going to turn to
specifics.

So as you know now, TDI was originally a secondary end point. It became
a primary end point after the studies were completed, but before the
data were blinded. And I believe that the studies may have been designed
and conducted differently if TDI had been defined from the outset as a
prospectively defined end point.

And this has important implications, as you will see during the rest of
my talk. For example, there is lots of issues resulting in the
implementation of the instrument. For example, there is issues regarding
the training and blinding of the interviewers, and the issue of recall
to baseline.

The second major area of our concern was the development of the index,
and the goals were to improvement clinical assessments of dyspnea and to
obtain a scale that could be used by different interviewers.

And the goal was not to develop the TDI for use in clinical trials for
new drugs. The clinical nature of the TDIs were reflected by these next
bullets. There is no evidence that patients were involved in generating
items reflecting aspects of dyspnea that are of concern to them, and it
appears that clinicial judgment was used.

And also that the TDI uses non-standardized questions. The population
used to develop the TDI was from the United States, and there were no
international settings used, and this is extremely important, because
the six month studies were conducted in 18 countries.

The third area of our concern is the validation of the TDI. The big
issue is the lack of validation of the TDI when it was translated into
other languages, and for use in other cultures.

And the validation needs to be specific to the format and wording of the
instrument. Every change in format and wording requires validation, and
this was not done, and I will show you some examples shortly.

Also in the clinical studies, TDI was administered immediately following
the SGRQ, and the ordering of the tests also requires validation, which
was not done, particularly in this study where the interviewers were
instructed to look at the SGRQ before administering the TDI.

The fourth area is the implementation of the TDI, and there is more
evidence in the NDA that interviewers were trained or were blinded to
the patient clinical status. This is a major concern of ours, because it
could lead to bias in the TDI assessments.

There is also much ambiguity in whoever completed the form. Was it the
interviewer or was it the patient who completed the TDI? Here again we
see the issues regarding the ordering of the instruments, the SGRQ, and
the TDI, and the multi-national location populations in the six month
studies.

The fifth area is the clinically meaningful difference of one unit.
Again, there is no evidence of patient involvement, and there is no
evidence of a pre-specified plan.

Ideally, the building plan for the TDI or any patient reported outcome
that is going to be used in a clinical study should have been
prospectively addressed as part of the development program.

Now I want to turn \-- and this is just a repeat of the slide I had on
earlier. I am going to go over the specifics of the slide that I had on
earlier. I am going to turn to the specifics of each of these five major
concerns; the clinical trial design, and the validation and
implementation of the instrument, and the definition of a clinically
meaningful difference.

And I know that my presentation is going to sound redundant at times,
but it is because many of the specifics, cross many of these five basic
areas. Okay. We are going to the major area of clinical trial design
issues.

The TDI was interviewer driven, but by this I mean that the interviewers
were instructed to review the SGRQ before administering the TDI. They
then asked open-ended questions, and both of these questions could lead
to bias in the results of the TDI.

Another major area was the blinding of the interviewers. There is no
indication that interviewers were blinded to the clinical status of the
subjects, their treatment status, and their adverse events.

For example, if a patient reported dry mouth, this might have led the
interviewer to believe the patient was receiving tiotropium because
tiotropium is an anti-cholinergic.

And as you know the SGRQ was administered before the TDI, and so the
interviewers were sensitized to the patient\'s reports of dyspnea. For
the training of the interviewers, we have no assurance that interviewers
were trained, and this is particular important because the questions to
patients are not standardized.

And here is the description of the open-ended questions and the intent
of the questions, and this comes from Dr. Mahler\'s article in 1984.
Open-ended questions concerning the patient\'s breathlessness, the
intent was to allow the observer an individual\'s dyspnea as part of the
usual or standard questions asked of a patient when taking a history of
respiratory disease.

And the applicant, as you heard earlier, is placed in your background,
and in a 1995 article by Eakin to support the validation of the BDI and
TDI, and she points out the need for creating in both indices as you
will see in my next two slides.

For the BDI, she says, in our experience to use this instrument
reliably, it was necessary for our four raters to discuss some
standardized questions, and to come to some consensus as to how ratings
should be made on each one of the three scales.

Ongoing assessments of inter-rater reliability to check for tendencies
of each rater to stray from initial standardization was also needed. So
here we see the need for the interviewers to come together to reach
consensus on grading the three aspects of the BDI, and the need for
ongoing assessment for inter-rater reliability.

And for TDI, she says that the TDI may be affected by bias on the part
of the patient and interviewer, because it asks both individuals to make
judgments about improvement, versus deterioration in the patient status
and space line.

And like the BDI, the TDI lacked standardized questions for raters. So
she highlights the potential for bias because of the requirements for
making judgment about the past patient status relative to baseline.

And she also points out the lack of standardized questions. The ordering
of the instruments is also critical. The TDI immediately followed the
SGRQ, and the SGRQ may have influenced both the patient\'s responses to
the TDI, and the interviewer\'s questions to the patients.

The recall for baseline is another issue because these studies were one
year and six months observation. For example, I personally would have
trouble remembering my health status six months ago, or even one year
ago, and Dr. Mahler\'s 1984 article and other studies in the literature,
to be very much shorter in duration, where a baseline may be much easier
to remember.

I will now turn to some of the issues regarding the development of the
TDI. First and critically, there is really no indication of patient
involvement. So key issues that have not been addressed include the
reading level, the comprehension, and the interpretability and recall of
the baseline on the part of the patients.

And we don\'t know if the three items in the TDI and their wording
captured aspects of dyspnea that are important to patients.

The responses appear to be equally spaced, but they are not \-- and I
won\'t take up time here, but if you look at some of the gradings for
the three parts of the TDI, you will see that they are not equally
spaced.

What is also very important is that the three items are simply added
together without any rationale being provided in the NDA, and so we
don\'t know if this is optimal or if there are items that are so highly
related that they are being double-counted.

When I initially looked at the data, it does appear that two of the
items are related. I think there is about 45 percent of patients who
would answer the same for two of the components.

Regarding the validation of the TDI, here are some general comments.
Again, there is on pre-specified plan, and most of the validation
information that you heard this morning was really for the BDI and not
the TDI.

I think there is about six slides for the BDI and two for the TDI. One
report for the TDI this morning was a rehab study, and another is
information that we have seen only for the first time this morning, and
it wasn\'t submitted to the NDA, and it is not in your backgrounder, and
so we have not been able to look at it.

And a few of the validation studies that are referenced by the NDA are
actually drug intervention trials. Again, there is the issue of the
order of the administration of the TDI and the SGRQ.

And in the paper that is in your backgrounder regarding or by Witek and
Mahler, I think it is going to appear sometime this year, the applicant
supports the validity of the TDI, but describing statistically
significant correlations between TDI and other outcomes.

And this again is reported both in the NDA and in this article. It is
important to realize that this information in this paper is from the one
year studies and most of the correlation given to you this morning was
for the BDI and not the TDI, and rather than focusing on P-values \--
and by the way it is not all that difficult to get significantly
significant correlation co-efficients.

It is really more important to look at the co-efficients themselves, and
they range from .22, or minus .2, to minus .35 in the one year studies.
The correlations are an indication of the linear relationship between
two variables.

Another way of looking at them are the R-squared value, and simply you
square the correlation co-efficients, and the amount of variation
explained ranged from 5 percent to 12 percent, and this says that the
amount of variation explained by fitting a straight line between TDI and
other outcomes wasn\'t related that much at all.

Now, turning to the validation that relates to the multi-national
studies, and there are quite a few problems here, all of the studies
referenced in the NDA supporting the validation of the TDI were
conducted in the United States.

The indication for dyspnea rests on the six months studies which were
conducted in 18 countries, and there were approximately 600 subjects per
study. In Study 130, 12-1/2 percent came from the U.S., and in Study
137, only 5 percent came from the United States.

There are numerous issues that we don\'t know about. We don\'t know
about the process that was used to translate the TDI, and we don\'t know
the background of the translators, the quality of the translators of the
translations, and there is no information on whether the translated
versions were actually validated in the language and culture that they
were being used.

So ideally we would like a translator who is fluent in both English and
the target language, and a translator who is knowledgeable about dyspnea
and is aware of cultural differences, and how that might impact the
wording of the TDI.

Also, when translating indexes, it is important to translate them back
to English so we can compare the translated version with the original
version. If the back translated version is much different from the
original, then it most likely needs to be retranslated again, and all
translated versions need to be validated.

There is a memo about he content validity, only because the patients
weren\'t involved. We don\'t know to what degree the TDI represents the
three areas of interest. Their functional impairment, the magnitude of
tasks, and magnitude of effort.

The validation also needs to be specific to the version, including the
wording and the format used in the clinical study. The formatting and
wording of the TDI that was used in these studies really is not the same
as was described in the 1984 paper.

The next two slides, I will show you some of the differences. The
differences that you have seen may be very subtle, but even very subtle
changes in the appearance of the index could be important.

And the best practice is to use the same format that has been validated.
Okay. You are going to look at this slide and the next and say, well,
what is the difference. But, moreover, if you are able to read this, I
have only selected out as you can see three scores from one of the
components.

And in this case it is the change in magnitude of task. It is important
to notice where the italics are used for the name of the component and
for each category, major deterioration, moderate, and minor.

And it is also important to notice that a line is preceding each score.
I have never been clear on whether interviewers were supposed to check
that, put an X, circle a number, and that wasn\'t discussed in the NDA.

Now, if you look at the next side, this is what is in the case report
form, and again this is just part of the case report form. So it loses
some of the visual impact. Each of the components now has a number
preceding it. Here we see number two preceding the change in magnitude
of task.

The line preceding each score has now been eliminated, and so the intent
was probably for the interviewer to circle the numbers, and now there is
also a box around each component.

So when you look at the case report form, you see these boxes popping
out at you. The font that is used is also different, and in a little
while I will show you an additional important difference regarding
instructions.

So who actually completed the TDI? There is a lot of confusion. The
answer is did the subjects, did the interviewers, and the answer is that
in some cases the patient did, and in other cases the interviewer did.
This is inconsistent with the proper way to administer the TDI.

And what led to this confusion is that the protocols are internally
inconsistent. One part of the protocol says the observer should ask
open-ended questions concerning the patient\'s shortness of breath and
how it affects their daily life.

The observer will rate the patient based on the responses to these
questions. And here the protocol indicates that an interviewer will
complete the form. And elsewhere the protocols indicate that the patient
will complete the TDI, and we see that patients will perform the shuttle
walking test, and complete the questionnaires; and if SGRQ, the Mahler
Dyspnea Indices.

The Division of Scientific Investigations audited two clinical centers,
and this is standard practice for the division to go out and look at
clinical centers, and they found that at one center that the patients
themselves read the questionnaires and completed the form.

And keep in mind that there are approximately 80 centers that remain
unaudited, and you heard that the applicant went to the U.K. and found
another center there where the patients had completed the TDI, but that
still leaves unanswered the question of what went on at these other 80
centers in the six month studies.

Another source of confusion about who is completing the TDI is the
instructions in the protocols. Here the protocol correctly suggests that
the interviewer does the TDI, and it says for the magnitude of task,
review the activities that cause breathlessness, ask the patient which
activities now cause breathlessness, and is there a change from baseline
in the selected rate.

But the instructions on the CRS suggest that the patients completed the
TDI. And here at the top, you see that it says to circle one answer
which describes best how your daily activities are influenced by your
respiratory disease.

And notice that this instruction does not appear in any way on the
original TDI described in the 1984 paper. I think it is also interesting
to note does the subject know what daily activities mean, and do they
really know what it means to be influenced by your respiratory disease.

I think all of us are probably comfortable with that, but in the general
population I am not so sure, and there is no evidence that was presented
to look at that. As I mentioned, bias may have been introduced because
interviewers were possibly unblinded to the patient\'s status.

Again, this is an ordering of the SGRQ and in the TDI there is the issue
of the recall of the baseline, and ideally we want an independent
interviewer who is unaware of SGRQ, and the FEV1, and other spirometry
data, adverse events, and other available patient status information.

Now, turning to the clinically meaningful difference, again there is no
piece specified plan in the development process. The Witek and Mahler
paper simply states a one unit improvement is likely quite meaningful to
the individual patient. There is no evidence of patient involvement in
determining a meaningful change.

And this morning the applicant put up a quote, and I just thought it
would be interesting to refer back to that from Guyatt. That a
clinically meaningful difference is the smallest difference in score
which patients perceive as beneficial.

Now, I am going to summarize my comments in a way that is slightly
different from the way that I presented them, and so here are some of
the issues that we have identified regarding this at the patient level.

There is an unknown level of involvement and this is important regarding
the importance to the patient of aspects of dyspnea and the magnitude of
the one unit change. There is the issue of their reading level,
comprehension, and interpretability of the TDI, and they may not be able
to recall to baseline at 6 months and 12 months.

At the interviewer level, we have this issue, and the blind indication
status, the trainings, nor assurance of the training, open-ended
questions, non-standardized questions, recall the baseline, reviews the
SGRQ, and possibly new other clinical data before administering the TDI.

So is a one unit change meaningful to patients, and we really can\'t be
sure, primarily because of the lack of patient\'s involvement, and the
absence of a pre-specified plan.

We don\'t know who completed the form, and in some cases it was the
patient, and in some places it was the interviewer. The issue of
multi-national populations in the six month studies showed up in several
areas that I have gone over.

There is the impact on the development and validation, and
interpretation of the results, and what I also want to emphasize is that
the linguistic and cultural issues, and the quality of the translations,
and the absence of validation studies and languages other than American
English, because British English and American English are actually quite
different.

The development was interviewer based, and was not patient-based.
Patients weren\'t involved in generating items that were important to
them, and the TDI was not developed for use in multi-national
populations.

The validation has not addressed the order of the administration, the
formatting used in the studies, and its use in multi-national studies.
So that completes my comments, and I would thank you for your time, and
now Dr. Sullivan will address the clinical aspects of the NDA.

DR. SULLIVAN: Good morning. My name is Gene Sullivan, and I am a
pulmonologist, and I am a medical officer in the Division of Pulmonary
and Allergy Drug Products. I am also the primary medical reviewer for
NDA 21-395, and I am going to spend the next hour or so summarizing the
findings of the agency\'s medical review of the application.

Before I begin, I want to be sure to acknowledge the contributions of
the reviewers from both the Division of Biometrics, and the Office of
Clinical Pharmacology, Clinical Biopharmacology, because some of the
points that I am going to make in my presentation were generated from
their reviews of the application.

This slide provides the structure of my presentation, and I am going to
begin with some background remarks, and in that section I am going to
highlight some of the division\'s thinking in regard to the labeling of
drugs for COPD, and I will touch on how labeling considerations may
sometimes impact the choice of clinical endpoints in the study of these
drugs.

Next, I will briefly touch on what I think are the clinically pertinent
pharmacokinetic and pharmacodynamic characteristics of the drug, and
then I will move to an overview of the Phase III clinical program, and I
recognize that you have seen a lot of this material already, and so I
can be fairly brief there.

Next I will address the most notable safety findings that came out of
our review. Now, in that section, I am going to focus primarily on the
one year placebo controlled trials, because I think that in general the
longer trials and trials that include a placebo control are the most
likely to provide interpretable data in regard to observed adverse
events.

I will, however, touch on some of the observations from the remaining
studies. Then I am going to move to efficacy findings, and following the
same pattern that the applicant chose, I am going to divide my comments
into the data which addressed the bronchodilator efficacy, and then the
data which address the purported efficacy on the symptom of dyspnea, and
then I will round it out with some remaining remarks about additional
efficacy variables that were examined.

Finally, I will summarize the most salient aspects of my talk, and then
after my talk, there will be time for the panel to ask any questions to
clarify any issues that I may have raised.

So as you have heard the applicant has proposed this indication for the
drug tiotropium. It would be to treat bronchospasm and dyspnea
associated with COPD, and as has been mentioned, no drugs that are
currently approved in the U.S. for COPD carry an indication for the
treatment of specific symptoms of COPD, or for the treatment of the
disease itself, and then in the next few slides, I will get to what I
mean by that.

Before I go on, I do want to comment sort of parenthetically that the
drug theophylline is somewhat of an anomaly in this regard. The
indications section of the labels for theophylline states that they are
indicated for the treatment of symptoms and reversible air flow
obstruction associated with chronic asthma, and other chronic lung
diseases, e.g., emphysema and chronic bronchitis.

I did want to point that out, but as you know, theophylline is a very
old drug, and the contents of the label for theophylline don\'t reflect
the current standards and practices.

So the currently approved drugs for COPD are all bronchodilators, and
probably for that reason the indications sections and the labels for
these drugs read that they are indicated for the treatment of
bronchospasm associated with COPD.

And that language is chosen specifically to create a distinction between
the treatment of bronchospasm in the setting of COPD, versus the
treatment of the disease itself. So the bronchodilators have been shown
to relax airways in the muscle, and relieve bronchospasm, but they have
not been shown to treat the disease.

And what I mean by that is bronchospasm, airway smooth muscle
contraction leading to lumenal narrowing, is only one component of the
very complex disease of COPD, and while we are very comfortable that
these approved drugs do treat the bronchospasm component, they have not
been shown to treat other important aspects of the disease, such as
mucous production, and such as structural changes in the lungs.

And certainly they have not been shown to effect the natural history of
the disease. So therefore we approve these drugs with the indications
stating that they relieve bronchospasm in the setting of COPD, and stay
away from saying that they are indicated for the treatment of the
overall disease.

And in order to establish that efficacy in regard to bronchospasm, we
generally use spirometric measures of bronchospasm, particularly the
FEV1, and we are fairly comfortable that the FEV1 can be considered a
direct measure of that degree of bronchospasm.

But if you start talking about treating the whole disease, meaning this
constellation of physical science and symptoms, the various
pathophysiolgic processes, and histopathologic features, then FEV1
quickly becomes more of a surrogate endpoint, and it is a direct
endpoint of bronchospasm.

Now, I just mentioned that FEV1 is generally considered a direct measure
of bronchospasm. But I want to emphasize the fact that the agency
generally would not approve a drug if its sole benefit, its only
benefit, were on some physiologic parameter, such as FEV1.

In order for a drug to be approved, there has to be some clinically
meaningful benefit to the patient. So implicit in our use of the FEV1 in
approving these bronchodilators has always been the assumption that
improvements in FEV1 for a COPD patient do result in something
clinically meaningful for the patient.

And I think that is borne out every day in clinical practice, and in
particular I would point out that the way that we use data regarding the
as needed use of bronchodilators in clinical trials.

So we look at the as needed use of albuterol in clinical trials as some
index of efficacy, and we do that because we know what patients know,
which is that when their symptoms worsen, they reach for their
albuterol, and they reach for their albuterol even though it was
approved because of a spirometric improvement, they reach for it because
it is going to improve their symptoms.

So what this means taken together is that, first of all,
bronchodilators, are bronchodilators only, and they relieve the airways
from the muscle contraction, and they don\'t claim to alter the other
pathophysiologic processes in COPD.

And, two, that although we have used FEV1 in the approval process, we
have always assumed that is not the only benefit to the patient, that
there is a real clinically meaningful benefit to the patient.

And in that context it is not clear that symptoms can be demonstrated on
the basis of a bronchodilator activity, merit or represents unique
specific indications for a bronchodilator drug other than what we would
normally expect for a bronchodilator.

This slide reviews some of the more common efficacy variables that we
see in the study of COPD drugs. It is not meant to be a background. As I
mentioned the drugs that we have now for treatment of COPD are
bronchodilators, and therefore the primary efficacy end point has
usually been some measure of bronchodilation and far and away the most
common and most accepted measure of that is the FEV1, because COPD is a
chronic disease, and these drugs are intended frequently for maintenance
therapy.

And we generally like to see the primary analysis of that end point be
performed after chronic use. Now, FEV1 can be examined in different ways
or illustrated in different ways. You can look at the peak FEV1 soon
after administration, when the effect reaches its maximum.

Or often we see an area under the curve type analyses of FEV1 time
curves, meaning that on a particular test day a patient undergoes serial
spirometry at several time points, and the FEV1 is then illustrated
along a curve according to the time, and that area under the curve is
compared between the drug and its comparator.

Then there are numerous secondary end points which are often used to
help support the efficacy of these drugs, and they include other
spirometry variables, such as the forced vital capacity.

As I mentioned we look at rescue albuterol use as a measure of efficacy.
We are seeking peak flow measurements used more and more in COPD
studies, and their primary use has been asthma studies, but they are
often included in COPD studies now, and they are usually
self-administered twice daily by the patient, and recorded in a diary,
and then analyzed in some way.

We are often also seeing some measure of expertise capacity of the
patients, and frequently something like the six minute walk test, and as
was mentioned, the shuttle walk test was used in some of these trials.

And then you can look at various ways to express the occurrence of COPD
exacerbations, and you can look at the number of exacerbations, and you
can look at the number of patients with at least one exacerbation, and
you can look at the time to the first exacerbation and so forth, and all
of those are usually included as secondary end points.

And then we see the inclusion of various so-called patient reported
outcomes, including the symptom scales, and the health related quality
of life type instruments. Moving to the Phase III program for
tiotropium, in all studies the applicant looked at a bronchodilator
measure, particularly the FEV1, as the primary, or at least as the
co-primary efficacy variable.

And as has been mentioned, the applicant chose to express or to look at
the FEV1 rather than at the peak at the trough, which is a predose
measurement. It is a very good idea in drug development programs to
include some measure of efficacy at the end of the dosing interval,
because that justifies the dosing regimen that is proposed.

If you lose efficacy by the end of the interval, perhaps the drug should
be dosed more frequently. And so we often see some measure of end of
dosing interval activity as a component of these studies.

It is less common for us to see it as a primary end point, although
certainly acceptable. The one potential problem with using the trough
variable as the primary efficacy variable is that in general we have a
little bit of less consensus regarding what magnitude of efficacy we
would expect of a drug at that time point, at the end of the dosing
interval.

So as I mentioned, you want to see continued efficacy throughout the
dosing interval, but exactly how much, we don\'t really have a consensus
on that. We have a much better feel for what constitutes a clinically
significant acute bronchodilator response.

Often a change of 200 mls, or 12 percent in the FEV1 is applies as a
minimal acute bronchodilator response. So it is a little bit hard. When
we look at a primary efficacy endpoint, we want to see whether it was
statistically significant, and really was it clinically significant, and
we have a little less experience assessing what we would require or
expect at that trough time point.

Now, as has also been mentioned, after four of the studies had been
completed and analyzed, the sponsor examined the data, and realized that
they might be able to detect a statistically significant drug effect if
they looked at one of the secondary end points, the TDI.

And in particular that in those four studies, the specific TDI analysis
was a mean value analysis, and so comparing the mean value in the
treated group to the mean value in the placebo group.

But they analyzed the data, and in those exploratory analyses realized
that if they defined a threshold of one as a responder, and applied a
responder analysis, they may be able to show a difference between their
drug and the comparator.

As you know, responder analysis is where we pre-specify some threshold
above which you will call the patient a responder, and below which you
will call the patient a non-responder.

So there were two studies that had been completed, but the blind had not
been broken, and the sponsor chose to amend the protocols to include
both the FEV1 co-primary and a responder analysis of the TDI as
co-primary analysis.

And as Dr. Kammerman has emphasized, this decision to elevate when the
protocol was written a secondary endpoint to a primary endpoint may be
important, because it seems that the protocol paid less attention to the
implementation of the TDI than it might have otherwise if it were
originally a primary endpoint.

So when you design a protocol and you have a primary end point, the
collection of the data that is going to go into that analysis is very
carefully guarded, and you want to be very clear and very sure that the
data is collected perfectly, but you may pay less attention when it is
one of numerous secondary end points.

Now I am going to spend a few minutes on the PK and PD characteristics
of tiotropium. The systemic bioavailability of tiotropium was explored
both after oral ingestion and after oral inhalation, and as you can see,
after oral ingestion, very little of the drug ends up in the
circulation. But after oral inhalation, a more substantial portion ends
up in the blood stream.

Now, ideally for a locally active pulmonary inhalation drug, you would
want to minimize oral inhalation bioavailability, and that way you can
dose the drug at a sufficient level to achieve your efficacy goals
without worrying about systemic absorption that could potentially be
associated with adverse effects.

Of course, that is not a consideration if the mechanism of efficacy is a
systemic delivery. After single dose administration oral inhalation, the
drug reaches its maximum blood concentration at five minutes.

That is often the first test or the first sample that was taken in these
studies. So in the first sample at five minutes, that is the Cmax. And
it falls away quickly, but it is detectable in the blood for about 2 to
4 hours using the assays that are available.

What is interesting is that the urinary excretion is quite prolonged,
meaning that if you administer a single dose of 108 micrograms \-- and
that is more than the proposed dose of 18 micrograms. But if you
administer a single dose of 108 micrograms, you can detect the drug in
the urine for 25 days after that single dose.

The last point on this slide is with regard to volume and distribution,
and the drug seems to distribute widely wide to the tissues, with a very
large volume of distribution of 32 liters per kilogram.

The kidney is very important in the elimination of tiotropium, and 74
percent of the drug is eliminated in the urine as the parent
unmetabolized compound, and initially that happens fairly quickly.

By four hours, 44 percent of the administered dose has been eliminated,
but then that subsequently slows down so that by 24 hours, only half of
the administered dose has been eliminated.

And when you go up to four days, still only 61 percent of the
administered dose has been eliminated. One other observation about the
renal handling of this drug is that it has been observed that the renal
clearance of the drug exceeds the creatinine clearance, and what that
means is that there is some sort of active renal secretion going on, and
you are likely using a transporter.

Now, I mentioned that three-quarters of the drug goes out in the urine
as the parent compound, and the fate of the remaining 26 percent has not
been very well established. It is apparent that it has metabolized
either through non-enzymatic hydrolysis and also a component through the
liver, using the cytochrome P450 system, specifically CYP 2D6, and to a
lesser extent, 3A4.

Using the urinary excretion data, the terminal elimination half-life of
tiotropium was determined to be 5 to 6 days. Now, there is a little
discrepancy between the terminal elimination half-life as determined by
that urinary data, and the apparent effective half-life.

And by that I mean that if you have a drug whose true effective
half-life was 5 to 6 days, and you administered it on a once daily
basis, you would expect an accumulation factor of approximately 8 to
9-fold.

The clinical studies with tiotropium instead showed an accumulation
factor of 2 to 3-fold, and what that suggests to us is that the true
effective half-life may be closer to 24 to 36 hours.

So those are two expressions of half-life; one, the terminal elimination
half-life, and one what we are calling the effective half-life. And
probably both of those have some clinical significance.

And at least for a systemically active drug, it would be the effective
half-life that you would use to help design a rational dosing interval,
and less so for a locally acting pulmonary inhalation drug, whose
efficacy may not mirror its pharmacokinetics.

But the terminal elimination half-life may become clinically important,
for instance, in the setting of an adverse drug reaction, in a drug
where the terminal elimination half-life is quite long, and if a patient
suffers an adverse drug reaction, it may take quite a long time for the
drug to be eliminated from the body.

The last point is that the pharmacokinetic characteristics that I have
described \-- and particularly I mean this very large volume of
distribution, and the long terminal elimination half-life, suggests to
us that what is going on is that the drug is distributed extensively and
binds tightly to the tissues in the body, and then is very slowly
released back into the circulation.

One pharmacodynamic characteristic, and I am been covering the
pharmacokinetics, that I thought was worth mentioning and has been
touched on by the sponsor, is worth mentioning because it differs from
the other orally inhaled bronchodilators that we have now.

And that is that the pharmacodynamic effect increases with multiple
daily dosing. So we have two sources of data to illustrate this point.
One source of data comes from the spirometry data in the Phase III
studies, and the other comes from a substudy which was performed in a
subset of patients who participated in the year long
ipratropium-controlled study, which was performed in Europe.

And in that substudy, 28 patients underwent more extensive spirometry
monitoring instead of what was specified for the remainder of the
patients, and they underwent six hours serial spirometry, and they
underwent it more frequently; at days 1, 2, 3, 8 and 50.

And I will show you the data from these in a second, but the
interpretation of this data is that he maximum effect is achieved by day
eight, and the sponsor has used the phrase steady state to indicate this
maximum effect which is achieved after multiple daily dosing.

So this slide shows the data, the FEV1 data from the two, one year
placebo controlled trials. These are the U.S. trials, Studies 114 and
115, and the FEV1 is expressed as the average value over the 3 hour
serial spirometry, and as the peak value that was achieved during that 3
hour serial spirometry for each day that it was measured, for tiotropium
and for placebo, for each study.

And the message on this slide is that the effects seen on the first day
in regard to the average or to the peak is not as large as the effect
that was seen after multiple daily dosing. The first time it was checked
here was eight hours or eight days.

Now, I did want to point out that at first glance it may look that the
pharmacodynamic effect begins to wane after day 50, but I don\'t think
we should over-interpret that observation, particularly in light of the
fact that the same type of pattern goes on in the placebo patients.

This slide is the data fro that substudy that I mentioned, and it was
called Study 129, and it was a substudy of one of the larger ones, and
here the FEV1 data is expressed both as trough, and as peak, and as
average.

The trough on day one is in fact the baseline, and it is before dosing,
and the remainder of the values are responses, meaning change from that
baseline value. And what this data indicate are that it is not really
until day eight that we start to see the maximum effect.

In addition, there is other data from this substudy where they looked at
daily morning peak flows, and found that the maximum effect was reached
at day six.

Now we will move on to the Phase III program again, and I know that the
applicant has already discussed this topic and so I will be fairly
brief. These tables show the six pivotal trials grouped according to \--
they were replicates or almost replicates. There were some subtle
differences between each of these.

The first group, 114 and 115, were performed in the United States, and
they lasted a year, and they compared tiotropium to placebo, about 450
to 470 patients in a 3-to-2 randomization, and as I mentioned the
primary end point was trough FEV1, and it was analyzed primarily at 13
weeks.

The second set of studies were European studies, and these studies did
not include a placebo control, but rather an active control,
ipratropium, which was administered QID. There were fewer patients here,
280 and 247, and they were randomized in a 2-to-1 fashion. The same
primary end point analyzed at the same time point.

And the final set of two studies are the six month multi-national
studies, in which there were three arms; tiotropium salmeterol, an
active comparator, and placebo in a 1-to-1 randomization, and there were
approximately 600 patients per study.

Again, as I mentioned, there were two co-primary end points, and they
were applied primarily at six months according to the protocol.

And as Dr. Kammerman mentioned, thee were multi-national studies, with a
very small fraction of patients coming from the U.S., 5 percent in one
study, and about 12-1/2 percent in the other.

You have seen the inclusion and exclusion criteria, and they are
essentially what we see customarily, with a couple of exceptions in the
COPD Phrase III trials, there are two things that I want to point out.

One is that baseline bronchodilator responscivity is sometimes measured
in studies, COPD studies, and that was not measured and was not a
criterion for exclusion or inclusion into the study.

In regards to the exclusion criteria, some patients with certain
conditions that I think may be fairly common in the COPD population were
excluded from the study. For instance, symptomatic prostate hypertrophy,
or bladder outlet obstruction, narrow angle glaucoma, and evidence of
some degree of active cardiac disease, such as having had a heart attack
in the last year, and having any cardiac arrhythmia which requires drug
treatment, or having been hospitalized for heart failure in the last
three years.

So I think it will be important to recall these exclusion criteria when
we are discussing and analyzing the safety data from these studies.

This table provides the baseline demographic features of the patients
who participated in each of the studies, and again these are the two
long U.S. studies, and these are the two year long European studies, and
these are the multi-national six month studies.

And what you can see here is that the studies primarily involved men,
particularly in Europe, and the patients were all Caucasian. Very few
studies or none had a percent Caucasian of less than 90 percent.

The average age of the patients was in the early 60s, and their smoking
history ranged from 33 to 34 pack years in Europe, to around 60 pack
years in the United States; and the multi-national studies were similar
and between, and they had a duration of COPD for about 10 years, and
FEV1 was a little lower in the U.S., about a liter, and about 1.22 or
1.23 liters in the European studies, and the FEV1 to FVC ratio was in
the low to mid-40s.

So one of the messages from this slide is that there are in fact some
differences between the populations studied in Europe and the U.S. in
regard to the pack years of smoking, and the FEV1 impairment.

Now I am going to move on to some of the salient safety findings. As has
been mentioned, a total of 13 hundred patients were exposed to
tiotropium in Phase III, and the safety evaluations that were performed
were what we commonly see for these studies; adverse events, vital
signs, examination, labs, and ECGs.

One comment about the ECGs is that normally the way that we like to see
the ECGs is that you check the ECG after the first dose to look for an
acute effect, and periodically after chronic dosing to look for acute
and chronic effects.

And you specify in the protocol that the ECGs be performed at or near
the time of the Cmax of the drugs, and so you want to know the maximum
concentration in the blood, and check the ECG around that time.

Very rarely the cardiac pharmacodynamics of a drug differ from the
pharmacokinetics of the drug, and if you know that, you time your ECGs
to the cardiac pharmacodynamics. But for the most part, we ask that the
ECGs be performed at the Cmax.

And that was not the case in these studies. The ECGs \-- the protocols
did not specify when the ECGs would be performed, and so they could be
performed at the individual center before or after, or so many hours
after the dosing.

We don\'t know, and that was not specified, and we couldn\'t find that
information. The other point about the Phase III studies is that none of
the Phase III studies included Holter monitoring, and that was done in
Phase II as I will talk about in a moment.

Now, I just mentioned a couple of relative deficiencies in the Phase III
safety data. I will say that in Phase II they did have some timed ECGs,
and that was in a multiple dose-ranging study, which examined doses up
to 44 micrograms.

So that the dose is higher than what are proposed for clinical use.
These were 29 day studies, and so we have only chronic exposure up to 29
days in regard to the timed ECGs, and the ECGs as has been mentioned
were performed at 1, 3, and 5 hours.

So the first ECG was beyond the time of the Cmax. A separate study in
Phase II did include Holter monitors in 72 patients before and on
treatment, and I will speak to that in a few moments.

Now, as I mentioned, when I discussed the safety database findings, I am
focusing primarily on the one year placebo controlled trials, primarily
because the longer duration, one year as opposed to six months, and the
presence of a placebo control helps us to more rationally attribute
adverse events as a drug effect.

Now, one other introductory comment is that sometimes when you are
looking at placebo controlled trials, the occurrence of adverse events
can be affected by the duration of exposure.

So if in a placebo-controlled trial more placebo patients are dropping
out of the study, perhaps due to lack of effect, then the occurrences of
certain adverse events may look lower than placebo simply on the basis
of the duration of exposure.

I say that to say that I don\'t think that potential bias as a
compounding factor is operative here because the median exposure was
similar in the two groups. The category of adverse events that were most
common were gastrointestinal and as has been mentioned the frequency of
dry mouth far exceeded that in the placebo group.

And in this slide, and in my subsequent slides, I will follow the
convention of providing the data for the tiotropium, and then followed
by the comparators. So this is the list of gastrointestinal \-- specific
gastrointestinal adverse events that were seen more frequently.

I will point out that constipation in particular because I am going to
address that in a subsequent slide as well.

In these year long studies, it was not uncommon for patients to develop
upper respiratory tract infection. However, the occurrence of upper
respiratory infection in the tiotropium group was greater than that in
the placebo group, and we will see that in other studies.

And these are the remaining respiratory system adverse events that
occurred more frequently in the tiotropium group. They may or may not
reflect the effects of drying on the mucous membranes of the upper
airway.

So we saw chest pain more frequently and rash more frequently, and
finally urinary track infection, and I want to point that out
specifically because again I will have further slides that will address
urinary tract infection, and also because there is at least a plausible
mechanism by which tiotropium could increase the risk of urinary track
infection.

And by that I mean if there is a systemic anticholnergic effect, it
could result in some degree of urinary status and put the patient at
increased risk of urinary tract infection.

This slide addresses the six month studies, and what we saw in the six
month studies is that there were actually fewer differences between
tiotropium and placebo. These were the adverse events which were more
common in the tiotropium group, as compared with placebo, and what I
have done is in yellow text indicate the adverse events signals that we
saw in the year long placebo controlled trials.

So in the year long trials, we saw dry mouth and we see it again here in
the six month trials, and in the year long trials we saw upper
respiratory tract infection, and we see it again here; pharyngitis and
sinusitis.

One side comment is that the overall occurrence of \-\-- you may notice
the overall occurrence of adverse events is lower in the six month
studies than they were in the one year studies likely just related to
the duration of exposure.

Now, I should mention that there were some data shown this morning by
Dr. Kesten in which all of the placebo controlled data was pooled, and
that is data that we have not seen before, and so I can\'t really
comment on it.

I would comment that p-values were included in the slides, and I don\'t
think that applying p-values to this type of data is relevant. The other
is that the data were presented in patient years, according to patient
years exposure, and there are certain assumptions that go into that type
of explanation of the data.

It assumes that the risk of that adverse event is constant over time,
and I am not sure that that can be assumed. So I will say that I can\'t
really comment further again because I have not seen that type of
analysis before today.

Now, for all new drug applications, we asked that the sponsor examine
both the safety and the efficacy data for any evidence of interaction
with certain demographic features. And so what this slide shows is the
safety interactions that were discovered in the one year placebo
controlled trials.

And we saw safety interactions in regard to age and gender. We were
really not able to perform interaction studies based on race because
there were so few non-caucasians.

So in order to assess for an age interaction for these adverse events
the populations were divided into patients who were less than 60,
patients who were between 61 and 70 years of age, and patients who were
more than 71 years of age, or 71.

And there were three adverse events that showed an interaction; dry
mouth, constipation, and urinary tract infection. So in the youngest
group of patients the occurrence of dry mouth was 11 percent, but it
increased as the patients got older, and the occurrence was 21 percent
in the oldest patients.

Likewise, for constipation, it was two percent in the youngest, and rose
to six percent in the oldest patients. And urinary tract infection rose
from 3.3 percent in the youngest to 12 percent of the patients in the
oldest group.

And we didn\'t see that type of interaction at all for the dry mouth or
for constipation. There was some evidence of a age interaction for a
urinary tract infection, likely meaning that in this population of
patients, as you get older that you are at an increased risk for
developing a urinary tract infection, but it appeared to us that the
interaction was stronger in the patients on drugs, suggesting a true
drug effect.

And in regards to gender, what we saw is that women develops dry mouth
much more frequently than men, and that is not something that was seen
in the placebo group. A few other safety observations.

Regarding urinary retention, there were four patients in these one year
placebo controlled studies who developed significant urinary retention
and all of those four patients were treated with tiotropium.

And what I mean is that all of these patients required a full catheter,
and in fact three were subsequently started on medication for BPH,
benign prostatic hypertrophy, following the event.

Keep in mind that patients with symptoms of benign prostatic
hypertrophy, or bladder outlet obstruction, were in fact excluded from
participating in these trials. Nonetheless, four patients developed
obstruction requiring a full catheter.

Then finally under a micturition disorder or micturition frequency, the
observation is that there was a greater frequency of patients in the
tiotropium group, as opposed to placebo patients developing adverse
events characterized by either of those two terms.

In regard to constipation, one other observation I mentioned was the age
interaction, and the other observation is that in fact there was one
patient who was treated with tiotropium, who in fact was hospitalized
with a fecal impaction.

The last observation here is of uncertain significance, because we
don\'t at this time have any mechanism to explain it. But the
observation from the data, and these are the one year placebo controlled
data, is that the adverse events characterized as diabetes or aggravated
diabetes, or hyperglycemia, were more frequent and occurred in 14 or
2-1/2 percent of the tiotropium patients, versus one or .3 percent of
placebo patients.

And as has been mentioned, we pay particular attention to potential
cardiovascular effects, both because of the mechanism of the action of
the drug, and because of the patient population which I will go into,
and we know very well that cardiovascular disease is quite common as a
concomitant disease in the COPD population.

And what we observed is that under cardiovascular effects, in the
category of heart rate and rhythm disorders, there seem to be a possible
signal of drug effects, meaning that adverse events in this category
were more frequent in tiotropium, as compared to placebo, and serious
adverse events.

So these are adverse events that reached the threshold for being
declared serious, and were also more frequent in the tiotropium
patients. I will point out that this signal was not seen in the
ipratropium controlled studies, and we have no data from that to suggest
an effect.

And as has been mentioned, we did not detect a safety signal on the ECGs
that we have available given their limitations.

In regards to death, the first and most important observation is that
the incidence of death was similar in all groups. However, there is one
observation that may be important, and probably is worth pointing out.
In the placebo controlled one year studies, 5 of the 7 deaths that
occurred in the tiotropium group were attributable to cardiac ischemia,
or arrhythmia.

And that compares with one out of the seven deaths that occurred in the
placebo groups. In the ipratropium controlled trials, there were \-- the
deaths due to MI were three of the nine tiotropium deaths, and none of
the three ipratropium tests.

I mentioned that there was Phase II data to support the cardiovascular
profile, and we did not see any safety signal on the Holter monitors,
which were performed in 72 patients before and on treatment.

There was one subject who developed a four-fold increase in ventricular
ectopy on tiotropium, but that needs to be taken into context, because a
number of other subjects actually exhibited decreased ventricular
ectopy.

I will point out that a number of patients exposed or that underwent
Holter monitoring is somewhat low. If you look at the label for
Serevent, they describe 284 patients who underwent five, 24 hour
Holters. These are COPD patients.

And although I have emphasized the placebo controlled trials, because it
is much easier to attribute a drug effect, you may be interested in
seeing how the adverse event profile compares in the ipratropium
controlled trials.

So these were the European trials, and we don\'t have a placebo arm for
a comparison. What these represent are adverse events that were more
common with tiotropium than with ipratropium, and they are only included
on the table if they were also more common in tiotropium than in placebo
in the year long placebo trials.

So we saw chest pain in the placebo controlled trials, and we see it
here again, and again we saw dry mouth, and we see it here again.

Perhaps worth noting is that the degree of dry mouth seems to be, or the
occurrence is more frequent certainly than in the ipratropium. And there
are some others here that might relate again to the drying effects in
the airway that are not clear.

Again in the placebo controlled trilas we saw upper-respiratory tract
infections more frequently, and here upper-respiratory tract infections
occurred in 43 percent in the tiotropium group, compared with 34.6
percent in the ipratropium group. And finally again we see urinary tract
infection, 3.9 versus 2.2.

Now I will move on to the efficacy data. Again, I have divided the
efficacy data into the bronchodilator efficacy, the dyspena, and
miscellaneous others. So this slide shows the results from the U.S.
studies, the year long, one year U.S. studies, 114 and 115, and as has
been mentioned, the primary end point in these studies was the trough
FEV1 response at week 13.

And the table shows that tiotropium was statistically significantly
superior to placebo in both trials, with a treatment effect size of
about 140cc\'s generated by an improvement in the tiotropium group and a
slight decline in the placebo group.

And if you look at the same variable, the trough FEV1 at the other
clinic visits, tiotropium was also statistically superior to placebo at
all of the other visits, and the effect sizes at this point were
110cc\'s to 160cc\'s.

Now, that is the trough, and I mention the distinction between the
trough, looking at the trough FEV1, versus some measure of peak, and
here tiotropium was also statistically superior to placebo on the peak
FEV1, and on the average FEV1 during those three hour serial
spirometries performed at each clinic visit.

The FEV1 data may be worth a little closer look. The mean peak FEV1
response at day one was about 240cc\'s, and on subsequent clinical
visits, as I mentioned, it increased to about 250 to 310cc\'s.

Now, although the mean peak at day one was 240, this should say the mean
FEV1 response at each individual time point on day one. So, at a
half-an-hour, two hours, three hours.

You look at each one of those, the mean response was always less than
200cc\'s, and we want to investigate why there was an apparent
discrepancy, and the reason is that the individual patients reached
their peak at different times during that spiral spirometry.

So that at any particular time, about a third or less of the patients
were actually reaching their peak, and the reason that I point that out
is that that could potentially have some impact on how we describe the
onset of action of the drug.

To round out these year long studies, tiotropium was also statistically
superior to placebo on the forced vital capacity response, whether it
was looked at the trough, average, or peak, and also for the peak flow
measurements, and again those were home measurements, and the mean over
each week was examined.

And that tiotropium was superior for most weeks, with effect sizes that
ranged from eight early in the course of the study to around 31 liters
in the morning, and 13 to 40 liters in the evening, liters per minute.

These are the European ipratropium controlled trials, and again the same
primary efficacy end point was used. I should make a note regarding this
primary efficacy variable. We know based upon the pharmacodynamics of
ipratropium.

That at the trough value after a previous evening dosing and then coming
into the clinic and measuring trough values, you are unlikely to detect
an effect of ipratropium based simply on its known pharmcodynamics.

So it would not be surprising that the tiotropium would show a similar
effect size against ipratropium as it did against placebo. And having
said that, tiotropium was superior to ipratropium on this variable in
all clinic visits, and the effect size again were around 110 to
180cc\'s.

This slide shows the data from the six month multi-national studies, and
focusing on the co-primary end point, which was again the trough FEV1
response. And again this slide shows that tiotropium was statistically
superior to placebo in both studies at week 24, with a treatment effect
size of about 110 to 140cc\'s, again because of an improvement in the
tiotropium group, and a slight decline in the placebo group.

Again, looking at the trough FEV1, the same variable. At all other
clinic visits, tiotropium was statistically superior, and the effect
sizes were similar, 110 to 150cc\'s.

Again, tiotropium was statistically superior to placebo on the peak
FEV1, and the average FEV1, during what was either a 3 hour or a 12 hour
serial spirometry, depending on the study.

And then finally as seen in the other studies tiotropium was superior to
placebo in regard to forced vital capacity looked at in several ways,
and in regard to the peak flow.

Now I will move on to discuss the dyspena findings, and Dr. Kammerman
has already reviewed some of the issues concerning the instrument
itself, the instrument that was used to establish efficacy in regard to
dyspena, both in the instrument and how it was validated and developed,
and so forth, and how it was implemented in these particular studies.

So I am not going to go into that further, but instead will just present
the data. This is the data from the six month studies that were used
primarily to support the dyspena claim.

And this is the responder analysis, again defining a responder as a TDI
score greater than or equal to one, applied at six months, and what we
see from this table that tiotropium was statistically superior to
placebo in regard to the percentage of patients who showed any
improvement on the TDI.

I phase it specifically in that way to emphasize the fact that because
of the instrument, and because of the way the applicant defined a
minimal clinically important difference, there was no degree of
improvement that a patient could indicate that would not be considered
to be a clinically meaningful response.

And that is again built into the instrument, and then in how it was
applied using the minimally important difference of one. So you could
score zero, but if you wanted there to be any positive improvement, that
is a clinically meaningful response.

Two other points that I wanted to make on this slide. One is regarding
the actual effect size that was shown. It is relatively small or modest.
In one study, 16 percent more of patients who were treated with
tiotropium achieved this TDI responder; and in the other study, 12
percent more of the patients received their responder.

So by giving tiotropium rather than placebo to these patients, you
achieved 16 percent more of them that became responders based on the
definition, and here 12 percent more. And the other point that I wanted
to make from this slide is that salmeterol, the active comparator, and
again a bronchodilator approved on the basis of FEV1, and a drug that
does not have an indication for dyspena, also faired fairly well on this
end point.

In Study 130, the difference between placebo and salmeterol was not
statistically significant. In Study 137, it was, and in fact in Study
137 the percentage of patients who were responders was numerically
greater than that with the tiotropium, and that is reflected in the
p-values here, where superiority over placebo met a p-value of .01, and
here the placebo value was .05.

One other comment about the analysis of the TDI at 6 months, is that the
datasets used for those six month analyses necessarily included fewer
patients that were randomized to treatment. So this slide shows the
numbers of patients who were randomized, versus the number of patients
who could be included in that statistical analysis.

And there really was no way of avoiding it for a few reasons. One is
that in the statistical analysis of the TDI, one of the co-variants in
the statistical plan was the BDI score. It had to be included.

So if a patient for some reason did not have a BDI score, they couldn\'t
be used in the TDI analysis. And likewise if the BDI score was scored in
a way that said amount uncertain or unknown, or short of breath for \--
or limited for reasons other than shortness of breath, they could not be
included in an analysis.

And the other reason why there is sort of a fall off in the number of
patients is that the first time the TDI was administered was at week
eight, and so that any patient who dropped out before week eight had no
TDI data that could be carried forward in a statistical analysis.

So the numbers aren\'t that dramatic, although in this placebo group
about 25 percent of the randomized patients couldn\'t be included in the
analysis. And I just would point that out because at some point in some
studies, when the number of patients who can be included in the
statistical analysis falls to some degree, it impacts the ability to
arise at firm conclusions based upon those statistical analyses.

Again, there is no way of avoiding it. That is how it had to happen. But
at some point when the numbers get too low, you start to wonder what you
are really learning from the data. And then finally regarding the
primary analysis, or primary efficacy variable or co-primary, is this
slide that looks at a number needed to treat analysis.

It is a different way of understanding the treatment effect size with
this drug, and according to the number needed to treat analysis, either
in the individual studies or the combined data, you would have to treat
approximately eight patients with tiotropium to achieve one patient over
than what would be expected with the placebo, who was a responder based
on this definition.

Now, of course, the TDI was administered on days or on visits other than
six months. It was administered at 8 and 16 weeks, and this slide goes
over the data from those studies, and the message is very similar.

Again, in each of the studies, at both 8 and 16 weeks, the percentage of
responders based upon the value of one, was superior, statistically
superior in tiotropium, as compared to placebo, and the same pattern was
seen with salmeterol, where statistical superiority was not achieved in
Study 130, but was achieved in Study 1137, with a low p-value, and in
both the 8 weeks and in the 16 weeks, again the percentage of responders
was greater in the salmeterol group than it was in the tiotropium group.

And then as has been mentioned, you can also look at TDI as mean values,
comparing the mean value in the treated, versus the mean value in the
comparator, and in fact as I mentioned, that was the specified analysis
for the four year long studies.

And this slide shows for each study \-- and remember that these four are
placebo controlled, and these four are actually active controlled with
ipratropium. In this column, you see the visits at which the TDI mean
score was statistically superior in the tiotropium group.

And in this column, you see the weeks at which that difference between
treatment groups exceeded one, and again I am using one as the
sponsor\'s proposed definition of what would be a minimally clinically
important difference.

And what you see is that it is very frequent to achieve statistical
significance from placebo, but less frequent to achieve a difference
that exceeds one. Now, the next few slides provide some additional data
that reflect on the efficacy of the drug in regard to the symptom of
dyspnea.

We have talked then about he primary efficacy variables, and let\'s look
at some of the secondaries. Studies 130 and 137, these are the same
studies that the TDI was used as a co-primary, including this post-dose
shuttle walk test.

So that was administered on day one, post-dose, and at weeks 8, 16, and
25, the same intervals at which the TDI was administered. The shuttle
walk test is a standardized test in which patients are told to walk back
and forth at a steady pace on a 10 meter course until they are unable to
maintain their required speed without becoming unduly breathless.

So this is the distance that they are able to walk and which is limited
by their breathlessness or dyspena. In conjunction with the shuttle walk
test the Borg Dyspnea Scale was applied both before and after each
shuttle walk test.

Many of you are familiar with the Borg scale. It ranges from zero, which
means nothing at all, to 10, which means maximal. It is a little bit
unusual in that when you get to five on this scale, you are already at
severe dyspena, and scores from 6 to 9 reflect very severe dyspena, and
then very, very severe dyspena, until you get to maximum.

So the data from those examinations are that in regard to the walking
distance, the distance that patients were able to walk without becoming
unduly breathless, there was actually no difference between groups in
either of the studies.

In fact, in one of the studies the placebo group was numerically,
although I emphasize not statistically, but numerically superior to
tiotropium in one study. And the walking distance did not increase
during the study in any of the groups.

So I think that this may impact your deliberations about the strength of
the dyspena signal. In regard to the Borg scale, with one exception,
there was no difference between tiotropium and placebo on that scale.

The only exception was week eight, when a statistical difference was
noted both pre-and-post exercise, and the value on this zero to 10
scales was \-- the effect size was 0.24 and 0.32, again on a zero to 10
scales.

The one other way to address dyspena would be this so-called COPD
symptoms score. I think the applicant showed you some of the data. That
was applied in several of the studies and the COPD symptom score is the
investigator\'s assessment of the patient, and their status over the
prior week in regard to several COPD symptoms.

And the investigator scored them on a four point scale, zero to three.
And the results showed that tiotropium was statistically superior to
placebo if you looked at the component shortness of breath. If you just
pulled that out and looked at shortness of breath, it was statistically
superior at most visits.

The effect size on the four point scale was 0.13 to 0.36, and I put it
in here, but I\'m really not sure how to interpret this data, because we
don\'t know how well validated it is, and I suspect that it has not been
validated, this symptom score.

Nor do we know if it is reasonable to pull out a component of the
symptom score and look at it. Nor do we know how to interpret this
effect size in regards to its clinical meaningfulness.

The next few slides will consider a few additional secondary end points
going by the groups of studies. These again are the one year U.S.
studies, and what was shown here in these studies in regard to the
remaining efficacy variables was that tiotropium was statistically
superior to placebo in regard to this physician\'s global evaluation.

Again, we don\'t have much information on its validation, nor do we know
how to interpret an effect side of 0.25 to 0.59 on a 1 to 8 scale.
Tiotropium in these studies was also superior to placebo in regard to
the as needed use of albuterol, with subjects required 5 to 6 fewer
doses of albuterol per week in the year long placebo controlled trials.

We did not see any consistent meaningful difference in these studies in
looking at COPD exacerbations, or COPD hospitalizations. We did not see
a consistent meaningful difference shown in the St. George\'s Hospital
Respiratory Questionnaire, or in the SF-36.

In regards to the European ipratropium controlled studies, we did not
see an effect on the as-needed albuterol use, or on COPD exacerbations
on hospitalizations. In the six month multi-national studies, tiotropium
was again shown to be superior to placebo on this physician\'s global
evaluation on all test days, except one, with effect sizes shown on a
scale of 1 to 8.

Again, it is hard to know how to interpret that. We didn\'t see any
consistent meaningful difference shown in as needed albuterol use
surprisingly. There was statistical superiority in one of the studies,
but in the other study, statistical superiority was not obtained.

Nor did we see a consistent effect on COPD exacerbations or
hospitalizations, or the SGRQ, or a patient satisfaction questionnaire.
So to summarize, the pharmacokinetic features of tiotropium are somewhat
unique among inhaled bronchodilators, particularly the very large volume
of distribution.

And a very long terminal elimination half-life, and the apparent tight
tissue binding with slow release back into the circulation. On the
safety side, dry mouth is common, and we saw both an age and an gender
interaction, and we observed in the year long ipratropium trials that in
fact the occurrence of dry mouth is more frequent with tiotropium than
with ipratropium.

There were several adverse events that occurred more frequently with
tiotropium than with placebo, and they may be reflections \-- some of
them may be reflections of the drying of the airways, and some could
reflect a systemic anticholinergic effect.

And then again we observed a possible effect in regard to heart rate and
rhythm, which may merit some further evaluation.

In regard to efficacy, tiotropium appears to provide clinically
meaningful bronchodilation, and its duration of action seems to support
once daily dosing. The maximum bronchodilator effect isn\'t reached
until after multiple daily doses.

And there is a demonstrable, at least statistically demonstrable, effect
on the TDI. However, the clinical significance of this effect is not
known. First of all, as Dr. Kammerman went into extensively, there are
issues with the instrument, and its implementation in these studies.

And then other issues about how to interpret the effect side and the
minimally important clinical difference and so forth. One other point
which I wanted to include is that the package didn\'t address either the
safety or the efficacy of concurrent as needed ipratropium, which may
occur in the clinical setting.

So with that, I will conclude my remarks, and invite any clarifications
that you may need.

CHAIRMAN DYKEWICZ: Thank you.

DR. SULLIVAN: Mark, I just wanted \-- I\'m sorry, but I wanted to point
out that Dr. Kammerman is going to have to leave, and if there are
biostatistical questions that may be directed to Dr. Kammerman, it is
better to do those early. Thank you.

CHAIRMAN DYKEWICZ: All right. We are open to questions from the
committee about the FDA presentation. Dr. Chinchilli.

DR. CHINCHILLI: Yes. When Dr. Kammerman said the sponsor was blinded
when they decided that they wanted to make TDI a primary outcome in the
two shorter term studies, the 6 month studies, does that mean that hey
were blinded to the data, or does that mean that they could see the
data, but were blinded to the treatment identity? So I was not clear.

DR. SULLIVAN: I think it may be best to have the applicant address
exactly what was known at the time.

DR. MENJOGE: This is Shailendra Menjoge, the biostatistian on the
project. We had the data in-house; however, we did not know any
treatment codes.

DR. CHINCHILLI: That\'s what I mean. So you saw the data, and you saw
there were differences in groups. You just did not know which group was
which?

DR. MENJOGE: No, we didn\'t. There was no way to find any differences or
anything. Basically, the data was collected and it was brought in-house,
some of the data, but there was absolutely no knowledge of any treatment
at all.

There were no analyses done or anything like that either.

DR. CHINCHILLI: Oh, okay.

CHAIRMAN DYKEWICZ: Dr. Swenson.

DR. SWENSON: Yes. A question for Dr. Sullivan. You presented your
interpretation of this COPD exacerbation rate somewhat differently from
what we heard from the company Can you share or address that issue,
because they came out with an indication or a suggestion that they
decreased the rate of exacerbation, and you told us otherwise.

DR. SULLIVAN: Sure. Right. It is our practice to look at individual
studies alone, and in the analyses that the applicant provided, there
were \-- the studies were grouped together, and so they met analysis if
you will. So what I have said is that we did not see a consistent
finding.

In other words, a statistical significance was not shown in either
study. If you group a bunch of the studies together, I believe that is
where the data from the applicant came from.

CHAIRMAN DYKEWICZ: Dr. Patrick.

DR. PATRICK: Dr. Kammerman, you mentioned that there was \-- that you
observed a fair amount of overlap or co-linearity between the three
components of the TDI. Is it possible that that co-linearity would then
drive the responders\' analysis?

DR. KAMMERMAN: Well, I am not sure that it would actually drive the
analysis. If somebody had a positive response in one of the components,
they were likely to also have positive responses in the other two
components. There were very few instances where the positive on one of
them would overcome a couple of negatives on the other two.

Where it could make a difference those is that if you started changing
the clinically meaningful difference thresholds, and let\'s say from 1
percent to 2 percent, or 3 percent \-- I\'m sorry, the unit of change
went to a three, then if they are related, the change of two many not
really mean that much more than a chance of one.

DR. PATRICK: Just one real quick follow-up. Wouldn\'t all f this depend
on where you started? So if you had dyspnea at rest, a one unit change
to eliminating dyspena when you could dress might be very much different
than going from walking on level ground to walking on a hill?

DR. KAMMERMAN: Yes.

CHAIRMAN DYKEWICZ: Dr. Sullivan.

DR. SULLIVAN: I just wanted to comment further on your question about
the exacerbations. Some of the difference between the presentations may
reflect the fact that I believe the data presented by the applicant had
to do with time to first exacerbation, and the analyses that I looked at
were the numbers of exacerbations.

So some of the differences may be explained in that way.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: Are there any other implications of dry mouth besides your
concern about sinusitis, like dental problems, for instance?

DR. SULLIVAN: We didn\'t see that. I think that one of the
considerations about the frequent occurrence of dry mouth has to do with
the blinding of the study as well. But as far as more serious adverse
events related to drying of the oral mucosa, I don\'t want to raise
that.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: Just following up on that. Since the incidence of dry mouth
when you adjusted for gender appeared to be a lot greater in women and
there weren\'t that many women in the larger trials, are there any
issues about other effects in women, in terms of cardiac effects
ultimately?

Were there enough women studied? I just worry when one variable appears
to be significantly increased? Is there reason to suspect that there
might be more problems?

DR. SULLIVAN: I think that is a very reasonable question. I can say that
I didn\'t see any gender difference in regard to the cardiac effects.
Again, it is hampered by the fact that a few women were exposed,
particularly in the European studies.

In the United States studies, it was a little bit more balanced.

CHAIRMAN DYKEWICZ: Dr. Swenson.

DR. SWENSON: To the question of the dry mouth, and maybe this is a
question to someone in the company. Do you really consider that a
systemic effect or is that possibly a combined systemic and local
effect?

DR. DISSE: I would like to address this from the systemic absorption by
inhalation, which I think every health drug has, and from the pattern of
onset, we believe that it is a systemic effect.

And also from animal pharmacology, you can follow up that the dryness of
salivary secretion is always the most sensitive anticholinergic signal
which appears first.

CHAIRMAN DYKEWICZ: Dr. Apter.

DR. APTER: I am concerned about the demographic distribution of the
population tested. Dr. Kammerman mentioned in the questionnaire that
there might be cultural differences, and language differences, but also
adverse effect differences.

And we know from the experience of ACE inhibitors, for example, that
African-Americans are much more likely to experience angio-edema than
Caucasians. So I am concerned when the study was set up and negotiated
between the FDA and the company that there were not more measures
instituted to ensure that there would be a broad range of minorities,
such as was seen in this country \-- African-Americans, latinos \-- and
you mentioned maybe there is some data about Asians. I don\'t know.

And the other issue, too, is that minorities have poor health across all
diseases than Caucasians. So they would be \-- and I don\'t know of Dr.
Menjoge\'s demographics, but these patients would be more likely to be
exposed to these medications.

DR. SULLIVAN: I think we are certainly sensitive to representing all
populations in these clinical studies. I can\'t speak to the discussions
that went on now several years ago before these pivotal studies were
being planned.

I know that it is our current practice to advise responders in Phase II
to be sure to include adequate representation. I should say that in that
CDCMMWR report, it is apparent that the occurrence of COPD is more
frequent in whites than in African-Americans.

So to some extent the disparity is explained by the burden of disease,
but I don\'t think it is entirely explained.

CHAIRMAN DYKEWICZ: Dr. Chowdhury, did you want to make a comment?

DR CHOWDHURY: I just wanted to make the same point here, that when a
study is planned and conducted, typically one would make an attempt to
have adequate representation of both the genders, and the way they show
racial distributions, and that is what is expected.

However, the fact is that the with the data that you have, that is the
data that you have, and I would ask you to comment on the overall data,
and that may be one of the considerations that you want to recommend
making to us.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: One thing that I couldn\'t clearly determine from the
literature provided to us is what other medications could these patients
be on when they enrolled in the trial?

It wasn\'t clear to me that there were specific exclusion criteria for
inhaled steroids, for example, which granted may not be approved, but
certainly that a lot of patients are on.

And my question is could patients be on alternate medications, and if
so, was the frequency of distribution the same between placebo and the
trial participants?

DR. DISSE: So as you can see here, this was a baseline pulmonary
medication on entering into the trials, and many patients were on
inhaled anticholinergics. Of course, these had to be withdrawn.
Beta-agonists were inhaled almost entirely in everybody, and these of
course could be continued on demand.

All the beta-agonists had to be withdrawn, and inhaled steroids could
continue on a steady level, and oral steroids could continue, and
theophylline oral could be continued, except in one set of our replicate
trials, and a few patients on oxygen.

DR. PARSONS: There is a bit of a difference in inhaled steroid use. Is
that statistically significant?

DR. DISSE: No, it is not statistically significant. There is some
variability also with our studies, and so this is the studies conducted
in the United States, and European studies in proportion on steroids was
at about 70 percent. So a lot higher.

DR. PARSONS: Is there any association between the concomitant use of
inhaled steroids and the change in TDI scores? And were the percent of
responders more likely to be on inhaled steroids?

DR. DISSE: We can show the subgroup analysis for FEV1, as well as for
TDI, and we have not seen an interaction here. So tiotropium was
effective no matter there is co-administration of inhaled steroids or
not.

CHAIRMAN DYKEWICZ: Dr. Morris, did you have a question?

DR. MORRIS: Yes. This is a question for Dr. Sullivan, and possibly for
Dr. Kesten. In regards to the cardiac Aes, and the data that was
presented, is there any clustering of the AEs, cardiac-wise, on drug
versus placebo in regards to time on drug?

DR. SULLIVAN: In our dataset, we weren\'t able to \-- the dataset that
we had available, we weren\'t able to look for that type of a pattern.
Perhaps Dr. Kesten has looked at it.

DR. KESTEN: We did look for that, and there was no clustering in this
specific time frame from cardiac AEs.

CHAIRWAN DYKEWICZ: Dr. Stoller.

DR. STOLLER: My question regards the agency\'s level of confidence in
the minimally important clinical difference. And in particular one of
the issues brought up in the applicant\'s briefing document regards \--
I mean, one of the other ways to examine this is recognizing that there
weren\'t a priori definitions of minimally important clinical difference
as, for example, has been shown in some of the other available indices,
CRQ and SGRQ.

One on the supportive arguments appears in the table on page 38, Table
3.2:3, which dichotomizes the TDI transitions, and then looks at in
those dichotomizes greater than or less than one TDI differences in the
SGRQ, for example.

And my question perhaps is really to Dr. Sullivan or Dr. Kammerman, and
it may be an invitation to the applicant, is did you have an opportunity
to look at the actual scatter of those data.

The actual distribution of the SGRQ \-- do you see where I am? Whether
you had an opportunity to look at the actual distribution of those data
as a way of either strengthening the idea that there is a relationship
with other a priori defined minimally important clinical differences,
and if you didn\'t, whether there is an opportunity to look at the
distribution of those data with regard to whether this is outlined based
or not.

You know, you have raised several concerns, some of which I share with
regard to the actual administration of the instrument, which is perhaps
separate from this issue. The other issue is how confident are we in the
minimally important clinical difference.

DR. KAMMERMAN: Well, I have not looked at this table in a while, but
when I first look at it, my impression is if we want to use this as
evidence to support a clinically meaningful difference in an evaluative
instrument, then patients would need to be classified in a different way
based on, for example, to three groups of patients whose clinical status
remains stable over time, and improved over time, or decreased over
time.

And then look at the responders in that fashion, and as for this, there
is still the problem that the SGRQ was administered right before the
TDI, and so we will see all patients with improved breathlessness had a
mean score of minus 6, and all patients with no change or worsening of
breathlessness, had a mean change of .74.

And there is still the issue here of the bias, but moreover, personally
speaking, I am not so confident about one unit as being clinically
meaningful. There is the degree that Dr. Patrick raised about the
overlap among the three items.

The scoring of each item was not consistent, and they were just simply
added together, and I still haven\'t seen really good evidence to
support the one unit change as being meaningful.

CHAIRMAN DYKEWICZ: Does the Sponsor wish to respond?

\` DR. WITEK: I would first like to answer that point, and then if you
would allow us to just address the issues that have come up in some of
the biases. If you can just please pull up Slide 2763.

To your point, Dr. Stoller, about \-- and you can display that, but the
analysis that was done by the agency, I think we respect that, but we
would like to point out some of the issues where we don\'t believe that
these biases have manifested, such as the dry mouth.

But if we look at a more objective measure to your point about just
dichotomizing and if you responded or not. Here you are just looking at
taking the entire cohort from the one year study. If you responded on
the TDI, you do see less albuterol than when you didn\'t.

And let me just show this as another way to correlate that these
measures are associated. So even with the point that the SGRQ was looked
at right before, this is a little bit more an objective measure. You can
take the slide off.

DR. KAMMERMAN: I have one question. Could you please address the issue
of missing data, and how that affected the TDI in the one year studies?

DR. WITEK: Could we just address them in the order and we will make sure
that we come back to that.

DR. KAMMERMAN: Okay.

DR. WITEK: Then just let me address one point of the biases, and then I
would like to have Dr. Jones to comment on some of his general
experiences. If we can just put up slide 2748, please.

It was discussed about correlation coefficients being low and explaining
very little variability. If we can just display the slide. These are
data from the multi-national studies, and I have to acknowledge that
this data were not presented to you.

But this is just looking at the associations between the BDI and the
change in SGRQ, and the dyspnea score, and the global evaluation, and
the FEV1 that was mentioned.

And one of the ways that we look at the question of the multi-national
biases is that we have made a dichotomy of these correlations, for
example, in the countries, and in the multi-national countries that were
native-English speaking, and then non-native English speaking.

Perhaps an indirect, but one of the ways that we can look at that, and
we see that the correlations here at the BDI, whether you looked at
native-English or non-native Engish speaking countries, are similar.

And the degree of these correlations are exactly what one would expect,
and less of a correlation between an objective measure, and a stronger
correlation here as you see between two dyspena measures.

And although they are different, we wouldn\'t expect a very high
correlation on things that would be measuring different things. For
completeness, if we can just go to the next slide.

CHAIRMAN DYKEWICZ: Let me just interject. You can present that, but
really because this data has not been presented to the FDA, or the
committee before this point, it should not be considered in our
deliberations.

DR. WITEK: Okay. So this is just showing for the deltas and we see the
same thing. I would just like with respect to the manifestation of some
of the potential biases, that Dr. Jones could discuss that and his
experience with his instruments specifically to ours.

And then we will come back to the question on the missing data.

DR. JONES: Dr. Kammerman makes a very important point, that bias in
clinical trials tends to with the unblinding observer of patient, tends
to lead to an over-estimation of the treatment effect.

One of the interesting things is that in other studies using our
instrument, we found that other agents are associated with a higher
number of side-effects have been associated with a decrement in the
observed treatment effect.

That has been with entirely different data, and long acting (inaudible),
but that is a phenomenon that has been observed. And in these particular
studies, we found that the TGI response in those who were reporting a
dry mouth was lower than in those who didn\'t.

Now, that is important because that is one of the indications whereby a
patient or the clinician may have judged the treatment that the patient
was receiving, the active treatment, because dry mouth is a symptom of
the active treatment.

If you could show me Slide 3, I think. No, the next. Thank you. This
one. These are data from the 6-month tio, albuterol and placebo studies,
and looking at the percentage of responders with the presence or absence
of dry mouth. So the y-axis is the percent of responders, and the pink
is the patient with no dry mouth, and blue is the patient with dry
mouth.

And we can see for each of the treatment groups the patient who had no
dry mouth had a higher response rate in the TDI than people who had the
dry mouth. So I think that is one concern that can be settled in the
specific context of this study. And if I could go back two slides,
please.

DR. KAMMERMAN: Could you put up that slide again, please? I am just
trying to absorb it.

DR. JONES: Shall I talk it through again or would you like to look at
it?

CHAIRMAN DYKEWICZ: Dr. Parsons, you had a question on that slide?

DR. PARSONS: On that slide, could you just walk us through what the n\'s
are, please?

DR. JONES: The n\'s at the bottom here, there were 32 patients with dry
mouth, and 316 with no dry mouth, and albuterol, seven patients with dry
mouth, and 333 with no dry mouth. Placebo, seven with dry mouth, and 302
with no dry mouth.

So it is very much a minority of patients who had a side effect signal,
whether or not they were receiving the treatment.

DR. KAMMERMAN: I want to make sure that I understand. We just look at
the patients who had the dry mouth, and the bar is on the left, and that
there was an effect, I think, because in the tiotropium, there were 30
percent responders than 10, or 15 and 15. What am I missing?

DR. JONES: Among the 32 patients who had a dry mouth, the response rate
on the TDI was 28 percent, and among the 316 patients who did not have a
dry mouth, the response rate on the TDI was 44 percent.

DR. KAMMERMAN: Well, just looking at it, there appears to be an
interaction because no dry mouth clearly is going down almost linearly,
but those with a dry mouth have an increase for tiotropium, and for the
other two arms, they level out. I think if you did an analysis with
contingency tables, you would see a correlation of some sort.

You may, but of course within there is a treatment effect as well. The
placebo presumably didn\'t have a treatment effect, and in some of the
studies, and in the TDI studies, salmeterol had a smaller treatment
effect than with Tiotropium.

So one would expect an interaction with the treatment, because it is an
active treatment.

DR. SULLIVAN: I wonder if you have a rationale for this observation. It
seems paradoxical to me if the dry mouth is a systemic manifestation of
exposure, then those with dry mouth likely had more drug delivered to
their lung, because that is where the absorption comes from.

And yet those patients with more drug delivered to their lung seem to
respond not as frequently. Is there a rationale for this observation?

DR. JONES: I think there are two rationales. One I see that Dr. Disse
would like to answer from the pharmacological perspective. I think that
there is a psychometric perspective; that we know that patient\'s
pre-inspection of breathlessness can be altered by blowing cold air on
to their face, or blowing air up their nose with no change in alterial
blind gases.

So sensations around the face alter patient\'s perceptions of
breathlessness. So one explanation of this is that a dry mouth makes
people feel less or more breathless, or they don\'t perceive a
symptomatic gain compared to when they do have a dry mouth.

CHAIRMAN DYKEWICZ: Yes, please proceed.

DR. DISSE: I think we have to take into account that dry mouth reflects
two things. One is of course sensitivity of the individual patient, and
the second may be elevated systemic levels.

But this has not necessarily to do with drug levels in the lungs. In
fact, we have analyzed patients with dry mouth and those without for the
FEV1 response and there is no difference.

DR. KAMMERMAN: I just want to say that \-- and I have just been thinking
about this, but that if there truly is no relationship between the
outcome on TDI and whether or not a patient was experiencing dry mouth,
you would see the same slope from tiotropium, to salmeterol, to placebo,
and that isn\'t want is being shown here.

DR. JONES: I think the basic factor in that start date, in that
analysis, is that patients with dry mouth had a smaller response rate
than patients who did not have a dry mouth across all treatment groups.

DR. KAMMERMAN: And I agree with that.

DR. JONES: But if we start looking at the end, and if I could have that
slide up again, please. The ends are now getting very small down here.
It is 7 out of 300, and so the power of any direct comparison is going
to be small.

But there is nothing in this data to suggest that patients with dry
mouth had a higher response rate. That is the only point that we can
make of it.

DR. KAMMERMAN: Well, it isn\'t so much that they had a higher response
rate. It is whether the response rates differ according to whether they
had a dry mouth. Among patients who had a dry mouth, their response
rates \-- am I explaining this correctly?

The question is if somebody is a responder, or has dry mouth, is the
difference between responses in tiotropium and placebo the same as the
difference between those who don\'t have dry mouth on tiotropium, versus
placebo.

And from the picture that you have drawn here, and I don\'t have the
numbers in front of me, it looks like that isn\'t the case.

DR. JONES: I think it is a reasonable hypothesis. The point is that we
would never be able to test it with the numbers, because as I pointed
out, they are too small. But as I said, there will be an interaction
because we would expect on the basis of the other data that the
tiotropium treated patients would have a higher response.

But I think we can take this higher response in the salmeterol treated
patients, but there are more patients with tiotropium who have dry mouth
and no dry mouth, compared to salmeterol and placebo, but we are putting
this slide up to show that there is nothing in this data that we can see
to suggest that people with dry mouth have more \-- were responders
rather than those that did not.

And I think that we would make no further point than that. May I go on
to \--

DR. KAMMERMAN: I\'m sorry, but this is my last comment. The question is
not whether people with dry mouth had different response rates than
those without dry mouth. The question is are those who are on tiotropium
and had dry mouth, did they have different response rates than placebo
patients who were on or had dry mouth, compared to those who didn\'t
have dry mouth at all?

DR. JONES: If I could have that slide back again. I think the \-- I
think I will need some notice of your question to fully interpret it.
There are a greater percentage of patients who have \-- we would need to
do a statistical analysis to see the size of that interaction. I think
that is all that we can say. I think that is all we can say. Could I go
on to another point?

CHAIRMAN DYKEWICZ: Please go on to the next point.

DR. JONES: May I have this slide, please. Another point is that
ipratropium and tiotropium both cause dry mouth. So that we \-- that if
the assumption is that there is a signal coming through about active
treatment, and what the cause is to responder bias in favor of
tiotropium, we should see that.

And we should not see so much of a difference between tiotropium and
ipratropium. May I show the third slide, please.

You have seen this slide before, and initially tiotropium had a bigger
improvement in breathlessness compared to ipratropium, and that
certainly we could not exclude the possibility of there being some bias
being introduced.

But if we then look at what happened to the ipratropium treated patients
during the study, they became worse. There was obviously some
underlying, other biological factor that was going on unrelated to the
treatment perhaps, but we see that the change in tiotropium treated
patients track that change in a very similar way.

And I think it is reasonable to postulate that if there had been
observer bias in terms of treatment effect, that that effect would have
at least have been sustained in some way, and we would not have seen
this tracking of what happened in the ipratropium treated patients.

And I would just remind you that these patients, also that some of them
had dry mouth as well, and in the other study, we see a similar picture.
There isn\'t quite as much fall-off in the tiotropium treated patients,
but again the patterns are very similar.

And I would argue that if there was consistent bias here that we
wouldn\'t have seen this pattern.

CHAIRMAN DYKEWICZ: What I would like to do is to have questions
specifically directed on this point, Dr. Jones, because then we will
break for lunch thereafter. All right. We will resume at 1:00 p.m.

(Whereupon, at 12:01 p.m., the committee meeting was recessed.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:03 p.m.)

CHAIRMAN DYKEWICZ: Okay. Let\'s reconvene. Welcome back. What we are
going to do organizationally is first give the session for open-public
hearing, which I think will be relatively brief, and then we will give
an opportunity to the sponsor to address some issues that were
unresolved prior to the break.

I would also say that the committee has received 55 e-mails discussing
the topic of discussion today. The Chair recognizes Dr. Wlodzimierz
Rozenbaum. Please identify your affiliations and any conflict of
interests, and your comments are limited to five minutes.

DR. ROZENBAUM: Good afternoon, and my name is Wlodzimierz Rozenbaum, and
I am the owner-moderator of COPD-ALERT, a non-profit, internet-based,
support and advocacy group for COPD patients, caregivers, and medical
professionals.

COPD-ALERT is a member driven organization, and we do not receive any
funds from any private organization or government agency. I also have a
personal stake in your hearing. I have severe COPD, and I was forced to
retire on disability more than two years ago.

On behalf of COPD-ALERT, and many thousands of COPD patients in the
United States, I wish to thank the agency and the committee for holding
a hearing devoted to Spiriva, and for making it possible for the
patients and the advocies to participate in and contribute in your
deliberations.

The name Spiriva evokes strong emotions among COPD patients. Medical
reports about successful clinical trials conducted around the world, as
well as comments about it, have been proliferating exponentially.

There is also quite a bit of anecdotal data from individual COPD
patients which adds the human dimension to the formal clinical reports.

This excitement is quite understandable. To this day, there is hardly
any COPD-specific drug available. This is despite the fact that COPD is
the fourth major cause of death in the United States, and that the
morbidity and mortality figures continue to climb.

There is a real danger that within the next decade that COPD will move
to the third place, if not higher. It is our hope that medical research
accelerates the development of COPD-specific drugs, like Spiriva, which
in addition to its proven therapeutic efficacy, causes no major
side-effects.

We must at least slow down the COPD deadly spiral, if we cannot stop it.
But COPD is not only about death. This is a crippling, debilitating
disease, tying patients to breathing support machines, and mercilessly
destroying their lives, breath by breath.

The Work Bank study suggests that some 25 percent of COPD patients will
die during their productive middle age, losing 20 to 25 years of life.
At the same time, millions of COPD patients who continue to struggle
with their disease are disabled and unable to work.

Now, the American Lung Association has described COPD as the second most
disabling disease for American workers. It is a small wonder that the
economic costs are enormous.

According to the Centers for Disease Control, more than \$50 billion per
year, a conservative estimate, is spent on COPD-related medical
expenditures, with an additional \$50 billion in indirect costs.

The primary source of medical expenses for COPD patients are extended
hospital stays and expensive medications. The University of
Washington\'s alarming study shows that while COPD patients constitute
10 percent of the patient population, they account for more than 70
percent of all medical care costs, and these costs continue to escalate.

COPD is a neglected disease. Insufficient attention is being paid to the
fact that there is an extreme shortage of viable treatment options.
Physicians have only two choices: to experiment with medications
developed for asthma, or to consider surgery.

Asthma medications relieve symptoms, but their effectiveness diminishes
over time, and they often have undesirable side effects. Surgery is an
option for very few patients. This is why Spiriva has evoked so much
interest and hope among COPD patients.

After all, tiotropium bromide is not a mysterious new substance. Both
asthmatics and COPD patients have been using its variation, Ipratropium
bromide, for many years. Altrovent, unlike many other bronchodilators,
is well tolerated and does not cause worrisome side effects.

As the clinical trials in this and other countries have shown, Spiriva
is well tolerated and provides a kajor relef for shortness of breath for
as much as 14 hours without causing any harm to patient\'s other organs
and systems.

It is my understanding that this Committee has received credible and
uplifting testimonials from individual COPD patients, who take Spiriva
under the supervision of their doctors.

COPD patients expect that this Committee and the FDA will move fast
forward towards the approval of Sprivia. We urge you to do so. Thank you
very much.

CHAIRMAN DYKEWICZ: Thank you. We will now proceed with the opportunity
for the sponsor to respond to questions about the instrument
methodology, and issues about the clinically meaningful response on the
TDI, and then also permit Dr. Jones to give some further clarification.

DR. WITEK: Thank you very much, Dr. Dykewicz, for this opportunity,
because it is very important that we put some of the comments into
perspective for better understanding.

There were several points raised regarding issues of training and the
lack of us documentating inter-rater reliability, et cetera, and the
reason why this is important to us in clinical development programs is
that these things must be guaranteed in order for us to show an effect,
because if they are not manifesting, we lose sensitivity.

And the fact that we have shown, as I have shown you consistently in
these studies the effect, we believe that those issues are acceptable
here. The other point before we get to the points of bias, and we will
let Dr. Jones finish his question, just a little bit about perspective
with respect to the differences, let\'s say, of 15 percent.

There are other drugs that are widely used that have used symptomatic
benefits in their clinical development program, and here we have seen,
for example, with antihistomines, for rhinitis, and NSAIDS for
osteoarthritis, and our own drug, Flomax, for BPH.

There in those studies, we are looking at responder rates to symptomatic
benefit. The range that is seen is in the range from an 8 percent
difference to a 15 percent difference between drug and placebo.

So that also gives you a little bit of a perspective regarding the
differences that we have observed here in our responder rates. What I
would like to do now is have Professor Jones finish his discussion
around the issues of bias, and then we will certainly be available to
answer any questions regarding my comments that were just made.

CHAIRMAN DYKEWICZ: Dr. Jones.

DR. JONES: Thank you for giving us the opportunity to respond, because I
am very sorry that Dr. Kammerman is no longer here, because she has
raised some very important issues. I think we were about two-thirds of
the way through. She raised concerns that \-- two concerns.

One is that the SGRQ, which is a health status instrument that addresses
issues around disturbances of activity, among other things, before the
patients responded to the questions about the TDI, she was also worried
that the clinician would know the patient\'s FEV1 response, and that may
have conditioned the way in which they scored the TDI.

I think there are two points about this. First, if we deal with the
SGRQ. The SGRQ and the TDI in some respects address very similar issues.
The TDI, or the SGRQ has got items such as being breathless, and walking
upstairs. That is the type of thing that is addressed by the TDI.

So one would expect concordance there. And it is very difficult to
imagine a circumstance whereby the information in the SGRQ should be
different from the information used for the TDI. They are very similar.

The point about the SGRQ is that it is a point estimate. The patient has
no idea what their previous score was. They are not given it, and they
are not given their previous questionnaires.

And as Dr. Kammerman pointed out, it is actually very difficult to
remember what your health status was in the past, which is why the TDI
refers to the patient\'s baseline index, and each time the measurement
is made, they refer back to the baseline index.

And there is no way that they know how they previously administered the
SGRQ. So I do not believe that there is any way that the SGRQ responders
should have contaminated the TDI response.

The other point that she made was about the FEV1. It is perfectly
feasible that if a patient has a big change in FEV1 that any reasonable
observer will think, okay, I can see a big change in the FEV1, and there
must have been a big symptomatic improvement.

If that were the case, one would have seen a tight correlation between
the TDI score and the change in FEV1, but it wasn\'t. It was at 0.21,
which is exactly at the level that we have seen in other clinical trials
and in other studies using similar instruments, and indeed with the TDI.

So I don\'t think it is a very real concern that she has had, but I
don\'t think that there is any evidence from this data that there has
been contamination of the observer by either the SGRQ or the FEV1.

CHAIRMAN DYKEWICZ: Thank you. Question from Dr. Schatz.

DR. SCHATZ: When you mention \-- the issue of recollection. Are patients
actually shown what their BDI is, and then asked to respond to that? Is
that the way it is done?

DR. JONES: Correct. That is the methodology.

DR. SCHATZ: And is there any particular reason \-- in other health
related quality of life instruments, the same instrument is just
administered, and sensitivity is looked at over time. Has that been down
with the BDI?

Is there any reason to think that the BDI administered, which doesn\'t
require any recollection, would have been an alternate way to do this?

DR. JONES: That is a good point. The original version of the Chronic
Respiratory Questionnaire was designed to be administered in the same
way as the TDI. The patients were given their first score, and then they
were asked to score the subsequent ones in relationship to the original
one.

Gordan Guyatt has not changed that and said that the patients don\'t or
aren\'t given their previous score, and a number of us have felt that
that was not necessary. Our instrument isn\'t referred to at baseline
state.

And I was discussing with Dr. Mahler yesterday abou why not just
administer the BDI as a point estimate at each time, and we both agree
that that is a very sensible way forward.

We should understand though that at the time that the CRQ and the TDI
were developed that psychometricians \-- and Professor Feinstein was one
of them \-- believed quite strongly that one needed to anchor a state to
get sensitivity to change.

I think the science has developed since then and we know more.

CHAIRMAN DYKEWICZ: Dr. Patrick.

DR. PATRICK: If the content of the SGRQ is similar to the TDI, then I
believe that we passed by a slide. Wouldn\'t you see very high
correlations between the changes in the SGRQ and the changes in the TDI?

DR. JONES: In the briefing pack, there are data showing the correlations
obtained in the tiotropium studies, and if I remember correctly, the
correlation between change in SGRQ and TDI is 4.5, which is lower than
the cross-section of correlation between the BDI and the SGRQ at
baseline.

DR. PATRICK: And is that what you would expect?

DR. JONES: Yes.

DR. PATRICK: Wouldn\'t you expect higher?

DR. JONES: No, I wouldn\'t, because the range of changes that you obtain
\-- and as you know, with all the longitudinal studies, the correlation
between two measures is nearly always lower than any cross-sectional
studies.

And the reason for that is the range of variation the data is generally
speaking smaller, and so one ends up with a weaker correlation.

DR. PATRICK: Okay. Just one last question on this. If we know the
minimally important difference in the SGRQ, wouldn\'t one way to do this
to anchor the TDI would be to anchor the changes in the TDI to the SGRQ,
and did you try that?

DR. JONES: It has been done, and it does then raise the question about
the validity of the four unit change in the SGRQ.

DR. PATRICK: Right.

DR. JONES: And there is an analysis showing that they are in fact really
quite closely related. But I think one gets \-- it is a peace of
evidence that supports the threshold for the TDI. It doesn\'t confirm
it.

As you know testing the validity of instruments such as this is brought
up through a body of evidence that shows consistency, and it is one
piece of consistent evidence.

CHAIRMAN DYKEWICZ: Thank you. Dr. Stoller.

DR. STOLLER: I have two questions, and one is a follow-on for that, and
it is really a follow-up to the question that I posed earlier with
regard to the minimally important clinical difference.

Recognizing the difficulty of identifying a gold standard for minimally
important clinical change, and the somewhat arbitrary nature of those
definitions, however well respected, I still \-- and leaving aside the
methodologic issues, I am still interested in the data distribution on
Table 3.3.2 with regard to when the data word dichotomized is greater or
equal to one DTI unit, there are mean values about those responders
versus non-responders.

And the table provides meaning and standard deviation data, but not
distributions. This paper was advanced as validation of the minimally
important clinical difference in the paper in press.

And so it becomes germane, recognizing that one is not anchored
necessarily on the other, and it is nonetheless advanced as a criterion
of further support of the relevance of a one unit change.

And I wonder if that distribution data are available so that one could
ascertain whether this mean value is due to a few outliers, or whether
it truly reflects some more homogeneous clustering of a greater than
four point unit as a correlate of greater than one unit. Does that make
sense?

That was the question that I asked before, and it got lost in the flurry
of other issues.

DR. JONES: No.

DR. STOLLER: Okay. My other question is to Dr. Jones, and it regards
some of the methodologic issues. You know, given the attention given to
the SGRQ with regard to British and American translation, and the
subtleties of the index and recognizing that it has been shown to be
reasonably good in that context in the one study of which I am aware, I
wonder if there is any concern about the very issues that we were
talking about before.

That is to say that the presence of correlation in non-English speaking
and English speaking is not quite the same level of precision of
attention to the reproducibility of the instrument as one would have in
a head-to-head comparison in as subtle a difference as British and
American English.

And so it gets to again this substantive concern that I think has been
raised about how one would approach the methodology of being convincing
if one designed this a priori as the primary outcome measure, as opposed
to the kind of methodologic afterthought of using this as a co-primary
outcome measure after the actual administration and training, and so on.

It gets to your level of concern, having studied this with the St.
George\'s about the \-- you know, about how much of an issue in your
mind, and how to explain the disparity between the level of attention
given to some other indices, in terms of minimally important clinical
difference, and the relative absence of that with regard to the index
used as the co-primary outcome here, the BDI and TDI.

And I ask that question as someone who has been very interested in the
Baseline Dyspnea Index and someone who has published, like Don, having
worked with Alvan on this very index. So I would be interested in
hearing your thoughts about that.

DR. JONES: You raise a whole host of very interesting points, and I will
try and keep my responses brief, although I would like to make them
longer. The first point is that I share your concern about adequacy of
translation, and I have written about validation in different countries,
and it is a very different process and difficult process.

These questionnaires I find remarkably robust in our hands. They are
much more robust than people thought they would be, but it is very much
dependent on having good translation, back translation, processes, and
that was done in this case.

So I think \-- and in fact I have written as an editorial saying that
there are now enough studies validating different translations of our
questionnaire, because we know that if the translation and
back-translation process is done properly, we can be sure that
questionnaires behave similarly in different countries.

And so with that first slide, we were not able to show the second slide,
which was that from the data from the Tiotropium studies, the
correlation analysis shows that correlation between the TDI and the BDI,
and the reference measures is very similar between English and
non-English speaking countries, as good as I could have possibly
expected.

The other important point about that is that these data are remarkably
consistent across clinical trials, and across continents, and across
languages. The size and effect of tiotropium compared to placebo in the
U.S. was really very similar to the size and effect seen between
tiotropium and ipratropium, an active drug in The Netherlands.

Another point about the translation is that one of the advantages of the
BDI and TDI is that they are interviewer administered. So that you have
to train fewer people. For example, there are fewer opportunities for
misunderstandings as a result of the translation process.

When one does this translation, back translation, process and have focus
groups, you find that you get the best possible cultural and linguistic
validation. Just one antedote. When the American version of the SGRQ was
created, the focus groups could not agree on one particular aspect of
it. So we incorporated both.

So even focus groups don\'t always get it right. But I am confident that
the translation and back translation process that was done here was
adequate. That the training of the interviewers was adequate.

As you know, if you don\'t get the interviewers to use the instrument
properly, it results in poor psychometric properties. It increases the
noise and reduces its sensitivity.

So quite clearly the agency\'s concern is going to be that somehow the
company has exaggerated the treatment effect, but really all of Dr.
Kammerman\'s concerns about the validity of the instrument in different
countries, and the way that it was applied \-- you know, I really want
these instruments to be trained and used properly.

I think they would work towards reducing the effect size and not
increasing it. I know of no study where bad technique, unless it is
unblinding leads to an exaggeration of the effect size.

So just as an independent observer, I believe that the methodology was
sound enough. I am sure \-- and I was not involved in the change to the
placebo, but I am sure that if this was going to be the co-primary end
point, more effort would have been put into it, which would have
tightened up the results yet further. It would not have reduced them.

CHAIRMAN DYKEWICZ: All right. Thank you. Dr. Apter.

DR. APTER: I am still confused. We are supposed to distinguish between
relief of bronchospasm and relief of dyspnea, and bronchospasm has a
physiologically accepted measure, the FEV1.

Nevertheless, if you relieve bronchospasm and you administer the TDI, I
am sure that patients would say that they could get dressed better,
dress breathlessly, walk up hills better.

So I am not sure \-- and we have no good physiologic measure of dyspnea.
We have the pO2, but that wasn\'t measured here and we are not really
talking about that in these patients.

I am not sure that we are able to distinguish between relief of
bronchospasm and dyspnea at the clinical level.

DR. JONES: My colleagues are looking to me to respond if you would like.
I think you raise a very important point. Dyspnea is a sensation, and
like pain, but far more complex than pain. It is a result of a number of
different pathways.

And we know that there are a number of different measurable
physiological variables that contribute to breathlessness. It is largely
related to the work of breathing, and the work of breathing depends to
some extent on the compliance, the stiffness of the lungs, and the lung
volumes.

So there are a lot of different factors that will influence the overall
perception of breathlessness, and a pharmacological agent, this is a
very simple pharmacological agent. All it does is that it dilates up the
airways.

But in fact probably more important in terms of breathlessness is that
it allows the lung volumes to reduce so that the work of breathing is
less, and so the patients feel less breathless, and there have been
various studies done not using tiotropium, but using other
bronchodilators, showing that the improvement in breathlessness
correlates better with the improvement in lung volumes and the work of
breathing, than the changing in FEV1.

So there is a link between bronchospasm and breathlessness, but it
probably is mediated through another, or two or three other
physiological mechanisms as well. I don\'t know whether that has
answered your question a little too tutorial.

DR. MAHLER: May I also address that question?

CHAIRMAN DYKEWICZ: Yes, you may.

DR. MAHLER: Your question hits a key area in our pulmonary community,
and that is that we have had an over reliance over the years, decades,
on FEV1 as a primary outcome measure, and I think as we have done
studies looking at dyspnea measures, whichever one you want to use,
health status measures, we see very modest correlations between FEV1 and
dyspnea, and health status.

And I think it means at least to me and to many of the people that I
interact with, that they are really measuring different constructs,
different components of the overall disease COPD.

So I think we can say, hey, FEV1, bronchodilation, dyspnea, a subjective
sensation that relates to air flow obstruction, that relates to
hyperinflation, and that relates to psychological issues, and that
relates to deconditioning, and all we are trying to do is say let\'s get
a global score for dyspnea, and let\'s get a global score for health
status.

And let\'s elevate that to comparable levels in looking at what we do in
treatment wise. And I think the goal guidelines that we are aware of and
that were published last year, illustrate what we are supposed to do in
COPD, and they say strictly that all of our evidence indicates that we
are treating the symptoms of COPD because none of our other
interventions treat any of the other major outcomes \-- survival or
change in FEV1\-- other than smoking sensation, in oxygen therapy. So at
least that is my perspective on your question.

CHAIRMAN DYKEWICZ: Dr. Patrick.

DR. PATRICK: I would just like to follow that up while you are up there,
because both of your opinions would be \-- and I think we are at one of
the hearts of the matter here, which is what makes the BDI and the TDI a
measure of dyspnea.

And having this as a measure of dyspnea, that is in some cases responded
to or recorded by the patients, and in other cases it is recorded by the
interviewers. According to the protocol, it was supposed to be by the
interviewers.

If this is subjective sensation, what makes this system, this system of
measurement, an idea system for measuring dyspnea, and is it a measure
of dyspnea, or is it a measure of the impact of dyspnea.

And I am very confused when I read the instrument. To me it is an impact
of dyspnea, because a patient could sit at home and do nothing, and not
have dyspnea.

DR. JONES: Could I first comment, and then let Dr. Mahler respond. I
very much understand your perspective, and it is related to that slide
that I showed showing the relationship between dyspnea and exercise is
complex.

There were levels of exercise that caused dyspnea, and there were levels
of exercise that can\'t be done because of dyspnea. I think the
important thing is that as I said the dyspnea measurements are grounded
in the metabolic costs of the activity.

Ideally, we would measure it in a laboratory, but we can\'t. We use
these reports of daily life. And we are assuming \-- well, we know that
there is a graded level of activity, and that that is the stimulus to
breathlessness.

But you are absolutely right. That if patients get breathless, they will
stop the activity. The two are inter-related and it is impossible to
deny that. However, the development of this instrument was very much
from a clinical perspective that the driver for the breathlessness was
the activity, rather than from my perspective, and to some extent your
perspective, the patient\'s view of the impact of the disease.

DR. MAHLER: Yes. Again, I would agree with your statement and what Paul
said. I mean, how do we measure pain? We say here is a visual analog
scale, and mark the intensity of your pain that you are having.

Is that really measuring paid? Not really. It is measuring the impact or
the perception of pain by that individual, and I think we are stuck with
that same circumstance in breathlessness. And the people who said, hey,
let\'s development some instruments for quantifying the sensation,
because we think it is important.

Yet, we don\'t have these perfect ways to measure it, but we are
developing more and more ways to understand it. And without going
through a lot of detail, we have got all kinds of validity, and
reliability, and responsiveness, captured around the BDI and TDI, that
at least have convinced a lot of people that it is a reasonable
instrument to use to look at outcomes when interventions are applied in
COPD and other chronic respiratory diseases.

CHAIRMAN DYKEWICZ: Dr. Schatz.

DR. SCHATZ: Just another methodology question that was brought up. The
concern that it is not clear that the three additive or the three
factors that are added are in fact added, and are in fact independent,
and that that is the best way to score that.

I wondered if you had any additional comments on that.

DR. JONES: Perhaps I should let Dr. Mahler comment first, and then \--

DR. MAHLER: Well, we set it up that conceptually functional impairment,
magnitude of task, and magnitude of effort, are distinct components or
contributions to the severity of breathlessness.

We have not done any formal testing saying, well, should we weight one,
versus another, and we have not done that. And I think how would you do
it? Well, there are statistical ways to go about it. On the other hand,
as was pointed out in this data, as well as in other data materials.

It is very seldom that the person gives a positive response on the TDI
in one component, and a negative response in the other component. And I
believe that emphasizes that everything is moving in the same direction
because I can do things easier, and I don\'t have to pause as often, and
all those things have enabled me to do my work outside the home or
inside the home, and they kind of parallel each other.

I can\'t say from a statistical point of view that they shouldn\'t be
weighted or there is no absolute overlap completely.

DR. JONES: May I add that I believe that redundancy of this type is
actually valuable, because it increases the precision of the estimate.
It is like triangulation or making duplicate estimates in our bioessay.

So in fact I learned when developing our instruments, I learned from
this approach, and I do believe that redundancy is actually valuable in
this instrument, because it does increase the precision.

CHAIRMAN DYKEWICZ: Dr. Sullivan.

DR. SULLIVAN: I just wanted a chance to follow up on one of your
comments regarding the call to baseline, and the extended duration of
these studies, as compared to perhaps the validation studies, and that
many of them are published on the TDI.

As you mentioned many of the validation studies are \-- some are
interventions, and most of them aren\'t drug interventions, and the drug
interventions tend to be shorter studies.

So one of our concerns has been how well the patient can think back, and
something that seems to comfort you is the fact that they are presented
with their BDI score, and then asked to say how they changed.

But I wondered if you could comment. You are allowed to show an
improvement of plus one if you discern a change within a grade. So the
BDI is \-- you are assigned a grade, and so presumably six months later
you are told what grade you were in before.

Now you are able to report a plus one change if you are better within
that grade. So doesn\'t that still mean that you have to recall quite
well how you were doing in that time past?

DR. MAHLER: Basically, the baseline information is given back to the
patient, and rather not the absolute grade, but here is what you told me
before. You have difficulty in certain tasks, and you have difficulty in
certain efforts.

That would be the intent in providing the information, and not saying,
oh, you were a grade one on magnitude of task, and have you changed a
half-a-grade here. That would be impossible.

DR. SULLIVAN: Perhaps the company can respond. Then you are saying that
there is more information available to the interviewer than just the
grade. There is notes from a clinical history taking, and I can see why
that would happen in the clinical setting, but I am not sure at a clinic
visit for a study whether the interviewers had the information you are
saying.

DR. MAHLER: Well, you would not have to necessarily have comments
written on the side. You could simply read the information, the
criteria, for that grade back to the person and say, well, you told me
that you had trouble walking up a hill, or whatever the specific
criteria is.

DR. SULLIVAN: So you would read or describe the grade.

DR. MAHLER: This is what you told me.

DR. SULLIVAN: But then they are able to say I am still that grade, but I
am better within that grade.

DR. MAHLER: And then the interviewer has these criteria for the TDI in
front of him or her, and then through the interviewer process tries to
tease out what the magnitude of change is, and that\'s why we think an
experienced interviewer, someone with knowledge and experience about
respiratory disease, should be an interviewer.

DR. SULLIVAN: It still seems to me that the patient will have to recall
where they fit within that grade back six months ago, and that it is not
\--

DR. MAHLER: They are going to have to recall how they were doing at that
time period.

And all I can say is that an observational study in COPD over two years,
we have seen a steady decline of .7 units over 2 years in our patients
with COPD who have had, quote, optimal treatment at our institution.

So I think that component fits with clinical experience; that is,
people\'s breathlessness tends to get worse, and at least on the TDI it
is represented by comparing to their baseline state.

DR. MAHLER: And of course their memory, and their recollection of how
they did two years ago may change it, and after a year or two, I may
think that two years ago I was better than I really was.

DR. SULLIVAN: And I think that is a potential limitation of the
instrument.

DR. JONES: Could I just answer that, Dr. Sullivan? It is a good point,
and in other areas in this field it has been known as response shift.

The point is that it leads to insensitivity, rather than increased
sensitivity, and if I were to design a measure for a one year study, I
wouldn\'t base it on this, because I would be concerned that there may
be a response shift and the failure to remember correctly would increase
the noise relative to the second.

DR. SULLIVAN: I understand that argument, and I guess sometimes it is
periless to determine what might have been shown if it had been done
more rigorously, and I can see why theoretically you would think it
would decrease the noise, but we have to address what was actually done
and what the data are.

DR. MAHLER: Can I also point out that if any intervention shows no
change over a period of time, and if you accept that the natural history
of the disease over that same time period is a negative direction, no
change or maintenance of your severity of breathlessness is actually an
improvement.

CHAIRMAN DYKEWICZ: Dr. Stoller, did you have a question?

DR. STOLLER: Again, with regard to the kind of methodology of the
administration of the instrument, recognizing that these studies were
conducted obviously in many countries, and in many centers, the question
is who were the actual interviewers?

What was their skill set, and who were they? You know,
characteristically, when this was developed by Dr. Mahler, this was
administered by lung doctors, and so on, and leaving aside the issues of
training, simply the skill set of the individuals administering it.

DR. WITEK: Yes, to get to your question, Dr. Stoller, I don\'t have the
exact education level or training level of the coordinators and the
people that were interviewing the patients, but I could say in general
that these are nurses, respiratory therapists, or lung function
technicians, to give you the range of those patients.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: Just to follow up on that. Was there any specific training
or was there a guide written for these people to follow? In other words,
if they didn\'t have experience administering this questionnaire before,
which is likely, were there some guidelines that they were taught, or
was there some attempt over 80 centers to make sure that everybody was
doing it right the same way?

DR. WITEK: Yes, and in our investigator meetings, as part of the process
of reviewing the protocol and learning how to use the centralized
spirometry, that is where we have the centralized training for all of
those individuals that participated in the study. So it was really
limited to that investigator meeting.

DR. PARSONS: But those weren\'t the people administering the
questionnaires?

DR WITEK: For the most part. I think I can\'t give you the exact number,
but the study staff that reports to the investigator meetings are
typically the ones responsible.

CHAIRMAN DYKEWICZ: Dr. Stoller, did you have a follow-up question?

DR. STOLLER: Just a clarification on Dr. Witek\'s comment. So do I
understand your response to be that every one of the study coordinators
was either a pulmonary function technician, respiratory therapist, or
nurse?

DR. WITEK: No, I can\'t give the hard data of the background, but in
general those are the types of individuals that are conducting the
studies, yes.

DR. STOLLER: Absolutely. I understand.

CHAIRMAN DYKEWICZ: Dr. Patrick.

DR. PATRICK: So if we go to the actual BDI and look at things like usual
activities, did the interviewer at BDI list those usual activities?

DR. WITEK: That I am not certain, but that would be on the SGRQ, the
last page.

DR. PATRICK: I know, but when they get to the follow-up, because what
Dr. Kammerman showed was very interesting, was some examples of things
like able to do things more rapidly, and able to do things with more
vigor.

Now, vigor and doing things rapidly are words that are not necessarily
on the BDI, but would be an interpretation by the interviewer having
discussed with the patient, I\'m assuming, what tasks they do do. And I
would imagine that we are blind to what is actually the content of what
those changes are. Is that correct?

DR. WITEK: That last point I am not sure of.

DR. PATRICK: Let\'s say that you \--

CHAIRMAN DYEWICZ: Please speak into the microphone.

DR. PATRICK: Let\'s say that you were \-- that your usual activity was
to go grocery shopping, and it was terribly difficult for you to go
grocery shopping at base line. So your BDI was that I had given up
grocery shopping, grade one.

So when you came back, and the interviewer talked to you, it would be up
to you to talk about grocery shopping, or would the interviewer say at
base line that you told us that you had given up grocery shopping. Are
you grocery shopping now?

DR. WITEK: I think the specific comments are not necessarily always
documented.

DR. MAHLER: A good interviewer would say, just like a physician taking a
medical history, what kind of activities are you doing now, and how are
you able to go grocery shopping now compared to six months ago.

Let\'s say the person stopped going grocery shopping and is just hanging
out at home. As part of the questions, you should also ask are there any
activities that you stopped doing or have abandoned, and if so, why. Is
that because of breathlessness

Now, again, you could say that is an advantage of this interviewer
approach, and you can get subtleties out of it, or you could say it is a
disadvantage because it depends on someone probing.

But as opposed to a self-administered, you simply have a few boxes to
choose, and you can lose that subtlety, and we believe that is important
in the responsiveness of the instrument.

CHAIRMAN DYKEWICZ: Dr. Sullivan.

DR. SULLIVAN: Dr. Mahler, I think that gets to maybe clarifying between
you and the applicant, but when you were discussing a good interviewer,
and that is the way that you designed the instrument, and so the good
interviewer would have the clinic notes from the last time.

And it says here the last time that I talked to you about grocery
shopping, and you have given it up. In the clinical trial, the
interviewer is going to have the case report forms.

DR. MAHLER: You would not necessarily have those comments, but \--

DR. SULLIVAN: But there would be no way to know about grocery shopping
unless the patient brought that up. You could ask generally on \--

DR. MAHLER: You could ask generally and then zero in on what activities
you are doing, and have you stopped doing anything, or are there some
new things that you are doing because you can breath better.

DR. SULLIVAN: I think that brings out an important difference between
the way the study was designed and is used in certain circumstances,
compared to the way that it is used in a clinical trial.

And where in the clinical setting, you have your notes. It says here
grocery shopping in my handwriting from six months ago. This is now six
months later, and I have nothing, and unless the patient offers that, I
ask the general questions, and perhaps the patient will remember that
six months ago I had given up grocery shopping and I am no longer doing
that.

Or grocery shopping used to be difficult and it is still difficult, but
I am a little better at grocery shopping. But I wanted to clarify that
point, because it is a point of concern that we have regarding how it
was implemented in the trial.

DR. MAHLER: I can\'t comment on how other sites or study coordinators
apply it. But certainly at our site, people frequently will scribble
things down on that sheet of paper as part of the form, and include
those activities, and whether that is done in other sites, I have no
idea.

But you should be able to in the interview process be able to pull those
things out relatively quickly.

CHAIRMAN DYKEWICZ: Thank you. Are there any further questions of the
sponsor or the FDA from the committee? Dr. Chinchilli.

DR. CHINCHILLI: Yes. This morning, Dr. Kammerman alluded to the fact
that there was some data imputation with the TDI, and I was wondering if
the sponsor could elaborate when the analysis was done, what form of
data imputation was there?

DR. MENJOGE: You know, there is no perfect solution for the missing
data. However, what we did was actually we used the last observation
carried forward method, and only in the case of the worsening of the
disease, which is about less than 5 to 10 percent of the patients, and
we used the last observation carried forward, and that is the techniques
that we used.

And we did the analysis with and without imputation, and they basically
showed the same results.

CHAIRMAN DYKEWICZ: Dr. Atkinson.

DR. ATKINSON: Yes. This morning, I believe they mentioned, or the
company mentioned that there were four patients that had had urinary
obstruction requiring catherization, and I was wondering how long, and
if they had any clinical information on how long that condition had
persisted, and how long it took to resolve.

DR. KESTEN: Those events were generally 24 hours to several days, and
there were one and two patients who had follow-ups with either
medication for BPH, and some subsequently had trans-retheral reception
of the prostate. But the period of catherization was temporary.

CHAIRMAN DYKEWICZ: Any final questions for the sponsor, or the FDA? All
right. What I am going to do now is move to the phase of the meeting
where we have discussion amongst the committee on the various topics.

And I am going to actually change the order a little bit, because we
have been having so much discussion since the return from the break
about dyspnea, it would be logical I think to continue on with that
discussion.

And so I would like to focus the committee though on several different
issues. First of all, and maybe because we have been talking so much
about it just recently, what do you think about the TDI as an instrument
for assessing dyspnea, and then following that, what do you think about
the execution of the administration of the TDI instrument in the studies
that are being presented for this new drug application.

I will open up things generally. Dr. Apter.

DR. APTER: I think for clinical use the TDI certainly is very useful. I
think it needs to be altered for clinical trials. I think there have to
be ways to write in what the patient said, and activities like the
grocery stopping.

For example, what activities in particular or even a set of activities,
like a group of activities that equal moderate activity, so that it can
be more formalized.

CHAIRMAN DYKEWICZ: Dr. Patrick.

DR. PATRICK: I think we are in the same realm here, and I guess it is
because of the age of the patients, and that we are somehow moving
towards interviewer administration. As we are in the field of
psychiatry, where we often do rating scales based on interviewer
questions and observations.

Even if we don\'t have the specific items, like grocery shopping, in
something like the brief psychiatric rating scales, all interviewers
would need to be trained at the same level of standardization.

And so that the inter-rater reliability was documented prior to using it
as an outcome measure in a clinical trial. It is my understanding that
was not done in this case, and therefore we don\'t know what was done.
Dr. Jones has been pretty convincing that if it was really terrible, we
might have seen much more noise and much more difference.

However, this is based primarily on the responder analysis, and not on
the mean changes, and the other methodological issues surrounding the
statistical analysis of the measure. So I think as the TDI, I would
agree with Dr. Apter that it is perfectly adequate as a clinical measure
as a staging measure, and for use in clinical practice.

For the use in clinical trials, the rigor of such an instrument needs to
be maintained at a very high level in order to be able to interpret the
findings, and we have not a clear demonstration that it was administered
consistently across the different sites, the translation questions, nor
the standardization of the interviewer training.

CHAIRMAN DYKEWICZ: Dr. Stoller.

DR. STOLLER: I would hold the view that as someone who has been
interested in the BDI and TDI that this a very clinically sensible
measure, and I think is applicable in clinical practice, and in
research.

In fact, its very strength, as I think Dr. Mahler pointed out, is that
it rests on the kind of information that clinicians would elicit from
patients that really go beyond the subtleties of filling out particular
boxes, and may escape the opportunity to capture that clinically subtle
information in the context of a somewhat more rigorously defined
instrument.

And in fact in conversations with Alvin Feinstein about it, in fact the
very strength of it was that it was clinically sensible. Now, that said,
the appeal of the instrument, therefore, requires the ability to
suddenly capture the information.

And so my concerns are not so much around the instrument itself, which I
think has the advantages as we have heard very eloquently stated by the
various conversants. But my concern is, and as I think I heard Dr. Jones
say, and echo, was that if one were to use this a priori as the outcome
measure in a clinical study, one would pay attention to validating its
ability to capture those subtleties in ways that were not possible given
the evolution of this as a co-primary outcome, with the data admittedly
still blinded, but already captured.

That understanding requires faith in the notion that a methodologically,
sub-optimally captured measure, would bias in the direction other than
the one that we see.

And I guess I am not willing to make that leap of faith in the context
of a clinical trial, in which the indication rests on the methodologic
solidarity of the instrument to capture that measurement.

So I would say that in response to your two-tier question, and I have
great faith in the instrument, and I believe that the instrument can be
very carefully calibrated, and I am sure that if Dr. Feinstein were
here, he would echo that strongly.

That was the impetus to develop a clinically sensible instrument at that
time. But I think he would also say that were he reviewing data in
advance of a rigorous conclusion around an outcome measure anchored on
this.

And he would say that the methodology needs to be more rigorous around
demonstrating the impact of this particular intervention on the outcome
measure. And I guess while respecting the breath of experience about the
way that bias goes with methodologically sub-optimally captured
information, I myself am not willing to make that leap of faith in
regard to this, and to the indication with regard to dyspena.

CHAIRMAN DYKEWICZ: Thank you. Ms. Schell.

MS. SCHELL: Thank you. I just have some concerns that I wanted to bring
up. I agree that the instrument is a valid instrument, and it has to do
with the skill of the interviewer, and not so much as the result, and
what I am trying to say is that sometimes the interviewer has to be
standardized all across, because as we know with many of our patients
that are being interviewed, their mental state has also deteriorated
along with their disease state.

And it is difficult to get answers from them, or correlate those
answers, and if the interviewer isn\'t trained or skilled in
interviewing, and getting those probing questions, it is difficult to
get a direct answer from the patient.

And so I think it is important that there is a standardization of the
interviewer for this process.

CHAIRMAN DYKEWICZ: Thank you. Dr. Parsons.

DR. PARSONS: The only other point that I would like to make is that even
\-- and I agree with all of the comments that have been made about the
TDI, but I think the one other part we have not discussed, or has not
come out quite as much is when there are subtle changes in the TDI, in
terms of numerical changes, what do those really mean, and it is not
clear to me that those really have been tightly correlated with and
going out to a group of patients and saying does this make a difference.

So, yes, indeed, your score may have changed, or you may go through the
grocery store a little bit faster and not to denigrate that, but that
may or may not make any difference ultimately to somebody\'s quality of
life.

And I think that to use the instrument for research purposes, it would
be tremendously helpful to understand what changes in those numbers
really mean to patients, and what it means to the quality of life, and
their ability to function.

So that you are not just looking at a raw number. You can actually then
say this is what the impact is on that number, and what that number
means.

CHAIRMAN DYKEWICZ: Thank you. Other comments on the TDI? If not, let\'s
continue to focus on the TDI, but from the perspective of the results
that were generated for the new drug application. Do you believe that
focusing only on the TDI results, that the improvement that has been
reported is clinically significant, clinically important. Dr. Apter.

DR. APTER: I guess I have to say because of all of the methodologic
problems, I don\'t know what to say. I can\'t be convinced, although it
may very well be a good drug.

CHAIRMAN DYKEWICZ: Dr. Meyer.

DR. MEYER: I hope I\'m not overstepping my boundaries here, but I would
suggest that this question might be helped by saying that if there were
no methodologic concerns, and if we had a perfect institution of this,
or incorporation of this into the clinical trials, and we saw these
results, what would people think of those.

CHAIRMAN DYKEWICZ: Dr. Patrick.

DR. PATRICK: I think Dr. Parsons answered this all before in my view,
and without knowing across these patients whether this was a minimally
important change to them, it is difficult to say that we have defined
this one unit as the MID.

In addition, there is only one possibility here, in the sense that one
unit is the minimum amount of change, in terms of the grading. And that
issue, in response to would a patient say that this was an important
change, or the smallest important change, is missing information for us.
So that is a pretty important piece in the MID.

CHAIRMAN DYKEWICZ: Dr. Chinchilli.

DR. CHINCHILLI: Yes, I agree. Just because there is statistical
significance, it doesn\'t translate into clinical significance, and from
what I gather, my clinical colleagues on the panel are struggling with
that, as to whether this is clinically meaningful.

So my interpretation of this is that I would say it is not condusive of
evidence to say that it is effective based on looking at dyspnea.

CHAIRMAN DYKEWICZ: I will add my own comment. I think that Dr. Sullivan
presented some very important analysis on this data, and that was where
he was looking at the dyspnea efficacy analysis and mean values in the
six studies that were being presented.

And on the question of whether there was a difference of greater than
one, which has been proposed as something that would be clinically
important, and if you look at what I would count up to be 27 or 28 time
points in these various studies, and bits of data, there were
approximately only 12 that there was achievement of either a difference
of one or greater than one.

So if you look at it one way, you could say that half the time or more
it really is, as Dr. Sullivan has indicated, is not supporting the idea
that there is a clinically important difference.

Now, the question also then, and it begs the question as to whether a
difference of one is a clinically important difference, and do you
potentially have to have even a higher threshold than that.

I think that Dr. Parsons\' comments have already addressed that, and I
just simply don\'t know, and whether you achieve a clinical difference
of one, whether that is going to represent a significant clinical change
or an important change shall we say in the patient outcome.

CHAIRMAN DYKEWICZ: Other comments on that point? Dr. Joad.

DR. JOAD: I would just say that it seems to me that if a change of one,
at least in the two of the categories, would be possible, and still you
would be within one of the categories within the basic test, and that
they have to remember six months back. It just doesn\'t seem possible
for me that that would be a clinically important difference.

CHAIRMAN DYKEWICZ: Dr. Stoller.

DR. STOLLER: Dr. Meyer put on the table the question of if this were a
methodologically ideal would we put credence in a difference of one, and
it really gets to what are the criteria, and how do we ascertain what is
a clinically important difference.

Others have put on the table feeding that back to patients in some
feedback and say do you regard this as clinically important. I would
regard much of the literature about establishing minimally important
differences has to do with the parallelism of other kind of clinical
anchors, other subjective measures and other objective measures that in
aggregate point towards establishing some threshold that we would regard
as minimally importantly different.

And in my own view, in some ways \-- and in fact the validation paper
that is in press, of course comes from this dataset, and in some ways
the establishment of minimally important difference comes from
correlations of lots of outcome variables from lots of different studies
that say that these things all move in the same direction or not.

And in that regard, I think leaving aside the methodologic shortcomings,
because that is the premise of the question, I would say that I find
that the datasets are somewhat convincing in helping me believe that a
difference of one is important.

I wouldn\'t say that I am absolutely from the available information sold
on the point, but it certainly moves that issue towards being more
convincing to me. Again, the premise of the question being if it were
ideally administered, and methodologically acceptable.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: Jimmy, can I ask you a question just for clarification. If
there was another drug that was studied in this patient population, and
the only outcome was TDI, greater than one, would you be comfortable at
this point saying that it correlates well enough with changes in FEV1?

In the past, we have been told that there is a significant change which
has been defined in FEV1, and that their assumptions that there are
clinical changes that go along with that, based on a lot of information
from the past.

So would you be comfortable flipping it at this point and saying if a
study came through and all that was measured was TDI, that a TDI of one,
a change of one, means that the physiologic variables occurred? I am
just curious.

DR. STOLLER: I\'m glad that you focused your question that way. I would
say at this point, no.

CHAIRMAN DYKEWICZ: Other comments on the TDI instrument, and the data
that has been presented? All right. Then going a bit broader, discussing
any other end points that were presented to look at the question of
dyspnea.

Is there anyone who would like to make some comments relative to an
aggregate, and do you believe that there is other data that would be of
sufficient enough validity or reliability to increase the assessment, or
the confidence of the assessment, that there has been some clinically
important change?

All right. Another point that I would like to have the committee discuss
is the concept of dyspnea itself as an indication for treatment with a
drug? As the FDA has pointed out to us today, this would be a departure
from previous practice.

Dr. Apter addressed this to some degree earlier, and I would like some
discussion about the indication of dyspnea. Is this something that is
important to have, or is this something that is not really of relevance
to the prescribing physician. Dr. Schatz.

DR. SCHATZ: To me the answer to that question has to do with the extent
to which dyspnea represents something above and beyond the
bronchodilator effect, and we have heard both some theoretical and I
think some data to suggest that dyspnea in fact represents more than
just a bronchodilator effect.

But I don\'t hear us feeling that we have seen enough data to answer
that question. So my answer would be that I think that dyspnea, to the
extent that it does represent something different than a bronchodilator
effect would be an important outcome.

Certainly it is an important patient center outcome, but we would need
to have, I believe, the clinical tools to be able to sort that out.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: As a general comment, it seems to me that I would like drugs
like this to be for an indication other than bronchodilation. As a
practicing physician, you don\'t give someone a drug because it changes
their FEV1. You give them a drug because it makes them symptomatically
better in some ways.

So I would very much like the indications to be based on a symptom, or
on a word like dyspnea. As a pediatrician, I never used the word
dyspnea, it just never comes up. Somehow I can take care of a lot of
pulmonary disease without that word.

And it is just a comment observing all of this, that it is such a
complex thought, and it includes so many different things, is it useful.
I just don\'t know if it is useful. I am just throwing that out as
whether it helps or whether it is just functionally what you can do, and
how much you try to do something, and how breathless you get, and your
total lung capacity.

I mean, there are so much things that people throw into dyspnea, is a
useful construct.

CHAIRMAN DYKEWICZ: Dr. Stoller.

DR. STOLLER: I should say that I applaud the attention to these
subjective outcome measures, because I think as has been amply been
stated, this is in fact what brings patients to our attention.

And so from a clinically relevant point of view, I deal with patients
with dyspnea all the time, and what brings them as I think has been
amply and eloquently stated, but what brings them to our attention is in
fact this very symptom.

And we have struggled, you know, clinically with whether these, as Dr.
Sullivan pointed out, whether these are really surrogate measures and
truly reflective of things that matter to patients.

And dyspnea is clearly that, and so there is no doubt in my mind that
the attention to this is an indication for a drug is laudable, and I
applaud the attempt to do so. The question in my mind is how convincing
has been the ability to do so given the laudability of the goal.

But there is no doubt in my mind that that is absolutely essential and
that more attention should be in fact given to these kinds of outcome
measures in the assessment of clinical interventions.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: I actually don\'t disagree with that at all, and obviously
the reason that I gave any of my patients who have COPD is to decrease
their symptoms. The one caveat that I just thought about was that I have
a great drug to treat dyspnea, and it is morphine.

And it is not practical. Okay? It is not a good drug for dyspnea in a
patient population that we are talking about. So, yes, I would love to
see dyspnea included as part of the evaluative process, but it can\'t
stand alone, because then we can treat dyspnea.

And morphine is a terrible drug and so we need to be sure that we keep
that in context. That as these more subjective measurements come along,
I think we have to have more ground rules. We need to see other changes
in a positive direction somehow related to physiology.

CHAIRMAN DYKEWICZ: Dr. Stoller.

DR. STOLLER: I take the point as to whether the outcome is clinically
sensible, and I think that you and I would agree that the dyspnea
benefits about morphine are at first pass not clinically sensible in the
context of the other effects of this drug.

But in the context of drugs that have other physiologic benefits, but
also by the way happen to improve a subjective measure, I don\'t think
you and I would disagree at all about the importance of anchoring an
indication for treating a patient, as well as perhaps approving a drug
on a symptom that brings people to our attention. There is no doubt
about it in my mind, no doubt.

CHAIRMAN DYKEWICZ: Dr. Apter.

DR. APTER: So what would be ideal would be a combination of measures
that get at the patient\'s perception and are tied in a physiologic
benefit that the physician can measure. And of course that doesn\'t
always happen, but that would be ideal.

CHAIRMAN DYKEWICZ: Dr. Swenson.

DR. SWENSON: Well, along those same lines, I wonder \-- and I am not an
epidemiologist, and I would throw this to those people that think about
this all the time, but at some point, particularly using this index in
the evaluation of drugs, would it be of some utility to throw the
question ultimately back to the patient to ask would they be willing to
sacrifice a certain amount of \-- for example, their income,
appropriately scaled to their own income.

But would they be willing to sacrifice for this benefit and this could
conceivably add some value to knowing whether an index of one is a
sufficient improvement.

CHAIRMAN DYKEWICZ: All right. Back to the question about whether it is
an important indication to state that dyspnea would be something that
would be treatable by a drug. I am just trying to look at it in
practical terms, as to whether the prescribing conduct, the prescribing
decision making of a physician, would really be altered by statements
about specific symptoms that are being relieved.

Symptoms such as symptoms of dyspnea, and maybe exercise tolerance, and
wheezing. I think in practice a drug that would state, or a drug insert
that would state that the product is for the indication of bronchospasm
related to COPD, in essence it is still going to end up being used for
treating patients who are presenting as Dr. Stoller\'s has, with
subjective complaints of dyspnea and potentially wheezing and so forth.

So I am not convinced that it is absolutely necessary to position the
appropriate use of this drug, and to have it listed dyspnea as an
indication. Other comments on that point?

CHAIRMAN DYKEWICZ: Ms. Schell.

MS. SCHELL: I also have some concern. I agree that an indication is a
good reason to put the drug out there for that, but when a patient looks
at the label and reads this is going to help my dyspnea, and they are
disappointed because their perception of their shortness of breath,or
their breathlessness is not improved, then we are putting out kind of a
message that this is \-- well, a hope for them that isn\'t being
succeeded.

Do you see what I am saying? That we are putting out that this is for
breathlessness, and I go to the doctor, and I say I want this drug
because it is for dyspnea and I have dyspnea, and I come back in six
months, and if I am not any better, then I have this perception that
this drug wasn\'t any good.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: Just to follow up on the complexity of the word dyspnea in our
conversation. When you mentioned that morphine would fix or might fix
dyspnea, it would fix breathlessness and shortness of breath.

You still couldn\'t walk up a hill and you still couldn\'t take a
shower, or whatever the problem is. So it just strikes me as such a
complex inability to do exercises is one thing, and the feeling of the
shortness of breath, or breathlessness is another thing.

And throwing them all together into one concept, and that then can be
carefully analyzed and given a number to, strikes me as a very hard
thing to decide to do.

CHAIRMAN DYKEWICZ: Other comments from the committee on the indication
for dyspnea just theoretically from any drug.

DR. SCHATZ: I would just agree with you that I think from the standpoint
of getting what appears to be an effective drug by the usual indicators
to the people who need it, whether dyspnea is listed as an indication or
not doesn\'t appear to be a major difference.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: I was just going to note that if Ms. Schell is concerned
that a number of patients who had hoped that their dyspnea would be
relieved, and then be disappointed when it wasn\'t based on the intent
to treat analysis that was done by Dr. Sullivan, approximately 6 out of
7 patients would be disappointed, and based on if they are responding to
that indication alone.

CHAIRMAN DYKEWICZ: Any further discussion on dyspnea or the tools, or
the instruments used to measure it? All right. Then organizationally I
would like to call the question, which is actually numbered as four on
our agenda.

And that is do the data provide substantial and convincing evidence that
tiotropium bromide inhalation powder, and that provides a clinically
meaningful effect for the symptom of dyspnea in patients with COPD.

And this will be a yes or no answer format, and what I will do is take a
poll of the members of the committee, and then at the end give an
opportunity for any qualifications or final comments that individual
members of the committee may have about the question. Dr. Kennedy. Okay.
He doesn\'t vote. Dr. Schatz. He doesn\'t vote. Dr. Patrick.

DR. PATRICK: No.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: No.

CHAIRMAN DYKEWICZ: Dr. Atkinson.

DR. ATKINSON: No.

CHAIRMAN DYKEWICZ: Dr. Morris.

DR. MORRIS: No.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: No.

CHAIRMAN DYKEWICZ: Dr. Stoller.

DR. STOLLER: No.

CHAIRMAN DYKEWICZ: And I vote no. Dr. Swenson.

DR. SWENSON: No.

CHAIRMAN DYKEWICZ: Dr. Apter.

DR. APTER: No.

CHAIRMAN DYKEWICZ: Dr. Chinchilli.

DR. CHINCHILLI: No.

CHAIRMAN DYKEWICZ: Ms. Schell.

MS. SCHELL: No.

CHAIRMAN DYKEWICZ: All right. Now, having made those votes, I would like
to give the opportunity for you to make any additional comments, but
along those lines, question five is really addressing what might be some
additional comments, and this might help focus additional comments in
general.

What quality and quantity of data would constitute substantial and
convincing evidence of a clinically meaningful benefit for the symptom
of dyspnea in patients with COPD. To put it another way, if a study
sponsor were to approach the FDA for the indication of dyspnea, what
sort of data, and what caliber of data would you like to see in order to
justify that indication. Dr. Apter.

DR. APTER: In addition to the things that have already been mentioned, I
wanted to reiterate that it would be validated in diverse populations,
ethnically, and gender.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: Actually, Dr. Joad\'s comments made me realize that
probably one of the first things that will need to be done is to define
dyspnea. I think actually I know realize now that I have thought about
it a little bit more, that we are probably all talking about something
different as we sit around the table, and we have never truly defined
what it is.

And actually if you look at the TDI, it is more of a change in ability
to do things perhaps. So I would say that like a lot of things in
medicine, we often times think we are all talking about the same thing,
and I don\'t think we are.

So I would suggest that we come up with or that a definition be
developed for what is truly being measured and looked at, because as a
clinician, I know what my patients look like, but it is clearly
different than pediatric, and it may be very different than others.

CHAIRMAN DYKEWICZ: Dr. Patrick.

DR. PATRICK: I would like to qualify, and I think they have gone a long
way, and so the word substantial might be \-- I might have said that
they provide substantial evidence. To me it was not convincing, because
I still am not sure how the instrument was used.

I would think that the data that would be useful would be a study
specifically on the minimally important difference, and that it included
a separation between the reports of the sensation, and the activities
that product that report.

And that it be a combination of a patient report and a clinician
interview, and that we would need specificity if it is going to be based
on a clinician interview of exactly what was the baseline.

I am not at all convinced, although I know Dr. Jones very well, that it
is big mistake in a condition like this to give people their baseline
activities. I am not sure that we can do it any other way.

This is an age-old thing, and so I would say that we need a test of that
as well. So I am just going to suggest the evidence for that.

CHAIRMAN DYKEWICZ: Dr. Morris and then Dr. Stoller.

DR. MORRIS: I think in an ideal world tying such a hard to understand
concept of dyspnea is something a little bit more concrete would be
useful. Something that is objective, and something that is reproducible,
and some activity of daily living and reproducible testing might be
something that we would strive for.

And something that could be tested in Europe or in the United States,
and with a certain amount of work being expanded and applying that then
also the rating of a dyspnea scale.

But some more concrete aspect of the test, rather than the subjective
language part of the test.

CHAIRMAN DYKEWICZ: Thank you. Dr. Stoller.

DR. STOLLER: I would again preface my remarks by saying that as has been
pointed out, there is no dyspnea meter. There is no gold standard so
that the rigorous attempt to define this really uses the functional
aspects of the symptom.

That said, these instruments about which we have heard much I think
represent tremendous methodologic advances in our ability to place
confidence in the measurement of clinically important outcomes.

Having said that, the kind of information that would be important to me
to persuade me that dyspnea was a reliable and credible outcome measure
in a clinical trial would be largely to address the methodologic issues
that Dr. Kammerman summarized.

I have as I said before, I have belief in the clinical sensibility of
actually several of the measures we have heard about through really the
vigorous work of those who have discussed them; Dr. Jones, Dr. Mahler,
and I am comfortable with either of those if ideally administered.

I would hope that there would be greater attention to the defining of
the minimally important clinical difference. I agree with the comments
made about demonstrating the reproducibility in different populations as
we apply these drugs to populations other than those of the narrow
clinical context of clinical trials, because in clinical practice that
matters.

And one would need to know the conclusions around dyspnea and outcome
measures are generalizeable, but I think most importantly my
reservations have to do with the methodologic shortcomings of applying
the outcome measure in a kind of after the fact.

And that a rigorously designed prospective study in which attention to
some of these methodologic details about the training, reproducibility,
translatability, generalizeability of the measure, in the context of a
reasonable demonstrated, minimally important difference, would certainly
convince me of the utility of these measures as an indication for a
drug.

CHAIRMAN DYKEWICZ: Dr. Schatz.

DR. SCHATZ: And as I alluded to before, in addition to all of this, it
would seem to me that being very concerned about recall issues, that I
would be in favor of seeing the longitudinal properties of the BDI in
this validation process.

That it would be the BDI that would be done over time, and compared with
other relevant clinical parameters.

CHAIRMAN DYKEWICZ: My own additional comments other than what have
already been said is that I think you would want to have an instrument
that is the patient reported symptoms of dyspnea. We know that in other
disease states that when there has been a physician assessment of
patient improvement, compared to improvement in patient symptom scores,
there can be some discordance.

And I think as much as possible should go right to the source, the
patient, and if possible devise a questionnaire that asks them directly
without filtering, even though it might be a learned intermediary, but
without filtering, ask the patient symptoms that could be used to
support whether there is actually an improvement in their symptoms. Dr.
Patrick.

DR. PATRICK: I might add on to that, and that one of the reasons that
the interviewer form is important is because is because of missing data,
and therefore, the data is highly unlikely to have been missing at
random, and so there needs to be an addition, an investigation of either
the surrogate endpoint from the clinician, as well as different methods
for imputation, in addition to last observation carried forward in the
data analysis.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: Well, if I am understanding you right, it seems like the crux
of the word dyspnea is how much work can you do before you become
dyspneic, and so it seems to me that it would be nice to validate it
with one of those kind of tests like they discussed.

You do a certain amount of work, and then at which point along that work
do you become \-- and that is like a real test in a real laboratory. And
then take the history, and see how valid and how.

CHAIRMAN DYKEWICZ: Thank you. Dr. Chowdhury.

DR. CHOWDHURY: Ye. Just a clarifying question on number five. We had in
our discussions quite a bit of input regarding the quality of data, and
I just wanted to also emphasize on the word quantity, and perhaps have a
brief discussion on that.

And whether TDI itself is enough for one to (inaudible) indication or
would somebody want some other measures to go along with it. I would
like to have some input on that regard.

CHAIRMAN DYKEWICZ: Well, I will give you my response Echoing what I said
just a few minutes ago, I think you would want to have both the TDI and
another bit of data, which is directly getting reports of symptoms from
the patient.

And I think there has to be a pairing of those two really for optimal
assessment of that. Dr. Patrick.

DR. PATRICK: This is just an addendum to that. You also want the
patient\'s global rating of the change that they have experienced, and
whether it is minimally important to them.

CHAIRMAN DYKEWICZ: Dr. Stoller and Dr. Swenson.

DR. STOLLER: I would say that actually many of the data elements that
would convince me of the efficacy of a drug that we have heard about in
the context of this study. That to fantasize, that were we to have been
shown a study that would have rigorously captured BDI and TDI data, SGRQ
data, pulmonary function tests, physician global assessment, patient
assessment, and that there were convincing evidence that those \-- you
know, moved in a concordant direction, that would provide a weight of
information from my point of view that would bolster and buttress the
idea that these important measures would measure different things.

And I should emphasize in response to comments that these explicitly
should and do measure different things. That the notion that we should
validate a subjective instrument on a single physiologic measure is to
my thinking clinically naïve, as it ignores the richness of clinical
material, and clinical experience that forms patient\'s symptoms, and
what brings them to our attention.

So if we really wanted to know what the VO2 max is, we should suspend
interest in these clinically symptomatic measures, and simply measure
VO2 max. We are explicitly interested in as clinicians, I believe, the
richer experience of patients as they experience their illnesses, and
these functional status measures in different dimensions, although there
is some co-linearity of some of these measures as I think we have heard,
they are designed to capture that.

What is missing is the convincing evidence that they were captured in a
way that would be \-- you know, to say that I am not convinced is to not
say that there is evidence that they don\'t improve dyspnea.

It\'s just that given the dataset, I am not convinced that these data as
presented to us do that. In the ideal, these data elements, should the
results be concordant in the way that I have described it, would
persuade me if I am in a methodologically perfect way.

And if we could satisfy the premises that Dr. Meyer put on the table
before, and if they were ideally captured in all of the close scrutiny
about the methodology was addressed, I would find this quantity of data
persuasive in my view.

CHAIRMAN DYKEWICZ: Dr. Meyer, did you want to comment specifically?

DR. MEYER: Actually, I wanted to ask Dr. Stoller just a follow-up for
clarification of his points. With regard to the dataset that we saw
today, realizing that they are in fact measuring different things, what
do you make of the fact that no effect was seen on something like a
shuttle walk test, when you have an effect apparently on the TDI?

DR. STOLLER: You know, you bring up the issue of concordance and
correlation between measures, and frankly I would ask or could ask the
same question of what is a minimally important difference in a shuttle
walk test, you know, that would define a basement threshold for what is
important.

And I as a clinician would be much more content to accept someone\'s
consistent reporting that they felt better could do more than if they
could walk 10 meters further. I have this difficulty with six minute
walk measures as outcome measures in studies that we read about
different pulmonary illnesses, pulmonary hypertension among them.

So I am not bothered by some discordance in terms of the individual
measures. If the weight of the evidence suggests that there is a general
trend among multiple measures that are indirectly measuring similar, but
not identical things, I would find that persuasive.

And I am not sure that one could ever be more precise about \-- you
know, when one gets into the arena of if you are going to measure
functional outcomes, one has to live with this non-complete concordance
of measures, and I am personally comfortable with that.

CHAIRMAN DYKEWICZ: Dr. Swenson.

DR. SWENSON: Well, just to repeat this thought that what is ultimately
most important is the patient and his or her evaluation of the effect of
the drug.

And that\'s why I raised this point, that possibly at the very end it
should be brought back to the patient as to is this meaningful to you,
and could we come up with some way to pose that to the patient and only
in a theoretical sense.

I don\'t mean to say that we should be advocating certain percentages of
income or whatever to the cost of drugs, but to place it in a
theoretical perspective. How much value is this to you, and would you be
willing to sacrifice for this.

If some tool of that caliber could come up, I would be then willing to
accept a value of one as being meaningful. Right now, we are still
floating about is one a number that anybody can really hang their hat
on.

CHAIRMAN DYKEWICZ: Thank you. Any other comments? Dr. Kennedy.

DR. KENNEDY: Thank you. I am sitting here thinking that there is
probably a number of people in the audience and folks who are listening
in, who are now planning dyspnea studies, and we are talking about it
like it just fell out of the sky. That it was the first study that was
ever done.

When in fact the Mahler paper was prepared because there was a need, and
it has been in place for a while. And I am sure that every pulmonary
drug that has been submitted to the agency in the last 15 years probably
has some measure of this.

The question that I would pose to you as a committee is to give some
consideration. If there are data on-hand now within the FDA that is able
to measure these changes more discreetly than the one unit change, and
found out that all of the data in place were .3, this change of a full
unit today would be something significant.

So what I am asking you to do is don\'t try and define the world on the
basis of this one or two studies that you have seen today, but ask our
colleagues at the FDA to help provide the industry with some input on
all of the stuff that has been done up to this point.

CHAIRMAN DYKEWICZ: Thank you. Dr. Sullivan.

DR. SULLIVAN: Just to partially address that, is that in fact in these
studies there was an active control of an approved drug for COPD, and
the data was presented regarding how they responded on that end point.

So there is some information about how other drugs out there behave with
this instrument.

CHAIRMAN DYKEWICZ: Any final comments on dyspnea or its assessment?
Since we are talking about efficacy, let\'s go to what is numbered as
Question Number 3 about bronchodilator effect of the drug, and question
3 is do the data provide substantial and convincing evidence that
tiotropium bromide inhalation powder provides a clinically meaningful
bronchodilator effect when used in the chronic treatment of patients
with COPD.

First, let\'s open this up to discussion. Well, I will say that I think
that it has been established, and I don\'t know if anyone would take
issue with that. Dr. Stoller.

DR. STOLLER: I would like to make one other point, and that is that once
of the novel aspects as I think has been pointed out of this particular
outcome measure is the trough or nadir level prior to dose.

And actually I applaud that as an end point, because although it has
been less well filled out, in terms of being unconventional, and
therefore not having the matrix of the magnitude of effect, it is from a
clinical point of view, I think as has been pointed out, far more
meaningful than a transcent peak effect.

And now it is convincing and reassuring to me to know that in fact the
peak and the trough outcome variables are the same with regard to the
data that we have seen. But I think the notion of looking at trough
effect, particularly in a long acting drug such as this, is a laudable
and significant advance in the assessment of drug efficacy. So I would
say that as a baseline.

CHAIRMAN DYKEWICZ: Thank you. Dr. Parsons.

DR. PARSONS: I just have a question. I totally agree that they have
shown a significant bronchodilator effect, and I actually like the
trough data as well.

In future studies will trough data be adequate? If we had not seen the
greater than 200cc change in the acute, would we know what to do with
the specific trough number?

DR. STOLLER: I think it gets to the issue what is the primary and
secondary outcome measure. As a primary outcome measure, as is indicated
here, I would favor the trough, but I would like you be absolutely very
interested in looking at the pharmacokinetics and the physiologic
response over time, which I think we have been shown.

And so the answer is that if I were on a desert island, and had to pick
one outcome measure, and would that suffice, I would say no. But of
course in the richness of clinical investigation, we are often given a
fuller dataset.

Now, if you were to ask me if the trough data were good, but there were
no significant rise in the peak, what would I do with that, and I guess
I would have to think about it. But I would actually find that more
reassuring clinically to find the trough data over time sustained than
even lower peaks.

So the answer I guess would be, yes, if I had to pick, in terms of
primary outcome measures, I would favor the trough as was done here, and
so I actually applaud that.

DR. PARSONS: Actually, my question was in terms of the agency, if they
came back and said what is an appropriate trough change, and so we know
the peak change is 200, and that is the number that we are using.

Do we now have a number for the change in trough level that we use?

CHAIRMAN DYKEWICZ: I don\'t see anyone volunteering.

DR. SHOLLER: Well, it gets to how the peak data were derived. I mean, in
fairness, the 12 percent and 200 ml with people sitting around in the
ATS spirometry statement saying what we in the FVC lab define as a
significant BD response.

Prior to that it was 15 percent without an absolute volume. So I am not
sure that 140 or 110 ml increment in a baseline population if the mean
you want is 1.04 to 1.2 liters, is any less convincing than an
arbitrarily embraced \-- and furthermore, just to get to the
arbitrariness of it, it is often accepted in the November 1995 ATS
document.

It is often accepted actually as an outcome. I think I should correct
that and I think it is in the spirometry statement and not in the
November \'95 COPD statement.

It is often accepted as an outcome measure for FVC, and yet we obviously
understand that patients with COPDs, and FVCs and not FEV6s are highly
sensitive to exploratory time. So that it is not uncommon to see in the
lab two successive blows; one at 12 seconds and one at 8 seconds.

There is obviously a 12 percent and 200 ml difference, which on that
criterion would satisfy bronchodilator responsiveness, but is in fact
not. It is simply related to the artifact of different durations of
exploration, knowing that these patients can blow out for 15 or 20
seconds and still continue to exhale gas.

So my comments simply address the relative arbitrariness of the 12
percent and 200 ml. I personally find \-- and to answer your question in
regard to the data with regard to the magnitude of trough effect as
building up, and an assembly of data that says this is a clinically
significant trough effect of a long acting drug, yes.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: I agree with you a hundred percent. I just am thinking that
six months from now when the next drug comes in, are we going with 140
or is a hundred okay? If I was in the audience, I would probably want to
know if there is any recommendations.

And I have no clue as to what he right answer should be. I mean, I think
the dataset shown today, in an aggregate, are convincing, but if you ask
me specifically would the trough level alone be enough, I would say,
boy, I have no guidance because I don\'t really know what the number
should be, even based on the good people at the ATS telling me, but they
haven\'t told me yet.

CHAIRMAN DYKEWICZ: Dr. Schatz.

DR. SCHATZ: What seems to me is that maybe you have answered your own
question, which is that we can\'t do it as a single measure, and that we
really have to take each case individually, and look at the aggregate.

But I would also say that knowing how this was part of an aggregate
would help me be more comfortable with something like 120cc\'s in a
future study, but I still would feel that I don\'t think we can answer
your question right now.

CHAIRMAN DYKEWICZ: As good a question as it was. Is there any further
discussion? Ms. Schell.

MS. SCHELL: Yes. I just would like to add that I am excited that the
dosing, the dosing on compliance on the patients that I care for. It is
very difficult to take them out of medications now and for one dosing to
get this result. It is exciting for me to see that, and I think it is a
plus.

CHAIRMAN DYKEWICZ: Any further discussion on the bronchodilator effect?
Then we will call for a formal vote. Again, do the data provide
substantial and convincing evidence that tiotropium bromide inhalation
powder provides a clinically meaningful bronchodilator effect when used
in the chronic treatment of patients with COPD? Dr. Patrick.

DR. PATRICK: Yes.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: Yes.

CHAIRMAN DYKEWICZ: Dr. Atkinson.

DR. ATKINSON: Yes.

CHAIRMAN DYKEWICZ: Dr. Morris.

DR. MORRIS: Yes.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: Yes.

CHAIRMAN DYKEWICZ: Dr. Stoller.

DR. STOLLER: Yes.

CHAIRMAN DYKEWICZ: Dykewicz votes yes. Dr. Swenson.

DR. SWENSON: Yes.

CHAIRMAN DYKEWICZ: Dr. Apter.

DR. APTER: Yes.

CHAIRMAN DYKEWICZ: Dr. Chinchilli.

DR. CHINCHILLI: Yes.

CHAIRMAN DYKEWICZ: And Ms. Schell.

MS. SCHELL: Yes.

CHAIRMAN DYKEWICZ: Thank you. We will now turn our discussion to side
effect profiles, and concerns about that. Because of a number of
different issues were raised, I would like to focus the committee on
several subtopics.

First of all, the issue of if you will anticholinergic side effects,
including dry mouth and some of the GI side effects. If we are looking
at obviously a drug that will be used in clinical practice, what is your
assessment about the risk benefit profile. Dr Schatz.

DR. SCHATZ: One of the things that impressed me was as common, and as
much more common as it was in the patients taking the drug, it was very
uncommon for patients to discontinue it because of that. So that makes
me much more comfortable with accepting those side effects.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: Could the FDA remind me what \-- when the word adequate is on
this question, what are the options. The options are to study more
patients, and the other option is to do Phase IV follow-up of some sort.
Could you just remind us if you choose to approve a drug, even though
you have some concerns about side effects, what are the options for
following that in the future?

DR. MEYER: Well, there are in fact options. I mean, generally the cut
that we make internally is are there any gaps in the safety knowledge
substantive enough that you wouldn\'t want to approve it. That you
don\'t know enough about the risk to benefit ratio to put it out there.

There will always be some gaps in our knowledge, because no matter how
many \-- and this is a fairly large program that Boehringer Ingelheim
did, but no matter how many patients they study, it is not until you get
into several million patients that you begin to understand some of the
more subtle signals, because a large trial such as in a database such as
this, may give us a reasonable chance of finding something with a one in
a thousand occurrence rate.

But if it gets into millions of patients, you are going to see some more
subtle signals. But in any case, given the fact that you may have gaps
that would preclude approving it, and given the fact that in the best
scenario that you will never have a good complete knowledge of the
safety, there is middle ground where there might be nagging questions
that don\'t preclude approval, but do warrant some phase four studies.

Commitments from the company to further allucidate some area. I am no
sure whether I have answered your question.

DR. JOAD: Yes, you did really well. I just have one more part of that. A
lot of the side effects are these ones that you would expect to happen
in this age group anyway. So they are not going to be an adverse \-- if
somebody dies of an MI, or somebody has a fecal impaction or something,
or a urinary tract problem, they wouldn\'t \-- it would not come in as
an adverse drug report probably. But that would be part of Phase IV to
pick up those.

DR. MEYER: Well, those might be situations where a specific study could
be warranted, because if it is something that occurs commonly in the
population, even if it comes in as an adverse event report, it may be
difficult to interpret that, because we don\'t really have a firm
denominator for those kind of post-approval data.

So those are situations where it is a potential that you would want a
Phase IV study, a rigorous study.

DR. JOAN: Can I ask one more question? The groups that were excluded due
to side effects for these studies, when this gets marketed, will they
\-- will the part in the package inserts say this, that those same
groups should not get this drug at all, or be careful, or \--

DR. MEYER: I am not going to answer that question because it is actually
the basis of our question, too, that we are putting to you. So I don\'t
want to put an answer into anybody\'s mouth.

CHAIRMAN DYKEWICZ: Dr. Swenson.

DR. SWENSON: Well, let me move to one concern that I have, and that is
the issue of the renal excretion of this drug. Although the total
absorbed dose is low, we have seen that the drug levels are measureable
over time, and we are seeing a slightly greater rate of complications on
the basis of anticholinergic effects with Spiriva as compared to the
standard in the field; that is, Atrovent.

So I would be worried that if the drug is used more widely, and people
would compromise renal function, that what may look just like going over
the top of a dose response curve, and possibly just leveling out, or
does that represent really an important steep portion of a dose
response, and that we would expect to see a lot more problems in people
with renal insufficiency?

CHAIRMAN DYKEWICZ: Other comments? Dr. Stoller.

DR. STOLLER: I guess my response to this has to do with several things.
One is what in my own mind is the magnitude of the risk, and what is the
magnitude of the clinical benefit, and what is the functional
performance of patients in the dataset with regard to the study, and
discontinuing the study drug.

And then the general reliability issue; are there subsets that were
explicitly not included in these studies for which the pharmacologic
properties would pose particular problems.

So I am imagining some potential patient subsets, for example, and
patients with significant co-morbidities of both, for example, kidney
and heart disease that were explicitly excluded from these studies, and
that as we heard before, might pose potential risks for a drug.

A patient with a creatine of four, and triple vessel coronary artery
disease, and who happens to have COPD, and that is not by any means an
impossible scenario. These are patients for whom either there might be
some language, cautionary language around the generalized ability of
these conclusions to that patient population with regard to safety.

Or alternately \-- and I am not sure how this is done, but some
attention to the specific performance of this drug. Now, admittedly,
those are patients not in this set. I have no concerns about the safety
profile of the drug as presented in the populations to us, because I
think that dry mouth is something as was pointed out that patients are
willing to tolerate for the sake of the clinical benefit that they
appreciate.

And I think that in the study population as we have seen it, large as it
is, there was ample evidence that these are tolerable, and not life
threatening, and not serious, and certainly not sufficient to deny
people the opportunity to use this drug.

I just think that perhaps some attention \-- and I am not sure what
specific recommendation to make, but some attention to these excluded
subsets, in which the pharmacologic profile might provide particular
concerns. Not that we have seen that, but on a theoretical basis, might
require some more attention.

CHAIRMAN DYKEWICZ: Dr. Joan.

DR. JOAD: Just to answer the gaps. I would say that the only gap that I
would want in an ideal world is Holter monitors on more patients. So
whether it is really indicated or needed at this point or not I think is
the issue, but it would have been really nice to have had that.

CHAIRMAN DYKEWICZ: Dr. Morris.

DR. MORRIS: I think in a broader sense the data presented in my mind do
show safety within the population study. I wish I had numbers to present
to show what frequency of the COPD population that will be interacting
with as a physician would represent the group that were excluded from
this study.

And in administering this product would we be introducing a potentially
life limiting event, and would their life not have had that life
limiting event, even though we are talking about a person who has
probably severe COPD and heart disease, and are relatively hypoxemic.

So I think that to me is an unanswered question; is how safety can I
bring it to my patient now, who might have significant underlying heart
disease, as well as COPD. I feel confident in the data on who were
studied, and that does not represent an untoward risk of cardiac events
from what was presented.

But there is still, I think, a significant population who were not
studied.

CHAIRMAN DYKEWICZ: Thank you. Dr. Atkinson.

DR. ATKINSON: I would like to add that probably there should be some
attention in marketing if this drug were approved that would make the
primary care doctors aware that this just isn\'t another long acting
ipratropium, but that it does have systemic absorption, and really
emphasized the fact that people with perhaps unrecognized prostatic
hypertrophy, and mild renal disease, there may be side effects that may
be unanticipated that you wouldn\'t see with ipratropium.

CHAIRMAN DYKEWICZ: Other comments? I might just say as a personal
comment that one thing that we are obviously dealing with is if we have
some populations that have been excluded from study, and those are going
to be populations in real life that are going to be treated with this
drug, there does need at some point to be some study of that population.

So I think there needs to be, even if it is post-marketing, some study
done on patients who have, let\'s say, coronary artery disease, and
significant cardiac disease, to assure the safety of the drug.

On the other hand, we are looking at a drug that is \-- although it is a
new entity, it is an anticholinergic agent. We do have a good amount of
experience with another anticholinergic agent, namely ipratropium.

So I think we probably already have some sense of any signals if there
would be because of that drug class a significant adverse effect on
cardiac status. So with the idea again, and with the reservation that I
would have preferred to have seen some data about the safety of this
agent in patients who have cardiac disease, I have some reassurance that
this is of a drug class that does have a good track record of experience
in the patient subsets that were excluded from this study. Dr. Morris.

DR. MORRIS: Just to play the converse of that. I think one of the
reasons why we see a trough effect and not with this item today, and not
with the ipratropiums, because they are different, and that because of
that difference, we have to say that the drugs are different.

And that the potential for unsteadied events that are realistic, and
potentially harmful, are out there, but yet we have not studied that
population.

CHAIRMAN DYKEWICZ: Dr. Schatz.

DR. SCHATZ: But I was reassured to hear about the theoretical aspects of
anticholinergics and electrophysiology of the heart. So that what I
think you said, Mark, is still correct based on that information.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: What I would like then if it would be Phase IV studies for
everybody on the effects of the drug, and the effects on urinary
obstruction, impaction, and arrythmias. And as you mentioned, I think
for the groups that haven\'t been studied, either they should be told on
the product label that they shouldn\'t get it or that there should be
studies on them for safety.

CHAIRMAN DYKEWICZ: Dr. Parsons.

DR. PARSONS: The only other areas that came up that we really didn\'t
discuss was the increased incidence of hyperglycemia and diabetes. It
was a little out of control as it was not that well-defined.

So it is not clear to me how big a problem that is, and if these are
people who really go into DKA. I don\'t think so. Or if they have
transient hyperglycemia. It seems like there was an increased incidence,
although totally unexplained based on what we know about the drug.

It should at least be monitored in some fashion because as it stands,
there are certainly a number of patients with COPD, especially those
with heart disease, who do have concomitant diabetes, and that could be
a potential problem.

CHAIRMAN DYKEWICZ: I second the recommendations of both Dr. Joad and Dr.
Parsons.

CHAIRMAN DYKEWICZ: Other comments? Does the FDA have any additional
questions they wanted to pose before we take a vote on the question? No?
All right. Then let\'s call the formal question, Question Number 1.
Again, a yes or no response.

Is the safety database for tiotropium bromide inhalation powder for the
treatment of COPD patients adequate for approval. Dr. Patrick.

DR. PATRICK: Yes, on the basis of the Phase IV recommendation.

CHAIRMAN DYKEWICZ: Well, we have to have an answer though. It can\'t be
qualified. It has to be yes or no. If you believe that the data that
currently exists is sufficient to approve the drug, or whether you would
defer approval, in which case you would say no. You would say no?

DR. PATRICK: No. Yes. Yes.

CHAIRMAN DYKEWICZ: You would say yes?

DR. PATRICK: Yes.

CHAIRMAN DYKEWICZ: Okay. Dr. Parsons.

DR. PARSONS: Yes.

CHAIRMAN DYKEWICZ: Dr. Atkinson.

DR. ATKINSON: Yes.

CHAIRMAN DYKEWICZ: Dr. Morris.

DR. MORRIS: No.

CHAIRMAN DYKEWICZ: Dr. Joad.

DR. JOAD: So if I don\'t know that there is going to be a Phase IV, I
have to say no.

CHAIRMAN DYKEWICZ: All right. Dr. Stoller.

DR. STOLLER: Yes.

CHAIRMAN DYKEWICZ: Dykewicz, yes. Dr. Swenson.

DR. SWENSON: No.

CHAIRMAN DYKEWICZ: Dr. Apter.

DR. APTER: Yes.

CHAIRMAN DYKEWICZ: Dr. Chinchilli.

DR. CHINCHILLI: Yes.

CHAIRMAN DYKEWICZ: Ms. Schell.

MS. SCHELL: Yes.

CHAIRMAN DYKEWICZ: All right. Thank you. Now, just to clarify, the
additional safety data that should be obtained, I think that we have
already had some good discussion of that, but to kind of give a final
opportunity to members of the committee, should the drug be approved,
are there any additional Phase IV studies that you would like to see in
different populations?

I would say one other thought would be looking at different demographic
groups, in terms of African-Americans, Asian patients, and I think that
would be important.

DR. APTER: Women, too.

CHAIRMAN DYKEWICZ: Women, yes. Dr. Chowdhury.

DR. CHOWDHURY: Just a comment. We had three notes here, and I was
wondering if you are going to ask the question what exactly would they
want in terms of safety data prior to approval.

CHAIRMAN DYKEWICZ: People who voted no. Dr. Morris.

DR. MORRIS: I believe addressing documentation in patients with
suspected heart disease or documented heart disease, dysrrythmias, that
there is no increased dysrrythmia activity and/or deaths.

CHAIRMAN DYKEWICZ: Thank you. Dr. Joad.

DR. JOAD: Just what I spoke to. I think it could be approved now with
prohibition of the groups who were excluded from the prior \-- in the
package insert to say they should not get this drug, the group that had
heart failure in the last three years, or has arrhythmias, on
medication, and have BPH, and to say that those people cannot have it
now.

And then have a Phase IV to say that they can have it, or can\'t, and
then also to follow long term the safety concerns, which I think are
substantial given that it will be given to a lot of people, and it has a
very long elimination half-life. I think you have to be very careful
with this drug.

CHAIRMAN DYKEWICZ: Dr. Swenson.

DR. SWENSON: I think that the issue of renal insufficiency is important
enough that this should be followed in Phase IV very closely. I think
what we saw with the atrovent versus the tiotropium suggests about a
two-fold increase in all of these anticholinergic potential problems,
and therefore I don\'t know where we exist on the relationship between
blood levels and these side effects.

I don\'t know whether we peaked out or whether we are on a steep dope
response portion. So I think that issue should be followed closely. We
certainly have \-- this is an elderly group of patients by and large.

They get many drugs that affect renal function, and so they may start
with normal renal function, but put on a drug such as a non-steroidal
anti-inflammatory agent, or something of that nature, and their renal
function will change. So I would be worried about that.

CHAIRMAN DYKEWICZ: Dr. Stoller.

DR. STOLLER: I would submit that the Phase IV monitoring should in fact
address all of the subsets not included in the dataset that we have
seen, and that it also should address the specific concerns, albeit
small, raised by the data that we have seen.

And in particular I would say that there ought to be monitoring with
regard to women and non-caucasian groups, since those are not amply
represented in the dataset that we have seen.

And that in addition the Phase IV monitoring should address some of the
issues raised. As Dr. Parsons said, diabetes, and combinations of
co-morbidities not represented here, particularly coronary artery
disease. I am less concerned about arrhythmia based on the convincing
data that we have heard.

But I am concerned about coronotropic effects in patients for whom that
may be a significant concern, particularly coronary patients with
significant coronary artery disease, recent MI and concomitant renal
disfunction; as well as patients with known BPH, all of whom were
excluded from these datasets, but for whom in clinical practice this
might pose morbidity not otherwise appreciated by the data that we have
seen.

So Phase IV monitoring should be broad in its scope, but focused on
these specific subsets in my view.

CHAIRMAN DYKEWICZ: Dr. Chowdhury, any additional questions to the
committee

DR. CHOWDHURY: No.

CHAIRMAN DYKEWICZ: Fine. With that, we will adjourn, but did you have
any final comments from the FDA?

DR. CHOWDHURY: Yes. I would first like to thank you for your
participation and a thank you to the committee for their participation
in this meeting. We really appreciate the time and effort that you have
put into meeting.

CHAIRMAN DYKEWICZ: And I would like to add my personal thanks and wish
everyone a safe trip home.

DR. CHOWDHURY: Just a couple of more small points that I want to make.
Here as I said before in my opening statement, we would take this into
consideration from the clinical standpoint. However, we did not ask an
overall approvability question in this meeting.

However, based on the questions that we had posed, what we have heard is
all votes in favor, in terms of safety. I take that back. In terms of
efficacy, and in terms of safety, the majority was again in favor for a
yes.

So overall what we hear is a strong recommendation in favor of approving
the drug from a clinical standpoint. I just wanted to reiterate that.

CHAIRMAN DYKEWICZ: I believe that is the overall consensus of the
committee. Thank you very much.

DR. CHOWDHURY: Thank you very much, and have a safe trip back.

(Whereupon, at 2:59 p.m., the committee meeting was concluded.)