1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
GASTROINTESTINAL DRUGS ADVISORY
SUBCOMMITTEE
ACS Conference Room
Room 1066
2
PARTICIPANTS
Ronald P. Fogel, M.D., Acting Chair
Thomas H. Perez, M.P.H., R.Ph.,
Executive Secretary
MEMBERS:
Alan Lewis Buchman, M.D.
Byron Cryer, M.D.
Alexander H. Krist, M.D.
John T. LaMont, M.D.
Robert A. Levine, M.D.
David C. Metz, M.D.
Weichung Joe Shih, Ph.D.
David B. Sachar, M.D.
Jose M. Vega, M.D.,
Industry Representative
DRUG SAFETY AND RISK MANAGEMENT
ADVISORY COMMITTEE (Voting):
Brian L. Strom, M.D., M.P.H.
Curt D. Furberg, M.D., Ph.D.
Arthur A. Levin, M.P.H., Consumer
Representative
CONSULTANTS (Voting):
Ralph D'Agostino, Ph.D.
Allen Mangel, M.D., Ph.D.
FEDERAL EMPLOYEE (Voting):
Maria
H. Sjogren, M.D.
FDA STAFF:
Robert Justice, M.D., Director,
Division
of Gastrointestinal and Coagulation
Drug Products
Robert Prizont, M.D., Medical Officer
Garry Della'Zanna, D.O., M.Sc.,
Medical Officer
Julie Beitz, M.D., Deputy Director, ODE III
3
C O N T E N T S
Call to Order, Introductions, Ronald
Fogel, M.D., 5
Meeting Statement, Thomas H. Perez,
M.P.H. 8
Opening Comments, Robert Justice, M.D.,
Director,
Division Gastrointestinal and
Coagulation Drug
Products
11
Novartis Presentation, Zelnorm, NDA
21-200:
Introduction, John R. Cutt, Ph.D.,
Novartis
Executive Director Global Head GI,
Drug
Regulatory Affairs 14
Chronic Constipation: An Unresolved
Problem for
Many Patients, Charlene M. Prather,
M.D., St.
Zelnorm: Efficacy and Safety in Chronic
Constipation,
Eslie
Dennis, M.D., Novartis Senior Medical
Director, GI Clinical
Develop and Medical
Affairs
40
Zelnorm: Safety Overview, Bo Joelsson,
M.D.,
Novartis
Senior Medical Director, Clinical R&D 69
Fatality Cases, Michael
Shetzline, M.D., Ph.D.,
Novartis Senior Medical Director,
Development and Medical Affairs 82
Zelnorm: Safety Overview (continued),
Bo Joelsson, M.D. 92
Benefit/Risk Assessment, Philip
Schoenfeld, M.D.,
University of
Questions on
Presentation
116
FDA
Efficacy Presentation, Robert Prizont, M.D.,
Medical Officer, Division
of Gastrointestinal
and Coagulation Drug Products 158
4
C O N T E N T S
(Continued)
Questions on Presentation 173
FDA Safety Presentation, Gary
Della'Zanna, M.Sc.,
Medical Officer, Division of
Gastrointestinal
and Coagulation Drug Products 199
Questions on Presentation 220
Open Public Hearing:
Jeffrey D. Roberts, B.Sc., IBS Self Help
Group 229
Linda Roepke
241
Clarification of Issues 249
Discussion of
Questions
295
Adjournement
364
5
P R O C E E D I N G S
Call to Order,
Introductions
DR. FOGEL: Good morning.
My name is Ron
Fogel.
I am acting chair for today's meeting of
the Gastrointestinal Drugs Advisory
Committee.
Today's meeting deals with the new drug
application
of Zelnorm for the proposed indication of
the
treatment of patients with chronic
constipation and
relief of associated symptoms of
straining hard or
lumpy stools and infrequent defecation.
There has been one change to
today's
agenda.
The agenda has been pushed back half an
hour so the tentative time of adjournment
is five
o'clock.
Why don't we start by going around the
table and introducing ourselves? If we could start
on my far left?
DR. VEGA: Jose Vega, from Amgen in
California.
DR. LEVIN: Arthur Levin. I am a member
of the Drug Safety and Risk Management
Advisory
Committee. I am a consumer representative and I am
a guest as a consumer representative here
today.
6
DR. STROM: Brian Strom, University of
Safety and Risk Management Advisory
Committee--I
have already forgotten the name of the
committee!
I am here as a special government
employee, though
that is not what is says there.
DR. FURBERG: I am Curt Furberg, from Wake
Drug Safety and Risk Management Advisory
Committee.
DR. D'AGOSTINO: Ralph D'Agostino, from
FDA.
DR. LAMONT: I am Tom LaMont. I am a
member of the GIDAC. I work at Beth Israel
Hospital in
DR. LEVINE: I am Bob Levine, State
member of the GI advisory committee.
DR. METZ: David Metz, University of
committee.
DR. PEREZ: Tom Perez, Executive Secretary
7
to this meeting.
DR. FOGEL: Ron Fogel, Henry Ford Health
System, in
DR. SACHAR: I am David Sachar, from Mount
Sinai School of Medicine, in
voyage on the GI drug advisory committee.
[Laughter]
DR. BUCHMAN: Alan Buchman, from
also my first cruise with today as well.
DR. MANGEL: Allen Mangel, Research
Triangle Institute. I am a special government
employee.
DR. CRYER: I am Byron Cryer, from the
committee.
DR. DELLA'ZANNA: Garry Della'Zanna,
medical officer in the GI and Coagulation
Drug
Product Division.
DR. JUSTICE: Robert Justice, Director,
Division of Gastrointestinal and
Coagulation Drug
8
Products.
DR.
BEITZ: Julie Beitz, Deputy Director
in the Office of Drug
Evaluation III.
DR. FOGEL: Thank you, all. At this point
Tom Perez will read the meeting
statement.
Meeting Statement
DR. PEREZ: Thank you and good morning.
The following announcement addresses the
issue of
conflict of interest with regard to this
meeting,
and is made part of the record to
preclude even the
appearance of such at this meeting.
Based on the submitted agenda
for the
meeting and all financial interests
reported by the
committee participants, it has been
determined that
all interests in firms regulated by the
Center for
Drug Evaluation and Research present no
potential
for
an appearance of a conflict of interest at this
meeting, with the following exceptions:
In accordance with 18 USC
Section
208(b)(3), full waivers have been granted
to the
following participants, Dr. Ronald Fogel
has been
granted a waiver for serving as a member
of the
9
sponsor's speakers bureau. His lectures are
unrelated to the matter at issue and he
receives
less than $10,001 per year.
Dr. Ralph D'Agostino has been
granted a
waiver for serving on a competitor's
advisory board
on unrelated matters. He receives less than
$10,001 per year.
Dr. Byron Cryer has been granted
a waiver
under 21 USC 355(n)(4), amendment of
Section 505 of
the Food and Drug Administration
Modernization Act,
for ownership of stock in a
competitor. The stock
is worth less than $5,001. Because this interest
falls below the de minimis exemption
allowed under
5 CFR 2640.202(a)(2) a waiver underlying
18 USC
208(b)(3) is not required.
Dr. David Metz has been granted
waivers
under 18 USC Section 208(b)(3) and 21 USC
355(n)(4)
for his spouse's ownership of stock in a
competitor
valued from $50,001 to $100,000.
Lastly, Dr. Allen Buchman has
been granted
waivers under 18 USC Section 208(b)(s)
and 21 USC
355(n)(4) for owning stock in a competitor
valued
10
from $25,001 to $50,000.
A copy of the waiver statements
may be
obtained by submitting a written request
to the
agency's Freedom of Information Office,
Room 12A-30
or the Parklawn Building.
In the event that the
discussions involve
any other products or firms not already
on the
agenda for which an FDA participant has a
financial
interest, the participants are aware of
the need to
exclude themselves from such involvement
and their
exclusion will be noted for the record.
We would also like to note that
Dr. Jose
Vega has been invited to participate as
an industry
representative, acting on behalf of
regulated
industry.
Dr. Vega is employed by Amgen, Inc.
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 product they may wish to
comment
upon.
Thank you.
DR. FOGEL: Thank you.
At this time I
will turn the meeting over to Dr.
Justice, of the
11
FDA, for opening comments.
Opening Comments
DR. JUSTICE: Good morning.
I would like
to welcome everyone to today's meeting of
the
Gastrointestinal Drugs Advisory
Committee, and I
would especially like to welcome members
of the
committee and special government
employees for
taking the time to provide us with your
advice.
As you have heard, today we
will be
discussing the application for Zelnorm
tablets for
the proposed indication of treatment of
chronic
constipation. Before going on to the
presentations, I would just like to
briefly go
through the questions so you will have
them in mind
as you listen to the discussions.
The first item is that we would
like you
to discuss the appropriateness of a
primary
efficacy endpoint of an increase of equal
to or
greater than 1 complete spontaneous bowel
movement
per week versus a total of greater than 3
complete
spontaneous bowel movements per week.
The second question is, is the
population
12
studied representative of patients with
chronic
constipation? If not, how do the populations
differ?
The third question is only 9 to
16 percent
of subjects were greater than or equal to
65 years
of age and the treatment effect was
significantly
smaller in older patients. Are these data adequate
for an indication that is common in the
elderly?
The fourth efficacy question is
that only
9 to 14 percent of the subjects were male
and the
treatment effect was smaller in males
than females.
Are these data adequate to support
approval of
Zelnorm for use in the treatment of
chronic
constipation in males?
The next question is are the
clinical
trial data adequate with respect to the
population
of non-irritable bowel syndrome patients
with
chronic constipation that is likely to be
treated
with Zelnorm?
The next efficacy question is,
is Zelnorm
effective for the treatment of chronic
constipation
and associated symptoms?
13
As far as the safety questions,
postmarketing access of ischemic colitis
and
serious complications of diarrhea were
not limited
to patients with irritable bowel
syndrome. What
are the implications of these adverse
events from
patients with chronic constipation?
The next safety question is
that the
incidence of diarrhea and discontinuation
due to
diarrhea was higher in patients 65 years
of age or
older.
Is there sufficient information that
Zelnorm is safe for use in this age
group?
The next safety question is do
the adverse
event data from the clinical trials and
postmarketing surveillance provide
adequate
evidence of safety of Zelnorm for the
treatment of
chronic constipation?
The next safety question is
should the
information on the postmarketing cases of
ischemic
colitis and intestinal ischemia be moved
from the
"precautions" section to the
"warning" section of
the package insert?
Then, the final question will
be the
14
overall question of should Zelnorm be
approved for
the proposed indication of the treatment
of
patients with chronic constipation and
relief of
associated symptoms of straining, hard or
lumpy
stools, and infrequent defecation?
With that, I will turn it back
over to Dr.
Fogel for Novartis' presentation.
DR. FOGEL: Thank you very much. At this
juncture I will turn the meeting over to
Dr. John
Cutt, Global Head of GI Drug Regulatory
Affairs for
Novartis, who will introduce the speakers
and the
presentations. Thank you.
Novartis Presentation
Introduction
DR. CUTT: Thank you.
First I would like
to thank Dr. Beitz, Dr. Justice--Dr.
Prizont is not
here yet--and Dr. Della'Zanna and the
rest of the
FDA reviewers, and Dr. Fogel and the rest
of the
advisory committee, and say good morning
to you.
My name is John Cutt. As Dr. Fogel said,
I am the executive director and the
global head for
the gastrointestinal regulatory group at
Novartis,
15
and it is my pleasure to share with you
today the
clinical data on chronic constipation
that we have
generated.
Let me start out with the
objectives, as
we see them today for the meeting. We would like
to share the Zelnorm Phase 3 clinical
data in
support of a new indication. Dr. Fogel read that
before, I will read it again. Zelnorm is indicated
for the treatment of patients with
chronic
constipation and the relief of associated
symptoms
of straining, hard or lumpy stools, and
infrequent
defecation.
The second topic that we are
going to
review today is the postmarketing safety
data that
we have generated since the approval of
the drug in
the United States in July of 2002. This approval
was for patients with irritable bowel
syndrome with
constipation.
A brief introduction of the
compound,
Zelnorm is tegaserod maleate. It is 5-HT
4 receptor
partial agonist with affinity for the
5-HT
4
receptor in the GI tract. For its pharmacologic
16
activity in the GI tract, Zelnorm
enhances
intestinal motility; increases intestinal
secretion; and inhibits visceral
sensitivity. We
have also demonstrated in clinical trials
that
Zelnorm can improve the constipation
symptoms in
patients with irritable bowel syndrome
with
constipation.
So, these data together are the
basis for
the hypothesis that Zelnorm could be
effective to
treat patients suffering from chronic
constipation.
Novartis-designed clinical
development
program for chronic constipation included
two
randomized, placebo-controlled pivotal
studies.
Both the studies were 12 weeks in
duration to
assess the efficacy, safety and
tolerability of the
drug.
We studies both the 2 mg dose and the 6 mg
dose BID versus placebo. In total, there were
2,612 patients that were studied. The program also
included one extension phase study which
was added
on to one of the pivotal studies. This was a
13-month extension for assessing the
long-term
safety of the compound. The other pivotal studied
17
included a 4-week withdrawal period. Today what we
are going to do is show you the results
of these
pivotal studies.
We will also share with you the
postmarketing clinical data that we have
collected
since the approval of the drug in the
United States
in July of 2002. That approval was for the
short-term treatment of women with
irritable bowel
syndrome whose primary bowel symptom is
constipation. The recommended dose is 6 mg BID for
a period of up to 12 weeks. At the time of the
approval we demonstrated the efficacy,
safety and
tolerability in 5,319 patients in the
clinical
trial program. At this point in time, now, we have
generated data on 11,600 patients in
clinical
trials.
These patients were all treated with
Zelnorm.
What this means is that it translates to
approximately 3,456 patient-year exposure
to the
drug in the clinical trials.
In terms of the worldwide
clinical
experience for the drug, Zelnorm is now
approved in
56 countries for the indication of IBS
with
18
constipation. We have also received approval for
the drug in 10 countries for the
indication of
chronic constipation that we are seeking
from the
advisory committee and the FDA.
We first made the drug
available to
patients suffering from IBS-C in January
of 2001 in
the rest of the world. So, at this point we have
over 3 years of postmarketing experience
with the
drug in patients. What this means is that we have
treated approximately 3 million patients
globally
with the drug and about 2 million of
those patients
have been treated in the United
States. This now
translates to about 362,000 patient-years
of
experience to Zelnorm.
The safety data from the
clinical trial
setting and the postmarketing environment
we
believe supports a favorable safety
profile for
Zelnorm.
So, our conclusion from the data that you
will see today during the presentations
is that
Zelnorm, at the recommended dose of 6 mg
BID, is
efficacious and safe for the treatment of
patients
with multiple symptoms of chronic
constipation.
19
What I want to do is review the
agenda
very briefly, the people that will be
presenting
for us.
First we have Dr. Charlene Prather.
She
is from the St. Louis University and will
speak
about chronic constipation. Her presentation is
title an unresolved problem for many
patients in
clinical practice.
She will be followed by Dr.
Eslie Dennis.
Eslie is from the Novartis clinical development and
medical affairs department. Dr. Dennis will
present the efficacy and safety data from
the
pivotal studies.
That will be followed by Dr. Bo
Joelsson.
He will present our overall clinical
safety data
and review some of the adverse events of
special
interest that we have agreed to talk
about with the
FDA.
Finally, Dr. Philip Schoenfeld,
who is the
chief of the gastrointestinal group at
the Veterans
Hospital in Ann Arbor, at the University
of
Michigan, will conclude historical
presentation
with a benefit/risk assessment for the
drug.
20
We also have four consultants
that have
joined us today to answer questions that
you may
have.
The first one is Dr. Felix Arellano.
He is
from the Risk Management Resources
group. His
expertise is pharmacovigilance,
epidemiology and
risk management. Then we have Dr. Gary Koch. Dr.
Gary Koch is from North Carolina, Chapel
Hill. He
is an expert in biostatistics. We have Dr. David
Lieberman. He is from the Oregon Health and
Science University. He will be here to answer any
questions you have on the core database
which is
part of the presentation.
Then we have Dr. Walter Peterson, a
gastroenterologist from the University of
Texas
Southwestern.
We have also a number of
scientists and
clinicians from Novartis who can answer
any of the
specific questions that you have on
Zelnorm.
Now I would like to invite Dr.
Prather up
to the podium.
Chronic Constipation:
An Unresolved Problem for Many
Patients
21
DR. PRATHER: Thank you, Dr. Cutt. Dr.
Fogel, committee members, ladies and
gentlemen, my
name is Charlene Prather. As you heard, I am from
St. Louis University. I am a gastroenterologist.
I have been in practice for over ten
years. My
career has been dedicated to the clinical
investigation and, importantly, the
clinical
treatment of patients with functional
bowel
disorders and gastrointestinal motility
disorders.
Chronic constipation is one of the very
common
problems that I see in my clinical
practice and it
is, indeed, an unresolved problem for
many of the
patients that come to see me.
First I would like to review my
presentation objectives. I will begin with a
definition of chronic constipation. I will discuss
epidemiology and resource utilization
that is
associated with chronic
constipation. I will
review available therapies and the
limitations that
some of these therapies may have. I will also
summarize for you my feelings regarding
the unmet
medical need associated with chronic
constipation.
22
First, beginning with the
definition of
chronic constipation, there are a variety
of ways
to define constipation. I have decided to define
constipation into either primary causes
of
constipation or secondary causes of
constipation.
First let's discuss the
secondary causes
of chronic constipation. Secondary causes include
things such as drug-induced
constipation. We are
certainly familiar with this with the
narcotics we
may give our chronic pain patients. Metabolic
factors--hypothyroidism, hypocalcemia may
be
associated with chronic
constipation. Importantly,
co-morbid medical conditions. We are certainly
familiar with a variety of neurological
disorders,
such as Parkinson's disease, multiple
sclerosis, in
which constipation is an important
complaint that
many of these patients may bring to
us. However,
this is not what I am here to discuss
today.
Today I would like to review
primary
constipation. Again, with primary constipation we
have learned much in the past several
years
regarding what causes primary
constipation. There
23
may be impaired colonic transit or motor
function,
certainly an area that I am very
interested in. We
often call this slow transit
constipation. This
may result from a failure of the
neurenteric
function of the digestive system or from
the
gastrointestinal reflexes that are involved. It
may also result because there is a
problem with the
muscle, a failure of the muscular
apparatus.
We also can look at chronic
constipation
as a subgroup having ineffective
defecation. We
also may call this functional outlet
obstruction.
This is really where there is a poor
coordination
in the muscular apparatus that is
involved in the
defecation process. There are some other
terminologies that may be used as well,
such as
pelvic dyssynergia or anismus may be a term
that
you have also heard. Most cases of primary chronic
constipation fall into neither of these
categories.
They are actually normal transit
constipation.
Constipation really isn't
defined by
physiologic testing; it is defined on the
basis of
symptoms.
In my practice the most common reported
24
symptoms that I see coming from my patients
are
complaints of hard or lumpy stools;
increased
straining. They may complain of infrequent bowel
movements, but often the sensation of
incomplete
evacuation, really outcome having a
satisfactory
bowel movement and, not uncommonly, the
complaint
of gloating or fullness. Typically, the longer
they have gone since they had a bowel
movement, you
know, they are feeling more full and they
may
describe that as a bloated sort of
sensation.
When I think about chronic
constipation,
this is more persistent than intermittent
or
episodic constipation. We are familiar with
transient constipation that may occur as
a result
of a dietary change. We may also see it in
relation to travel. When I think about what is the
definition I will use for chronicity, it
needs to
have been present for several months
duration and
quite commonly, in my practice, these
patients have
had their constipation for years,
frequently dating
back to early adolescence or sometimes
even
childhood.
25
Well, how valid are my ideas
about what my
patients bring me with those
symptoms? There
actually have been some studies that have
taken a
look at this. One of the first studies, performed
by Dr. Robert Sandler, in North Carolina,
took a
look at a group of young adults, those around
the
university community. These were individuals who
had constipation and the symptoms they
reported
most often were, indeed, straining 52
percent of
the time; hard stools, 44 percent of the
time;
wanted to have a bowel movement but were
unable to,
34 percent of the time; with infrequent
stools
being reported just 32 percent of the
time.
Now let's think about
this. Physicians
were often called upon to think very
quantitatively
so we often think about the frequency as
being the
most important symptom in
constipation. But,
clearly, our patients seem to be telling
us
something a bit different. Now, this was not a
population-based study so what actually
happens in
the population when we discuss symptoms
and
constipation?
26
I have two studies to review
with you.
First is a study on the left, a large
population-based, epidemiologic study by
Stewart.
He took a look at the symptoms most
commonly
reported in constipation. Again, at the top we see
the complaint--an incomplete bowel
movement 83
percent of the time. Unsuccessful bowel movement,
being called a stool but being unable to
65 percent
of the time. We see complaints of abdominal
discomfort, needing to press on the
abdomen in
order to have a bowel movement; some
abdominal
bloating in a group of patients; but, again,
down
at the bottom of this list is frequency,
with less
than 3 bowel movements per week being
reported by
only 13 percent of this cohort.
On the right hand of the slide
is another
population-based study by Pare. Again we see
similar findings, with straining right at
the top.
Again, near the bottom less than 3 bowel
movements
per week being less frequent in this
case, in this
population, 36 percent of the time.
Now, I previously mentioned the
subtypes
27
of primary constipation that I
considered. Might
it be slow transit constipation; might it
be an
outlet problem; or is it normal transit
constipation? Well, unfortunately, the symptoms
don't help me differentiate between those
different
physiologic groups. Fortunately, that is not
necessary because in practice we don't
use
physiologic testing, nor do we use the
patient
symptoms to define which subgroup they
belong in.
This has been information we have really
found out
over the past several years. We would like to
think their symptoms will tell us exactly
which
subgroup they belong into but that just
hasn't been
the case.
In clinical practice and in clinical
trials we really don't try to define the
subtype of
constipation based on either their symptoms
or on
physiologic testing.
However, it is important that
we have
criteria for the use of clinical testing
and having
a relatively homogenous group of patients
that we
can take a look at. An important stab at this has
been the Rome criteria. I would like to review
28
with you the Rome II criteria that are
used in the
diagnosis of functional constipation.
The Rome II diagnostic criteria include at
least 12 weeks, which not be consecutive,
in the
past 12 months of 2 or more of the
following
symptoms:
These symptoms include straining, lumpy
or hard stools, a sensation of incomplete
evacuation, a sensation of anorectal
obstruction or
blockage, or having to use manual
maneuvers, such
as digitation, to facilitate
defecation. You see
an asterisk by these because these need
to have
been present on at least a quarter of
defecations.
The other criterion is less than 3
defecations per
week.
Looking back at the top line,
we see that
it is 2 or more of the following
symptoms. So, a
patient may have straining, lumpy or hard
stools 25
percent of the time and this would be
consistent
with the Rome II criteria for chronic
constipation.
Or, it could be that they do have less
than 3
defecations per week and a sensation of
incomplete
evacuation. For this criterion loose stools must
29
not be present and there should be
insufficient
criteria for irritable bowel syndrome.
A caveat with the Rome criteria
is that
one of the criteria that they say is that
I cannot
use these criteria if my patients are
already on
laxatives. So, these are criteria that are really
appropriate for individuals who are not
currently
using laxatives.
Using these definitions and,
again, the
Rome I definition was for the criteria
from before,
how common is chronic constipation in the
general
population? These are some population-based
studies and, depending on the criteria
that have
been used, we see a prevalence in the
range of 4
percent up to 16 percent. This is a lot of
patients that are complaining of
constipation.
However, not all of these patients are
actually
coming to see us. A few of these studies actually
looked at how many of these patients or
individuals
had actually sought physician care for
the
evaluation and treatment of constipation.
What we see is that it is only
about 25
30
percent that actually come in to the
physician's
office in order to seek some sort of
treatment.
A little bit more about the
prevalence,
when we think about constipation we need
to know
what age groups might be affected. In the Pare
study he was able to divide this
out. In the green
bars we see the Rome I criteria and in
the magenta
bars the Rome II criteria. There are some slight
differences, again, depending on the
definition
that has been used. This is true of all of the
epidemiologic studies, that we really
need to
understand the criteria.
Well, what we see is that
actually
constipation is a bit more common in the
younger
age group, the 18-34 year-old age
group. This is
consistent with my clinical
practice. We see that
the prevalence is relatively flat when we
take a
look at the 35-49 year-old age group; the
50-64
year-old age group; and even the over 64
year-ole
age group. So, constipation really affects all age
groups.
To summarize the epidemiology
related with
31
constipation quite briefly, chronic
constipation
is, indeed, common in the general
population.
Again, not all of these individuals come
to see us.
Approximately 25 percent actually seek
physician
care.
In data I have not presented, it is slightly
more common in women than it is in
men. The female
to male ratio ranges from 1.3 to
2.5. Importantly,
constipation affects all age groups.
Now, how does this really reflect with
what I see in my clinical practice? In my clinical
practice generally I see females. Now, this may be
because I am a female gastroenterologist,
that is
the obvious. However, when I discuss this with my
male colleagues they tell me that they
too are
seeing predominantly women that come to
see them
for chronic constipation. Most of my patients have
been symptomatic for many years,
typically over 10
years.
The majority have tried life style changes.
They have tried fiber. They have used
over-the-counter laxatives prior to even
seeking
initial care from their primary care
physicians.
Most of them manage their constipation with
32
combinations of these, a combination of
fiber and
laxatives. The patients that come to me in my
practice are predominantly referred to me
by
primary care physicians and I am also
going to see
patients that come from other
gastroenterologists.
Again, I really like my patient
population
and I like taking care of patients with
functional
bowel disorders. These are not all crazy patients
as I know some gastroenterologists
think. They
actually cope reasonably well with their
condition,
however, they are not completely
satisfied and they
are looking for something a little bit
better.
So, what is the impact of this condition?
Is it just kind of a minor annoyance to
my
patients?
I would like to present some data
related to the impact this condition has
in
patients.
First I would like to take a look at
quality of life. There haven't
been that many
studies.
I will present three of the four studies
I am aware of.
In Olmstead County, Minnesota,
individuals
with chronic constipation reported a
significant
33
impact in quality of life with reduced
SF-36
scores.
Similarly, in Canada, people who have
either self-reported or Rome II
constipation also
had worse SF-36 scores compared to the
normal
population. In Australia, people with constipation
had significantly worse SF-12 scores on
both the
mental and the physical components. So, there is
certainly an impact on these individuals'
quality
of
life.
Not only does chronic
constipation impact
quality of life, but it is also
associated with
increased healthcare utilization. In this next
slide we see that 5.7 million
constipation-related
outpatient visits do occur annually; 4.1
million of
these are physician office-based
visits. However,
there are 991,000 emergency room visits
and 587,000
hospital outpatient visits each year.
The cost is a little bit
difficult to get
at as it relates to how expensive is this
condition. The one study that I found was from
1997, a study by Rantis and colleagues,
who found
in patients who had been referred for
tertiary care
34
evaluation had costs for additional
testing on the
average of $2,752. Again, in 2004 dollars I am
sure that may be a bit more. But the point is
really that this disorder does have an
impact both
from a quality of life and from a
healthcare
utilization perspective.
So, if this is affecting my
patients'
lives I would like to be able to treat
them
appropriately, and my goal of therapy is
that I
would like to be able to improve GI function in
order to obtain relief of the key
symptoms that my
patients are bringing to me, and we have
reviewed
what these symptoms are.
Well, what do we have available
in order
to do this? Certainly we have fiber; laxatives, be
they osmotic or stimulant laxatives. We can use
enemas or suppositories and we do have
some
miscellaneous agents that we use. We can use a
cholinergic agonist, such as
bethanchol. I don't
think too many of the gastroenterologists
have used
that actually for treatment of
constipation but it
is available for us and we have used it
in the
35
past.
We may use a prostaglandin analog called
misoprostil and we have also used
colchicine--again, certainly not ideal
agents but
they are things that we do have available
for us.
Well, there are some challenges
with these
agents.
My patients tell me that they really
aren't consistently getting relief. There is a
variable treatment response. Importantly, for the
constellation of constipation symptoms
that we see
the efficacy really has not been
evaluated or
demonstrated for most of these agents.
Importantly, chronic constipation is just
that, it
is a chronic problem and most agents are
indicated
for less than or equal to 2 weeks of
therapy. I
would certainly like to be able to offer
my
patients something on an ongoing basis.
There are other limitations
associated
with these agents. First is the worsening of some
of the constipation symptoms that I am
actually
trying to treat. I mean, who among us has not
given fiber to patients only to have them
come back
a week or two later complaining of
increased
36
bloating and gas? Likewise, these agents can also
cause cramping, abdominal pain or colicky
stools.
Fortunately, complications are not common
with the
treatments that I use for treating
constipation. I
do worry in some patients should they
develop
severe diarrhea which can result in
hypovolemia or
electrolyte disturbance. Metabolic disturbances
can occur, such as hypokalemia or
hypomagnesemia
depending on the agent I may have used.
There are also other adverse effects
which, fortunately, also are not too
common. We
can see interference with concomitant
drug
absorption. For instance, some laxatives when
given with cipro may result in poor
absorption of
that medication or with theophylline.
I am not too concerned about
the
structural changes that may occur in the
gut
mucosa, things such as melanosis coli or
the abuse
potential or dependency, although I can
tell you my
patients and many physicians do consider
these to
be obstacles to use of many of the agents
that are
currently available. My patients certainly tell me
37
that there is diminished therapeutic effect
that
they see that occurs over time when using
these
agents, causing them to have to escalate
the drug
usage and often with additional side
effects
associated with this.
I am talking to my patients not being
satisfied, and can I get at is there
truly a
quantitative effect that tells me how
satisfied are
patients or physicians with these
therapies? Well,
there really isn't much out there. Fortunately, a
colleague of mine, Dr. Larry Schiller,
has shared
with me an abstract that he has submitted
to The
American College of
Gastroenterology. This is an
Internet-based study that was done, and a
group of
physicians were asked are your patients
completely
satisfied with treatments for
constipation? The
physicians overwhelmingly, 82 percent,
said no, my
patients are not completely satisfied.
If you take a look at the box
on the
right, the reasons for dissatisfaction
included
lack of efficacy, 93 percent; safety or
side
effects, 57 percent; or other reasons
such as taste
38
or compliance in 27 percent. In this group of
physicians, 60 percent of physicians
agreed that
they do not have adequate products for
treating
their patients with chronic constipation,
and 90
percent of these physicians wanted better
treatment
options.
Physicians cited frustration with the
current treatments as one of the top 3
reasons
patients state for seeking care for their
condition.
Another study, a
population-based study,
also Internet based, took a look at
patients who
had seen a physician for constipation
within the
past year. In this group of 557 patients, they
were asked are you completely satisfied
with your
treatment for constipation? Nearly half said no,
they were not completely satisfied. So, again,
these are patients that have seen a
physician
within the past year that were obtained
through a
national database survey. The reasons for
dissatisfaction included efficacy,
similar to the
physicians, in 82 percent. Patients weren't quite
as concerned as physicians were about
safety or
39
side effects but still an important concern
of
theirs in 16 percent. Other reasons, such as taste
or not wanting to take the agents
regularly, in 17
percent.
At the bottom of the slide we
see two
other references, one from Irvine and one
from
Ferrzzi.
These data support the findings that they
found in their studies related to patient
concerns
regarding the currently available
treatments for
constipation.
In conclusion, chronic
constipation, in my
opinion, is a condition that is truly in
need of a
better approach. Constipation is characterized by
a constellation of symptoms and we need
to
recognize what the symptoms are that our
patients
bring to us as being most important,
including the
complaints of straining and incomplete
evacuation.
Certainly, we want to remember frequency
but this
is not our patients' primary
concern. Chronic
constipation is associated with high
resource
utilization and does have a significant
negative
impact on our patients' quality of
life. The
40
current pharmacologic agents have some
limitations
and many patients and their physicians
are not
completely satisfied with the available
therapies.
I truly believe that better treatment
options are
needed for this condition.
Thank you for allowing me to
share with
you today my thoughts about chronic
constipation.
This is obviously a topic of great
importance to me
and to my patients. I am looking forward to
hearing more from the other speakers
today what I
am sure will be a very lively and
interesting
discussion.
Zelnorm: Efficacy and
Safety in
Chronic Constipation
DR. DENNIS: Thank you, Dr. Prather. Dr.
Fogel, members of the advisory committee,
FDA
representatives, ladies and gentlemen,
good
morning.
My name is Eslie Dennis and I am one of
the senior medical directors for
gastroenterology
at Novartis Pharmaceuticals. I am delighted to be
here today to be able to share with you
our chronic
constipation program, and I thank you for
the
41
opportunity to do so.
Over the next 30 minutes I will
provide
you with our rationale for studying
patients with
chronic constipation. I will then highlight the
study objectives of our Phase 3 program,
walk you
through the study design, and provide
more
specifics around the patient population
that was
studied.
Then I will present the efficacy data
from our primary and secondary endpoints
and,
finally, the safety data for the 12-week
double-blind, placebo-controlled studies
and the
safety data from the 13-month blinded
extension
study.
Zelnorm is a 5-HT
4 receptor partial
agonist.
It is representative of a new class, the
aminoguanidine indole, and it was
designed
specifically to act at 5-HT
4 receptors in the
GI
tract.
The molecular structure of Zelnorm is based
on serotonin which we know plays a
crucial role in
the normal functioning of the GI
tract. We also
know that the action of serotonin at
5-HT
4
receptors is prokinetic.
42
Our mechanism of action and
preclinical
data have demonstrated that tegaserod is,
indeed, a
promotility agent. Tegaserod has been shown to
augment peristalsis, thereby enhancing
gut motility
and decreasing transit time. Furthermore, animal
studies have shown that tegaserod
increases
chloride and water secretion which would
improve
stool consistency independent of the
promotile
effect of the drug. In addition, we have the data
from our IBS with constipation studies
that confirm
the significant improvement with Zelnorm
compared
to placebo on stool frequency, stool
consistency
and straining--all important benefits
when treating
chronic constipation.
On the basis of our IBS with
constipation
studies, we felt that we could proceed
directly to
Phase 2 trials in chronic constipation
without a
formal Phase 2 program, and that we would
use the
same doses that were tested in our IBS-C
Phase 3
trials.
Let me now walk you through the
Phase 3
chronic constipation program. The study objectives
43
were to evaluate the efficacy,
tolerability and
safety of 2 doses of Zelnorm, 2 mg BID
and 6 mg
BID, compared to placebo over a 12-week
treatment
period in patients with chronic
constipation.
We had 2 large randomized, double-blind,
placebo-controlled clinical trials in our
program.
Study 2301 was conducted in 128 centers
in 16
countries in Europe and in Australia and
South
Africa.
The design consisted of a 2-week baseline
period, followed by a 12-week treatment
period with
either Zelnorm 2 mg BID, 6 mg BID or
placebo.
One thousand, two hundred and
sixty-four
patients were randomized. We chose the time line
of 12 weeks of treatment for the core studies
in
keeping with the Rome committee
guidelines
regarding duration of clinical studies in
functional bowel diseases for chronic
therapies.
The 2 doses of Zelnorm and the BID
regimen were
based on our experience with the previous
dose-ranging and Phase 3 studies that
were
conducted in IBS-C patients.
The initial 12-week treatment
period was
44
then followed by an optional 13-month
extension
period.
This extension period was double-blinded
but there was no placebo arm. So, patients who had
received Zelnorm 2 mg BID or 6 mg BID
remained on
these doses and patients who had received
placebo
then received Zelnorm 6 mg BID in the extension,
and 842 patients entered the extension
study.
The primary aim of the
extension study was
to provide long-term safety data for the
2 doses of
Zelnorm.
Study 2302 was conducted in 105 centers
in 7 countries in North and South
America. The
study design was very similar, with a
2-week
baseline period and a 12-week treatment
period.
However, in this study the 12-week
treatment period
was followed by a 4-week drug-free
withdrawal
phase.
A similar number of patients were
randomized, 1,348.
Patient inclusion and several
of the
endpoints, including the primary
endpoint, were
based on the number of complete,
spontaneous bowel
movements of CSBMs. Let me clarify this
terminology that we have used. BMs refer to all
45
bowel movements. SBMs refer to spontaneous bowel
movements. Spontaneous means a non-laxative
induced stool, in other words, no
laxative or enema
in the preceding 24 hours. These can be stools
with either complete evacuation or
incomplete
evacuation. CSBMs refer to complete spontaneous
bowel movements. Complete is a subjective
definition of a bowel movement that
results in a
sensation of complete evacuation. We know that
there are constipated patients out there
who have
more than 3 bowel movements a week but
these are
often small amounts of hard and lumpy
stools with
straining and incomplete evacuation, and
these are
patients that are not satisfied with the
quality of
their bowel movements. So, complete spontaneous
bowel movement captures the quality of a
bowel
movement that is not laxative induced and
is a
measure of both the quality and
frequency. We felt
that this endpoint best captured what
patients
complain of, based on expert opinion and
the
published literature.
A recent state-of-the-art
review on
46
chronic constipation in The New England
Journal of
Medicine referred to the large study that
Dr.
Prather has shown you, stating that
constipation
had been identified in this study as an
inability
to evacuate stool completely and
spontaneously 3 or
more times a week.
Given that there is no
recognized gold
standard for endpoints in chronic
constipation, it
seemed very reasonable to use the SCBM
endpoint as
our primary endpoint. In fact, this is a more
stringent endpoint than using just bowel
movements
alone.
However, we recognize that different
experts might request different analyses
and
different endpoints and so we defined a
priori a
number of secondary endpoints
representing the
multiple symptoms of chronic constipation
that I
will also be presenting to you today.
We included males and females
over the age
of 18 years with chronic
constipation. Chronic was
defined as at least 6 months of
consistent
symptoms. Constipation was defined as less than 3
complete, spontaneous bowel movements per
week and
47
one or more of the following 25 percent
of the
time, very hard or hard stools, sensation
of
incomplete evacuation, or straining at
defecation.
These criteria were based on the
well-established
Rome criteria.
Patients were also required to
have had a
normal endoscopic of radiological evaluation
of the
bowel within the past 5 years and after
the onset
of symptoms. In addition, there had to be no
history or evidence of alarm features
such as
weight loss, rectal bleeding or anemia
since the
evaluation was performed.
Patients were excluded if they
had
constipation for which the cause was
known, in
other words, secondary constipation as
you can see
listed on the slide. So, we studied patients with
chronic constipation of unknown
cause. In
addition, patients on concomitant
medications that
could affect GI transit were excluded, as
well as
patients with fecal impaction requiring
surgical or
manual intervention. These criteria were excluded
based on a comprehensive history,
thorough physical
48
examination, as well as baseline ECG and
laboratory
assessments.
At the end of a 2-week baseline
period and
just prior to randomization additional
exclusion
criteria were applied. Patients were excluded if
constipation could not be confirmed by
the number
of CSBMs, straining and/or very hard or
hard stools
recorded in daily diaries. They were also excluded
if they had loose or watery stools for
more than 3
of the 14 days and if they used laxatives
outside
of the guidelines for more than 2 of the
14 days.
Patients were deemed to be non-compliant
with diary
completion if they entered less than 11
days in the
daily diary and were subsequently also
excluded.
On a daily basis we assessed a
number of
parameters related to bowel
habits--straining,
stool frequency, stool form that we measured
using
the Bristol Stool Scale, and whether
evacuation was
complete or incomplete. Patients were required to
collect this data for each individual
bowel
movement, and we determined which bowel
movement
was spontaneous based on the daily diary
data
49
reflecting the time of administration of
any rescue
laxatives.
On a weekly basis we asked
about
satisfaction with bowel habits, as well
as
bothersomeness of constipation,
bothersomeness of a
bowel movement distention or bloating and
bothersomeness of abdominal discomfort or
pain.
Let's look at the patient
disposition.
Over 80 percent of randomized patients
completed
the study, with fewer than 20 percent
discontinuations. The most common reason for
discontinuation was for unsatisfactory
therapeutic
effect, with the largest percentage being
in the
placebo group, as we might expect. Adverse events
accounted for similar numbers of
discontinuations
in the placebo and Zelnorm 2 mg BID
groups, with a
slightly higher percentage in the 6 mg
BID group
which was not statistically
significant. The
pattern of disposition was similar in the
2 trials.
Let's look at the results,
starting with
the demographic data. These were very similar
between the two studies. The vast majority of
50
patients, 86 and 90 percent, were
female. The mean
age was 46 and 47 years, with a similar
age range,
from 18-88 years. Fourteen percent and 12 percent
were 65 years or older, and just under
half the
female population was
postmenopausal. The vast
majority were Caucasian, more so in the
European
study.
Patients were required to have
had at
least a 6-month history of constipation
symptoms.
As you can see, the mean duration of
symptoms was
considerably longer, 14.7 and 19.5 years.
The means of the
characteristics of bowel
habit by history and during the 14-day
baseline
period are shown on the slide here. However, as
these baseline parameters would not be
normally
distributed in a constipated population
it may be
more relevant to look at median data at
baseline.
When we do so, we see from the history the
duration
of symptoms was 10 and 15 years, with
hard or very
hard stools 90 percent of the time and a
median
number of one SBM per week. Now, in clinical
practice the Rome criteria are applied to
the
51
history to make a diagnosis of chronic
constipation.
From the baseline diary data we
see that
the median number of CSBMs was zero and
SBMs 2.5
and 2.9.
So, these patients fulfilled the
inclusion criteria of having less than 3
CSBMs per
week.
In fact, they had less than 3 SBMs per week
by history and by baseline median
data. In
addition, the number of SBMs with
straining per
week was 2.0 and 2.5 so the majority of
spontaneous
bowel movements were associated with
straining.
This confirms that the patient population
was,
indeed, constipated and, indeed, had
chronic
constipation.
I have outlined the study
design, the
patient population, demographics and the
baseline
characteristics. Now let's look at the primary
efficacy variable. For this endpoint we defined a
responder as having an increase of at
least one
complete spontaneous bowel movement per
week on
average during the first 4 weeks of the
treatment
compared to the 2 weeks at baseline. They had to
52
have had at least 7 days of treatment.
The results were positive. In study 2301
the responder rates for Zelnorm were 35.6
percent
for 2 mg BID, 40.2 percent for 6 mg BID
compared to
26.7 percent for placebo.
In study 2302 the responder
rates were
41.4 percent with 2 mg, 43.2 percent with
6 mg BID
compared to 25.1 percent on placebo. The p values
were significant. The 6 mg BID dose was
consistently more efficacious, with
deltas of 13.5
percent and 18.1 percent for the 2
studies.
Now, in order to confirm
sustained
efficacy of Zelnorm we analyzed those
patients with
an increase of at least one complete
spontaneous
bowel movement per week on average over
the entire
12-week trial duration, compared to the
baseline
period of 2 weeks.
Again the results were positive
and
consistent with the results for the
primary
efficacy variable. A treatment effect for the 6 mg
BID dose over placebo of 13 and 18
percentage
points for the 2 trials respectively was
53
demonstrated.
When we look at weekly responder rates
using this responder definition, we can
see that
the effect of Zelnorm is seen early,
within the
first week, and is sustained throughout
the entire
treatment period. In study 2302 we can see that
the treatment effect is lost once the
drug is
withdrawn. The percentage of responders in both
Zelnorm groups reached the level of
placebo within
2 weeks after termination of
treatment. The
results with the 6 mg BID dose are
consistently
superior to placebo, and here I am
showing you the
data for this dose alone so that you can
more
clearly see the benefit.
When we look at the number of
CSBMs, there
is a marked increase within the first
week of
treatment with a significant improvement
over
placebo.
The number of CSBMs decreased on
withdrawal of the drug, approaching but
not
reaching the level observed during the
baseline
period.
There was no rebound effect demonstrated.
The effect was again more consistent with
the 6 mg
54
BID dose, which you can see more clearly
on this
slide.
In order to further assess the
benefit of
Zelnorm, we conducted analyses on other
constipation assessments which we defined
a priori.
Let me share these results with you. Let's start
with satisfaction with bowel habits. Now, this is
an important endpoint and an important
measure of
clinically relevant benefit. The Rome committee
has advocated the use of global endpoints
and
satisfaction really is a composite
subjective
assessment by the patient. We asked the question
how satisfied were you with your bowel
habits over
the past week? We used a 5-point ordinal scale,
with zero being a very great deal
satisfied and 4
being not at all satisfied. So, improvement was
represented by a decrease in the
satisfaction
score.
Here we defined a responder as
having a
mean decrease of 1 or more on the 5-point
scale
over 12 weeks compared to baseline. We
subsequently have validated this data
relating
55
satisfaction scores to a relative shift
in
distribution, and we have looked at
baseline
standard deviations and week 12 standard
deviations
and
a 1-point change on this score is associated
with significant effect sizes. We saw significant
superiority of both doses of Zelnorm
compared to
placebo in this satisfaction endpoint.
Stool form is another important
marker of
constipation, and also showed significant
improvement
on Zelnorm. Stool form was 2.5 and 2.8 at baseline
in the 2 studies respectively and on
treatment with
Zelnorm.
On treatment with Zelnorm this was
maintained at around a score of 3.5 on the
Bristol
Stool Scale.
On this slide you can see the
change from
baseline in stool form, which showed
significant
benefit over placebo for nearly all
weeks. Again,
we can see the loss of benefit during the
withdrawal period.
What about straining, yet
another
important symptom of constipation? For each bowel
56
movement we asked the question did you
have any
straining? This was a 3-point scale and the
possible responses were zero, no
straining; 1,
acceptable straining; and 2, too much
straining.
We did not capture straining in the
absence of a
bowel movement. We subsequently analyzed straining
scores for spontaneous bowel movements
and saw
significant improvement on Zelnorm
compared to
placebo which was consistent over time,
as we saw
with the other variables.
Now, what about the
bothersomeness
questions? On a weekly basis patients were asked
to evaluate the bothersomeness of
constipation.
Now, this is a global assessment in
keeping with
the global satisfaction assessment.
In addition, we looked at the
bothersomeness of a bowel movement
bloating and
distention and bothersomeness of
abdominal
discomfort. As you heard from Dr. Prather earlier,
patients with chronic constipation can
present with
bloating and abdominal discomfort, and we
can see
significant improvement in the
bothersomeness of
57
constipation on Zelnorm for both doses in
both
studies.
For abdominal bloating and distention and
abdominal discomfort and pain we saw
improvement in
these symptoms in both studies, reaching
statistical significance for the 2 doses
in study
2302.
As you also heard from Dr. Prather, many
of the currently available therapies for
constipation in fact aggravate the
symptoms of
abdominal bloating and abdominal
discomfort so this
is another important benefit of Zelnorm.
So, I have presented several
secondary
endpoints. Now the question we asked ourselves was
is there an association between
responders for the
primary endpoint and responders for the
secondary
efficacy variables. Well, as you can see on this
slide, there is a strong positive
association
between responders for the primary
endpoint and
response to secondary variables. Remember, the
primary responder definition was an
increase of at
least one CSBM per week compared to baseline
over
the first 4 weeks of the treatment.
58
Improvement on stool form is
represented
by a positive increase, while improvement
on the
other variables is represented by a
decrease in
scores.
You can see the clear-cut difference
between responders and non-responders,
which is
significant for each endpoint, which
supports the
CSBM primary endpoint.
Now I will walk you through
some of the
additional analyses that were done. In discussions
with the FDA early last year, some other
responder
analyses were requested prior to database
lock.
One of these define a responder was
having at least
3 CSBMs per week for the first 4 weeks of
the
study.
Now, this was a fixed
definition with no
comparison to baseline, and this was a
high hurdle
to achieve considering that the patient
population
had a median number of CSBMs of zero and
a mean
number of CSBMs of 0.5 at baseline. So, reaching a
level of greater than or equal to 3 CSBMs
per week
represents on average a 6-fold increase
required to
meet this responder definition. As you can see
59
though, Zelnorm was significantly better
than
placebo.
Both doses in both studies were
significant, with deltas of 9 percent for
the 6 mg
BID dose in the 2 studies. We saw similar results
using this responder definition over the
12-week
treatment period, with deltas of 9 and 11
percent
for the 6 mg BID dose.
So, we have demonstrated significant
benefit of Zelnorm compared to placebo
for our
primary endpoint, and we have
demonstrated
significant benefit of Zelnorm compared
to placebo
in these analyses that were requested by
the FDA.
Let us now look at the effect
of the
number of bowel movements at baseline on
response.
Now, bearing in mind that we used the
concept of
complete spontaneous bowel movements,
which is a
relatively new concept, we wanted to see
if
baseline number of bowel movements, and
that is
all-comers, would affect our primary
efficacy
variable.
So, we looked at patients who
had less
than 3 bowel movements per week at
baseline. What
60
you can see is that Zelnorm is equally
effective in
the group that has less than 3 bowel
movements per
week as it is in the group that has more
than 3
bowel movements per week at baseline.
We also did various subgroup
analyses.
These were planned prospectively but we
did not
attempt to meet a minimum number of
patients in any
subgroup.
Subsequently, some of these groups had
very few subjects and this is reflected
in the wide
confidence intervals. It is important to remember
that the purpose of subgroup analyses is
not to
demonstrate efficacy as these analyses
are not
powered to detect statistical
significance. The
purpose of subgroup analyses is to ensure
that the
effect in any subgroup is consistent with
the
overall effect and that we are not seeing
any
negative trends.
Here I am showing you the data
for the 6
mg BID dose, and we can see the positive
odds
ratios for almost all the subjects that
we
analyzed.
In the group 65 years and older there
was a total of 88 patients in the 6 mg
BID group
61
and 117 patients in the placebo group,
with an odds
ratio of 1 for the overall population.
For the male patients, there
were 106 on 6
mg BID and 93 on placebo. The odds ratio was
positive at 1.36, and improvement on
Zelnorm was
seen for most variables in men.
One of the issues I want to
address now is
the question how many of these patients
in this
chronic constipation program were, in
fact, IBS
patients, and did this have an effect on
our
results.
We did not actively exclude IBS patients
from the study but when we went back to
the patient
history only 4 percent of patients had a
diagnosis
of IBS in their history.
As we did not administer the
Rome
questionnaire for IBS, we decided to take
a
conservative approach to try and identify
patients
that we thought may be potentially
IBS-like. So,
we identified all patients in whom
abdominal pain
was the main complaint at baseline, and
this was
about 12 percent of our patients. In addition, we
included patients who had abdominal pain
that may
62
not necessarily have been their
predominant symptom
but they also had diarrhea together with
this
abdominal pain. So, criteria (a) and (b) on this
slide come from the history and criteria
(c) comes
from the baseline diary data.
We came up with a total of 22
percent of
our patients as possibly having IBS. These were
equally represented in the 3 treatment
arms. So,
we felt confident that almost 80 percent
of our
patients were, indeed, chronic
constipation
patients and did not have IBS. However, we were
interested to see what the efficacy
results would
look like if we excluded those patients
who were
IBS-like.
Here is the pooled data. In this group,
without IS-like features, in other words,
the pure
chronic constipation population, you can
clearly
see the benefit of Zelnorm with
improvement over
placebo of 40 percent in the 2 mg BID
group and 18
percent in the 6 mg BID group. We can compare this
to the deltas in the pooled ITT primary
efficacy
analysis in which there was a 13 percent
delta in
63
the 2 mg BID group and 16 percent delta
in the 6 mg
BID group. So, in this pooled subgroup analysis
the results in the pure chronic
constipation group
are even more robust than in the ITT
analysis.
So, I have presented data here
that
demonstrate the efficacy of Zelnorm in
patients
with chronic constipation. The onset of action is
early.
The effect is sustained, and there is no
rebound phenomenon.
We have measured the efficacy
of Zelnorm
using a number of parameters and Zelnorm
is
efficacious for multiple symptoms of
chronic
constipation which include straining,
hard stools
and infrequent stools, with overall
improved
satisfaction. The 6 mg BIT dose has emerged as
consistently more efficacious than the 2
mg BID
dose.
Now let's look at the safety
data. I am
going to go through the 12-week data
looking at
exposure, adverse event profile, serious
adverse
events, and laboratory evaluations, and
then the
long-term safety profile from the
extension study.
64
This was a 13-month extension study,
providing a
total of 16 months of data for the groups
that
received Zelnorm in the core study.
Let's start with overall
exposure. The
intended study duration was 84 days. Exposure was
comparable across all treatment groups. The mean
duration of treatment was 80 days, and 84
percent
of patients completed at least 11 weeks
of
treatment and 69 percent had more than 85
days of
exposure in this 12-week period. The total number
of patients who experienced any adverse
event was
60 percent in the placebo group, 57
percent in the
6 mg BID group and 56 percent in the 2 mg
BID
group.
The most frequent adverse events were
headache, nasopharyngitis , diarrhea,
abdominal
pain and nausea. The only notable adverse event
seen more frequently with Zelnorm was
diarrhea, as
you would expect given the
pharmacodynamic action
of this drug.
When we look at the most
frequent adverse
events leading to discontinuation, we see
abdominal
pain, diarrhea, abdominal distension,
nausea and
65
headache.
On this table we have included all
discontinuations in which there were at
least 5
patients on any dose of Zelnorm. Overall, the only
one where discontinuations appeared to be
dose-dependent was diarrhea, with a
discontinuation
rate of less than 1.0 percent on the 6 mg
BID dose
and 0.3 percent for the 2 mg BID dose.
Let's look at the diarrhea in
more
detail--4.2 percent with the 2 mg BID
dose, 6.6
percent with the 6 mg BID dose versus 3
percent
with placebo. Over 80 percent of patients who
experienced diarrhea had only a single
episode, and
the median duration of the first episode
was about
2 days.
Most diarrhea occurred on the first day of
treatment.
When we look at the
characteristics of the
stool on the first day of diarrhea, the
median
number of bowel movements was 3 in the
placebo
group, 2 on Zelnorm 2 mg BID and 3 in the
mg BID
group.
The median stool form was essentially
similar across all treatment groups at
5.7 for
placebo and 6 and 6.3 for the 2 Zelnorm
doses
66
respectively.
Most patients who had diarrhea
continued
on their medication and took no
action. There were
more patients on 6 mg BID who adjusted
their dose
or temporarily interrupted therapy but
there were
very few patients who discontinued
permanently
because of diarrhea. None of these cases met the
definition of a serious adverse event or the
definition of clinically significant
consequences
of diarrhea such as hypovolemia,
hypokalemia or the
need for IV fluids or electrolyte
replacement.
Let's look at serious adverse
events.
Incidence rates were comparable across
all
treatment groups. There were very few
discontinuations due to these serious
adverse
events.
There were no deaths during the course of
the study but there was one death 67 days
after the
last dose of study medication in study
2302. This
was an 85 year-old man who had been on
Zelnorm 2 mg
BID.
He died from respiratory failure and
mesothelioma secondary to preexisting
asbestosis.
We also evaluated a number of
laboratory
67
parameters. There was a low frequency of notable
abnormalities which were essentially
similar across
all treatment groups.
The incidence of any abdominal
or pelvic
surgeries in the Zelnorm-treated group
was lower
than in the placebo group. One patient in study
2302, on Zelnorm 6 mg BID, had a
cholecystectomy.
The investigator assessed the event as
not related
to study medication. The incidence of other
surgeries was well balanced between
Zelnorm and
placebo.
Now let's look at the 13-month
extension
study, and 842 patients entered the
extension
phase.
And, 61.7 percent were exposed to at least
12 months of Zelnorm; 46 percent of
patients
discontinued over the 13 months. Most
discontinuations were for unsatisfactory
therapeutic responses, with very few
discontinuations for adverse events. The same
adverse events predominated as during the
core
period.
Frequencies followed the same pattern as
seen in the core studies, although the
incidence
68
rates were generally higher due to the
longer
duration of exposure. No relevant differences were
seen in the rates between the 2 doses of
Zelnorm.
There were no deaths in the 13-month
extension.
So, to summarize our safety
conclusions,
the incidence of adverse events on
Zelnorm in
chronic constipation is similar to
placebo, except
for diarrhea, which is what we would
expect from
the pharmacodynamic profile. There were low
discontinuation rates due to adverse
events. The
long-term safety profile was similar to
the profile
in the core 12-week studies. Zelnorm, therefore,
as been demonstrated to be safe and well
tolerated
in patients with chronic constipation.
What are our final overall
conclusions?
Zelnorm is effective in the treatment of
multiple
symptoms of chronic constipation, with
the 6 mg BID
dose consistently more efficacious than
the 2 mg
BID dose.
Zelnorm improves satisfaction with bowel
habits; straining; hard and lumpy stools;
and
infrequent bowel movements. In addition, Zelnorm
has a favorable safety profile.
69
Therefore, we are asking for an
approval
for Zelnorm for the treatment of patients
with
chronic constipation and relief of
associated
symptoms of straining, hard or lumpy
stools, and
infrequent defecation.
That concludes my
presentation. Thank you
very much. I would now like to introduce Dr. Bo
Joelsson, vice president and head of
clinical
research and development for gastroenterology,
who
will present the general safety
overview. Dr.
Joelsson?
Zelnorm Safety Overview
DR. JOELSSON: Good morning, Dr. Fogel,
advisory committee, representatives from
the FDA,
ladies and gentlemen. My name is Bo Joelsson and I
am the head of GI research and
development at
Novartis.
Today I will review with you
the overall
safety experience with Zelnorm, and
demonstrate to
you that Zelnorm is a safe and
well-tolerated drug.
This is what I am going to review with
you today.
First I will show that the positive
safety profile
70
of Zelnorm that was established at the
time of
approval in July, 2002 is confirmed in
our chronic
constipation clinical program. Secondly, I will
briefly present a few safety topics that
we have
agreed with the FDA to discuss at this
meeting:
serious consequences of diarrhea; rectal
bleeding;
ischemic colitis and other forms of
intestinal
ischemia; biliary tract disorders and
ovarian
cysts.
Finally, I will summarize our experience
demonstrating that Zelnorm is a safe and
well
tolerated drug.
The three most common adverse
events that
were reported at approval in July, 2002
were
headache, abdominal pain and diarrhea,
and the
incidence of diarrhea was higher on
Zelnorm.
This slide shows that the adverse
event
data from the chronic constipation
clinical trials
compared favorably to the IBS
constipation data.
Headache incidence is similar between the
treatment
arms.
Abdominal pain was less common in the
chronic constipation studies than in the
IBS
trials, demonstrating that the chronic
constipation
71
population is different from the IBS
population
which is characterized by abdominal
pain. The
incidence of abdominal pain in Zelnorm
and placebo
treated patients indicates that abdominal
pain as
an adverse event is not related to
Zelnorm
treatment. As in IBS, the reported incidence of
diarrhea is higher on Zelnorm. Adverse events
leading to discontinuation are also low
in the
chronic constipation clinical trials.
At approval in July, 2002 the
incidence of
serious adverse events was low. This was 1.6
percent on Zelnorm as compared to 1.1
percent on
placebo.
Serious adverse events leading to
discontinuation of study drug were 0.7
percent on
Zelnorm and 0.6 on placebo.
The incidence of serious
adverse events in
the chronic constipation clinical trials
was
similar to that in the IBS clinical
program. The
incidence of serious adverse events
leading to
discontinuation was lower and identical
in Zelnorm
and
placebo treated patients.
The clinical trial adverse
event data
72
collected in chronic constipation
clinical program
supports and strengthens the positive
safety
profile established at the time of
approval. With
the exception of diarrhea, the Zelnorm
safety
profile is similar to that of placebo.
We have at this time experience
with use
of Zelnorm both from clinical trials in
patients
with IBS, chronic constipation and upper
GI
indications, as well as postmarketing
clinical use.
In clinical trials more than 15,000
patients have
been included and more than 11,000
subjects have
taken Zelnorm, which corresponds to 3,456
patient-years of Zelnorm experience. More than
10,000 patients have been involved in
controlled
clinical trials and close to 7,000 of
them have
been on Zelnorm.
Zelnorm is currently registered
in 56
countries worldwide. It has been available since
January, 2001 and here, in the United
States, since
July, 2002. Approximately 3 million patients have
been treated, 2 million in the United States. That
corresponds to more than 350,000
patient-years of
73
treatment and more than 230,000
patient-years in
the United States.
We have agreed with the FDA to
discuss
several specific safety topics at this
advisory
committee meeting. The first of these is serious
consequences of diarrhea. Diarrhea is an expected
effect of Zelnorm in some patients due to
the
mechanism of action. The diarrhea is generally
mild, is generally transient and
self-limiting, and
rarely leads to serious consequences.
A patient is defined as having
a serious
consequence of diarrhea if one or more of
the
following took place: A serious adverse event was
reported as defined by regulatory
requirements; if
hypokalemia occurred; if hypovolemia was
diagnosed;
if IV fluids were administered; or any
medically
significant events related to diarrhea
occurred,
such as hypotension, syncope or cardiac
effects.
We carefully reviewed our
clinical trial
experience of more than 11,000 patients
using this
definition in order to identify cases of
serious
consequences of diarrhea, and this is our
clinical
74
trial experience. Six cases of serious
consequences of diarrhea were found in
the clinical
studies on Zelnorm with more than 11,000
patients.
Four of these patients required
hospitalization.
Two received IV fluids. Two had actually possible
other causes. One reported gastroenteritis and one
reported antibiotic-induced diarrhea. All patients
recovered without complications and four
of them
were actually able to continue on study
medication
after these episodes.
From the postmarketing
experience in
approximately 3 million patients, 30
cases have
been reported; 16 were hospitalized; 11
received IV
fluids; 8 exhibited hypotension; 4,
syncope; and 4
were considered life-threatening by the
reporting
physician; 1 had hypokalemia. One fatality from
aspiration pneumonia was reported in a
patient with
acute pancreatitis and chronic liver
cirrhosis.
This demographic information on
the 30
patients with serious consequences of
diarrhea in
the postmarketing experience. There was a wide age
spectrum, 18 to 82 years. The median age was 49
75
years and only 9 patients were older than
65,
indicating that this is not an elderly
specific
issue.
As is expected, most were women, reflecting
the label in most countries. Serious consequences
of diarrhea mostly occurred in patients
on 12 mg of
Zelnorm per day but were also reported in
some
patients on a lower dose.
In clinical trials diarrhea
usually
occurred during the first days of
treatment, as we
heard before. This was also true for serious
consequences of diarrhea in the
postmarketing
experience. It occurred within 5 days in all cases
and the median time was 1 day.
In conclusion, serious
consequences of
diarrhea are rare in clinical trials and
very
rarely reported in the postmarketing
experience.
All cases resolved without sequelae.
Rectal bleeding is of special
interest
because of its possible relationship with
serious
colon conditions. We have carefully reviewed our
clinical trial data for terms that
indicate the
presence of rectal bleeding, such as
rectal
76
hemorrhage, melena, hematochezia, etc.,
etc. We
found that the presence of rectal
bleeding was very
similar in patients on Zelnorm and
placebo in our
controlled clinical trials.
From the postmarketing
experience of
approximately 3 million patients, 82
cases of
rectal bleeding were reported. Twenty-one
were
reported in conjunction with suspected
ischemic
colitis; 1 from another form of
intestinal
ischemia; 3 from other forms of
colitis. In 23
cases hemorrhoids were a possible source
of
bleeding.
The rest of the cases listed on this
slide show varying etiologies. Fifteen of the
patients were not investigated.
Our clinical trial data
indicated a
similar reporting rate in Zelnorm- and
placebo-treated patients. There are rare reports
of rectal bleeding from postmarketing
experience,
which indicates that Zelnorm therapy is
not
causally related to the rectal bleeding.
Now, the occurrence of ischemic
colitis
and other forms of intestinal ischemia is
a concern
77
with drugs used to treat IBS with
diarrhea. These
drugs block the 5-HT
3 receptor and, thus, have a
very different mechanism of action than
Zelnorm,
which is a 5-HT
4
receptor
agonist used to treat IBS
with constipation. Nonetheless, since these are
potentially serious conditions and
Zelnorm affects
the serotonin receptor, it is important
to
carefully assess whether Zelnorm therapy
could
increase the risk of intestinal ischemia.
Ischemic colitis is a rare
condition in
the general population. When it occurs, it is
potentially serious but is generally mild
and
transient. It is characterized by mucosal erosions
seen at colonoscopy, with rectal bleeding
and
abdominal pain being the most common
clinical
presentations. Usually no specific treatment is
needed and surgical intervention is
rarely
indicated.
While ischemic colitis is very
rare in the
general population, it is more commonly
reported in
IBS patients. In a study from the Medi-Cal claims
database, 179 cases per 100,000
patient-years were
78
found in IBS patients versus 47 cases per
100,000
patient-years in non-IBS patients. In a study from
the United Health Care claims database,
with a
younger patient population, the
corresponding
numbers were 43 in IBS patients and 7 in
non-IBS
patients.
In the CORI database which collects data
from endoscopy units all over the United
States,
ischemic colitis was found in 93 per
100,000
colonoscopies in patients with IBS-like
symptoms
while there were 21 cases per 100,000
screening
colonoscopies in asymptomatic
individuals. All of
these cases were endoscopically verified
and in
most cases supported by histology.
It has been suggested by Dr.
Brinker et
al., from the FDA, that the increased
incidence of
ischemic colitis in IBS is the result of
misdiagnosis. Dr. Brinker published this analysis
from the patients from the United Health
Care
study.
He found evidence for misdiagnosis during
the first 3 weeks after IBS
diagnosis. However,
when patients with IBS were followed for
more than
a year, he still found an increased rate
of
79
ischemic colitis, 53 per 100,000
patient-years.
Thus, ischemic colitis can be
misdiagnosed
as IBS during the first weeks of
treatment, but
patients with a stable IBS diagnosis for
more than
1 year still have an increased risk of
ischemic
colitis diagnosis.
Now, there are two, maybe more,
possible
hypotheses why the rate of ischemic colitis
in IBS
is increased. Ascertainment bias because of the
documented fact that IBS patients are
investigated
two to three times more than the general
population, and/or because there are
currently
unknown common pathophysiological
mechanisms that
we don't know about today.
We carefully reviewed all cases
of rectal
bleeding, colonoscopy and reports of
colitis in our
clinical trials to identify possible
cases of
ischemic colitis and there were no cases
of
ischemic colitis identified in any of our
clinical
trials involving more than 11,000
patients on
Zelnorm.
However, one placebo case with ischemic
colitis was identified in our clinical
trials.
80
From postmarketing experience
as of June
1, 2004, 26 cases of suspected ischemic
colitis
have been reported. This corresponds to a
reporting rate of 7 cases per 100,000
patient-years
worldwide and 12 per 100,000
patient-years in the
United States. This rate is consistent with the
background rate incidence in IBS
patients.
The reported cases of ischemic
colitis do
not exhibit any distinct pattern with
regard to
duration of treatment, dose of drug, age
of
patients, co-morbid conditions, or other
demographic subgroups. The absence of ischemic
colitis cases in clinical studies and the
low
reporting rate in postmarketing
experience suggest
that Zelnorm treatment does not increase
the risk
of ischemic colitis.
Now, these findings are not
surprising
since Zelnorm is not expected to cause
vasoconstriction as there are no
5-HT
4 receptors in
the human vascular system. This is further
supported by preclinical studies. In vivo animal
studies have demonstrated no effect on
colonic
81
vascular conductance which is a measure
of vasal
activity.
In addition, although tegaserod has
negligible affinity for the 5-HT
3
receptor,
tegaserod has affinity for the 5-HT1B
receptor but
it does not cause vasoconstriction, as illustrated
in this graph.
This graph depicts the results
of adding
sumatriptan and ergotamine, which are two
known
5-HT1B agonists, and tegaserod to a
preparation of
isolated coronary arteries from non-human
primates.
As expected, ergotamine and sumatriptan
cause
marked contraction while tegaserod has no
effect.
In conclusion, there is no
evidence for a
causal relationship between Zelnorm and
ischemic
colitis.
Preclinical studies have clearly
demonstrated that tegaserod has no
vasoconstrictive
potential. There have been no cases of ischemic
colitis in clinical trials on Zelnorm,
and the
reporting rate in the postmarketing
experience is
consistent with the background rate of IC
in the
IBS population even taking
under-reporting into
account.
These data indicate that Zelnorm does not
82
increase the risk of ischemic colitis.
Now, there have been four
spontaneous
reports of fatalities in patients with
intestinal
ischemia from postmarketing reviews. We take these
reports very seriously and have
investigated them
thoroughly. Based on our individual and careful
review of each case, we are confident
that Zelnorm
did not cause these fatalities.
The four fatalities are as
follows: One
case with untreated central line sepsis and
ischemic colitis; one case of untreated
chronic
abdominal angina; one case with untreated
hypothyroidism leading to severe fecal
impaction;
and one case of multi-organ failure from
unknown
cause.
Dr. Shetzline has carefully
investigated
these cases and he will now discuss them
in some
detail with you. Please, Dr. Shetzline?
Fatality Cases
DR. SHETZLINE: Thanks, Dr. Joelsson. I
am Michael Shetzline, an
gastroenterologist and a
senior medical director at Novartis,
responsible
83
for Zelnorm in the United States. Myself and Dr.
Christian Avery are clinical safety
experts
responsible for evaluation of these
cases.
I would like to review these
cases in some
detail.
Given the complicated nature of the cases,
it is important for us to go into some
detail in
order to separate out and look at the
medical
issues and make them clear. The first case is a 76
year-old woman. Her past medical history is
significant for 16 years of
constipation. She had
IBS with constipation diagnosed in the
year 2000
and started on Zelnorm in November of
2002. She
also had dementia of the Alzheimer's
type.
In late August of 2003, after
282 days of
Zelnorm use the patient was found
"down" at home.
She presented at the emergency department
and was
admitted with abdominal pain, vomiting,
hypotension, hypothermia and altered
mental status.
Her urine eventually grew E. coli and an
abdominal
CT noted dilated loops of small bowel,
consistent
with partial small bowel obstruction,
diverticulosis and focal ischemic changes
of the
84
left colon. She was treated with antibiotics and
hydration.
During this admission she had a
colonoscopy for an incidental episode of
guaiac
positive stool, and this revealed sigmoid
and
splenic flexure ulcers with areas of
regeneration
and healing, consistent with ischemic
colitis.
Zelnorm was discontinued at this
time. Biopsies
were consistent with ischemic colitis and
she was
placed on bowel rest and provided total
parenteral
nutrition.
She was eventually transferred
to an
extended care facility and had two
colonoscopies on
September 17th and 19th. Both noted improved
colonic mucosa, resolving ischemic
colitis. This
is the usual expected course of ischemic
colitis.
However, she remained on TPN, total
parenteral
nutrition. She became hypotensive with E. coli UTI
and was readmitted on September 26th for
failure to
thrive, febrile and more acutely ill.
After discussion with the
family and
patient, no heroic surgical interventions
and/or
85
CPR were to be performed; only supportive
care.
She was diagnosed with central line
sepsis and,
given her medical co-morbidities and discussion
with the patient and family, a "do
not resuscitate"
order was initiated. Her antibiotics were
discontinue on October 1st and she
expired. In
summary, this event of ischemic colitis
resulted
from hypotension and possibly urosepsis.
The second case is a 66
year-old female
who had a past medical history of
hypertension,
chronic obstructive pulmonary disease and
tobacco
abuse.
She had a prior stroke in 1997 due to small
vessel disease, and carried a prior diagnosis
of
non-specific chronic colitis. Significantly, she
had symptoms of abdominal angina for 2-3
years
characterized by chronic abdominal pain
with food
intake, and this resulted in 36 lbs of
weight loss
during this interval. Her IBS was diagnosed in
January of 2000.
In October of 2003 she had
continued and
more severe post-prandial abdominal pain
and
constipation. On October 10th she was given
86
samples of Zelnorm, 6 mg BID, by her
primary care
physician. She was not given a prescription and
her caregiver, who was responsible for
administering all her medications, the
medications
taken by the patient, does not recall the
patient
taking Zelnorm. He does specifically recall her
increasing use of Vicodin due to this
more severe
abdominal pain.
On October 15th she was
admitted to the
hospital with severe abdominal pain and
bloody
diarrhea.
Zelnorm was not listed as an active
medication in any of her admission
documents.
On the 19th she developed acute
abdomen
and had an exploratory laparotomy for,
quote,
probable chronic intestinal ischemia,
acutely
worse, end quote. The laparotomy revealed
infarcted bowel from the ligament of
Treitz to the
terminal ileum, cecum, and proximal
ascending
colon, consistent with occlusion of the
superior
mesenteric artery. Given the extensive bowel
necrosis, comfort measures were provided
and she
expired.
The cause of death was listed as bowel
87
infarction due to peripheral vascular
disease. In
summary, this is the natural history of
end-stage
chronic abdominal or mesenteric angina
and it is
likely Zelnorm was not taken by this patient.
The third case is a 41 year-old
woman who
had a very significant past medical
history of
chronic obstructive pulmonary
disease. She had a
very extensive history of tobacco abuse,
with 60-90
pack-years of tobacco use for a 41
year-old woman.
She also had asthma, prior alcohol and
illicit drug
use, as well as obsessive-compulsive
disorder. She
had peripheral vascular disease with
claudication,
constipation, recurrent urinary tract
infections
and hypothyroidism. She also had a significant
abdominal event due to appendectomy with
a rupture
which resulted in abscess formation and a
partial
colectomy. She had medical and medication
non-compliance, as noted in a primary
care visit
from November of 2003.
This individual was presumably
prescribed
Zelnorm in March of 2003, however, these
documents
were not available for review. We have no
88
follow-up from the March presumed
prescription and
the November primary care records which
document
her non-compliance. She developed severe abdominal
pain and she collapsed with a cardiorespiratory
arrest.
After an emergency medical service call
she was resuscitated and admitted.
It is important to note that
admission
documents list only her Lithobid and
Seroquel as
active medications. They do not list Zelnorm or
her thyroid supplement. These documents include
emergency medical service notes at home,
admission
notes and multiple physician evaluations.
On admission, her abdominal
x-ray revealed
free air in the abdomen and an exploratory
laparotomy demonstrated a rectal sigmoid
densely
packed with rock-hard stool. She had ischemic
colitis and enteritis involving the colon
and
terminal ileum and early gangrene of the
distal
bowel.
She had marked dilatation, a picture
consistent with toxic megacolon.
She had a sub-total colectomy
with
ileostomy and was treated with
ventilatory support,
89
broad-spectrum antibiotics and
vasopressors. A
subsequent neurology evaluation revealed
anoxic
brain injury with diffuse edema and a
suspicion of
herniation. She developed multi-organ failure and
expired three days after admission. In summary,
this patient had a bowel obstruction from
likely
untreated hypothyroidism due to her
medication
non-compliance and a secondary
perforation. Given
her medical and medication non-compliance,
it is
likely she never took Zelnorm.
The last case is a 67 year-old
woman who
had a very significant history of heart
disease,
with known coronary disease, a prior
coronary
bypass graft procedure, angioplasty with
stent
placements, known occluded grafts,
congestive heart
failure, hypotension, atrial fibrillation
and
diabetes.
She had chronic and acute renal failure.
She was on Zelnorm 6 mg BID for an
unknown
indication from June 16th to August 7th,
the date
of this event.
She as admitted at this time
with
progressive shoulder and chest pain, as
well as
90
shortness of breath, and was
hospitalized, on
telemetry for a rule-out myocardial
infarction, on
August 7th. On admission, her abdomen was soft,
non-tender. Her lungs had few bibasal rales and
her extremities showed trace pedal edema.
It is important to note that at
this time
she had no diarrhea, no melena and no
bright red
per rectum. On hospital day 3 she complained of
abdominal pain and nausea, and surgical
consult
indicated a soft abdomen which was not
distended.
She did, however, have left lower
quadrant
tenderness and a questionable
diverticulitis. An
abdominal x-ray at this time showed a
large amount
of fecal material in the colon There was no
gaseous distention or free air.
On the same day laboratory
results
indicated an amylase of over 7,000 and a
lipase of
over 400.
A pulmonary consult for dyspnea
indicated respiratory failure and she
required
mechanical ventilation. At this time she was
evaluated for bronchitis, pneumonia,
rule-out
abdominal sepsis, rule-out ischemic
colitis,
91
coronary disease and hypotension.
A clinical evaluation noted, quote, in
view of her acute deterioration and
chronic medical
problems, her prognosis is extremely
poor.
Consequently, continuation of heroic
interventions
may be inappropriate, end of quote. A cardiologist
summary indicated hypotension and it was
felt that
the patient had a catastrophic abdominal
event.
This may have included ischemic bowel,
possible
perforation, pancreatitis, acute renal
failure, all
in
addition to her known co-morbidities of ischemic
cardiomyopathy, congestive heart failure,
renal
failure and diabetes. The patient was made a "no
code" and died on hospital day 4.
The death certificate listed
cardiorespiratory failure as the primary
immediate
cause of death. Other factors included shock,
pancreatitis and inflammatory bowel
disease. In
summary, this patient experienced
cardiovascular
collapse with a history of coronary
disease and
congestive heart failure, as well as
other medical
co-morbidities. This was likely unrelated to
92
Zelnorm.
Now I would like to return the
safety
update to Dr. Joelsson.
Zelnorm: Safety Overview
(continued)
DR. JOELSSON: Thank you, Dr. Shetzline.
In summary, these four cases, as you may
understand, are very complicated. In two cases it
is actually unclear if the patients
actually took
Zelnorm in the first place. In our opinion and
those of external experts that have
reviewed these
cases, the evidence does not support that
the death
of these patients was caused by or
contributed to
by Zelnorm.
At the time of approval in
July, 2002,
biliary tract disorders were discussed
because
there was an imbalance of
cholecystectomies
introduction he clinical trials. When pooling the
clinical trial data, there is still an
imbalance in
favor of placebo, although smaller than
was seen in
the approval trials.
An adjudication was performed
with outside
experts, resulting in a rate of 0.06
percent in
93
Zelnorm-treated patients versus 0.03
percent on
placebo.
In the postmarketing experience
there were
30 reports of biliary tract events in
approximately
3 million patients, and 18 were
cholecystectomies;
2 were cholelithiasis; and 10 were other
events.
There were no serious sequelae reported
from these
patients.
In order to further elucidate
the possible
effects of Zelnorm on gallbladder
function a very
thorough study was performed using
dynamic
ultrasound measurements. No effect on gallbladder
function was detected. There was no impact on
ejection fraction, ejection rate and
period, or
maximal emptying. There was no impact on fasting
and residual volume, and there were no
stimulus
effects on gallbladder contraction during
fasting.
Based on this data, it is unlikely that
Zelnorm
affects gallbladder function.
At approval there was also
discussion
about ovarian cysts. However, ovarian cysts are
very well balanced in the clinical trials
and there
94
are very rare reports from the
postmarketing
experience. Our conclusion from these data is that
Zelnorm treatment does not increase the
risk of
ovarian cysts.
Zelnorm has been extensively
studied in
clinical trials and postmarketing
experience, and
the safety profile of Zelnorm is very
favorable.
In fact, Zelnorm has the overall safety
profile of
placebo, with the only exception being
diarrhea.
However, serious consequences of diarrhea
are very
rare and do not result in significant
clinical
sequelae.
Evidence from either clinical trials or
postmarketing experience does not suggest
that
Zelnorm increases the risk of rectal
bleeding,
ischemic colitis, other forms of
intestinal
ischemia, cholecystectomies or ovarian
cysts.
Zelnorm is a safe and
well-tolerated drug
that has a safety profile that supports
its use in
chronic constipation patients. Thank you.
I would
now like to introduce Dr. Schoenfeld who
will
discuss with you his benefit/risk
assessment.
Benefit/Risk Assessment
95
DR. SCHOENFELD: Well, good morning, Dr.
Fogel, members of the advisory committee,
FDA
officers, audience members. I am Philip
Schoenfeld, a gastroenterologist at the
University
of Michigan School of Medicine. It is my pleasure
to present a risk/benefit analysis of the
use of
tegaserod and traditional therapies for
the
management of constipation.
Now, I sympathize with the
members of the
advisory committee. You have been sitting here now
for over an hour and a half. I imagine that I
should keep this presentation brief but
also as
stimulating as possible to maintain your
attention.
I am going to present an evidence-based
medicine
analysis, revising the randomized,
controlled trial
data about the efficacy for tegaserod and
traditional therapies in the management
of
constipation, and review the best
available
clinical trial data about the safety of tegaserod
and traditional therapies in the
management of
constipation.
I think it is particularly
important to
96
consider the risk/benefit analysis not
only for
tegaserod but also for alternative
therapies for
constipation because, as a practicing
gastroenterologist, when I am treating a
patient
with constipation I have to consider the
risk/benefit analysis for all of these
possible
treatments when I select the best
possible
treatment for my patient, and I certainly
think
this is an important topic. As Dr. Prather pointed
out during her presentation, constipation
is
common.
It negatively impacts the quality of life
for patients who actively seek medical
care, and
many constipated patients are
dissatisfied with
available treatments.
Let's stop for a moment and
think about
that last statement, and look at the
randomized,
controlled trial data about traditional
therapies
for constipation to try to determine why
constipated patients might not be
satisfied with
available therapies.
This is a partial list of the
commonly
used treatments for constipation. They include
97
surface-acting agents like dioctyl sodium
sulfosuccinate--I had to practice saying
that and
hereafter I will refer to it as Colace;
bulking
agents like psyllium; stimulant laxatives
and
osmotic laxatives like PEG-3350. These are all
FDA-approved treatments for constipation.
Dr. Prizont, in his efficacy
section in
the FDA briefing document, provided a
brief but
very balanced review about traditional
therapies
for constipation. He specifically noted that there
are some randomized, controlled trials
looking at
the benefits of traditional therapies for
constipation but many of these were
conducted under
deficient designs. In other words, many of these
studies did not meet the Rome committee
criteria
for appropriate design of a functional GI
disorder
trial.
They had inappropriately small sample
sizes.
They had inadequate blinding.
They had
very vague or imprecise criteria to
identify
patients with constipation.
Now, in the briefing document
Dr. Prizont
concluded that these trials revealed little
98
differences between laxatives and modest
improvement over placebo. He actually referenced
the most recent and most comprehensive
meta-analysis about traditional therapies
for
laxatives, conducted by Jones and Nick
Talley and
colleagues. In fact, the actual title of that
meta-analysis is "The Lack of
Objective Evidence of
Efficacy of Laxatives in Chronic
Constipation."
That is quite a provocative title.
Let's delve into that study a
little bit
further to see how they came up with
that. In
brief trials of 4 weeks or less in
duration, they
found that laxatives increased stool
frequency by
about 2 stools per week compared to
baseline.
Placebo increased stool frequency by
about 1 stool
per week compared to baseline. But as you note,
the 95 percent confidence intervals here
for
placebo and laxatives are superimposed,
not clearly
demonstrating a difference in efficacy.
For trials of 5-12 weeks in
duration the
results are less impressive. Laxatives increased
stool frequency by only 1 bowel movement
per week
99
versus placebo-treated patients who had
an increase
in stool frequency of 1.5 bowel movements
per week.
Now, I think we should be
cautious about
interpreting these results. This is a
meta-analysis that provides a single
summary
statistic and combines the results from
bulking
agents, stimulant laxatives and osmotic
laxatives.
So, it might be more beneficial to look
at a
systematic review that at least separated
out
bulking agents from other types of
laxatives.
That is actually
available. The other
well-designed, systematic review about
traditional
therapies for constipation comes from Tramonte
and
Cindy Mulrow and colleagues, at the
Cochrane Center
in San Antonio, Texas. They separated out bulking
agents versus laxatives and found that
bulking
agents increase stool frequency by about
1.4 stools
per week compared to baseline and
laxatives
increase stool frequency by about 1.5
stools per
week compared to baseline. So, their study
conclusions were that fiber and laxatives
do appear
to modestly increase stool frequency over
placebo.
100
They also concluded that it was unknown
if these
agents would improve general well being
or global
satisfaction because this endpoint wasn't
examined
in many of these trials.
Now, it is beyond the scope of
my
presentation to individually review each
of the
randomized, controlled trials looking at
traditional therapies and I am sure you
wouldn't
want to sit through all of that. But I will
conclude by noting that the randomized,
controlled
trial evidence for psyllium, PEG-3355 and
lactulose
consistently demonstrates significant
increases in
stool frequency versus placebo. On the other hand,
other commonly used and FDA-approved
treatments for
constipation, such as bisacodyl, Surfak,
Colace,
consistently do not demonstrate a
significant
increase in stool frequency versus
placebo. It
doesn't necessarily mean that these drugs
are
ineffective. As Dr. Prizont noted, most of these
RCTs were carried out under deficient
designs and
if appropriately designed studies that
met the Rome
committee criteria were conducted, we
might be able
101
to demonstrate efficacy. Nevertheless, when I am
selecting a treatment for constipation I
have to
consider not just my clinical experience
but also
the randomized, controlled trial data of
efficacy
as well as the clinical trial data of
safety.
There are several other issues
for
discussion today. First, whether or not the
clinical trial data are adequate with
respect to
the chronic constipation population that
is likely
to be treated with tegaserod. I would just
reemphasize part of Dr. Dennis'
presentation, the
two Novartis randomized, controlled
trials
contained inclusion criteria that are
very similar
to the Rome II committee criteria for
functional
constipation. In fact, in some ways they are more
stringent.
Patients had to have greater
than 6 months
of
symptoms by the Novartis criteria, whereas the
Rome criteria require only 12 weeks,
which need not
be consecutive, of symptoms in the
previous year.
The Novartis criteria required that
patients have
fewer than 3 spontaneous bowel movements
per week.
102
That is not an actually requirement to
meet the
Rome committee criteria for functional
constipation. A patient, for example, who just had
straining and lumpy, hard stools for 12
non-consecutive weeks would meet the Rome
committee
criteria for functional constipation.
Certainly, I think it is very
true that 78
percent of the patients in these RCTs
appear to
have chronic constipation while as many
as 22
percent had some symptoms of abdominal
discomfort
that might have led them to be classified
as IBS
with constipation. Nevertheless, Miss Mealey, the
FDA statistical reviewer, in her very
thorough and
comprehensive statistical review noted
that the
responder rates for the constipated
patients in
these trials who didn't have IBS-like
symptoms were
similar to the overall responder
rates. In fact,
they tended to do better than the overall
response
rates that were recorded.
Certainly, the issue has been
raised about
whether or not we may have subtypes of
patients
with slow transit constipation included
in this
103
trial.
As a clinician, my main point about that
would be that the AGA's medical position
statement
about that provides essentially identical
treatment
algorithms whether somebody has normal
transit
constipation or slow transit
constipation. So, my
choice of therapy wouldn't necessarily
differ based
on whether or not there might have been
some
patients with slow transit constipation
included in
these trials.
Another issue for discussion is
the
appropriateness of a primary endpoint of
an
increase of 1 or more complete
spontaneous bowel
movements per week compared to baseline
versus the
percentage of patients who attained 3 or
more
complete spontaneous bowel movements per
week.
This is a difficult issue. The Rome II committee
actually couldn't come to a consensus
about what
was the most appropriate endpoint for
trials of IBS
and functional constipation. They recognized that
there are multiple symptoms present in
patients
with these lower GI functional
disorders. They
actually stated that in addition to
whatever
104
primary endpoint is chosen, there should
be a
select number of a priori defined
secondary
endpoints that reflect the multiple
symptoms that
are present in patients with these
functional GI
disorders.
In fact, Sander Van Zanten and
his
colleagues, who were on the subcommittee
of the
Rome committee who laid out the
appropriate design
of a trial of a functional GI disorder,
actually
stated that global improvement in
satisfaction may
be the most appropriate endpoint. That is an a
prior defined secondary endpoint in the 2
Novartis
randomized, controlled trials, that
patients on
tegaserod 6 mg BID were significantly
more likely
to be responders for global satisfaction
than
patients that were on placebo. This is not only a
significant difference but, in my
opinion, a
clinically important difference where the
magnitude
of benefit is 9-12 percent more for
patients on
tegaserod 6 mg BID who were responders
for global
satisfaction compared to patients on
placebo.
Again, there were a select
number of a
105
priori defined secondary endpoints
included, to try
to contrast that with traditional
therapies that
patients on tegaserod 6 mg BID had 1.9 to
2 more
spontaneous bowel movements per week compared
to
patients on placebo who had about 0.9 to
1 more
spontaneous bowel movements per
week. These are
statistically significant differences.
If we do decide to apply the
FDA's
criteria that patients have to have 3 or
more
spontaneous bowel movements per week, and
we look
at the proportion of patients who
attained what is
a pretty high therapeutic goal, we still
see that
almost twice as many patients on
tegaserod
experienced 3 or more complete
spontaneous bowel
movements per week compared to patients
on placebo
and the magnitude of this difference,
whether we
look at 4 weeks or the entire 12-week
trials, is
approximately 10 percent. Again, in my opinion,
that is a clinically important
difference.
So, in conclusion for efficacy,
I would
state that the randomized, controlled
trial data
about the efficacy of tegaserod is very
robust and
106
precise.
These are the best designed, most
comprehensive trials about treatments for
constipation that are available among all
the
treatments that we have available for
constipation.
The
study population does reflect patients with
chronic constipation and the a priori
defined
primary and secondary endpoints do
reflect the
multiple symptoms that patients with
constipation
have, and these RCT data consistently
demonstrate
that tegaserod produces significant and
clinically
important improvement in the multiple
symptoms of
constipation.
Let's move on to safety. Unfortunately,
there is very little data about the safety
of
traditional therapies for
constipation. The most
recent and comprehensive meta-analysis by
Jones,
Nick Talley and colleagues actually
didn't even
address the issue because the data were
so scant.
If we do go back to the systematic review
performed
by Tramonte and Cindy Mulrow and
colleagues from
the Cochrane Center in San Antonio,
Texas, they
specifically noted that few studies used
107
standardized techniques to assess adverse
events.
They also did note that they did not
identify any
significant differences in adverse events
between
laxatives and placebo. So, they concluded that
although there is no evidence that
laxatives are
unduly harmful, the data available are
very limited
and short-term.
Thus, we are really left with
looking at
the prescribing information and case
report data to
try to get an idea about what adverse
events are
associated with commonly used
laxatives. We see
for bulking agents that fecal impaction
and large
bowel obstruction have been reported, and
even
acute esophageal obstruction when bulking
agents
aren't taken with adequate amounts of
water.
Anaphylaxis has been reported with
psyllium. Among
osmotic agents all different types of
electrolyte
abnormalities have been reported,
specifically with
magnesium-based agents that are used on a
regular
basis.
Stimulant laxatives have been associated
with both electrolyte imbalances as well
as
abdominal cramps. All of these agents have been
108
reported to have been associated with
diarrhea.
So, another issue for
discussion is
whether or not the clinical trial data
and
postmarketing surveillance data provide
adequate
evidence of safety. I pause here for a moment,
looking at the title of this slide, to
just note
that the clinical trial safety data where
patients
are followed per protocol probably
provides at
least the most precise safety data that
we have
available to us. When we look at the clinical
trial safety data available for tegaserod
we see
that in the Novartis 2 randomized,
controlled
trials over 2,600 patients with
constipation were
enrolled.
Over 1,700 received tegaserod. In
the
whole clinical trial safety database you
have over
11,000 patients treated with tegaserod
and over
3,400 patient-years of tegaserod use
followed
within the context of clinical
trials. I would
suggest that infers that there is very
robust and
precise clinical trial safety data for
tegaserod,
certainly more robust and precise
clinical trial
safety data than what we have available
for any
109
other treatment of constipation.
That very precise data allows
us to
estimate what is the likelihood of
serious adverse
events for constipated patients using
tegaserod or
placebo.
We see essentially similar rates.
And,
that very robust and precise safety data
let's us
quantify the likelihood of diarrhea as an
adverse
event.
Among constipated patients we see that it
is reported as an adverse event in 5
percent of
patients in clinical trials versus 3
percent in
patients on placebo. We see that 0.6 percent of
patients treated with tegaserod actually
discontinued the medication because of
the severity
of their diarrhea. When we look at the entire
clinical trial database we can estimate
that the
likelihood of clinically serious
consequences of
diarrhea--going to the emergency
department because
of dehydration and getting IV fluids,
virtually
being hospitalized because of syncopal
episode--occurs in 0.04 percent or 1 in
2,500
patients treated with tegaserod.
To conclude, let's turn to the
safety
110
issue about ischemic colitis. Obviously as
gastroenterologists, as primary care
providers for
patients, we are concerned about the
issue of
ischemic colitis because it has been
brought to our
attention by our clinical experience with
alosetron. Alosetron, again, is an antagonist of
the 5-HT 3
serotonin receptor
as
opposed to
tegaserod that is an agonist of the
5-HT
4
serotonin
receptor.
We know from the clinical trial data
that there were 17 cases of ischemic
colitis among
the 10,805 alosetron-treated patients in
those
clinical trials. That calculates out to a rate of
5.9 cases of ischemic colitis per 1,000
patient-years based on the clinical trial
data.
I would also like to point out
the fact
that among placebo-treated patients with
IBS the
rate of ischemic colitis was 1.1 cases
per 1,000
patient-years. Even in the context of this
clinical trial, there was a background
rate of
ischemic colitis among patients treated
with
placebo.
So, what can we do about comparing
the
111
issue of ischemic colitis with tegaserod
patients
treated for constipation versus other
patients
treated for constipation? The only other treatment
for
constipation that has any breadth of clinical
trial safety data is PEG-3350. In their new drug
application to the FDA they reported a
rate of
ischemic colitis in their clinical trial
safety
data of 3 cases per 1,000 patient-years. I want to
emphasize that that is an
extrapolation. The exact
number is that there was 1 case of
ischemic colitis
among 300 patient-years of clinical trial
safety
data when they submitted their new drug
application. That is the only other treatment for
constipation where we have any breadth of
clinical
trial safety data to estimate the
likelihood of
patients experiencing ischemic colitis.
What is the data for
tegaserod? Zero
cases among 11,640 tegaserod-treated
patients
studied over 3,400 patient-years of
exposure
versus, among all the clinical trial
database for
placebo-treated patients, 1 probable case
of
ischemic colitis among 4,267 placebo-treated
112
patients followed for 780 patient-years
of
exposure.
Now, the FDA officials wanted
to identify,
based on that clinical trial data--zero cases
among
all the patients followed in the clinical
trial
database--what would be the maximal rate
of
ischemic colitis that still could be
occurring
within 95 percent confidence
intervals. So, they
did their statistical analysis based
initially on
the 7,000 tegaserod-treated patients in
clinical
trials that they had reviewed and they
came up with
a maximal ischemic colitis rate, within
the
confines of 95 percent confidence
intervals, of 1
case in approximately 2,000 patients, based
on the
fact that there were zero reported cases
among over
7,000 patients.
If we give the up to date
analysis based
on all 11,640 tegaserod-treated patients,
then a
similar statistical analysis would shoe that
the
maximal rate within 95 percent confidence
intervals, considering there are zero
cases among
11,640 patients, would be 1 case in 3,883
patients.
113
In order to be balanced, I
think we should
consider the placebo patients too. The same
statistical analysis shows that their
maximal rate
would be 1 case in 867 placebo-treated
patients.
This analysis is still based on
very few
cases of ischemic colitis. So, I certainly
understand the need to look at
postmarketing
surveillance data. In the U.S. over 2 million
prescriptions, accounting for over
233,000
patient-years of use; 26 reported cases
of possible
ischemic colitis, equating to a rate of
approximately 12 cases per 100,0000
patient- years.
Again, as pointed out during
Dr.
Joelsson's presentation, patients with
irritable
bowel syndrome seem to be diagnosed with
ischemic
colitis more often than the general
population. It
may be an ascertainment bias because
these patients
tend to be scoped more frequently. It may be due
to an unknown pathophysiologic
factor. Obviously,
there is recent research to indicate
there are true
pathophysiologic differences among IBS
patients.
But regardless of which epidemiologic
study we look
114
at, all the available epidemiologic data
indicates
that patients with IBS are 3-4 times more
likely to
be diagnosed with ischemic colitis than
is the
general population, and the rates vary
depending on
the age of the population that is
examined.
Obviously, the Medi-Cal population tended
to be
older than the patients studied in the
United
Health Care study and, thus, we are
seeing a higher
rate of ischemic colitis both in the
general
population and in the IBS population.
I certainly comment Dr.
Brinker. He did a
very interesting analysis of the United
Health Care
base and identified that, clearly, when a
patient
is diagnosed with IBS their rate of
getting
subsequently diagnosed with ischemic
colitis within
the next 3 weeks is very high. Those patients
almost certainly are patients that are
misdiagnosed
with IBS when they really have ischemic
colitis.
Nevertheless, the same analysis found
that patients
who had a stable IBS diagnosis for over 1
year
still had a rate of 53 cases per 100,000
patient-years compared to the general
population
115
where it was 7 cases per 100,000
patient-years.
I do want to make particular
note here.
When I talked about the clinical trial
data my
denominator was 1,000 patient-years. We have now
shifted.
All the postmarketing surveillance data
is based on a denominator of 100,000
patient-years
of use.
Postmarketing surveillance data
for IBS
patients treated with tegaserod is 12
cases per
100,000 patient-years, which is 4- to
15-fold lower
than the expected rate, although I
certainly
understand there may be some
under-reporting, and
it very difficult to get an estimate for
how often
that occurs.
So, in conclusion, I certainly
think that
the clinical trial safety data for
tegaserod is
more robust and more precise than it is
for any
other treatment that we have available
for
constipation. This safety data allows us to have a
very precise estimate of the likelihood
of
clinically serious consequences of
diarrhea, but
the evidence doesn't support an
association between
116
tegaserod and ischemic colitis.
When I do a risk/benefit
analysis I see
the benefits being this robust clinical
trial data
that demonstrates that tegaserod is
efficacious for
the treatment of constipation, especially
the
multiple symptoms of constipation, and
that the
safety data is more robust than it is for
any other
treatment I might choose and that safety
data from
clinical trials demonstrates to me that
there is a
very low but finite risk of clinically
serious
consequences of diarrhea.
So, that analysis demonstrates
to me that
tegaserod has a very favorable
risk/benefit profile
in the management of chronic
constipation, and that
it compares very favorably with the
risk/benefit
analysis for any other therapy that I
might choose
to use to treat patients with
constipation. Thanks
very, very much for your attention and I
will turn
the program back over to Dr. Fogel.
Questions on
Presentations
DR. FOGEL: I would like to thank the
presenters for their informative
presentations. At
117
this juncture we turn the meeting over to
the
committee for questions to the
presenters. Dr.
D'Agostino I think had his hand up first,
and then
Dr. Sachar.
DR. D'AGOSTINO: When I saw there was a
two-hour presentation I said, my God,
they will
never take that long but it actually was
a great
presentation. Thank you very much.
I have a comment about the
subset
analysis, which we will have to address
later. I
understand that you look at subsets for
consistency
and not necessarily expecting to see
significant
results, but shouldn't we be concerned
that we are
not seeing the effect lying on the right
side with
the elderly greater than or equal to 65 and
the
males, and the Blacks? Can you give us some words
on how we can feel comfort that you
aren't seeing
the effect in greater than or equal to 65
year-old
individuals and also males, and I would
like
something on the Blacks also.
DR. DENNIS: Thank you for that question.
Yes, absolutely. Can I have slide AQ-16, please?
118
We will start off with the elderly
population since
that was the question that you asked
initially. As
you know, we only randomized 13 percent
of our
patients that were 65 years or older, and
this is
the responders by age group looking at
our primary
efficacy analysis.
What we can see in the group
that is 65
years and older is that we are seeing a
treatment
effect in the patients that are on
Zelnorm. We are
also seeing an effect in patients on
placebo as
well.
So, the interesting thing though is that we
can break this down further by looking at
the older
population by age and by gender.
If I could have the next slide,
please,
which is AQ-17, let me show you what
happens when
we break it down into further
subsets. On the top
row we are seeing female patients and on
the bottom
row we are seeing male patients. The patients that
are less than 65 years old--if we start
with that
column on the left-hand side, we can see
that the
effect in the younger female population
is similar
to the effect in the younger male
population.
119
Remember that we have much fewer numbers
in terms
of the male group so we don't reach
statistical
significance because, as I said before,
these
subgroup analyses are not powered to
detect
statistical significance. So, I think we are
seeing a consistent effect in the men
that are 65
years and younger that we are seeing in
the female
population.
If we look at the slide on the
right-hand
side, and let's turn to the elderly
population, we
do see an effect in female population. Of course,
the effect size is slightly
smaller--again, small
numbers of patients, and when we will
look at the
male patient population that are 65 years
and older
we are seeing that there really is no
effect
looking at it on this particular
analysis.
But I am going to take it one
step further
and take out those patients that we felt
were
probably IBS-like because, if you
remember, in our
overall efficacy analysis when we took
that group
out the efficacy was slightly more
robust.
So, if I can have the next
slide, which is
120
AQ-18, this shows you what happens when
we take out
those patients that are IBS-like. I am going to
focus your attention on that male
population that
is 65 years and older. You can see that in the
previous analysis--here we have really
small
numbers of patients. We are dealing with 20
patients in that group that are on 6 mg
BID. So,
the responders that we saw in the
previous analysis
were all chronic constipation patients
and when we
take out the other patients that have IBS
obviously
our denominator changes and, you know, we
see a
much more different effect looking at
these
numbers.
But I do want to caution that these are
very small numbers when we are looking at
these
subgroup analyses.
But if we look at the four
different
quadrants I think we can see the effect
in the
patients less than 65 is similar in men
as it is in
women.
I think we are seeing an effect in elderly
females, and I think we are seeing an
effect in
elderly males when you take out the IBS-like
subset.
121
DR. FOGEL: Dr. Sachar?
DR. SACHAR: With the permission of the
chair, if I could address some questions
to each of
the four major presenters, Dr.
Schoenfeld, when you
presented your efficacy data in slides 13
and 14
you appeared to have limited your
analysis only to
the highest dose tegaserod of 6 mg
BID. Yet, when
you discussed the adverse effects you
combined the
2 mg and the 6 mg doses. It would seem to me if
you really want to look at a benefit/risk
ratio we
really ought to look at a comparison for
the same
doses.
If we were to do that, we would find in
your slide 21 that it really isn't 5.4
percent of
patients but is actually 6.6 percent of
patients
who had some adverse effect with diarrhea
at the
equivalent dose, at the 6 mg dose.
I am not a professional statistician but
if we go a little further we might say
that since
the number needed to treat--to get some
benefit,
some demonstrated benefit from this drug
is
approximately 10. It ranged between 9-11 in all
the analyses. It is approximately 10. The number
122
needed to treat to see some adverse
effect from
diarrhea is actually about 2.8 at the
equivalent
dose.
So, would it be fair to say that for every 3
patients who get some benefit from this
drug 1 will
experience some diarrhea?
DR. SCHOENFELD: No, I would not go along
with that and I think there are multiple
points
there to address. The first one is that all of us
have conducted clinical trials and, as we
recognize, reporting an adverse event in
the
context of a clinical trial is not the
same as
suffering a clinically important adverse
event.
When these patients are followed in the
context of
clinical trials, to paraphrase, your
study nurse
may say, "anything unusual happen in
the past
week?" And, if the patient says, "I had a
little
bit of diarrhea last Thursday," that
becomes an
adverse event. What is probably a much more
appropriate adverse event category to
assess,
clinically important adverse events, is
how often
patients stop their medication due to
diarrhea.
Obviously, here it is 0.6 percent.
123
Having said that, I certainly
take your
comment appropriately, that if you look
at the 6 mg
BID dose the rate at which diarrhea was
reported as
an adverse event is about 6.6 or
6.7. For the
broader issue though of safety, my own
experience--and there are other experts
here that
have far more experience in safety
issues--is that
when we look at efficacy we want to look
at what is
going to be most likely the dose that is
utilized.
But in safety we tend to look at multiple
different
dose ranges to find out what the benefit
is.
Having said that, I think a
subgroup
analysis about what the rate would be for
6 mg BID
versus 2 mg BID would be helpful,
although I will
mention for the most serious adverse
events that we
are concerned about here, which in my
mind are
really ischemic colitis, when you look at
6 mg BID
or 2 mg BID it is still going to be zero
events.
You are just going to change your
denominator a
bit.
And, the majority of patients in these trials
were treated with 6 mg BID.
DR. SACHAR: Agreed.
When you talk about
124
the diarrhea issue that brings me to the
one
question for Dr. Joelsson, and that is
simply that
you did discuss the physiologically
serious
consequences and those were obviously
very, very
low.
Did anybody record whether any patient with
diarrhea had any episode of incontinence?
DR. JOELSSON: We have not that recorded.
I
cannot answer that.
DR. SACHAR: Because that is sort of an
impact thing.
DR. JOELSSON: Yes.
DR. SACHAR: And for Dr. Dennis, in slide
46--
DR. DENNIS: I will flash it up on the
screen.
DR. SACHAR: Yes, it is very important, as
everybody has indicated, that when you
excluded IBS
from the analysis you still showed
efficacy. I
think that is a very important
point. But you
showed us the data for doing that only at
week 1-4.
DR. DENNIS: Yes.
DR. SACHAR: Do you have any data on that
125
for the 12-week point?
DR. DENNIS: It looked similar. I don't
have the data on a slide but it does look
similar
over the 12-week treatment period.
DR. SACHAR: It is the same approximately?
DR. DENNIS: Yes.
DR. SACHAR: Great, fine.
In slide 13 you
showed us that, in terms of the inclusion
criteria,
they had to have a bowel evaluation
within the past
5 years.
Do I take that to mean that if some
patients had early constipation symptoms
3 years
ago or 4 years ago or 5 years ago and
they had a
barium enema, and then more recently the
symptoms
persisted or worsened and they represent
that they
would be eligible to go in this study
without any
new reexamination?
DR. DENNIS: If they had had a bowel
evaluation that was after the onset of
symptoms and
the symptoms remained the same within the
past 5
years there was no need for them to have
a
reevaluation. However, if there was any change in
the symptoms or if there were any alarm
features,
126
as I said, anything that suggested rectal
bleeding,
hemorrhage, anemia or any change in the
pattern,
those patients would have had to have a
new
evaluation. But it was stable patients who had
been having symptoms that had remained
the same
within the time they had the evaluation.
DR. SACHAR: Great!
My last question is
for Dr. Prather. I am not actually familiar with
the Canadian study of Pare et al., but
you
indicated it was a population study. Does the
population in that study represent the
group
receiving and taking medications for
chronic
constipation? Is it a clinic-based or a true
population-based study? Because if it is truly
population based it doesn't reflect
people who are
taking medications for their constipation.
DR. PRATHER: It was, indeed, a
population-based study but that would
include
all-comers with constipation that were
actually in
the population. So, it didn't discriminate against
individuals who may or may not have seen
a
physician for their constipation.
127
DR. SACHAR: Right, so that means that in
Larry Schiller's study that you showed in
slides 19
and 20 with all the dissatisfaction, that
included
patients who had taken over-the-counter
preparations or had seen a GP, or
something, and
had been perfectly satisfied? Or, was it only the
dissatisfied patients who sought out GI
specialists
who were in that study?
DR. PRATHER: This included
individuals--it was a study that was done
through
the Internet that was representative of
the U.S.
population, but with the initial
questions,
actually to get into the study they had to
have
seen a physician within the past 12
months for
constipation.
DR. SACHAR: A physician or a
gastroenterologist?
DR. PRATHER: Actually, these were primary
care physicians predominantly, yes.
DR. FOGEL: To increase the number of
questions that we can ask during our time
frame, I
would like the members of the committee
to keep
128
their comments brief. I am going to take the
prerogative of the chair and ask my
questions of
Dr. Dennis.
Can you provide us additional
details
regarding the question that you asked for
subjective global assessment, and can you
tell us
how the data was analyzed and whether
responders
had a persistent response over the 12
weeks of the
study?
DR. DENNIS: We asked the question how
satisfied were you with your bowel habits
over the
past week? And, the responses were a very great
deal satisfied; a good deal satisfied;
moderately
satisfied; hardly satisfied; and not at
all
satisfied. We defined a responder as having a
decrease of 1 on the satisfaction score.
I am going to first show you
some data on
the persistence of satisfaction response
and then I
will call one of the statisticians to
actually come
up and explain to you the statistical
analysis that
was done.
If I could have slide AQ-58,
please? This
129
is an analysis that we did where we said
to those
patients that met the score of a very
great deal
satisfied and a good deal satisfied, so
zero and 1,
for at least 50 percent of the weeks of
the whole
trial, which is 12 weeks. What we can see on the
study is definitely a significant benefit
of
Zelnorm versus placebo when we look at
patients
that had satisfaction over 6 weeks of the
12-week
treatment period. So, I think we are seeing
persistence of the satisfaction result.
I am going to call upon Dr.
Jeen Liu, who
is our statistician, to come and respond
to your
question about how these were actually
calculated.
DR. LIU: My name is Jeen Liu. I am the
statistician from Novartis responsible
for this
project.
The slide that Dr. Dennis just showed was
a response rate that we
defined--actually, she
showed two slides for two time intervals,
weeks 1-4
weeks and 1-12. What we did was we took the
patient score at each week, averaged them
over the
respective time intervals, either 4 weeks
or 12
weeks, and compared that with the
baseline score
130
that each patient had during the 2 weeks
prior to
treatment, and got the difference and
compared with
it was a decrease of 1 or more. If it is 1 or
more, it is a responder; otherwise the
patient was
a non-responder. Thank you.
DR. FOGEL: Thank you.
Dr. Metz?
DR. METZ: Great, thanks. Just in the
interest of time, I am going to float a
few
questions to you. I want to thank you for a nice,
comprehensive presentation. Three areas to
address, first of all, the problem with
the
subgroup analysis, as has been alluded
to. Can you
perhaps tell me why you chose 65
years? I would be
more interested in actually seeing a
median age
above and below, perhaps divided into
quartiles
above that and see where you actually see
your
cut-off.
I am not sure why 65 is necessarily
relevant.
The second question will be a
little bit
about the loss of efficacy in one of your
two
pivotal trials in the 2 mg group. It appears to me
more because of the placebo effect
increasing up to
131
reach the 2 mg, but it makes one wonder a
bit about
a tolerance response, and that brings me
to why you
really chose the first 4 weeks. This is something
people are going to be using way beyond
12 weeks.
So, why the first 4 weeks; why not 12
weeks and
beyond as your primary outcome
measurement?
The third question is use of surrogate
measurements, which you actually have in
your
binder but didn't talk about at all
today. That is
the use of rescue medication and seeing
any
difference there as a sort of idea of,
you know,
you are seeing an effect because of using
less
rescue?
Can you address those three points,
please?
DR. JOELSSON: While Dr. Dennis is
thinking about the second question I can
take the
first question. The analysis of patients above 65
years and below 65 years is a very
traditional
analysis that we do, which is based on
what the FDA
wants us to do. This is kind of the cookbook thing
you do.
So, it is not that it was anything that we
came up with; this is the traditional way
of doing
132
it, and we don't have the data the way
that you
describe.
I am sorry about that.
DR. METZ: Do you think that would be a
useful examination to go through?
DR. JOELSSON: Yes, I agree.
DR. DENNIS: let me address the other
questions. I am first going to tackle the question
that you asked about loss of
efficacy. I think
what we see in these clinical studies is
that the
treatment effect of Zelnorm was sustained
throughout the entire treatment
period. We did not
see a decrease in the number of responder
rates.
There is certainly nothing to suggest
that we saw a
loss of efficacy in terms of the drug
response
itself.
Placebo responses, as we know, are not
uncommon in clinical trials and we see
them in all
clinical trials. You know, the issue is in some
clinical trials placebo responses
continue to rise.
If I could go back to my core
slide CE-28,
this shows you the weekly responder
definition over
the 12-week treatment period, and I just
want to
really point out again that we are seeing
that the
133
efficacy is sustained throughout the
entire
treatment period.
Maybe I can get a clarification,
Dr. Metz.
Were you referring specifically to the 2
mg dose in
the 2301 study?
DR. METZ: That is correct. Clearly, you
don't see that in the 2302 but you do see
it in the
2301.
DR. DENNIS: Absolutely.
You know, I
think the 6 mg BID dose has emerged
consistently as
being more efficacious and that is why we
are going
for that dose as an indication. We have actually
looked at what are the reasons that could
have, you
know, determined why we are seeing this
in 2301 and
not 2302 because these two studies were
essentially
identical in the core period. The only differences
that we can find are geographical. 2301 was done
mainly in Europe and 2302 was done in
North and
South America.
To address the question of why
we chose a
4-week duration period, I think that was
because
when physicians prescribe the drug they
want to
134
look at the effect size within 4
weeks. They want
to know is this drug going to work within
4 weeks
or not.
So, we looked at 4 weeks as our primary
endpoint but we also looked at it over 12
weeks to
make sure that we would see sustained
efficacy.
So, we have the data for both of those
two
endpoints.
DR. METZ: Right, but the point I am
making is that this is a chronic
problem. You are
defining chronic constipation as
something that has
been around for more than 6 months--
DR. DENNIS: Sure.
DR. METZ: --and you are not going to
treat for 4 weeks and then stop.
DR. DENNIS: And that is why we have a
12-week treatment duration.
The last question that you had
was
laxative use. There were very strict guidelines
for laxative use in these studies. Patients were
only allowed to take laxatives if they
had not had
a bowel action for 96 hours. So, they had to wait
96 hours from the time of their last
bowel action
135
before they could have a laxative. When we looked
at laxative intake in these particular
studies, we
measured how many patients took at least
one dose
of a laxative throughout the entire
12-week
treatment period, and we found that about
50
percent of patients in the study took a
laxative at
some point during the study. But when we really
break this down and we say how frequently
were
laxatives actually being taken, we find
that
laxative intake, in fact, was quite
infrequent.
This slide I am going to show you is going
to show you laxative use by mean number
of days.
If you look at the baseline period, we
see that
laxatives were used about once every
11-12 days.
In the double-blind, placebo group we see
that
laxatives were used about once every 14
days and
about once every 18 days on Zelnorm.
If I could have the next slide,
which is
AQ-62, this is going to show you the
median days
data.
Here we are seeing by median data of use
that the baseline laxative use was about
14 days a
week.
The median use of laxatives in the placebo
136
group goes down to 0.11, which translates
to 1
every 64 days. When you look at the
Zelnorm-treated group we are seeing that
that goes
down to 0.08, which translates to once
every 88
days.
So, when you really look at it, laxative
intake is really very infrequent.
However, to speak to your
point, we are
seeing that there is more laxative use in
the group
on placebo than there is on Zelnorm, and
if we are
expecting to see a confounder because of
that, we
would expect to see it more in the
placebo than we
would in the Zelnorm.
DR. FOGEL: Dr. Cryer?
DR. CRYER: Dr. Dennis, I would just like
to follow-up on this theme of the
subgroup analysis
in those who were greater than 65 and
those who
were men.
You very strongly make the point that
Zelnorm, as you just showed us, has
maintained
efficacy over the 12-week period. However, all of
your slides that you showed us to support
its
observations in the subgroups of those
who were
greater than 65 or those who were men
were the
137
4-week data points. So, I am wondering whether you
can show us that, in fact, the sustained
12-week
data in that subgroup of men and those
who were
greater than 65.
DR. DENNIS: Right.
The reason why we did
the subgroup analysis on the 4-week data
initially
was because that was our primary endpoint
and so
that is why we determined to do that.
I don't actually have the
slides with me
right now to show you the actual week 12
but I will
just confer with my colleagues and make
sure we
have those before the end of the
presentation.
DR. CRYER: I think this is a very
important point because when you consider
the
potential target group for therapy, many
of them,
as we have learned from Dr. Prather, are
going to
be greater than 65 year-old age
population. So, I
think in the assessment that we are
making today it
would be very, very helpful for us to
specifically
look at the effects in a target
population.
DR. DENNIS: Right, and I will make sure
we have those slides and we will come
back to that.
138
DR. FOGEL: You can present those slides
later.
DR. DENNIS:
Right, thank you.
DR. FOGEL: The next question is by Dr.
Buchman.
DR. BUCHMAN: To further follow-up on the
12-week issue, letting aside the 4-week
issue,
number one, I am wondering what the
rationale was
for the chosen 12-week interval rather
than 52
weeks for example, given that this is a
problem
that your patients had for an average of
at least 6
years.
That is the first question.
Secondly, I want to know if you
have any
data on either on-demand or intermittent
use
because for a benign problem, outside of
a clinical
trial, compliance for medication use is
very poor.
So, what I am wondering is whether with
intermittent use does tolerance develop, for
example, and is there a loss of efficacy
at that
time.
In regard to the first
question, and I do
have a few others, my sub-question to
that is if,
139
indeed, you have efficacy at 12 weeks, is
your
indication really only for 12 weeks use
rather than
long-term use, because you have not shown
long-term
use data?
DR. DENNIS: Absolutely.
We chose the
12-week treatment duration in keeping
with the Rome
committee guidelines, and the Rome
committee gives
us guidelines for chronic functional GI
disorders,
and their recommended length for treatment
trials
was 8-12 weeks. So, we were within the Rome
committee guidelines for doing this, and
the
indication that we would be seeking is
for 12 weeks
treatment.
DR. BUCHMAN: And what about the
"on-demand" therapy? Do you have any data on that?
DR. DENNIS: We do not have any data for
"on-demand" therapy in chronic
constipation.
DR. JOELSSON: Maybe I can add to that.
Luckily enough, we just did a study in
IBS with
constipation and we did show that if we
had a good
effect during the first treatment period
it was
just as good, or maybe even better, on
the second
140
treatment period when they had a relapse. So,
there is no evidence from our data that
you don't
respond just as well the second time as
you did the
first time.
DR. BUCHMAN: One quick question, and I
understand that other people have to ask
some other
questions, there is some question whether
the
increase in bowel movement by one per
week is
clinically significant. So, my questions for that
are, number one, what is the data that
you have to
indicate a priori that that increase of
one is
clinically significant? Number two, what is your
data on patients who had an increase of
two or more
bowel movements per week?
DR. DENNIS: I showed you the slide from
my core presentation that looked at the
association
between responders and non-responders,
and we
showed a clear-cut difference in terms of
the means
when you had a non-responder versus a
responder
looking at the primary endpoint and
comparing it to
the secondary variables.
Can I go back to the slides
from my core
141
presentation, please? Do we have a slide from the
core presentation? I am looking for the
association between the endpoints. Here we are.
So, this is the slide where we looked at
the
association to say the mean changes from
baseline
were quite different in the responders
versus the
non-responders, and this is significant
at all time
points.
I think what I am going to do
to really
delve into your question further is to
say, well,
is what we are seeing clinically relevant
for the
patient population, and I think we see
this is a
clinically relevant response looking at
this
particular analysis but I am going to ask
Dr.
Prather to come up and give her opinion
as to
whether she thinks, you know, a change of
one CSBM
per week is clinically relevant, bearing
in mind
that at baseline these patients had 0.5
CSBMs by
mean values and zero CSBMs by median
values at
baseline.
So, seeing an increase of one CSBM per
week, in our minds, we felt was
clinically
relevant, but I will let Dr. Prather give
her
142
opinion.
DR. PRATHER: Thank you.
It is always
difficult when I have my patient in the
office to
figure out how am I going to translate
this
research data to the patient in my
office. What I
have to remember is that I am being
presented with
means, meaning that there are some
patients who
responded well and some patients who
didn't. When
you are talking about constipation, for
my group of
patients anyway, going from having no
bowel
movements that are spontaneous per week
or half a
bowel movement per week that is
spontaneous and
increasing that to, you know, one or more
spontaneous bowel movements, that is
going to be a
significant finding in my patient.
The other thing to realize is
that when we
are talking about bowel function we have
to
actually recognize that there is a
balance, that we
want to make them better but we can't
make them too
much better because too much better turns
them into
diarrhea, and that is just as difficult as
it is to
have constipation. At least, that is what my
143
patients tell me. So, I would rather see something
that has, you know, a modest by definite
effect
than something that is a bit too powerful
that I am
going to have difficulty managing.
DR. FOGEL: Dr. Strom?
DR. STROM: Thanks.
I would like to first
congratulate the group on a superb series
of
presentations and a really very
impressive pair of
studies.
I have three questions. One is on
age
breakdown. You cut it at age 65. Age 65 is
becoming younger every day. Many of the people who
are going to suffer from the problem who
are going
to use it, in fact, are a lot older than
that. So,
both in terms of your population data,
Canadian
data or other population data, and in terms of
your clinical trial can you show us the
breakdown
of people over age 65? For example, what
proportion of people over age 75 or 80
have
constipation in the general population,
and how
many of those people do you have in your
study?
That is the first question.
DR. DENNIS: I think the first thing to
144
address is the fact that constipation, as
we have
defined it, is not a condition of the
elderly. I
mean, I think Dr. Prather showed you the
data that
came from the epi study and from the Pare
study
that really showed that constipation, as
we have
defined it, is actually a disorder of all
ages.
DR. STROM: That is what I would like to
see, to see those data greater than 65
broken down
more finely in order to confirm that
statement.
DR. DENNIS: For the population-based
studies?
DR. STROM: I would like to see it both
for the population-based studies--I mean,
to make
the claim that it is not a problem in the
elderly I
don't want to see 6 year-olds, I want to
see 80
year-olds.
DR. DENNIS: Yes. I
am going to ask Dr.
Prather to comment as well, but would you
like to
see the age distribution for our
particular
clinical studies? This is a slide which shows you
the pooled data from 2301 and 2302,
looking at the
breakdown of ages that we studied in the
clinical
145
studies.
As you can see, as I said, the mean age
was 46 and 47 years but we did have
representation
of different ranges.
DR. STROM: But just to get a gestalt,
over age 75, it looks like you had 10
patients?
DR. DENNIS: We had very few patients in
this age group.
DR. STROM: Ten percent, sorry. And, how
does that compare to the population data?
DR. DENNIS: Dr. Prater will come up and
respond to that question.
DR. PRATHER: Thank you for asking that
question because I actually have a
special interest
in GI motor and functional disorders that
are
associated with aging, and I have looked
carefully
at the epidemiologic data and,
unfortunately, they
are fairly flawed when it comes to taking
a look at
elders.
For instance, the Drossman Householder
study actually cut it off at age 45. The ones that
actually used the Rome I or the Rome II
criteria
cut it off at 65. So, those were strict criteria.
We really don't have a good breakdown
above the age
146
of 65.
Now, we do have information
about
self-report constipation. We need to be a little
bit careful when we talk about
self-reports. Again
thinking of my own patient population,
some of my
elders that don't have a bowel movement every
day,
or if they don't have their bowel
movement in the
morning and instead have it after lunch,
they may
not be satisfied and they may actually
report that
as constipation.
We do know in general from the
epidemiologic studies that there appears
to be an
increase in self-report constipation over
the age
of 70.
The studies that we have and, again, I
don't have a slide for this but I do have
information from a review--in a couple of
the
studies that took a look at individuals
over the
age of 70 we see that self-report
constipation--again, not using the strict
criteria
but what patients think--that at the age
of 55-59
it is 28 percent; 60-64, 29.7 percent;
65-69, 32.8
percent; 70-74, 37.3; 75-79, 42; 80-84 is
up to 48.
147
But, again, we are getting very small
numbers in
those larger groups and, again, this is
self-report
constipation and, again, this isn't
really a forum
for me to talk about my research
interests but,
again, when we talk about functional
bowel
disorders and constipation and aging,
there are
also frailty issues that go along with
that,
locomotion, motor issues that contribute
to the
difficulties that these individuals do
have with
their bowel function.
DR. STROM: Thank you.
That is very
helpful because obviously it is
self-report
constipation that is likely to lead to
treatment.
The second question--you have
enormously
rich data on different types of diarrhea
and
symptoms at baseline as well. When you see a very
consistent pattern of efficacy like this
but a very
small increment over placebo, that sort
of smells
like you have some people who respond a
lot and
other people who don't respond at all
and, in fact,
we heard that as a comment. Can you give us
predictors of who is going to be a
responder and
148
who is not? You have shown us some data--age,
gender race. How about baseline symptoms? Can you
tell within your very rich database which
baseline
symptoms will lead to people likely to be
responders and which will not?
DR. DENNIS: Let me show you a couple of
slides.
If we can start with slide AQ-81?
Let's
look at the responders looking at
baseline
characteristics, and we are going to
start by
looking at those patients by number of
complete
spontaneous bowel movements a week. So, let's look
at this particular analysis.
This is responders broken down
by the
number of complete spontaneous bowel
movements per
week at baseline. We can actually see that Zelnorm
is equally efficacious in all of these treatment
groups.
The very right-hand group obviously is
very small numbers of patients and those
would have
been protocol violators.
If we go to slide number AQ-82,
this will
look at the responders by duration of
constipation.
So, here we are looking at whether people
have had
149
constipation for 6-12 months all the way
up to, you
know, 12 years of constipation. Again we are
seeing efficacy in all of these different
subgroups.
The next one that we can look
at as well
would be responders by baseline
constipation
assessments. So, if we could have AQ-83, remember,
we asked those bothersome questions, how
bothersome
was your constipation, and we broke it
down by
looking at baseline and whether these
patients had
moderately bothersome constipation or
good deal
bothersome constipation or a very great deal
bothersome constipation and, again, we
saw no
difference in efficacy amongst those
treatment
groups.
We can also look at efficacy by
looking at
patients that took laxatives at baseline,
if we
could have AQ-67. Again we saw no difference
whether patients take laxatives or don't
take
laxatives at baseline. So, in fact, we didn't
really find any predictors to say there
was one
particular group in any of these baseline
150
characteristics that would be more likely
to say,
you know, Zelnorm would work more
effectively in
that particular group or not.
DR. STROM: How about people whose major
complaint was frequency, versus people
whose major
complaint was straining, versus people
whose major
complaint was hard, lumpy stools, versus
abdominal
pain, versus bloating, looking at the
very rich
symptom data to see how well that
predicts
response?
DR. DENNIS: We have looked at that data
as well and we haven't seen any clear-cut
predictors of response looking at those
baseline
symptoms.
DR. STROM: The last question relates the
database studies. A big point was made that it was
irritable bowel syndrome that causes
ischemic
colitis or is associated with ischemic
colitis
rather than the treatments. As someone who has
been using these databases for 25 years,
I am very
skeptical. Those are not people with irritable
bowel syndrome; those are people with
claims for
151
irritable bowel syndrome. Did you get the medical
records on those patients who had
irritable bowel
syndrome and who had ischemic colitis and
their
bowel syndrome before that to be able to
see
whether that was really an established diagnosis
or
was, in fact, people who were being
misdiagnosed?
DR. JOELSSON: Well, these are not studies
that we have performed. These are published
studies but, as far as I understand, at
least in
one study there was a subset of patients
that were
reviewed with medical records which was
consistent
with the overall data.
DR. FOGEL: Dr. Levine?
DR. LEVINE: I have some concerns about a
lack of or presence of a dose
response. First a
point of information, in your IBS study
initially,
where you got approval, was there any
difference
between 2 mg and 6 mg?
DR. DENNIS: In our IBS studies 6 mg BID
was consistently more efficacious for all
the
variables so we are seeing a consistent
pattern.
DR. LEVINE: But in the current studies,
152
symptomatically you may have seen some differences
when you pooled the data, as shown in
slide 31
where you state that there is effective
treatment
of multiple symptoms of chronic
constipation, but
when you go back to looking at the weekly
stool,
the stool data, etc. you find a weakness
in 2301
versus 2302. It is very hard for me, going through
this and looking through all the data to
discern
whether you really think there is a
difference
between 2 mg and 6 mg through everything,
including
this particular data, page 14 and page 17
for
instance, the stool change from baseline
where,
indeed, there is a big difference between
the two
suggesting perhaps dose response, and
then again
2301 on page 14 where there is no
difference in
2302 and there is a slight difference in
2301. So,
I wondered across the board, besides
symptoms, did
you actually see dose response in every
aspect that
you looked at?
DR. DENNIS: I think we saw a more
consistent dose response in study
2301. As I said
earlier, we went back to say, well, what
were the
153
reasons that we were seeing this dose
response in
2301 and we didn't see it in 2302 and we
looked at
a number of parameters, baseline
parameters, to
say, well, were there any differences in
the
patient population because the studies
were
identical in design, and the only
differences we
could come up with were really
geographic. 2301
was done in Europe mainly and 2302 was
done in
North and South America. Beyond that, we haven't
got any explanation for why we see it in
one study
and not in the other study, but the
bottom line is
that the 6 mg BID dose is consistently
efficacious
across both studies, and that would be
the dose
that we would be looking at.
DR. STROM: Thank you.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: I have a brief question for
Dr. Dennis about baseline matching. There is a
table on page 21 of the Novartis briefing
document,
entitled Table VI-2. My question relates to the
category percent SBM with sensation of
complete
evacuation. It looks like they are not balanced at
154
baseline and I would just like to hear
your comment
about whether these groups were balanced
and
comparable at baseline because the
numbers look
different, for example, 8 versus zero
versus zero;
1.4 versus 9.1 versus 8.3. They seem to be wildly
different there, and would that confound
any
results that we have already seen?
DR. DENNIS: I have the table up here.
So, we are looking at the percentage of
SBMs with
the sensation of complete
evacuation. I think what
we have to bear in mind is that when we
look at
this particular analysis, percentage of
SBMs, it
really is a ratio. So, we are saying of the number
of SBMs that you are having, how many of
those are
actually complete spontaneous bowel
movements? I
think when we looked at patients coming
into the
study the criteria for them to get into
the study
was less than 3 complete spontaneous
bowel
movements per week. Looking at the percentage of
SBMs with sensation of complete evacuation
doesn't
tell us very much about how these
patients are
doing.
For example, you could have 2 SBMs and you
155
could have 1 of those being complete and
your
percentage would be 50 percent. You could have 4
SBMs and you could have 2 of those
complete and
your percentage would be 50 percent. So, I think
looking at just the percentage is not a
very
reliable statistic on its own. We should really
look more at the number of SBMs and the
number of
CSBMs at baseline.
DR. LAMONT: So, in terms of that bottom
rank there, you consider those to be
matched?
DR. DENNIS: I don't think it is relevant
when we look at the other members--
DR. LAMONT: You are saying it doesn't
matter.
I have a second question for Dr. Joelsson
regarding cholecystectomies. Looking at page 20
and page 21 of your slides, it looks like
there is
an increase in cholecystectomies in
patients that
are on Zelnorm, if I am interpreting this
correctly. Can you tell us then that the 14
cholecystectomies in the Zelnorm-treated
patients
versus 1 in the placebo is not different?
DR. JOELSSON: I think I said it was
156
different. I tried to say that we tried to find
out does this drug really affect gallbladder
or is
this a chance finding. So, we did this very
thorough study looking at gallbladder
function and
we could see no effect of tegaserod on
gallbladder
function.
Also the second point I would
like to make
is that patients with IBS do have a
higher rate of
cholecystectomies so the rate we have
seen in our
clinical trials is not higher than you
would expect
in patients with IBS or in our
postmarketing
experience. So, if anything, the placebo group is
a bit low.
DR. LAMONT: On the other hand, this might
be something we would want to warn
clinicians
about, that in fact it might increase the
rate of
cholecystectomy because, first of all, a
comment
about this statement that Zelnorm does
not affect
gallbladder motility, I accept your data
here but
don't forget that patients who have gall
stones
have already abnormal motility. Virtually 90
percent of them have delayed gallbladder
emptying
157
by any clinical criteria, and I assume
that this
test, Fisher et al., in press is on
normal
subjects.
Is that correct?
DR. JOELSSON: It is patients with IBS,
not with gall stones.
DR. LAMONT: Right.
So, you could make
the case then that patients with
preexisting gall
stones who take Zelnorm may have an
increase in
contractility because of the drug that you
wouldn't
see in normals, and that that would force
a stone
into the neck of the gallbladder into the
cystic
duct which is the definition of what
happens with
acute cholecystitis and is the usual
cause for
cholecystectomy.
DR. JOELSSON: This issue is actually
already in our prescribing
information. It is not
a warning but it is mentioned there as
one of the
issues we had at the earlier application.
DR. FOGEL: My timekeeper indicates that
we already way behind schedule. There will be an
opportunity for additional questions this
afternoon. Are there any questions that remain to
158
be asked right now that cannot wait until
the
afternoon?
[Laughter]
Why don't we take a ten-minute
break and
then we will continue with the FDA
presentation?
[Brief recess]
DR. FOGEL: I would like to call everybody
back to their seats. Ready?
FDA Efficacy
Presentation
DR. PRIZONT: My name is Robert Prizont,
and Implementation an FDA medical officer
in the
Division of Gastrointestinal and
Coagulation Drug
Products.
DR. PEREZ: Excuse me, Robert, can you
hold on one second? We are trying to get your
slides up.
DR. PRIZONT:
Ready? For those of you who
don't know me and that is the majority of
you, I am
Robert Prizont. I am an FDA medical officer in the
Division of Gastrointestinal and
Coagulation Drug
Products.
Zelnorm oral tablets at a dose
of 6 mg
159
twice a day are approved for the
treatment of women
with constipation-predominant irritable
bowel
syndrome, abbreviated C-IBS. The indication for
treatment was not extended to men with
constipation-predominant irritable bowel
syndrome.
Novartis is now seeking approval for
Zelnorm use at
a dose of 6 mg twice a day for the
treatment of
chronic constipation in both women and
men. To
support the proposed indication Novartis
submitted
a prospective study protocol and results
from two
multicenter placebo-controlled pivotal
clinical
trials.
In sequential order, my
presentation will
review a definition of constipation,
relevant
issues of the prospective study protocol;
provide a
brief summary of the sponsor's efficacy
results;
discuss the patient representation for
the
selective constipation subtype; comment
on the
chosen primary efficacy endpoint; and
finalize with
concluding remarks.
For the last 39 years the core
of defining
constipation has relied on the frequency
of bowel
160
movements. In 1965 a study on variation in bowel
habits was reported in the British
medical journal.
In this study between 83 percent to 99
percent of
655 women and 400 men who were free of
gastrointestinal symptoms had a frequency
of bowel
movements ranging from 3 bowel movements
per week
to 3 bowel movements per day. These results
suggested that more than 3 bowel
movements per day
or fewer than 3 bowel movements per week
are
unusual.
The 1975 Federal Register on
over-the-counter laxatives included the
results of
the English survey. In 1988 worldwide experts met
in Rome to set guidelines for the
diagnosis of
functional bowel disorders and published
what is
now known as the Rome criteria for the
diagnosis of
functional bowel disorders. The criteria for the
diagnosis of constipation included fewer
than the 3
bowel movements per week parameter.
In 1989, the large U.S. NHANES,
National
Health and Nutrition Examination Survey,
on bowel
habits was published. This U.S. survey was
161
conducted in two phases. The initial phase lasted
four years, from 1971 to 1975, and
included 14,407
subjects.
The second phase or follow-up lasted two
years, from 1982 to 1984. The results on number of
bowel movements revealed that over 85
percent of
the U.S. men and women surveyed had 3 or
more bowel
movements per week.
In 1999, the Rome II criteria
were
published. The Rome II criteria also included
fewer than 3 bowel movements per week
bowel
movement frequency in the definition of
constipation.
In 2000, the American
Gastroenterological
Association published a technical report
on
constipation and stated as limits of
normalcy the
frequency range established in the first
English
study, i.e., 3 bowel movements per week
to 3 bowel
movements per day.
According to the protocol
design,
eligibility to participate in the
Novartis studies
required compliance with components
included in the
Rome II criteria definition of
constipation. The
162
passage of fewer than 3 bowel movements
per week
and the perception of completeness in
bowel
evacuation were the objective and
subjective
components required to define patients as
constipated and eligible to enter the
studies.
Straining was an additional subjective
component
included in the requirement.
Rather than applying the
established
definition of constipation, the
protocol's primary
efficacy endpoint was based on the
increase of a
single spontaneous and complete bowel
movement per
week.
Moreover, efficacy response was limited to
the first month of a 3-month study
period.
The protocol stated that the
aim of
performing these studies was to
demonstrate the
effect of Zelnorm on bowel habits in
patients
suffering from chronic idiopathic
constipation.
Idiopathic constipation is a subtype of
chronic
constipation. It has generally been known as
functional constipation.
The other subtypes are outlet
obstruction,
slow peristalsis constipation and the
constipation
163
associated with irritable bowel syndrome,
or IBS.
Slow peristalsis has also been referred
to as
idiopathic slow transit constipation.
Differentiation between slow transit
constipation
and outlet obstruction constipation
requires
specialized techniques, such as
measurement of
colon transit time. A potential concern in
conducting clinical trials with the use
of Zelnorm
in idiopathic or functional chronic
constipation
was the inclusion of
constipation-predominant IBS
subjects.
The trials on Zelnorm in women
with
constipation-predominant IBS were
conducted long
before the chronic constipation trials
and were
initially submitted to this agency in
December of
the year 2000. The design of the studies for use
of Zelnorm in constipation-predominant
IBS had
already included the Rome criteria. The Rome
diagnostic criteria for irritable bowel
syndrome
provide the elements and parameters to
separate the
constipation-predominant IBS from other
types and
subtypes of constipation. Yet, the prospective
164
protocol for the Novartis studies for
chronic
constipation lacked any provision to
exclude
patients with constipation due to irritable
bowel
syndrome.
As mentioned, since July, 2002 Zelnorm
is approved for women with
constipation-predominant
IBS.
Novartis performed two pivotal
studies.
Study 2301 was conducted in Europe with
contributions from centers in Australia
and South
Africa.
Study 2302 was conducted in the U.S.,
Canada and a few South American
centers. And, 416
to 451 patients were enrolled in each of
3
treatment groups, namely, 6 mg BID, 2 mg
BID or
placebo.
The first month results
revealed that
40-43 percent of those assigned to
Zelnorm 6 mg met
the protocol's definition of
efficacy. The Zelnorm
response was statistically superior to
25-27
percent placebo response, and provided a
therapeutic gain ranging between 15-18
percent.
Two doses of Zelnorm were
tested in the
trials, 2 mg BID and 6 mg BID. The average
165
efficacy in 12 weeks revealed a dose
response in
only one of the two studies. It should be noted
that the Zelnorm efficacy over placebo
was
translated in an average weekly increase
of less
than one complete spontaneous bowel
movement.
Intermittently, 50 percent to 60 percent
of treated
patients, including those treated with
Zelnorm,
were helped by a well-known laxative,
bisacodyl. A
number of patients exceeded the
protocol's
specified use of laxatives, including between
15
percent to 25 percent of the patients
treated with
Zelnorm 6 mg BID.
The results from the studies
raise the
first question, was the treated patient
population
representative of idiopathic
constipation? This
graph illustrates the gender distribution
in the
various subtypes of constipation. The figure is
from a large study on 10,000 subjects
with various
subtypes of constipation. Starting on the right
side of the graph, we can see that the
mixed IBS
outlet obstruction subtype, the outlet
obstruction
subtype and the constipation IBS subtypes
have a
166
preponderance of women, particularly the
subtype of
outlet obstruction constipation. This is
in
contrast to the almost equal proportion
of men and
women observed in functional or
idiopathic
constipation shown on the left bars of
the slide.
This, in other studies,
revealed
considerable symptom overlap amongst
subtypes.
Investigators also differ on where slow
peristalsis
is a part of outlet obstruction or a
separate
subtype of constipation. Despite the overlap and
differences in subtype nomenclature,
there is
overall concurrence that gender is the
characteristic of outlet obstruction,
while the
predominance of abdominal symptoms
distinguishes
constipation-predominant irritable bowel
syndrome.
The Zelnorm studies enrolled 90
percent
women with a mean age of 47 years. Men 65 years
and older represented around 13 percent
of the
patient population. The addition of completeness
to the spontaneous bowel movements
allowed
enrollment of a large proportion of
patients who
otherwise would not have met the
definition of
167
constipation based just on number of
spontaneous
bowel movements. Just to illustrate this point,
about 50 percent of patients had an
average of 3
spontaneous bowel movements per week that
were not
perceived as being complete. These patients would
have not qualified for a constipation
trial. The
introduction of a complete bowel movement
in the
definition of constipation transformed
these
patients from not being constipated into
being
constipated. It is noteworthy that up to 45
percent of patients entering the studies
referred
to abdominal symptoms as the main
complaint of
constipation.
As a consequence of a lack of
provision in
the protocol to exclude IBS patients the
studies
did include irritable bowel syndrome
patients.
Novartis estimated that 23 percent of
patients had
IBS-like symptoms. Actually, a few patients
already carried the medical diagnosis of
IBS prior
to entry to the studies. Though it is difficult to
estimate retrospectively the
characteristics of
enrolled patients, it is likely that the
proportion
168
of patients with IBS-like symptoms was
higher than
23 percent, particularly if we consider
the main
complaint of abdominal distention as part
of the
constipation-predominant IBS.
Let's now examine the
protocol's primary
efficacy endpoint. A relevant question pertains to
whether the protocol's primary efficacy
endpoint
represents efficacy based on the
established
definition of constipation included in
the Rome
criteria.
As mentioned, the Rome criteria
defines
constipation by less than 3 spontaneous
bowel
movements per week with a perception of
completeness in less than 25 percent of
bowel
movements. It follows that efficacy based on the
average increase of just one complete
spontaneous
bowel movement per week would include as
responders
constipated patients. Perhaps not surprisingly,
estimates of efficacy by the 3 or more
complete
spontaneous bowel movements resulted in a
drop of
the proportional responders. Post study,
and at the
agency's request, the sponsor included
efficacy
169
analysis based on established frequency
of 3 or
more bowel movements.
This table shows the results
for the first
month in study 2302, analyzed by the 2
endpoints.
Efficacy, based on the 3 bowel movements
per week
rule cuts in half the proportion of
responders, and
there is a parallel drop in the
therapeutic gain in
treatment with Zelnorm 6 mg, from 18
percent when
analyzed by the protocol's endpoint to 9
percent
when efficacy is based by the traditional
endpoint
of 3 or more spontaneous bowel movements.
Although the studies were of 12
weeks
duration, the sponsor's efficacy for
chronic
constipation was based on the first month
of study
results.
Efficacy in the 12-week study period was
the average increase of one complete
spontaneous
bowel movement per week extended to the
12 weeks,
regardless of whether dose responders had
actual
participation in efficacy for the 12
weeks.
By the sponsor's analysis, the
comparison
of efficacy reached a 45 percent response
rate in
Zelnorm 6 mg if efficacy is the average
increase in
170
one complete spontaneous bowel movement
but
decreases to 22 percent if efficacy is the
average
of 3 or more complete spontaneous bowel
movements.
We, therefore, decided to calculate
efficacy based
on the response for each one of the three
months,
as shown in the numerator, with
participation in
each one of the three months, as shown in
the
denominator.
This table is our analysis of
responders
for a 3-month study period in patients
who
participated in all 3 months. The first point to
make is that the requirements of
participation plus
efficacy response to all 3 months
decreases Zelnorm
6 mg efficacy to 26 percent even if
calculated by
the protocol's endpoint of an increase of
1
complete spontaneous bowel movement. The
combination of full 3 months of
participation and
efficacy, analyzed by the 3 or more
complete
spontaneous bowel movement rule, drops
the 6 mg
response to a very low 12 percent.
Efficacy based on 3 or more
complete
spontaneous bowel movements plus full
participation
171
results in a uniformly lower response to
Zelnorm 6
mg expressed in 1-month efficacy, 2-month
efficacy
or efficacy for the entire 3 months of
the study
period.
We conclude that the clinical
significance
of an efficacy endpoint for constipation
based on
the increase of 1 complete spontaneous
bowel
movement per week is uncertain. Based on the
definition of 3 or more complete
spontaneous bowel
movements per week, the proportion of
responders
for all 3 months is small. The intermittent use of
bisacodyl, a well-known laxative, further
confounds
the assessment of effectiveness.
There is a plethora of
laxatives presently
available over-the-counter. From 1975 until 2003 6
monographs on laxative use and abuse were
published
in
the Federal Register. I counted over 25
laxative products just in the first
monograph. A
few laxatives are given under
prescription but so
far all remedies are for occasional
constipation.
The sponsor now proposes the use of
Zelnorm for
chronic constipation seemingly for all
subtypes
172
though the protocol aim was to study the
idiopathic
subtype.
It is unclear which constipation
subtype
benefited from Zelnorm. The contribution to
efficacy of the constipation-predominant
IBS and
outlet obstruction patients is unresolved
because
90 percent were women, many with a
predominance of
abdominal symptoms. A benefit of Zelnorm for
laxative abusers, heralded as one reason
for the
studies, is unknown for laxative abusers
were
excluded from the trials.
Men were
under-represented. In subset
analyses no statistical differences
between
treatments were observed in men. Patients 65 years
of age and older, frequent sufferers of
chronic
constipation, were similarly
under-represented.
The few treated in the studies, 10-13
percent of
all patients, revealed no statistical or
numerical
differences between treatments. Patient
representation, in whom it should be
prescribed,
the rationale for the indication, those
inappropriately included or excluded are issues
to
173
be resolved by this expert advisory
panel. Thank
you.
Questions on
Presentation
DR. FOGEL: Are there questions for Dr.
Prizont?
Dr. Cryer?
DR. CRYER: Dr. Prizont, you make the
comment that about 50-60 percent of the
subjects
were taking concomitant bisacodyl. I am trying to
get a sense of what the response rate
would be in
the Zelnorm only users. Did you do an analysis
which removed the bisacodyl
subpopulation?
DR. PRIZONT: I did not do that analysis.
Let me check with the statistician
first. Dr. Joy
Mele, maybe she can help.
DR. MELE: I did do an analysis
where I
just looked at the patients who never
took a
laxative at any time during the trial,
and I am
trying to get to that page. It is in my review
that is in your packet. It is on page 31 of my
review.
The treatment effects were about 11
percent difference between the Zelnorm 6
mg and
placebo--16 percent, actually, in the
2302 study
174
and 11 percent in the 3201 study.
DR. SACHAR: Just a point of information,
apparently laxative use here is defined
as
bisacodyl use--
DR. PRIZONT: Right.
DR. SACHAR: --but there was no exclusion
for the use of bulk laxatives throughout
this. So,
is there any information at all as to
what was
happening with the use of bulk laxatives
during the
study?
I am not even sure it was recorded.
DR. PRIZONT: You mean bulk-forming
agents?
DR. SACHAR: Bulk-forming agents, yes.
DR. PRIZONT: The proportion of patients
who took bulk-forming agents was very,
very small
and, you know, those who took bulk-forming
agents
prior to entering the studies continued
to use
bulk-forming agents but the proportion
was very
small.
DR. FOGEL: Dr. Metz?
DR. METZ: Thank you.
My earlier question
to the sponsor was why they didn't divide
this by a
175
median age and then maybe go into
quartiles. I was
told that that was an FDA mandate for the
65-year
cut-off.
Now, they managed to slice and dice
everything else by all sorts of other
combinations
but I still haven't yet seen anything
sliced by
decade using the median. Do you have any kind of
information for that from a statistical
point of
view??
My other concern, as an aside
but also
quite important, is that it seems to me
there has
been a lot of goalpost moving in this
situation.
Usually what happens is you will submit a
protocol
for review. The agency will have a look at it and
say we like this protocol or we don't
like this
protocol.
Somewhere along the way here it seems
there has been a disconnect and we have a
definition that should have been, I
assume, agreed
on
up front which is now being criticized.
So, can
you give me a bit of the history of how
that
developed?
DR. PRIZONT: Let me clarify, you are
talking about the efficacy endpoint?
176
DR. METZ: Yes.
DR. PRIZONT: Let me first go to the
mandate.
Dr. Justice, Dr. Beitz, do we have a
mandate on 65 and older, and can we break
it up? I
am transferring it to management.
[Laughter]
DR. BEITZ: I would just say that 65 is
the regulatory definition of elderly,
over 65. So,
that tends to drive analyses to look at
over and
under 65 but there isn't any reason why
folks
couldn't look at over 75 or over 80.
DR. FOGEL: Dr. Justice?
DR. JUSTICE: Dr. Mele has done an
analysis on other age groups. I don't know if she
would like to comment.
DR. MELE: I did look at the results by
the median age and we still see an age
effect even
when we cut it at the median, such that
the
treatment effect for the patients over 46
is 10
percent.
This is comparing 6 mg to placebo.
For
instance, for the patients under 46, the
treatment
effect is 21 percent.
177
DR. PRIZONT: Yes, but my understanding is
that they are talking about 65 years old,
not 46
years old.
DR. MELE: But he asked about the median
so cutting it at the median--
DR. METZ: What I would like to see is
whether there is an effect--in quartiles,
say, is
it possible that the first quartile has a
great
effect, the second quartile doesn't so
well and you
see a decline as time goes on. I mean, I think
that 65 is an arbitrary number and my
concern here
is that the agency seems to be saying
elderly
patients aren't properly
represented. I want to
get a feel for the distribution, number
one and,
number two, I want to see does the effect
fall off
progressively in response as you go up in
decades.
DR. MELE: For the cut points I used it
does.
I mean, when you look at 46 as a cut point
the treatment difference is 10
percent. When you
use 60 as a cut point it is 8
percent. When you
use 65 it is 2 percent.
DR. PRIZONT: So, basically the response
178
is that the higher we go in age the lower
the
response.
Now let me address the second part of
your question. You are right, four years ago the
agency somehow agreed with the protocol
and I
suppose with the endpoint. But whether we agree or
disagree, we still have two points to
make.
The first point is that this
endpoint of
the increase of one spontaneous bowel
movement has
not been validated, at least has not been
validated
independently. You know, somebody may say, well, I
see patients and I think that one
complete
spontaneous bowel movement has a clinical
significance but we don't have a trial,
an
independent trial or two trials
validating that
particular endpoint.
The other point to be made is
that when we
compare the prospective endpoint, the
increase of
one complete spontaneous bowel movement
which we
consider not validated, to established
three bowel
movements per week endpoint the results
are
completely different. The proportion of responders
starts to drop rather markedly. Those are the two
179
points I can make to respond to your
question.
DR. METZ: There still was statistical
significance for a number of those,
right?
DR. PRIZONT: Let me clarify before I go
on.
There was statistical significance between
Zelnorm and placebo in most of the
analyses, you
know, with the exception of the elderly
and men.
But the question is are we going to rely
only on
the statistical significance and not
placing it in
light of the clinical significance of
laxation? We
are talking here about laxation. Ten percent of
responders for a laxative would be rather
small, to
say the least. But, you know, that is my view;
perhaps the committee has a different
view.
DR. FOGEL: Dr. Mangel?
Dr. Prizont, I
have two questions. The first is for your slides
on the primary efficacy endpoint--
DR. PRIZONT: Yes?
DR. MANGEL: --I agree with your point
that the more common definition of
constipation is
hovering around the 3 per week.
DR. PRIZONT: Right.
180
DR. MANGEL: However, if I am
understanding the slides correctly, and I
think
that is going to impact greatly upon the
absolute
magnitude of the numbers, these are all
cut on
greater than or equal to 3 complete
spontaneous
bowel movements per week.
DR. PRIZONT: That is correct.
DR. MANGEL: Do you have those same data
for spontaneous bowel movements per
week? Because
the reason I am concerned is when I look
at the
sponsor's briefing document, page 30, and
there was
not a slide on that, I guess I actually
see a
robust response. They are looking at spontaneous
bowel movements per week. Their baseline is
hovering, as you said, around 3 and I
think your
comment was that the median was less than
3 but
their baseline is hovering around 3, and
with
treatment it looks like it goes up to
about 5.
DR. PRIZONT: You mean with
completeness?
DR. MANGEL: No, just spontaneous. So, if
you are going to impose the criteria of 3
being
your cut-off, would it be more
appropriate to look
181
at spontaneous bowel movements than
complete
spontaneous?
DR. PRIZONT: I am going to refer to Dr.
Mele about the spontaneous bowel
movements. Let me
answer the question in a different
way. We have
now the Rome II criteria. The Rome II criteria
include at least 25 percent or at least
less than
25 percent of completeness in order to
make the
diagnosis of constipation and 3 bowel
movements per
week or less and straining as well since
the
baseline.
The sponsor already defined that
baseline.
What is constipation? They picked
two
elements of the Rome criteria, which were
frequency
of bowel movements and completeness. I follow that
particular definition set by the
protocol. You
know, that is a little bit of the paradox
here that
I see, that we have one definition of
constipation
for baseline and a different definition
of no
constipation-predominant for a responder.
DR. MANGEL: But the Rome criteria
actually don't mandate complete
spontaneous bowel
movements. You know, of the criteria, straining is
182
one of the criteria that could be met
greater than
25 percent of the time; lack of complete
evacuation
less than 25 percent; or the bowel
frequency. It
seems like a harder hurdle and,
therefore, I am not
surprised that the absolute responder
rates go down
when the entities are combined. If you would have
the data cut also for your slides for
spontaneous
bowel movements, you know, independent of
complete
spontaneous--
DR. PRIZONT: Yes, you have a point, of
course.
Probably if I selected spontaneous bowel
movements the numbers would be a little
bit higher
than what complete spontaneous bowel
movements
show.
The Rome criteria state that selection of
two of the elements or parameters of the
list that
they have in their own criteria will
define
constipation. The sponsor selected two criteria,
completeness and frequency of bowel
movements.
Now, they could have selected something
else but
that is what they selected and I follow
that
selection.
DR. MANGEL: Dr. Prizont, before we move
183
on, the survey and epidemiology data in
which you
are looking at 95 percent of responders
being
within 3 bowel movements per day to 3 per
week is
talking about spontaneous bowel
movements, not
complete spontaneous. So, if you are coupling to
the 3 number, the 3 number is derived for
spontaneous bowel movements.
DR. PRIZONT: Yes.
DR. MANGEL: And that is what the Rome
criteria actually use.
DR. PRIZONT: You are talking about the
survey of NHANES, the one with 14,000
patients?
DR. MANGEL: Well, there have actually
been several.
DR. PRIZONT: There have been several but
that is probably one of the largest. The reason
that they placed that is to exemplify
that, other
than the British study, there was a newer
study
which was large and had two phases, as I
mentioned,
and they defined, or they found because
that was a
survey, that most of the people
responding to the
survey had normal people, had between 3
or more
184
bowel movements per week, basically
almost the same
as what the British study found.
DR. MELE: Can I make a comment on this
question?
About half the patients, remember, had 3
spontaneous bowel movements at
baseline. So, to do
an analysis where you look at an increase
to a
level of 3 or more spontaneous, you could
only do
it on half the patients. What we did do is look at
the baseline spontaneous bowel movements
and cut it
using those and looked at the primary and
secondary
endpoints that we have been discussing. The
sponsor did this also and found
significant
results, statistically significant
results.
DR. PRIZONT: But do you have the numbers?
Because my understanding is--
DR. MELE: There are a lot of different
numbers.
DR. PRIZONT: --looking at the numbers, if
there was a difference between the
numbers in the
complete spontaneous bowel movements and
the
spontaneous bowel movements.
DR. MANGEL: Well, I think my point was
185
that you are absolutely correct when you
go from
greater than 1 to greater than 3, the
rate of
responders dramatically drops because it
is a
harder hurdle.
DR. PRIZONT: It is still statistically--
DR. MANGLER: Still statistical but the
absolute rate, but I am not convinced
that the
proper comparison is comparing greater
than 1 to
greater than 3 complete spontaneous. If you wanted
to look at greater than 1 complete
spontaneous or
just greater than 3 spontaneous, and I
think that
is what your statistician just said, but
I guess
the question is does the responder rate
for those
with less than 3 at baseline--what type
of
responder rates are we looking at for a
primary
analysis?
DR. MELE: For patients with less than 3
spontaneous bowel movements at baseline and
looking
at which endpoint?
DR. MANGEL: Well, it would be greater
than or equal to 3 per week for
spontaneous.
DR. MELE: Yes, we didn't look at it that
186
way.
We looked at 3 or greater for complete
spontaneous.
DR. PRIZONT: But, you know, I think the
comparison in some ways may not be fair
because we
are comparing an increase of 1 complete
spontaneous
bowel movement to just a spontaneous
bowel
movement.
So, I think the comparison may not be
completely fair in that sense because we
are
including complete in one of the arms of
the
comparison and not in the other one.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: Regardless of whether we use
spontaneous or complete spontaneous bowel
movements, there is still obviously a
difference
between someone who goes from zero bowel
movements
a week to 3 bowel movements and someone
who goes
from 2 bowel movements to 3. So, my question for
you is if we just take the responders to
Zelnorm,
what was the mean number of increase in
bowel
movements versus placebo? For example, was the
mean 1; was it 2; was it 3? This would give us
some sense of perhaps the clinical
significance.
187
Rather than just looking at the percent
of
responders, what was actually the mean
number of
increase in bowel movements?
DR. MELE: I can answer that question.
The average increase over the 12 weeks
was 1.3
complete spontaneous bowel movements in
the 6 mg
group versus 0.7 complete spontaneous
bowel
movements in the placebo group.
DR. PRIZONT: This is for the 12-week
response.
The difference was 9 percent.
DR. BUCHMAN: This is actually looking at
the percentage but I am actually looking
at a
different figure, which is the mean. But I think
that is what we were just told. The difference was
0.7 versus 1.3.
DR. MELE: And that is averaged over the
whole treatment period.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: Some of the questions
that I was interested in have been asked
but one
still remaining question is I hear what
you are
saying in terms of the magnitude, and so
forth, but
188
give us a feel for what clinical
significance there
is because you are not talking about
statistical
significance because it is there. So, you are
moving the discussion to the clinical
significance.
Could you give us some reference numbers
so we can
judge these, why aren't they good or why
are they
satisfactory? Given the fact that we are moving to
a different endpoint, we have this
complete
spontaneous, and so forth, so give us a
context,
please.
DR. PRIZONT: My response has to be based
on what we know what is normal and what
we know
about constipation. The problem with my response
is what I mentioned about subtypes. Not all
subtypes of constipation are the
same. The
functional type of constipation is sort
of the less
severe of the types of constipation. In those
cases, I would expect that 3 or more
bowel
movements could be clinically
significant.
Now, if you take the other
subtypes of
constipation, if you take the outlet
obstruction
constipation, which is usually in women,
younger
189
women, they have more severe type of
constipation,
then, you know, we can discuss but there
is no
uniformity. There is no universal agreement on
what is the improvement for all
constipation.
DR. D'AGOSTINO: Yet you are telling us,
if I hear you correctly, that you are not
satisfied
with these numbers, that they don't show
us
clinical significance.
DR. PRIZONT: Because I don't know
what it
means, that endpoint of increase of 1
complete
spontaneous bowel movement. Therefore, I am not
sure how much improvement there is in the
constipation.
DR. FOGEL: We all like counting bowel
movements because it is easy. We have great
difficulty when it comes to dealing with
subjective
symptoms like straining, incomplete
evacuation and
symptoms like that. In his work, Drossman tries to
get around that issue by talking about
subjective
global assessment and whether or not you
feel
better.
I mean, I think that is the important
clinical outcome that we are interested
in. You
190
haven't presented on this global
assessment as to
whether or not you are better by taking
therapy.
Do you have any information about that?
DR. PRIZONT: Well, the sponsor has
information about the global assessment.
DR. FOGEL: Is there any analysis though
that was done by the FDA?
DR. PRIZONT: The sponsor did an analysis
on what they call secondary
endpoints. They have
abdominal discomfort, and so on. Referring to the
secondary--
DR. FOGEL: No, not the individual
endpoints, but this global
assessment. Are you
better taking the medication than not
taking the
medication? Or, are you better on tegaserod as
opposed to taking placebo, and is that
difference
significant?
DR. PRIZONT: I will relinquish for that
information to the sponsor. I think they did the
analysis.
I don't have any firm grasp of that.
DR. FOGEL: Dr. Beitz?
DR. BEITZ: We don't have an analysis on
191
the global but we have some other
endpoints that
you
might be interested in seeing.
DR. PRIZONT: But he is not interested in
the other endpoints. He is interested in the
global, right?
DR. MELE: The global did show significant
effects.
DR. FOGEL: Do you think that that is of
clinical significance?
DR. PRIZONT: I may think that is of no
clinical significance; you may think that
it is of
clinical significance. That is the difference in
what we are dealing with now in terms of
constipation, which is a sensation of
infrequent
evacuation and difficult evacuation, as
one
dictionary has defined it. That is the problem,
that we don't have uniformity in terms of
definition of constipation.
DR. FOGEL: Dr. Justice?
DR. JUSTICE: I think the point is we are
really seeking the committee's advice on
that. You
know, we would appreciate your input as
to the
192
clinical significance of these findings.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: It might be useful to
consider the data as showing either
complete
response, that is, patients who are no
longer
constipated by the Rome criteria and that
may have
been shown, but I wonder if you could
just remind
us of those data again.
DR. PRIZONT: That was 3 or more bowel
movements per week.
DR. LAMONT: But there are other criteria
for constipation that were listed by the
sponsor
based on the Rome II criteria. So, I guess my
question is what percent of patients were
no longer
constipated by those criteria, either
number or
subjective symptoms, at the end of 4 or
12 weeks?
The second comment I have is
that in most
clinical trials we look at things like
partial
response and complete response. For example, in
rheumatology trials they look at 20
percent
response, 50 percent response and 70
percent
response by American Rheumatology Society
criteria.
193
So, I wonder if we couldn't look here at
complete
response being no longer constipated by
Rome
criteria and some other partial response.
DR. PRIZONT: I am going to transfer the
question you asked me to you. You know, what is
complete response?
DR. LAMONT: Well, by the Rome criteria
that they used for entry, that they no
longer
qualify for constipation by those
criteria, which
are established and I think validated.
DR. PRIZONT: Well, according to their
criteria an increase of one single bowel
movement,
complete one single bowel movement is not
constipated per week.
DR. LAMONT: But that wouldn't apply to
the Rome criteria though. The Rome criteria
wouldn't accept that as no longer being
constipated, I don't think.
DR. PRIZONT: Right.
That is what I was
trying--
DR. LAMONT: No, no, I understand.
Therefore, greater than one complete
spontaneous
194
bowel movement per week is some sort of
partial
response.
But I am asking what about complete
response, no longer constipated by Rome
criteria?
DR. PRIZONT: The data is there and I
cannot add too much to the data.
DR. LAMONT: I wonder if anybody else has
parsed the data.
DR. PRIZONT: As I said, you know, the
Rome II criteria--and I had a small
contribution in
that--included two parameters to define
constipation. You can pick and choose those two
parameters. They already picked the two parameters
which were frequency and
completeness. Based on
that, that is the data.
DR. FOGEL: Dr. Beitz has a comment.
DR. BEITZ: Oh, just that we were going to
ask if the sponsor had done what you
said.
DR. FOGEL: Does the sponsor have any
comments?
DR. DENNIS: Could I have slide AQ-92,
please?
Remember, we have to put all these into
context in terms of definitions. What we applied
195
here was to say, okay, let's look at the
definitions we applied at the beginning
at the
study and we said, okay, patients had
less than 3
complete spontaneous bowel movements and
they had
one of the others 25 percent of the
time. Right?
We took out the patients that were
IBS-like so they
weren't confounding factors. Then we said, okay,
let's look throughout the course of the
study with
the week 12s and let's look at patients
that met
that definition at baseline and met that
definition
within the 12-week treatment trial.
Remember, we did not set out to
cure
constipation in this trial. We set out to improve
constipation, and we have to look and see
what are
the placebo patients doing versus what
the Zelnorm
patients are doing. We see that at weeks 12 86
percent of patients on placebo are still
constipated and on Zelnorm we have 72
percent of
patients that would still meet that
definition.
So, to speak to the previous
point about
complete responders, we are seeing some
people that
are completely responding, looking at
that
196
reduction but, of course, we don't take
into
account with this definition improvement
in the
constipation symptoms which is what we
have seen
before.
Remember, patients had at baseline
a
median number of CSBMs of zero and a mean
of 0.5.
So, really to get them over that was
quite a high
hurdle, and this is just looking at a
number but it
doesn't take into account the improvement
in the
symptoms that we see as well.
DR. FOGEL: Thank you.
One quick question
and then we are going to move on.
DR. BUCHMAN: Just a quick question on
that slide, why were not all the patients
constipated at baseline? How did you have 15
percent of patients that were in a study
on
constipation that weren't constipated
when they
entered the study?
DR. DENNIS: Unfortunately, even though we
have strict criteria for getting into the
study,
you always have protocol violators that
come in.
When you go back and analyze the data
that is what
197
we find by these definitions.
DR. BUCHMAN: So, wouldn't they have been
excluded when the monitor went by to see
them
before they completed the study?
DR. DENNIS: Well, that should happen in
most cases but you know that the
challenge of a
clinical trial design is that it doesn't
always
happen so we have to accept that this is
what we
have seen in our study.
DR. BUCHMAN: Because that is a pretty
high number, 15 percent; it is not like 2
percent.
DR. DENNIS:
I am going to ask our
statistician to come and comment on how
we handled
that.
DR. LIU: Jeen Liu.
I am the
statistician. Actually, I can only add to what
Eslie said, that for the baseline constipation
criteria we had criteria as she had
presented. It
is very difficult actually for the
investigator to
check that. We tried our best. The percentage
that you see there, part of it comes from
the fact
that when we went back to double check
the data
198
some of the patients barely missed the
criteria and
some of them had too many missing values
to be
qualified for this rigorous analysis.
DR. SACHAR: But the therapeutic aim was
4.8 percent.
DR. LIU: No, 14.
DR. SACHAR: No, no, no--
DR. LIU: I think you are looking at the
wrong treatment. We should really look at the
first column--
DR. SACHAR: Right, which is 1.9 and the
last column which is--oh, I see, 14, yes.
DR. BUCHMAN: Did you analyze patients
separately by those who were constipated
at
baseline and exclude the 15 percent that
didn't
qualify?
DR. LIU: I am not following your
question.
DR. BUCHMAN: If you excluded the 15
percent of patients that were not
constipated at
baseline, that really failed study
criteria, were
they analyzed separately?
199
DR. LIU: No, no, we didn't do that. I
think you are going to get almost the same
result
because you basically are just reducing
the
denominator by 15 percent.
DR. FOGEL: Thank you.
We will move on
now.
The last presentation of the morning is by
Dr. Della'Zanna.
FDA Safety Presentation
DR. DELLA'ZANNA: I have the benefit of
being the last person presenting so I
will try to
keep things moving. My name is Gary Della'Zanna.
I am a medical officer in the Division of
Gastrointestinal and Coagulation Drug
Products. I
will be presenting some of the agency's
concerns
regarding safety issues that were
identified during
the postmarketing period. For some of this
presentation I will be referencing postmarketing
data that was received through the
agency's Adverse
Event Reporting System and was analyzed
by the
Division of Drug Risk Evaluation. At this time, I
would like to acknowledge the work of Dr.
Allen
Brinker and Ann Corken Mackey who are
members of
200
that Division. Following this presentation they
will be available to answer any
postmarketing
questions.
Through 15-day postmarketing
safety
reports the agency became aware of
several adverse
events that we defined as special
interest. These
included serious consequences of diarrhea
such as
hypotension and syncope. I will also present
updated information on whether the use of
Zelnorm
is associated with an increased risk of
abdominal
and pelvic surgeries in humans. I will then focus
the remaining portion of the presentation
on
postmarketing reports of ischemic colitis
and other
forms of intestinal ischemia.
As already stated by Novartis,
Zelnorm is
a 5-HT 4
partial agonist. It
also
has moderate
affinity for the 5-HT
1B receptor. The therapeutic
mechanism of action is believed to be
based
primarily on its 5-HT
4 agonist properties. The
proposed dose for the chronic
constipation
indication is the same as the approved
dose for the
constipation-predominant IBS. If approved, Zelnorm
201
would be the first drug to be granted an
indication
specifically for chronic constipation.
In response to postmarketing
15-day safety
reports, the agency worked with Novartis
to revise
the Zelnorm package insert. These revisions were
finalized at the end of April, 2004. The label now
includes a warnings section about the
serious
consequences of diarrhea, including
hypovolemia,
hypotension and syncope. A precautions section
describes ischemic colitis and other
forms of
intestinal ischemia. In addition to this labeling
change, Novartis also mailed a "dear
doctor" letter
outlining these changes. Both of these documents
were included in your background package
as
Appendix 1 and 2.
This table shows the most
frequent adverse
events during the 12-week portion of the
chronic
constipation trials. These studies did not
identify any new safety concerns. The incidence
and type of adverse events were similar
to what is
already included in the current
label. Other than
diarrhea, there was no appreciated dose
response to
202
adverse events.
The incidence of adverse events
was higher
during the 13-month extension study. The increase
in AEs was most likely due to an increase
in time
exposure.
Many of the Division's safety
concerns
that were identified during the
postmarketing
period were not seen in the chronic
constipation
trials.
For the remaining portion of this
presentation I will be focusing on
adverse events
identified during the postmarketing period
as AEs
of special interest. I will be referencing
spontaneous postmarketing reports
received through
the agency's MedWatch program. This reporting
program is a passive surveillance system
that is
designed to detect rare and unexpected
events
associated with drug therapy.
To help define the safety
profile of
Zelnorm, I will present the postmarketing
data as
well as relevant safety data from the
chronic
constipation trials and other completed
trials for
different indications that had similar
design.
203
Because of the postmarketing
reports,
serious consequences of diarrhea were
identified as
an adverse event of special
interest. This
included cases of diarrhea or
complications from
diarrhea that led to an emergency room
visit or
hospitalization. You may notice that the numbers
that we present differ from the
sponsor's. This is
because cases were excluded from the
analysis if
the diarrhea was caused by another
identifiable
process such as infection.
For this presentation the
agency used
April 15, 2004 as a cut-off data for
analyzing
postmarketing safety reports. As of April 15, the
Office of Drug Safety received 22 reports
of
serious complications of diarrhea. Consistent with
the prescribing patterns, the majority of
the cases
occurred in female patients. These patients ranged
in age from 24-82 years, with an average
age of 56.
The time to onset of the diarrhea ranged
from 1 day
to 210 days, with 5 of the cases
occurring on the
first day of therapy and half the cases
occurring
during the first week. Fifteen of the 22 cases
204
required hospitalization; 3 were
described as
life-threatening. In addition to diarrhea, the
complications from the diarrhea included
dehydration, abdominal pain, hypotension,
electrolyte disorders and shock.
During the chronic constipation
trials the
frequency and severity of diarrhea was
dose
related.
These findings are not surprising
considering Zelnorm's mechanism of
action. And,
6.6 percent of the patients in the 6 mg
group
reported diarrhea as an adverse
event. This
compares to 3 percent in the placebo
group. Eight
patients in the 6 mg group discontinued
from the
study due to diarrhea compared to 2 in
the placebo
group.
Additionally, 7 patients in the 6 mg group
developed severe diarrhea compared to 2
in the
placebo group.
There was an increase in the
incidence and
a slight increase in the severity of
diarrhea
during the 13-month extension study. A total of
840 patients continued in to the
extension study.
Patients who were receiving placebo
during the core
205
study were changed to Zelnorm 6 mg BID
for the
extension study. Overall, 9.5 percent of the
patients reported diarrhea as an adverse
event
during the extension study. For the proposed 6 mg
BID dose this incidence was 10.2. This is relevant
considering the proposed indication is
for chronic
therapy.
There was also a higher incidence
of
diarrhea in older patients. For the proposed 6 mg
BID dose 12.5 percent of the patients 65
years and
older reported diarrhea as an adverse
event. This
compares to only 6 percent in patients
younger than
65.
Also, there was a higher proportion of older
patients who discontinued treatment due
to
diarrhea.
This is significant considering the
efficacy seen in this population and the
potential
number of elderly patients who will be
treated for
constipation.
As part of the recent labeling
changes,
hypotension is now listed in the warning
section of
the current label as one of the serious
consequences of diarrhea. As of April 15, 2004 the
206
agency received 15 reports of
hypotension. Many of
these cases were confounded by underlying
medical
conditions and concomitant medications.
One interesting case, however,
occurred in
a 45 year-old female with no past medical
history
of cardiac or blood pressure
abnormalities. Prior
to starting Zelnorm, the patient's blood
pressure
was recorded at 138/80. Approximately 2 weeks
after initiating therapy the patient
experienced 2
syncopal episodes after standing. The patient's
blood pressure was recorded as 75/60 at
the time.
Additionally, it is worth mentioning that
hypotension was reported in at least 2
other cases
of ischemic colitis.
During the Phase 1 development
of Zelnorm
rare cases of hypotension in healthy
subjects were
identified. Because of this, hypotension was
closely evaluated during Phase 3
trials. The
incidence of orthostatic hypotension was
balanced
between treatment groups in the IBS as
well as the
chronic constipation trials.
This slide demonstrates the
incidence of
207
orthostatic hypotension during the
chronic
constipation trials. This was defined as a drop in
systolic blood pressure of 20 or more
mmHg or a
diastolic drop of 10 or more after
standing. Since
hypotension is listed as a complication
of diarrhea
in the current label, it is worth noting
that none
of the cases of hypotension during the
chronic
constipation trials were associated with
diarrhea.
Syncope is another adverse
event of
special interest. It is also listed in the
warnings section of the current label as
a serious
complication of diarrhea. As of April 15, 2004 the
agency received 8 postmarketing reports
of syncope
or loss of consciousness in patients
receiving
Zelnorm.
Most of these patients had other
confounding factors that may have
contributed to
the event, however, the role of tegaserod
could not
be completely ruled out.
The chronic constipation trials
did not
identify any signal for syncope. Four syncopal
events were reported. Two occurred in the Zelnorm
group and 2 in the placebo group. Again, it is
208
worth noting that none of the patients
who
developed severe diarrhea during the
chronic
constipation trials experienced a
syncopal episode.
At the time of the original
approval,
there remained questions of whether the
use of
Zelnorm was associated with an increased
risk of
abdominal and pelvic surgeries. Nine cases of
symptomatic ovarian cysts were reported
during the
IBS trials. Eight of the 9 cases occurred in
patients treated with Zelnorm. Only 1 occurred in
the placebo group. Five of the 9 cases required
surgery, all from the Zelnorm group.
An analysis also identified an
imbalance
in the number of cholecystectomies
performed in
patients receiving Zelnorm. These differences,
however, were not statistically
significant.
To help identify whether the
use of
Zelnorm is associated with an increase in
abdominal
or
pelvic surgeries, Novartis committed to a Phase
4 pharmacoepidemiology study which is
presently
ongoing.
They created an adjudication board
consisting of independent consultants who
review
209
all surgeries in a blinded fashion.
As stated earlier, the agency's
Adverse
Event Reporting System is designed to
detect rare
safety signals. It is not designed to track
postmarketing reports of common
surgeries. Looking
at the clinical trials, the number of
abdominal and
pelvic surgeries performed under chronic
constipation trials were too small to
identify an
imbalance. Two ovarian cyst surgeries were
performed, one in the Zelnorm group and
one in the
placebo group. There was also one patient in the 6
mg Zelnorm group who had a hysterectomy
due to
hypermenorrhea. Only one cholecystectomy was
reported.
This occurred on the 12-week study in a
patient receiving 6 mg Zelnorm BID.
Novartis also analyzed the
incidence of
surgery for all completed
placebo-controlled
clinical trials of similar design. The frequency
of abdominal and pelvic surgeries in this
pooled
indication population was comparable
across
treatment groups, but there was an
imbalance in the
number of cholecystectomies. Looking at all cases
210
of cholecystectomies, the incidence was 4
times
higher in the Zelnorm treatment
group. Even after
the adjudication board excluded 4 cases
from the
Zelnorm treatment group, the incidence in
the
Zelnorm group was still twice the placebo
group.
The clinical significance of this is
uncertain.
Due to postmarketing reports of
ischemic
colitis and other forms of intestinal
ischemia,
they have been identified as adverse events
of
special interest. From the time of approval
through April, 2004 an estimated 2
million
prescriptions for Zelnorm have been
filled in the
United States.
As stated earlier, for this
presentation
the agency will present cases of
intestinal
ischemia that were reported through April
15, 2004.
As of April 15, the agency received 24
postmarketing reports of bowel ischemia.
Considering the "dear doctor"
letter was not
finalized until the end of April, this
cut-off date
does not allow for the increased
reporting which
typically occurs when physicians become
aware of a
211
problem.
For example, the agency received 9
additional cases of intestinal ischemia
between
April 15 and June 1. A summary of these cases was
provided in the background packet under
Appendix 3.
For the safety review, the
agency
separated out ischemic colitis from other
forms of
intestinal ischemia, focusing on the 20
postmarketing cases of ischemic colitis
received
through April 15. Nineteen were female, ranging in
age from 26-82 years, with an average age
of 55.
The time to onset of ischemic colitis
ranged from 1
day to almost 400 days. As for the safety reports,
the majority of the patients who
developed ischemic
colitis were treated for IBS. Four patients were
treated off-label, 2 for constipation, 1 for
postoperative ileus and 1 for an unknown
indication.
Thirteen of the 20 patients
required
hospitalization. One of these required surgery and
one died.
The agency is concerned that these cases
represent a drug-induced ischemic
colitis.
However, a causal relationship is
difficult to
212
prove.
But it is suggestive when one considers
that these 5 of the 20 reported cases had
no
documented risk factors. Three cases occurred on
the first day of therapy and 2 of the 3
cases
occurred in patients with no documented
risk
factors, as in case 6 and 8 on this
slide. The
remaining 15 patients had 1 or more
identifiable
risk factor such as hormonal therapy,
tobacco use
or vascular disease, but that does not
exclude the
possible relationship with Zelnorm.
The Division assigned the
definition of
other intestinal ischemia to cases of
ischemic
bowel that resulted from a large vessel
process
such as a mesenteric artery
occlusion. All 4 cases
meeting this definition occurred in
female patients
ranging in age from 41 to 67 years. Postmarketing
reports described 3 of the 4 patients
were treated
for IBS.
One was treated off-label for
constipation. All 4 were hospitalized, with 3 of
the patients requiring surgery. One had a bowel
resection. The other 2 had exploratory
laparotomies. Three of the 4 patients died. The
213
Division acknowledges that all 4 patients
had
significant confounding medical
conditions but the
role of tegaserod cannot be completely
ruled out.
The Division concluded that a
thorough
review of the chronic constipation
trials, as well
as a focused review of the IBS studies
and other
completed clinical trials of similar
design did not
identify any cases suspicious for
ischemic colitis
out of approximately 12,000
patients. Using the
available data, the Office of Drug Safety
estimated
that approximately 7,000 patients were
randomized
to Zelnorm among the placebo-controlled
trials that
were at least of 3 months duration. Based on
application of Poisson distribution, it
would
suggest that, with 95 percent confidence,
ischemic
colitis occurs no more often than 1 in
2,000 in
this type of patient.
The agency is seeking the
committee's
advice on whether reference to ischemic
colitis and
other forms of intestinal ischemia should
be moved
to the warning section of the package
insert. It
is the agency's position that the
appearance of
214
these events in young patients in close
temporal
association with Zelnorm is
concerning. These
conditions are generally considered a
disease of
the elderly. Consider 7 of the 20 cases occurred
in patients less than 49 years of age,
with 2 of
the patients less than 30. As stated before, 5 of
the 20 cases had no documented risk
factors. Three
cases occurred on the first day of
therapy, with 2
of the 3 cases occurring in patients with
no
reported risk factors. In the month following the
labeling change and "dear
doctor" letter an
additional 9 cases were reported. Since June 1, 5
more cases have been received. This brings the
total to 14 new cases reported since the
labeling
change.
These cases have not been formally
adjudicated with the sponsor.
The agency would also like the
committee's
opinion on whether the patients with IBS
have a
higher background incidence of ischemic
colitis.
Novartis argues there is no causal
relationship
between the use of Zelnorm and the
development of
ischemic colitis. It is our position, based on
215
several published studies conducted
within
administrative claims databases, that there is a
higher background incidence of ischemic
colitis in
IBS patients. The agency reviewed the available
data Novartis used to support an
association
between ischemic colitis and IBS and
found no
compelling evidence to suggest that a
clinically
robust diagnosis of IBS is associated
with any
increased risk for ischemic colitis.
In contrast, it is the agency's
position
that an association between IBS and
ischemic
colitis is attributable to the use of a
non-specific ICD9 code used in the
databases. This
code includes IBS and other bowel
processes. We
believe this resulted in a
misclassification or a
misdiagnosis of patients who were
actually
undergoing a workup, the code
representing an
interim diagnosis.
Novartis also defends their
position
stating that no mechanism of action has
been
identified in the animal models. It is the
Division's opinion that a mechanism of
action has
216
not been ruled out and that there may be
cross
reactivities with other receptors and
ligands that
have not been identified. Zelnorm is a 5-HT4
partial agonist with moderate affinity
for the
5-HT1B receptor. There is recent medical literature
proposing a link between Zelnorm and the
develop of
Raynaud's phenomenon, a vascular disorder
that can
affect the fingers and toes.
The article presents a case
history of a
21 year-old female with no prior history
of
Raynaud's who developed painful
discoloration of
her fingertips after cold exposure. This occurred
2 days after initiating Zelnorm. Symptoms
disappeared completely after the drug was
discontinued. Although a mechanism of action for
this process has not been identified,
causality is
strongly suggestive considering the
patient had no
prior history of Raynaud's, was not on
any
concomitant medications and the symptoms
resolved
after discontinuing Zelnorm.
Another article discusses the
potential
risk for Zelnorm-induced coronary-artery
spasm.
217
The article, titled,
"Tegaserod-Induced Myocardial
Infarction: Case Report and
Hypothesis," proposes
that since tegaserod has moderate
affinity for the
5-HT1B receptor, it is plausible that
tegaserod
could cause coronary-artery contraction
and spasm
similar to other 5-HT
1 receptor agonists on the
market, such as those used for treating
migraines.
Although these 2 articles are
not
conclusive, they do support the
Division's position
that a mechanism of action explaining an
association between Zelnorm and ischemic
colitis
has not been completely ruled out. In response to
the agency's concerns, Novartis has
agreed to
perform additional mechanistic studies.
In summary, chronic
constipation trials
did not identify any new safety
concerns. The
Division is concerned that there are
limited safety
and efficacy data on male patients, as
well as a
questionable risk/benefit profile for
patients 65
years and older. Only 12 percent of the patients
enrolled in the chronic constipation
trials were
male.
The efficacy of Zelnorm in patients 65 years
218
and older was similar to that of
placebo. These
patients also had a higher incidence of
diarrhea as
an adverse event. Additionally, considering how
common constipation is in the elderly,
only 13
percent of the patients enrolled were
older than
65.
Many of the Division's safety
concerns
that were identified during the
postmarketing
period have been addressed with the
recent labeling
changes.
Serious consequences of diarrhea are now
listed in the warning section of the
label.
However, the chronic constipation trials
demonstrated that elderly patients had
little
efficacy and may be at higher risk for
developing
complications from diarrhea. The label should be
revised to reflect this.
The question of whether the use of
Zelnorm
is associated with an increased risk of
surgery
remains unknown. Phase 4 studies are ongoing. The
background incidence of ischemic colitis
in the
general population, as well as the IBS
population
continues to be debated. The Division questions
219
whether the available data justifies
placing
ischemic colitis in the warning section
of the
label.
I do have one update that I
would like to
share with you. We got this from an AERS MedWatch
report update yesterday. It is case 25 in my
background pack. Initially I just had a
description term of a young female with
findings
consistent with ischemic colitis and I
had no other
information. We got an update. That patient was
31 years old. She was treated for IBS. Prior to
therapy she had a clean upper and lower
endoscopy.
Approximately 5 months after initiating
therapy she
presented to the emergency room with
rectal
bleeding and had a colonoscopy performed
that day
that demonstrated superficial epithelial
necrosis,
acute hemorrhage, and the biopsies were
consistent
with ischemic colitis. Stool cultures were
performed. They were negative. Hypercoagulative
workup was also negative. The patient's medical
history only included constipation,
endometriosis
and
complete hysterectomy and GERD. The
patient
220
was on no other concomitant medications.
Also of interest that I would
like to
comment about, the month prior to this
event the
patient decreased her dose to 3 mg every
other day.
Any questions?
Questions on
Presentation
DR. FOGEL: Are there any questions for
Dr. Della'Zanna? Dr. LaMont?
DR. LAMONT: Yes, has the agency or the
sponsor collected any information from
outside the
United States on ischemic colitis? Has everything
we have seen here related to U.S.
patients only?
DR. MACKEY: One of the ischemic colitis
cases was from Canada, and we have had no
other
cases outside the U.S.
DR. FOGEL: Dr. Metz?
DR. METZ: Thank you very much for a very
nice summary. I am starting to realize that the
older you get, the less the effect; the
more
concern for a confounding diagnosis that
is going
to end up like a secondary causal
constipation or
maybe, you know, not a true idiopathic
constipation
221
patient, and maybe more of a worry about
potential
diarrhea or ischemia.
With the postmarketing data
that is out
there, I want to know how much exposure
we really
have to measure these patients. The briefing
document, unfortunately, photocopied very
badly.
The IMS is really the only data we
got. I mean,
the other postmarketing stuff is isolated
reports
and it is not very robust, but with IMS
you can
actually get an idea. How many patients, what
percentage of patients at various age
groups have
actually received this drug for any
length of time
both split by gender and split by
age? That would
be very useful to me.
DR. DELLA'ZANNA: I would like to
introduce Dr. Allen Brinker.
DR. BRINKER: I will speak to that just
briefly.
Yes, IMS can give us a very good handle
on drugs.
The kicker with the use of Zelnorm is
the short-term use. So, it has been my position
and I have argued that it is very
difficult to
model use at all because of the
short-term use
222
data.
So, I think this is akin to the triptans in
that regard because some people are going
to use it
for a week. It is indicated only for short-term
use and people are going to stop it
really quick.
So, I am reluctant to try to tell you
that I have a
good handle on where the patient years
are to help
you with the denominator. Perhaps the sponsor
could try to outline--I mean, we have
some profiles
on prescriptions only but I am not going
to tell
you
that I know that those distributions accurately
reflect how patients end up taking the
drug.
DR. LAMONT: With the IMS data you
actually can see when the prescription
is, repeat
prescription as opposed to a new prescription,
and
you can get that information and you can
get the
ages of those patients too.
DR. BRINKER: There are databases where
you can do that and with claims databases
you can
do that, that is correct. But then you have to
decide for yourself whether or not those
are
representative of the population at
large, and we
have chosen not to do that. Most of our analyses
223
have been qualitative.
DR. FOGEL: Dr. Joelsson, do you have a
comment?
DR. JOELSSON: We have some data we can
show you and we can discuss how relevant
they are
or not.
We have a pie chart here which shows the
distribution of age. As you can see, the majority
is in patients under the age of
60--slightly young.
Does that answer your question?
DR. LAMONT: Do you have it by gender as
well?
DR. JOELSSON: I think so, yes. Can we
have the gender slide? So, 7 percent male have
tried this drug--mostly women. So, 7 percent male
and 93 percent women.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: I was curious about the
motivation for the opinion requested and
changing
from a precaution to a warning,
considering that
the label change was just a few months
ago. Is it
because you are concerned about the
increased
number of reports following the "dear
doctor"
224
letter and label change, or is it a
convenience
issue because the committee happens to be
meeting
now?
In your briefing document you mention that
the first case came in, I believe, in
March, 03 and
the label change occurred in April,
04. To make a
change now, I am curious--
DR. DELLA'ZANNA: What is our motivation?
DR. MANGEL:
yes.
DR. DELLA'ZANNA: To keep things on base,
we were in negotiations for where we were
going to
put this in the label. We were initially hoping to
put it in the warning section. We were in
negotiations, that were prolonged, with
the
sponsor.
We could not reach an agreement but we
also didn't want to be completely
one-sided. We
agreed to meet and place it into the
precautions
section and discuss it at the advisory committee
meeting.
This was a compromise on both of our
parts.
DR. MANGEL: Could I ask a follow-up to
that?
If there would be a label change--you
probably might not have concluded this,
would there
225
be a "dear doctor" letter,
etc.? With increased
communication about it, it may be
confusing for the
prescriber whether or not there has been
a new
signal in the next three months or with
the
original placement was just
incorrect. Have you
thought in terms of there would be a
label change
what type of communications would
accompany that?
DR. DELLA'ZANNA: Well, I don't know
whether I would say that the placement
was
incorrect. Okay?
This is a developing signal
possibly.
We are looking at an increased number of
cases which also might increase our
concerns. So,
I don't know if I would agree with you
that we
didn't place it correctly the first
time. The goal
was to come to an agreement; be able to
get a "dear
doctor" letter out to make the
public aware and
physicians aware of our concerns as soon
as
possible without having to go through any
further
delay of releasing this information.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: I would like to express my
general unhappiness with the way the
safety data
226
have been presented, particularly by the
sponsor.
It is a very one-dimensional way,
basically giving
the cumulative frequency. Adverse effects have
other dimensions--very little about
severity. The
other one would, for example, be
pain. They are
equating a single episode of pain to
constant pain
for six weeks. I wish we had a little bit more
information about those aspects, the
other
dimensions, because I am unwilling to buy
the fact
that the drug has very few adverse
effects just
based on the cumulative frequency.
DR. FOGEL: Thank you.
Dr. Cryer?
DR. CRYER: As I think about this issue, I
am
really kind of focusing in on the subgroup
analyses of the subpopulation where there
was
modest or no treatment effect shown,
specifically
again the older age and the men. In kind of making
that comparison, you showed us nicely a
breakout of
this adverse effect of diarrhea by
age. I was
wondering if you have done a similar
analysis by
gender, the incidence of adverse effects
or
specifically diarrhea.
227
DR. DELLA'ZANNA: I do not have that with
me.
I have it as part of my final review.
I don't
remember it off the top of my head.
DR. FOGEL: Yes?
DR. DENNIS: This is a slide showing
adverse events broken down by males. So, this is
the slide that shows you that in the male
population the adverse event that was
seen more
frequently was diarrhea, which is what we
saw in
the female population where diarrhea was
more
frequent than in the placebo--the males
and the
females.
DR. CRYER: Thank you.
That answers my
question.
DR. FOGEL: I would like to thank the FDA
for their presentations. We are going to break now
for lunch. We will resume again at 2:15. For the
committee, we are going to be taken
across the
street to Cafe Gallery. We will start again at
2:15.
[Whereupon, at 1:10 p.m., the
proceedings
were recessed for lunch.]
228
A F T E R N O O N P R O C E E D I N G S
Open Public Session
DR. FOGEL: Good afternoon. I would like
to start the afternoon session, if I can
have
everyone's attention, please. The first item of
business this afternoon is the open
public hearing
and there are three presenters. Before we call the
presenters to the podium, there is a
statement that
has to be read.
Both the Food and Drug
Administration and
the public believe in a transparent
process for
information gathering and decision
making. To
ensure such transparency at the open public hearing
session of the advisory committee
meeting, FDA
believes that it is important to
understand the
context of an individual's presentation.
For this reason, FDA encourages
you, the
open public hearing speaker, at the
beginning of
your written or oral statement to advise
the
committee of any financial relationship
that you
may have with the sponsor, its product
and, if
known, its direct competitors. For example, this
229
financial information may include the
sponsor's
payment of your travel, lodging or other
expenses
in connection with your attendance at the
meeting.
Likewise, FDA encourages you at the
beginning of
your statement to advise the committee if
you do
not have any such financial
relationships. If you
choose not to address this issue of
financial
relationships at the beginning of your
statement,
it will not preclude you from speaking.
The first speaker will be
Jeffrey Roberts.
MR. ROBERTS: Thank you.
I am Jeffrey
Roberts, and I am here today representing
patients
and sufferers. I have paid all my own expenses to
be here.
Members of the committee, thank
you for
the opportunity to appear before
you. I am the
president and founder of the Irritable
Bowel
Syndrome Self Help and Support Group and
founder of
the Zelnorm Action Group. The 10,000 member
Irritable Bowel Syndrome Self Help Group
has
endeavored, since 1987, to educate and
provide
support for people who have functional
230
gastrointestinal disorders, and to
encourage both
medical and pharmaceutical research to
make our
lives easier via a successful Internet
website for
sufferer.
I have been a sufferer of
diarrhea-predominant irritable bowel
syndrome for
over 25 years. Much like chronic constipated
individuals, there are challenges that I
face each
and every day in order to cope with my functional
gastrointestinal disorder. It affects my family's
lives, my career and I am constantly
reminded of my
own physical limitations because of this
very
burdensome illness.
Today I have the support of the
Zelnorm
Action Group, Irritable Bowel Syndrome
Self Help
Group and Irritable Bowel Syndrome
Association. I
am privileged to act as the
representative today
for all those members who were too ill to
travel
here today. I would also like to acknowledge all
of the efforts today.
Functional constipation is a
common
problem in our community, with its
prevalence
231
rating from 2 percent to 28 percent. Its diagnosis
is made by careful delineation of its
duration and
characteristics. Constipation classification into
subtypes results in overlapping symptoms
and
blurring between the subtypes. The distinction
between IBS with constipation and
functional
constipation is important as a focus in
treating
functional constipation is to improve
bowel habits
alone.
In an IBS patient abdominal pain and other
symptoms must also be addressed. Most chronically
constipated patients do not require
diagnostic
studies beyond a careful history and
physical
examination. For clarification purposes, my
presentation today refers to individuals
with only
functional constipation lasting longer than
6
months, and widely given the name of
chronic
constipation.
As I am a focus in the
community for
information about functional
gastrointestinal
intestinal disorders, I communicate with
a great
many people who have run out of
options. They do
not know where to turn and their quality
of life
232
has greatly suffered. Many current approaches to
chronic constipation, including the use
of fiber,
osmotic and stimulant laxatives,
biofeedback
training and surgery, often fail to
control the
patient's symptoms adequately. They produce
problematic side effects or lose
effectiveness with
time.
Most available and approved drugs for
constipation have been passed down from
antiquity
and have not been tested in modern
well-designed
studies.
Primary care physicians and the
sufferers
believe there are very few other options
available
to them because chronic constipation is
not usually
deemed of clinical importance until it
causes
physical risks or impairs quality of
life.
Physicians often prescribe drugs for
constipation
with which they are familiar and
comfortable and in
most cases anything will do.
Chronic constipation is a very
unpleasant
disorder and in some cases individuals
who suffer
from chronic constipation do not have a
bowel
movement for up to 21 days. Their quality of life
233
is greatly diminished by this basic
impaired
function that most individuals take for
granted.
They may pass hard stools; lack the
ability to
defecate on demand; or strain at every
bowel
movement.
I am here today to tell you that chronic
constipation is a condition which cries
out for
more attention. It demands the continued use of a
medication, Zelnorm, already proven in
treatment of
functional constipation and
IBS-predominant
constipation. This committee must provide clear
indication to the medical community that
Zelnorm
should additionally be made available for
the
indication of chronic constipation
without any
further burden to the physician or
patient in
prescribing this medication or getting
access to
this medication.
As with Lotronex, a drug with the opposite
effect of Zelnorm, i.e., for severe
functional
diarrhea individuals, this committee
listened to
myself and others from the Lotronex
Action Group in
April, 2002 make presentations as to how
difficult
it is to live with gastrointestinal
disorders.
234
Although many of us do now have access to
Lotronex,
we are challenged by physicians who lack
the
knowledge or are fearful of prescribing a
medication because of a negative message
about its
use.
Zelnorm has an admirable safety
record in
clinical trials in general use. Its virtue should
be celebrated and not limited in its
usefulness as
a medication to ease the suffering of a
chronic
constipation individual.
An electronic survey was
recently
conducted by the Zelnorm Action
Group. Individuals
were screened so that results were
recorded only
for those prescribed Zelnorm after
indicating their
symptoms of chronic constipation to their
primary
care physician.
While taking Zelnorm, chronic
constipation
sufferers report a quality of life that
is
dramatically better. Seventy-nine percent of those
surveyed indicated that they had no
significant
side effects at all.
The Zelnorm Action Group is
prepared to
235
place educational information about
Zelnorm on
their website in order to reach out to
the chronic
constipation community. This provides an effective
forum for educating chronic constipation
sufferers
about Zelnorm's proper use.
In conclusion, the quality of
life of
constipation sufferers was dramatically
improved
with access to Zelnorm. The medical community
should be informed that a treatment is
available
which will improve the patient's
outlook. Adverse
events should not deter either the
pharmaceutical
or the FDA from maintaining the drug's
availability.
Zelnorm has a place as an
effective
treatment for chronic constipation
sufferers and
should be indicated as such to the
patient and
medication community. Thank you.
DR. FOGEL: Thank you.
The second speaker
is Constance Hill.
MS. HILL: Good afternoon. I also am here
on my own behalf and I haven't been paid
by anyone.
Mr. Chairman and members of the
committee, my name
236
is Connie Hill and I have chronic IBS
with
constipation. I have had this terrible disease
since I was about 18. Over the years my symptoms
became increasingly worse and eventually
became so
severe and debilitating that I had to
make
significant life-altering changes to
survive.
In 1996, I had to quit my job
as a legal
assistant and stop working
altogether. My husband
and I even moved from the hustle and
bustle of
Fairfax County, Virginia to the country,
hoping
that a slower pace of living would ease
my
symptoms.
Even these drastic life-style changes
did not help. Over the years I have consulted with
many physicians and tried every remedy
and drug
that doctors recommended but none of the
treatments
worked.
The doctors seem to find IBS as baffling
as do the millions of Americans who
suffer daily
from this disease.
I was told by one well-known
gastroenterologist that I have a terrible
mental
problem and until I came to grips with it
I would
never get well. I was sent to a psychiatrist for
237
several months, at the end of which I was
no
better.
One department head at Fairfax
Hospital
told me I have a floating rib and
prescribed muscle
relaxers.
Others recommended biofeedback and
acupuncture, which I also tried and
failed. But
none of these treatments gave me any
relief from
the daily pain and discomfort that I had
to endure.
I became so desperate I even resorted to
exploratory surgery to determine whether
or not
adhesions from an earlier surgery were
causing the
problem.
Unfortunately, this was not the case.
The bottom line is the medical
professionals don't
really understand IBS and are very
frustrated by
their inability to effectively treat
it. I have
sensed over the years that most
physicians would
rather not deal with difficult cases of
IBS. This
was so discouraging to me, and I am sure
other IBS
victims encountered the same indifference
from the
medical community.
Zelnorm is the one and only
drug that has
given me any relief and restored any part
of a
238
normal life for me. My life before Zelnorm was a
living hell. I suffered daily with pain and
discomfort, reaching head-banging
proportions. I
never got a day off from the pain and the
misery.
One weekend shortly after I got the
definitive
diagnosis, I sent my family away for the
weekend
and planned to kill myself. I couldn't deal with
the fact that I was told I would have
this pain and
suffering for the rest of my life. I was working
at the time. I spent a lot of time either in the
ladies' room or crying at my desk. I couldn't
explain to all the people at work what I
was
dealing with, it is so embarrassing that
unless you
own this problem you can't possibly
understand what
it does to you and your loved ones. It is
degrading and demoralizing. It breaks your spirit
and kills your ability to smile and enjoy
anything
normal.
After getting through the
workday you just
want to go home, rip off your clothes and
crawl
into the fetal position. I lived like this from
1985 until I was forced to retire from
the job that
239
I loved, in 1996. In 1997, we moved out of the
city.
I became a couch potato. I would
rush to
get
dressed by 6:00 p.m. so that when my husband
came home from work he wouldn't know I
spent the
entire day unable to do anything. There are no
vacations, movies, dinners, cookouts and
other
normal day-to-day activities for someone
with IBS.
It is not life-threatening per se but it
leaves you
riddled with pain, kills your spirit and
makes you
a prisoner in your own home.
I have been a member of the
on-line
support group for many years. I have tried
everything that was suggested and
failed. When I
first heard about Zelnorm, in late 2001,
from the
support group it was only available in
Mexico. I
was planning to go there but then learned
that it
was also available by prescription from
Switzerland. I was able to make contact with a
pharmacy in Switzerland. I have a wonderful
internist who agreed to write me a
prescription and
I received my first box of Zelnorm a few
weeks
later.
After working to get the correct dose, I
240
started to be able to do a few
things. I didn't
spend all day on my couch. I actually had part of
the day when things were relatively
normal. It
wasn't the panacea I had dreamed of but
it was a
major step forward.
I have taken Zelnorm now for
two and a
half years. It is a dramatic improvement for me.
Although not a complete cure, it has
greatly
enhanced the quality of my life. Before Zelnorm
was developed I prayed daily for guidance
to help
me out of the hell hole I was in. I thank God for
the guidance to the support group which
helped me
find this life-altering drug.
I am not only speaking for
myself but for
the millions of people in the U.S. and
all around
the world who suffer daily with this
terrible
disease.
There is no other effective treatment for
IBS with constipation. If Zelnorm was ever taken
off the market, you will be condemning me
and many
other IBS sufferers to the same torturous
existence
that we had to endure without hope before
Zelnorm.
If you do that, I don't know how I will
be able to
241
go on.
I strongly object to the
recommendations
of some groups that a change in diet will
relieve
the suffering of constipation. Their suggestions
for alternative treatments are so naive.
Obviously, they have not had to live with
this
disease and do not understand that these
simple
steps do not bring relief to people who
suffer from
severe IBS with constipation. I have tried their
suggestions and they don't work. Zelnorm is the
only treatment that makes a difference
and I
beseech you to enhance its
certification. Thank
you.
DR. FOGEL:
Thank you. The third speaker
is Linda Roepke.
MS. ROEPKE: Good afternoon, everyone.
Mr. Chairman, thank you for allowing me
to have
time today to come up and say a few words
about how
Zelnorm has affected my life.
Allow me first of all to
introduce myself.
My name is Linda Roepke and I am from St.
Louis. I
am very blessed in that I work at St.
Louis
242
University and I work with a fine staff
of
different physicians. I work with the Chairman of
Internal Medicine.
Today I am not only blessed but
very lucky
to have a very good GI doctor who has
helped me
through many years of a chronic problem with
constipation. Prior to finding my specialist in
the GI division today, my primary care
physician
for the last 20 years of my life really
did not
know anymore how to treat my constant
stomach
aches, as I will refer to them because I
don't know
how else to describe to you--I am sure
most of you
have been constipated at one time or
another and
you know that heavy feeling that you
have. That
was a very chronic thing for me. Being bloated is
supposed to be a "woman" thing
so, you know, I will
give the medical profession part of
that. However,
that bloatedness can take the average
waistline,
whether you are male or female, from a 26
to a 30,
or from a 32 to a 38 in no time.
My general health is very good,
with the
exception of irritable bowel which has
caused more
243
chronic constipation than it has
diarrhea. It is a
most serious condition to live with. I tell you
these things for two reasons. Number one, during
the years that I have suffered with
constipation,
as anyone else who has had the same
problem will
tell you, life is not real normal. It is very
miserable. You have many low points. You are not
able to contend with a lot of daily
normal life's
instances. I also tell you this to testify to my
own credibility.
As a child I not only knew, I
had a lot of
stomach aches, too much pain in my
abdomen. My
parents certainly knew it. I was a main topic of
their conversation for years. By the time I was 12
my mother was telling me that, you know,
once you
start menstruating you are going to feel
better.
This feeling in your abdomen will get
less and
less.
During high school years I obviously had a
written excuse for the majority of our PE
classes
because I didn't have the energy to
really do them.
My family doctor at the time, our family
physician,
eventually, in my senior year in high
school, too
244
me for an exploratory surgery, again, not
knowing
really what to do. I hopes of finding something
wrong for the sake of not having to have
this
embarrassing problem, I was hoping for
just about
anything.
Unfortunately, nothing was found.
My
bowels just move slow, quote/unquote, is
what is
written in my charts going back to 1964.
I had a spastic colon which
would force me
to go through surges of either diarrhea
or then
maybe five, six, seven days with not
being able to
go to the bathroom. During those years my mother
and our family doctor would give me
little Elephon
[?] pills from Walgreen's. I don't know, I think
most of you are of an age that you
probably
remember this. That was their laxative of choice,
both of them. My bowels would straighten out for a
while and then they would get wacky
again. The
sluggishness and diarrhea made even
dating
difficult. I continued with over-the-counter
laxatives for the next 30 years, fighting
abdominal
pain, cramping, embarrassing situations,
playing
with laxatives, and I have tried them
all. Many of
245
them have been prescribed, with it be
from
Metamusal, Duclolax, suppositories, it
doesn't
matter--been there; done that.
This is not an easy thing to
try to work
with your doctor and being certain that
you are
keeping your body physically as fit as
you can.
Many times I walked around, looking at
though I
could be four months pregnant--always
not.
Everywhere I worked, most people have
learned--I am
always a topic of conversation, I guess I
should
say.
I have been the topic of more than one
laughing piece of conversation about
"don't follow
her into the bathroom because you might
hear just
an explosion." These are embarrassing things for
any of us out there. This is a delicate topic in
the first place. It certainly isn't one I choose
to share with my co-workers.
In 1994, I drove myself to an
emergency
room.
The final diagnosis was that I needed a
series of tests again run. I wonder how many blood
samples I have had taken to find out that
I am
chronically constipated. The doctor did a complete
246
upper and lower GI series with the barium, hoping
to find something. Again, nothing was found.
Again, I was referred to a
nutritionist. Again, I
was told that I eat a far better diet
than the
majority of the people out here and my
exercise
content was pretty good.
My doctor at that time
prescribed Senokot,
laxatives and more fiber--35-40 grams of
fiber is a
lot of fiber. So, 40 years later I found myself in
the same situation. When I finally walked into--I
didn't walk into our GI division, I
barged into my
doctor's academic office, embarrassed and
knowing
that working for the chairman of internal
medicine
I resent people who try to get past me,
the guard,
and, yet, I just pulled the same thing
with her. I
had tears in my eyes. She looked up from her
computer, because this is not in a clinic
setting,
and said, "what's up?" The tears rolled down my
face, "can you help me?" to
make a long story
short.
She continued to say, yes, there is help
and I do not need to keep suffering like
this.
This is ridiculous and she will get me
into her
247
clinic and she will get several tests set
up for
me.
So, for the next many months we went through a
battery of different things because,
again, it is
important that we stress that
constipation is just
constipation. I don't have cancer; I don't have a
grapefruit in my stomach; I don't have a
large
cyst.
So, I got very lucky. I went through an
anorectal manometry, colon transit and a
colonoscopy. Considering the many medications I
was trying to take, it is with great
thankfulness
that I finally was able to find Dr.
Prather. At
the age of 50 I finished college and I
completely
started a new career. Today I am planning a
wedding which has been many years in the
making, to
someone who is healthy as what I am. My stomach
feels and looks more normal, not swelled
up like a
puffer fish. I no longer need to stay constantly
constipated. I can begin to enjoy life more today.
I am looking forward to a huge mission
trip through
my church that I have wanted to go on for
the past
five years and have been too embarrassed
to do
248
this.
I could have gone last year; I look forward
to it this year. Zelnorm has helped to make this
possible.
Am I willing to risk any side
effects from
this drug today? Absolutely.
I would like for any
of you in this room to tell me of a drug
out there
that we do not have some side effects
from. I see
many advertisements for many medications
with much
worse side effects than Zelnorm and they
are still
on the market, indeed.
I also need to interject that I am
definitely one of the few lucky
ones. I just went
through with you how fortunate I am to
have my
career path in an area where I could
barge into a
GI doctor's office, a specialist at
that. What
about these people who cannot and do not
have that
access, people that are in rural
communities, which
is probably why in 1994 my doctor didn't
know what
to do with me then? Of course, Zelnorm wasn't out
at
that time.
In conclusion, I just need to
let you know
that I have lived with chronic
constipation for the
249
majority of my life and Zelnorm has been
the only
thing which has provided consistent
relief, and it
has made an entirely new person out of me
today,
with lost less embarrassment and a lot
more regular
lifestyle. Thank you so much.
Clarification of Issues
DR. FOGEL: Thank you.
At this juncture
we are going to turn the meeting back to
Novartis
for some clarification of issues that
were raised
in the morning's discussion.
DR. JOELSSON: Thank you, Dr. Fogel. I
would like to clarify a few things that
were raised
during the presentations this
morning. First I
would like to talk a little bit about Dr.
Della'Zanna. He said that we had some discussions
about the label text and that in the end
we agreed
upon a precaution but that he felt maybe
it should
have been a warning.
Can I have the first
slide? I would like
to clarify why we think it should be a precaution
and not a warning. It is really based on the
regulatory definition of a warning. The labeling
250
shall be revised to include a warning as
soon as
there is reasonable evidence of an
association of a
serious hazard with a drug. A causal relationship
need not be proved.
I think I made it pretty clear
during the
presentation earlier that we don't think
there is a
reasonable association of reasonable
evidence of an
association of a serious hazard. So, we thought
that a precaution would be adequate at
this time
point.
If things changed, we would have a
discussion again.
So, this is what the precaution
looks like
in our label today: Ischemic colitis and other
forms of intestinal ischemia have been
reported in
patients receiving Zelnorm during
marketed use of
the drug.
A causal relationship has not been
established.
So, this is part of the
prescribing
information. It is part of the "dear doctor"
letter that was sent out. As you know, "dear
doctor" letters are usually sent out
when there are
warnings but we suggested that we would
include
251
this into our "dear doctor"
warning letter too
because we think this is important
information to
have out there.
Can I have the next slide,
please? In
relation to whether something has
happened or not
since the label change, is there any
reason for us
to discuss a label change, this is what
the monthly
reporting rate of ischemic colitis looks
like in
the United States right now. As you can see, after
a slow uptake when the drug was marketed
in August,
2002, there have been no dramatic changes
in the
reporting rate of ischemic colitis during
the last,
let's say, year. So, in my mind, nothing dramatic
has happened since we had our label
negotiations
and currently we do see an increased
reporting rate
as a part of the "dear doctor"
letter, and we know
that is a well-documented effect of a
"dear doctor"
letter.
However, the increase of reporting has not
been dramatic.
Another point I would like to
make is in
relation to young patients getting
ischemic
colitis.
In addition to the fact that there is a
252
background rate either in the general
population or
in IBS patients, misdiagnosed or not, it
is also
the case that some young people are
diagnosed with
ischemic colitis. It is less common but it is
still well known in patients who don't
take
medication. For instance, in the United Health
Care study 3 percent of the patients were
between
age 20-29 and 9 percent were between
30-39.
I can also say that in the CORI
database,
the database where endoscopies are
collected from
all over the United States, there are
patients
reported there who are also between 20-29
years of
age.
So, this is known. So, it is not
surprising
that we do get cases, young cases, also
with
ischemic colitis.
Next slide, please. You saw this slide
before, saying that we don't have any
cases of
ischemic colitis in our clinical trials
in more
than 11,600, but we have one patient on
placebo
that has ischemic colitis. I would like to show
you some details of that case.
May I have the next slide,
please? I am
253
showing this case just because Dr.
Della'Zanna was
talking about a young patient that was
recently
reported.
By the way, it is not a new report; it
is an updating report so that is already
included
in the numbers--just to make sure we
understand
that.
But it is obviously a case that raises your
eyebrow because there are no factors
explaining
this ischemic colitis in a young patient.
This is our patient on
placebo. She was
24 years old and she was part of our
chronic
constipation efficacy study. She was basically
healthy.
She had no other reasons to have an
ischemic colitis. She was reported as a segmental
erosive colitis on colonoscopy.
We have discussed
it together with Dr. Della'Zanna and we
agreed that
that is a probable case of ischemic
colitis. So,
even on placebo you can get reports on
young
patients without any evident reasons for
why they
should have ischemic colitis. So, it is not
surprising that we also get such cases on
tegaserod
reported.
Can I have the next slide,
please? Just
254
in relation to Dr. LaMont's question, I
just want
to show this slide again. After adjudication we
had an imbalance, 0.03 percent versus
0.06 in the
cholecystectomy indications
population. As you
heard from Dr. Della'Zanna, we currently have
a
prospective study to study abdominal
operations,
including cholecystectomies. There will be 10,000
patients in each arm and that will tell
us what the
truth is.
Finally, However, what I want
to tell you
is that currently there is a
contraindication in
our label for Zelnorm in patients with
gall stone.
So, it iq already there. Thank you for that. Are
there questions about this?
DR. LEVIN: Could you comment on whether
it wouldn't be prudent to include the
postmarketing
data in the precautions statement? I mean, you are
only presenting the clinical trial data
which says
there are no cases, but we have
postmarketing
experience that tells there are
cases. Without
getting into the precautions versus the
warning
issue, it seems to me only reasonable to
include in
255
the precautions statement what we know
about the
drug to date in ischemic colitis and that
would
include the postmarketing reports through
some
cut-off date.
DR. JOELSSON: I think we could consider
having a discussion with the FDA about that.
DR. LEVIN: Again, not getting into a
debate of warning versus precautions, but
if you
are going to have a precautions statement
that then
says here is the experience and we have
no cases,
when we know there are cases--that is not
a good
precautionary statement.
DR. FOGEL: Is there a comment from the
FDA?
DR. LEVIN: You said there are none out of
7,000.
DR. JOELSSON: We are talking about giving
numbers.
I understand what you are talking about.
Thank you. I think that is clear.
DR. FOGEL: Is there an FDA comment?
DR. BEITZ: Just that we think the first
sentence does include postmarketing.
256
DR. JOELSSON: Yes, I think he is saying
we should have numbers in there. We will talk
about that.
DR. BEITZ: Right, the difficulty
with
putting in numbers is that they are out
of date as
soon as we print the label.
DR. BUCHMAN: It is unfairly weighted the
way that it is written because there are
many more
words associated with the fact that there
aren't
any.
When you read these quickly, it looks like it
is a stronger emphasis that there aren't
any cases.
So, I would agree. I think it just needs to be
reworded so that it is equal. If you have a
multiple choice question, all the answers
need to
be the same length. If you have one that is
longer, it has actually been shown that
that is the
one that is picked most frequently.
DR. FOGEL:
Dr. Cryer?
DR. CRYER: Thank you for that very nice
explanation. I would like to make a couple of
comments just from my perspective after
hearing
your rebuttal to Dr. Della'Zanna's
presentation.
257
That is that, you know, with respect to
the comment
that there have been no cases of ischemic
colitis
identified in the placebo-controlled
trials,
whether it be the 7,000 or the 11,600
patients, I
would at least argue from my perspective
that the
risk in a younger female population may
differ from
a potentially older population with
respect to
their underlying co-morbidities.
With regard to his comment about the
mechanistic plausibility of this
relationship,
although there has not been a definitive
cause-effect relationship shown, you had
a slide
earlier in your presentation, which I
think was
your slide CS-26, which talked about its
effect on
isolated coronary-arteries of non-human
primates,
suggesting the possibility of a
mechanistic
plausibility. My comments about this is that, one,
this would be non-human primates and so
it doesn't
really suggest to us what we might expect
to see in
a human trial, although I understand you
couldn't
do exactly this type of trial in human
observation.
The second comment that I have
would be
258
that my understanding of tegaserod's
effects at
plasma concentrations when clinically
dosed is that
in that slide I think the concentrations
fall
towards the right-hand side of the slide,
at which
point it looked like the two curves
apparently
seemed to separate from placebo.
So, all this is just to say
that I do
think that there is at least some
mechanistic
plausibility and, secondly, that the lack
of
observations in the clinical trial
experience is
probably a different patient population
than we are
discussing.
DR. JOELSSON: Those are very good
comments.
Actually, we do have data in humans
also.
Can I show those data? Can I get
this on
the screen?
Maybe Dr. Pfannkuche, who knows
so much
more than I do about this, could come
up. He is
our head of preclinical research and he
has been
responsible for these studies. I only showed one
of them; he has done many.
DR. PFANNKUCHE: Hans Pfannkuche, I am
259
working in the preclinical pharmacology
department.
Actually, it is a very reasonable
question. Dr.
Della'Zanna pointed out that triptans
have been
associated with cases of ischemia
coronary
problems.
I think Dr. Joelsson indicated in his
slide that we did study in these monkey
preparations coronary vessels, and there
is no
agonist activity associated with this
drug. In
fact, it is a silent antagonist at this
receptor
subtype, defined as 1B receptor.
As agreed upon with the FDA, we started
looking into human preparations, and in
this case
human mesenteric arteries. It is interesting to
know that we find exactly the same
pattern as we
observed in the coronary vessels. So, with the
human mesenteric arteries, as you can see
here, the
first curve, which goes very up, is
response to
serotonin, our reference compound, and
the second
curve in between the X axis and the
highest curve
is the sumatriptan response that you
would
anticipate. It is still a low number of samples
here but you have some very high and some
moderate
260
responders here. You may ask, okay, what about its
affinity?
Actually, the affinity, again,
translates into a silent antagonist
property.
Maybe on the next slide I can
give you an
example, slide PI-41. On this slide you can see a
parallel shift that you would expect from
a
competitive antagonist at this receptor
site. So,
you can see that the affinity translates
into
inhibition of sumatriptan-induced
contractions in
this human mesenteric artery
preparation. In
addition, I could show you another slide
where we
did the same for monkey mesenteric artery
preparations.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: Yes, I just want to make a
comment and then I have a question. I guess I have
an alternative opinion than some of the
members of
the committee. I think the data that come from
11,000 patients in the clinical trial are
much more
robust and allow much greater degree of
quantitation than the postmarketing
database,
especially at this juncture of time and
perhaps it
261
won't be a question at the end of the day
whether
or not there is an increased incidence in
IBS
patients.
I mean, for the clinical trials the
presumption is if there is a case, you
capture it,
especially if there is a case of ischemic
colitis.
The missed cases were probably covered by
the near
equal frequency of rectal bleeding
between the
placebo and the active group. So, that is just an
alternative opinion.
I did have a question though,
Dr.
Joelsson, on your frequency over time of
ischemic
colitis slide that you just showed. The question
is from the FDA presentation and briefing
document
the impression I had is that there were
24 cases
prior to April 15 reported and 7 or 9
cases
afterwards. I guess on that slide where the X axis
did go to June, 04 I didn't see a bump
reflecting
that.
DR. JOELSSON: There is actually a small
bump but it gets very small because of
the big
denominator. But I can tell you that it is
interesting what the effect of a "dear
doctor"
262
letter has. Before the "dear doctor" letter we
had
between 0-4 cases maximum reported per
month.
During the month after the "dear
doctor" letter we
had 7 cases reported.
DR. MANGEL: I appreciate the fact that
increased news coverage will increase
reporting. I
just didn't appreciate on the graph--you
know, to
me it looked like the rate should have
gone up by
about 25-30 percent and I guess I wasn't
seeing it
on that, unless the denominator over
those 2.5
months markedly increased as well.
DR. JOELSSON: Yes, it does.
The
denominator increases and the number of
cases
accumulate. That follows each other very nicely.
We don't see a quicker uptake of cases
versus the
use of the drug. It is very parallel, as would be
expected.
DR. MANGEL: And that was even after the
"dear doctor" letter.
DR. JOELSSON: There is a small bump. As
I told you, it is a small bump but on
that curve it
doesn't look very big.
263
DR. FOGEL: Dr. Beitz?
DR. BEITZ: I just had a question
regarding the preclinical data that were
shown on
the human mesenteric vessels. Are those from
patients or normals? What is the source of that
human material?
DR. PFANNKUCHE: This is patients who had
to undergo surgery for colon cancer, with
no
history of IBS for example. The report has been
finished right now and will be submitted
to the
agency shortly.
DR. BEITZ: It may just be useful to see
similar types of studies done in vessels
from IBS
patients, if they are available.
DR. JOELSSON: They are hard to get
though.
DR. BEITZ: I agree, but if you wanted to
look at the vasoreactivity of the IBS
vasculature
you would have to look at IBS patients.
DR. FOGEL: Dr. Sachar?
DR. SACHAR: I do have a request for a
clarification but first I wanted to
reinforce Dr.
264
Cryer's comments and maybe take a little
issue with
Dr. Mangel. All of the sponsor's safety
presentations today have estimated the
incidence of
serious diarrhea and of ischemic colitis
on the
basis of all patients who have taken
Zelnorm, but
they have not presented their estimates
on the
basis of the populations at maximum risk,
namely
the oldest population. The precaution statement
refers to 7,000 patients. The presentations today
have referred to 11,000 trial patients
and 3
million marketed patients [sic], but I am
not yet
convinced that these figures accurately
reflect the
potential incidence in the elderly
population and I
think that some of those estimates ought
to be
recalculated on the basis of a different
denominator. That is just a point I might make.
The request for the clarification has
to
do with the data on the extended
trial. We weren't
given any efficacy data at 13
months. It would be
nice to have them. Maybe they will come later.
But we were told that 46 percent of
patients
discontinued the drug and evidently not
because
265
they were all better. Did that 46 percent include
the placebo patients? If not, what percent of
patients on the active agent discontinued
for
whatever reason within that year?
DR. DENNIS: The extension study was a
double-blind study, but there was no
placebo arm so
it was uncontrolled. Patients who had received 2
mg and 6 mg BID in the study continued on
those
doses in the extension study, and those
patients
who had been on placebo went onto 6 mg
BID in the
extension study.
DR. SACHAR: Well, it says 842 patients
entered the extension trial--
DR. DENNIS: Correct.
DR. SACHAR: --but only 518 were exposed
to Zelnorm. So, what were the other 324 taking?
DR. DENNIS: That number I gave you were
exposed to Zelnorm for greater than 12
months.
DR. SACHAR: Oh, I see, the sentence
continues.
DR. DENNIS: In that extension there were
no patients on placebo.
266
DR. SACHAR: So, 46 percent of patients on
Zelnorm stopped taking it within a year.
DR. DENNIS: We had discontinuations of 46
percent throughout that treatment period.
DR. SACHAR:
And they were getting it
free?
DR. DENNIS: They were in the study.
DR. SACHAR: And they still stopped taking
it.
DR. DENNIS: Well, I think the point is
that in long-term studies of this nature,
it is not
uncommon to see these discontinuation
rates. One
of the questions that you asked earlier
on was for
the efficacy. Remember, this was a study we
designed to do safety assessments.
DR. SACHAR: Oh, sure, and I see all the
reasons--unsatisfactory response,
withdrew consent,
administrative, adverse effects. I don't see
anybody who stopped taking it because
they were
better.
DR. DENNIS: Patients who were better
continued taking the drug.
267
DR. SACHAR: Exactly, and 46 percent
stopped.
DR. DENNIS: Forty-six percent stopped.
DR. FOGEL: Before we begin our
discussion--
DR. JOELSSON: Dr. Fogel, I have a few
more points to clarify. Is that okay?
DR. FOGEL: That will be fine.
DR. JOELSSON: Thank you.
Dr. Schoenfeld?
DR. SCHOENFELD: Thanks.
Could I have
slide CB-12? This is certainly an interesting
process.
It is an enjoyable one to go through.
I first wanted to try to
clarify the point
about appropriateness of endpoints for functional
lower GI disorder studies, specifically
about what
the Rome committee says about those. I want to be
very clear about exactly what the Rome
consensus
document states, first author Dr.
Whitehead. It
specifically stated that experts in this
field
recognize that people with lower
functional GI
disorders have multiple symptoms. The specific
quote from the paper says that no
consensus could
268
be reached on any single primary efficacy
endpoint.
It goes on to state specifically that
they feel the
best approach is to specify a primary
endpoint with
a few select a prior defined secondary
endpoints to
try to encompass the multiple symptoms in
these
functional lower GI disorders.
Having said that, in the
section of the
Rome committee document on the
appropriate design
of a functional GI disorder, Sander Van
Zanten and
colleagues said, just as Dr. Fogel
alluded to, that
probably the best endpoint is global
satisfaction
with your functional GI symptoms.
DR. PRIZONT: I think I was one of the
authors.
DR. SCHOENFELD: Actually, you were, Dr.
Prizont.
DR. PRIZONT: I don't recall talking about
common constipation as such. We were talking about
constipation-predominant irritable bowel
syndrome
in that particular quoting. But, in any case, you
are right. Those who applied the Rome criteria had
the choice of selecting the
endpoints. Like you
269
said, you know, you can choose one
endpoint,
another endpoint and so on, and you chose
them.
You chose the 3 bowel movements with
completeness.
In your clinical trials in order to make
the
diagnosis of constipation, you said in
the protocol
patients will be considered constipated
if they
have less than 3 bowel movements per
week; if those
are incomplete; and if they have more
straining
than what is established in the Rome
criteria. So,
you
picked them.
DR. SCHOENFELD: I think that responds to
a different point but I will go
ahead. Can you go
to slide CB-10? I just want to make sure we are
very clear about what the Rome committee
criteria
are
for functional constipation. A patient
need
not have fewer than 3 bowel movements per
week in
order to meet the Rome committee criteria
for
functional constipation. If a patient, for 12
weeks which need not be consecutive in
the past
year, has some combination of straining,
lumpy or
hard stools, a sensation of incomplete
evacuation,
sensation of obstruction or blockage--if
they have
270
any 2 of those 4, even if they are having
4 bowel
movements per week, that meets the Rome
committee
criteria for functional
constipation. I want to
make sure we are clear on that
point. Go ahead,
Dr. Sachar, please.
DR. SACHAR: Well, that is the Rome
criteria.
I just want to be sure that you don't
set up the Novartis criteria for your
protocol and
then dredge your outcome by the Rome
criteria.
DR. SCHOENFELD: Absolutely.
I was just
going to that point. So, having said that, the
criteria for Novartis studies, although
they are
not exactly as the Rome committee
criteria, are
certainly pretty darned close, and I
would note
also, going back to risk/benefit analysis
of all
laxatives, they come closer to meeting
the Rome
committee criteria for identifying
patients with
functional constipation than essentially
any other
randomized, controlled trial that has ever
been
done for a laxative.
DR. PRIZONT: I concur with that. I said
that in order to define constipation,
Novartis used
271
the wrong two criteria. You just mentioned that
you are applying the wrong two criteria
to define
constipation. The question was not whether you
defined constipation based on the Rome
criteria.
The question was how you define
efficacy--
DR. SCHOENFELD: Absolutely, and I would
like to go to that point.
DR. FOGEL: Actually, can I ask a question
before you go to efficacy? What about validation
of outcomes? We have a lot of data about the Rome
criteria global subjective assessment, what
about
the Novartis outcome?
DR. SCHOENFELD: Well, what I would
suggest is this, if we can go to slide
CB-13, which
goes back to your point which was to say
are there
any
data about global satisfaction with bowel
habits?
As we see here in both studies, we see
that patients who are tegaserod 6 mg BID
demonstrated a statistically significant,
and, what
is to me, a clinically important improvement
in
global satisfaction with bowel
habits. Now, what
is that based on? Obviously, the absolute
272
difference is that between 9 and 12
percent more
patients compared to placebo said they
had global
satisfaction with bowel habits.
I do want to be very careful as
we talk
about placebo-controlled trials. Sometimes we talk
about using number needed to treat, which
I am a
huge proponent of, but it is probably
best to use
when you are comparing two alternative
therapies.
If I say the number needed to treat here
because of
an approximately 10 percent difference is
a number
needed to treat of 10, that infers that
instead of
prescribing a drug like tegaserod I am
going to
prescribe a placebo. That is actually not an
alternative for me. Nevertheless, it gives us an
idea about the incremental benefit over
placebo.
Second, going back to validation of this
global satisfaction endpoint, responders
were
defined as patients who have had an
increase of 1
on a 5-point Likert Scale for their
global
satisfaction. Now, what does that mean clinically?
In other studies of functional disorders,
including
functional respiratory disorders, it has
273
consistently been validated that an
increase of 1
point on a 5-point Likert Scale is a
clinically
important benefit. But to be balanced, has that
been validated? Not specifically for functional
constipation, not to my knowledge. If you chose
instead, though, to say what is the
proportion of
patients who get complete or
near-complete
satisfaction with the bowel habits, a
score of 0-1
on that 5-point scale, the proportion of
patients,
although it is small in both the
tegaserod group
and the placebo group, is still
significantly
higher in the tegaserod group than it is
in the
placebo group, although I would say this
was a
population of patients with fairly severe
constipation and that is a fairly
difficult
threshold to get, that they had complete
or
near-complete satisfaction with their
bowel habits.
DR. FURBERG: Could you explain the
footnote?
I mean, you are really comparing
baseline to any time between week 1 and
12, or are
you doing it at the end of the study?
DR. SCHOENFELD: I think that question may
274
be better answered by Dr. Dennis.
DR. FURBERG: This question relates to
some other papers you have shown as
well. I mean,
what is important to us is what is the
global
satisfaction at the end of the treatment
period.
You should not carryover and if you have
some
benefit early on take credit for that if
the
patient stopped taking the drug.
DR. DENNIS: Sure.
What we did when we
did these calculations was an average but
we did
look at weekly satisfaction scores, and
when we
look at those weekly satisfaction scores
we can see
significance at all weeks as well.
DR. FURBERG: I would like you to show a
graph where you have the baseline and the
end after
12 weeks.
We need to know what is the effect on
global satisfaction after 12 weeks of
therapy and
no carryover.
DR. DENNIS: Right.
AQ-50, please. This
is really showing you the weekly response
for
satisfaction scores by study. You can see
significant difference throughout the
trials. You
275
look at the beginning and you look at the
end and
we are still seeing a significant
difference on
these weekly analyses.
DR. FURBERG: It is hard to see the scale
there.
DR. DENNIS: Remember, this was a 5-point
scale and the responder improvement is
shown by a
decrease in the score.
DR. FURBERG: So, the improvement is less
than half a point.
DR. DENNIS: We have done some statistical
analyses to look at validation of these
as well,
and I would like to ask Dr. Gary Cook to
come up
and discuss the statistical significance
of these
results as well.
DR. COOK: Yes, I am Gary Cook from the
Biostatistics Department, University of
North
Carolina.
One of the things I wanted to see is
CE-37.
While that is being put up, the primary
endpoint and many of the other endpoints
are
averages over periods so there are
averages over 4
weeks for the first 4 weeks or they are
an average
276
over 12 weeks for all 12 weeks. An analysis of the
primary endpoint was done as a continuous
measure.
As you recall, the responder variable is
a success
if the patient has a change of CSBM of
greater than
or equal to 1. But that variable was also analyzed
continuously as a continuous
variable. The
background standard deviation is 2. So, an
improvement of 1 is half a standard
deviation.
Many times half a standard deviation is
thought of
as
a meaningful effect size.
In this particular display is
an analysis
that is addressing the extent to which
the study
validates the primary endpoint. As was previously
stated, there were not previous studies
that
address validation but these studies do
address
validation. Now, what are the criteria for
validation? One criterion is, is the endpoint
sensitive to detecting treatment effects,
particularly when other criteria detect treatment
effects?
In these studies other criteria did
detect treatment effects and the primary
endpoint
did as well.
277
Also, over here you are basically
seeing
the extent to which there are differences
in means
of some of these other criteria for
responders and
non-responders. The magnitudes of those
differences in means vary from roughly a
half to 70
percent of the standard deviation. So, the
differences in means for the responders
and
non-responders, again by being roughly
50-70
percent of the standard deviation, are
reflecting
meaningful effect size differences and
also
reflecting the fact that the primary
endpoint
responder versus non-responder is,
indeed,
significantly correlated with other
criteria.
Now, I say correlated because
whenever you
have a dichotomous variable and you are
forming the
ordinary Poisson correlation coefficient
between a
dichotomous variable and a continuous
variable,
that correlation coefficient, if you do
the
algebra, is proportional to the
difference in means
for the dichotomous variable. So, the differences
in means that you are seeing here are,
indeed,
proportional to what the correlations
would be.
278
The correlations are scaled by ratios of
standard
deviations. These differences that you are seeing,
as I said, are about 50-70 percent the
background
standard deviation and, as I said, the
criterion of
a change of 1 for the CSBM parameter
relative to a
background standard deviation of 2 was,
indeed,
about 50 percent of the background
standard
deviation.
DR. FOGEL: If we can go back to your
previous slide, I think there are some
other
questions. Dr. Metz?
DR. METZ: Thank you.
I think a lot has
been made today about what the endpoints
are and
how you can vary what endpoints you are
discussing
and which one is actually going to be
better or not
better.
I will accept that the bottom line, as Dr.
Fogel said, is if you are feeling better,
you are
feeling better and if you stop the drug
you are
feeling worse.
Let's go back to that global
figure that
was shown a little earlier. Do you have those sort
of data divided by age? Can you show me the global
279
response in the elderly population?
DR. DENNIS: We don't have the analysis by
age.
I just want to reiterate that when we do
subgroup analyses the purpose of subgroup
analyses
is not to prove efficacy. The purpose of subgroup
analyses is to see that the effect that
you are
seeing within a subgroup is consistent
with the
overall effect and that there are no
negative
trends.
DR. METZ: That is exactly why it is so
relevant.
The whole point for me here is that we
know that the dangerous potential group
are going
to be the elderly people who don't
necessarily have
functional constipation, who have outlet
obstruction, who have hypothyroidism that
hasn't
been realized--those are the people who
are going
to have a lower response rate but they
are the
people at most risk for potentially
getting into
trouble.
That is why I want to see that data.
DR. DENNIS: Right.
Can I get AQ-17? I
first of all just want to reiterate that
we did not
study this drug for treatment of patients
who had
280
secondary constipation. So, that is not the
patient population that we are indicated
for.
Let me address the data that we
do have by
age and gender because I told Dr. Fogel
that we
would get back to you with these data so
you can
have a look at that. Just to remind you of what I
showed you earlier this morning, this was
our
primary endpoint. We looked at it by age and
gender.
Females are in the top row, males in the
bottom row. If you look at the younger patient
population, which is on the left-hand
side and the
older population is on the right-hand
side, males
and females under the age of 65 were
seeing a
treatment effect. If we look at the older
population, 65 years and older, what we
see in
these 65 year-old patient population is
that there
is a treatment effect but in each of
those
different treatment groups. When we look at the
males younger than 65, of course, we are
not seeing
any benefit in that group of patients,
which is the
smallest group of patients where we had
98
patients.
281
Can I have the next slide? This is what
happens when you take away the IBS-like
patients.
You can see what happens in that quadrant
that
looks at the male population.
If we go to the next slide,
this is
looking at the cut of the data using the
FDA
responder definition of patients having
greater
than 3 CSBMs per week. This was the fixed
definition with no relation to the
baseline.
Let's focus on that younger
patient
population that are less than 65. Females on the
top and males on the bottom. I don't think there
is any doubt that we are seeing a
significant
effect in that male population even given
these are
smaller numbers of patients that we are
seeing
here.
So, I think when we are looking at that age
group, males and females, the efficacy is
consistent.
Let's look at the older population. The
female population, the results that we
are seeing
for this particular responder definition
are
similar to what I have shown you for the
primary
282
efficacy variable as well.
DR. PRIZONT: Let's talk about
extrapolation of results from females to
males.
The difference between placebo and the 6
mg is
about 10 percent in females. What is it in males?
I think it is about 21 percent.
DR. DENNIS: Right.
DR. PRIZONT: Which, in some ways--this is
my view--it may be showing that the
response are
different and the differences may be
real. You
know, somebody pointed out that males may
have a
different response to placebo. There was a higher
placebo response. That response may be real. I
see some sort of a danger of
extrapolating the
results that you have in females to the
males
because, you know, the results, although
they seem
to be the same, are different in some
ways.
DR. DENNIS: But if we are going to look
at comparing data and say we are going to
accept
that the negative data is real and we are not
going
to accept that the positive data is
real--we are
looking at these subgroup analyses to
determine
283
whether there are trends. I think that is the
issue.
Are we seeing negative trends? I
think on
this slide that I am showing you we are
seeing that
in that older male population, yes, there
is a
difference between that group and the
other groups
that we are seeing here.
DR. CRYER: But, Dr. Dennis, I also recall
from Dr. Fogel's earlier request that
morning that
we are interested in knowing the 12-week
durable
response and these, as I see it, are 4-week
data.
DR. DENNIS: Yes, they are coming. I just
wanted to show you these because we
hadn't shown
them to you earlier on.
Can I have the next slide,
please? This
is what happens to that FDA responder
definition
when you take out the IBS-like
patients. Again, we
see a similar effect to what happened
with the
primary endpoint.
Slide AQ-160. This is what happens over
weeks 1-12. This is in the overall patient
population.
If I can have 161, it shows you
what
284
happens when we take out that IBS-like
group.
DR. FURBERG: But you are not showing the
results at 12 weeks. You are taking the average
between 1 and 12.
DR. DENNIS: Correct.
DR. FURBERG: That is not the way to
present the information.
DR. DENNIS: Dr. Cook is going to come and
respond to that.
DR. LEVIN: Wasn't the previous slide 3
SCBM and this is 1? It is a different metric.
DR. COOK: I think your point is very well
taken in terms of your concerns about
average
versus time point by time point. Now, previous
displays have given you results time
point by time
point.
There were any number of displays in the
main presentation that went week by
week. Fixating
on week 12 isn't necessarily that useful
in the
sense that the patient probably cares
about how
they are doing every week, and one
particular week,
like week 12, may or may not be that
important
compared to the other weeks.
285
Now, if one only has one number
to somehow
describe what happens for every week, the
average
does that. When one wants to know more about what
is going on week by week, then one looks
at the
week by week figures, which are the types
of
displays that have been presented
previously.
DR. D'AGOSTINO: I think the concern is
are the 12-week data as you are
presenting the week
1-12 so overwhelmed by the early
experience, and we
want to get that end experience.
DR. FURBERG: Gary, the other thing is if
we are talking about treatment for an
extended
period--this is a chronic condition, and
you are
mixing in the results after a week or
two. I find
that misleading. You can present it your way, that
is fine, but in addition I think you
should be
honest and present the data at the end of
the
treatment period. That is the standard in any
treatment comparison.
DR. COOK: Well, again, the sponsor is
going for a treatment period of 12 weeks,
as I
understand, and if a patient's condition
is
286
relieved after 12 weeks they would not
receive
continued treatment until again they
requalified
for treatment. So, I do not believe they are
asking for an indication where they would
be
treated continuously, although it is
possible that
they would be treated for 12 weeks and
then, if
their symptoms recurred 6 months later,
they might
get treated for another 12 weeks.
Again, the analyses that showed
the
displays week by week, which Dr. Dennis
can go back
to, basically are looking at the real
data week by
week for each of the criteria. There was an
analysis that she showed for percent of
people that
had a CSBM greater than or equal to 1, a
change
greater than or equal to 1. There were also
analyses she showed that were for
actually the mean
change.
Perhaps maybe she should go back over the
week by week displays that are in your
handout.
But
that is addressing the comparisons at week 12.
They were not highlighted in graphs like
this. But
the week by week displays gave you the
information
at week 12.
287
DR. BUCHMAN: Could we have a
clarification from Novartis actually as
to what the
indication was that was submitted? Because on the
slide that was shown it said nothing
about limiting
treatment to 12 weeks. Has that changed since this
morning?
DR. JOELSSON: No, nothing has changed
since this morning, I hope. The indication that we
are seeking is for chronic constipation.
DR. BUCHMAN: So, not limited to 12 weeks.
DR. JOELSSON: Obviously, somewhere in the
label it will be stated that clinical
trials have
been performed up to 12 weeks.
DR. SACHAR: Could somebody tell us
whether there would be anything useful in
taking
the 12-week data and dividing it into the
first
half and second half at least, and seeing
whether
the first 6 weeks have efficacy and the
second 6
weeks have no efficacy? That might be useful
information.
DR. JOELSSON: We have shown week by week
data--
288
DR. SACHAR: Right.
DR. JOELSSON: --and we have shown that it
is very consistent all the way through
the 3
months.
We showed many of those slides earlier
today.
DR. CUTT: There is one point I wanted to
address.
The dosage and administration section of
the label is where it clearly outlines
the 6 mg BID
dose for a period of 12 weeks. The indication is
what it is indicated for. The rest of the label
addresses that.
DR. FOGEL: Dr. Levine?
DR. LEVINE: You had a slide way back
where you showed some global symptoms and
you
compared the two studies, and that was an
example
where it was difficult to see, in fact,
if there
was a dose response. I think dose response is
something we have to clarify. I heard from
Novartis that there was no significant
dose
response in this study as in the previous
IBS study
that originally got approved. I heard from Dr.
Della'Zanna that there was no
difference. Here you
289
are saying there was a difference, 6 mg
was more
efficacious than 2 mg. When I look back at the
slide you showed a couple of times ago
that was up
there, that was one of the typical ones
where I
could not discern a difference between 2
mg and 6
mg.
Dr. Della'Zanna said there is no dose
response; you are saying there is a dose
response.
I think in a study like this where there
are high
placebo numbers and rather marginal
changes, I
think it is important that we know if
there is or
is not a dose response in all the various
aspects
that have been looked at.
DR. JOELSSON: Yes, when it comes to the
primary endpoint, as you saw in the European
study,
6 mg BID did better than 2 mg BID. In the American
study there was no difference. Now, if you look at
the overall picture, if you look at all
the
secondary endpoints, 6 mg BID is more
consistent.
It is more consistent, significantly
better than
placebo.
DR. LEVINE: You pooled the difference?
Is what we are seeing in the slides the
pooled
290
number--I assume the pooled number, the
lumped
number of everything when you say there
is a
difference in spontaneous improvement,
etc. using
both trials, not just the U.S. trials.
DR. JOELSSON: If you add them together
there will be a small difference between
2 mg and 6
mg.
I think what you need to do is to look at the
overwhelming amount of data, as somebody
said here,
and if you look at all the endpoints that
we have
looked at 6 mg BID is more consistent
from endpoint
to endpoint. That is why we are suggesting 6 mg
BID.
DR. FOGEL: Before we deal with questions
from the FDA, one last question for Dr.
Dennis.
DR. COOK: We wanted to show this week by
week display since a number of people
have decided
that they would rather the difference at
week 12
had been the primary endpoint rather than
the
average over weeks 1-4 or 1-12. This display is
showing [not at microphone; inaudible]...
and there
is no imputation of missing data; this is
the
actual data, as I understand, and this is
the
291
second study.
PARTICIPANT: You have to speak up.
DR. COOK: Sorry, but the discussion is
sufficiently animated and it is easier
for me to
point sometimes. In this particular display the
data at week 12 is the head-to-head
comparison of
the arms at week 12 for the responder
variable, not
a pre-stated primary endpoint but a
descriptive
analysis of the time course, and the
differences at
week 12 are statistically significant. So, had the
primary endpoint been how did the
treatment groups
compare at week 12 for percent responder,
which
would be a change from baseline greater
than or
equal to 1 at week 12, this is the
display that
sought to address that.
DR. STROM: And you have comparable data
on global satisfaction? It goes back to what David
was asking for before.
DR. COOK: I believe there was a backup
display that showed that. I believe statistical
significance applied to that backup
display. The
effect size was smaller in terms of the
magnitude
292
of the difference. But, otherwise, statistical
significance was still there. It also depended
upon whether you looked at the global
satisfaction,
I believe and maybe Dr. Dennis can
clarify this, as
the proportion who had at least a 1 unit
improvement or whether you looked at it
as a mean
of the scale. I think the former was probably more
meaningful. Can you clarify that, Dr. Dennis?
DR. DENNIS: I showed you some data
earlier on where we looked at
satisfaction, saying
how many people belonged to those groups
of a great
deal satisfied and a very great deal
satisfied for
6 out of the 12 weeks and for 2 out of
the 4 weeks
and, again, we showed statistically
significant
benefit for those patients.
DR. STROM: But I am looking for what does
it look like at 12 weeks.
DR. SACHAR: That is slide 33 and it is
the only one that is a bar graph instead
of a
linear curve.
DR. DENNIS: Here we go.
So, this is the
pooled data. Just to speak to the question of what
293
would this look like when we pool the
data, we can
still see that the 6 mg BID dose is more
consistent
with this.
DR. BUCHMAN: But in terms of this patient
satisfaction though, it is interesting
how subgroup
analysis is only shown if it shows
efficacy and it
is not shown if it doesn't show efficacy. If we go
back to Dr. Prather's introduction
statement, she
showed what she said were the only three
studies
that looked at quality of life in
patients with
idiopathic constipation. In two of the three they
used the SF-36 and in one of the three
they used
the SF-12. Why are you only doing a subgroup
analysis here with one single outcome
measure? It
is like looking at a tree instead of at a
forest.
So, the patients are happy with their bowel
movements but are they happy with their
life? Has
it changed their life?
DR. COOK: Typically, in a regulatory
environment you have protocol-planned
analyses, and
all of the analyses have to be planned and
one will
produce a certain number of analyses on
an
294
all-patient basis for all the endpoints
and on the
primary endpoint one will do exploratory
analyses
across a variety of subgroups. Indeed, it is
possible to do all possible analyses all
possible
ways, but at some point one has to decide
when one
can extrapolate.
DR. BUCHMAN: Well, the bottom line is you
didn't do a validated quality of life
measure on
these patients.
DR. FOGEL: Last comment?
DR. DENNIS: Let me answer that. I think
we have to remember that when we look at
quality of
life measures as an indication of
treatment
response, that is different to looking at
what is
the quality of life in a particular
population at
any one time. When we look at quality of life as a
measure of treatment response,
disease-specific
tools are far more sensitive. All right?
Now, at the time that we did
these studies
we did not have any disease-specific
tools
available to us looking specifically at
quality of
life.
So, we did look at the SF-36 and when we
295
looked at the SF-36--as you know, SF-36
is generic;
it is non-specific. Our initial a priori analysis
looked at the summary scores only, which
is the
broadest possible analyses for these
scores. On
those analyses we did not actually see
any
significant difference between Zelnorm
and placebo.
However, we have gone back and looked at
the
analyses of the individual scores, and
this is what
you can see on here. Bearing in mind this is a
non-specific tool that is not designed to
detect a
treatment difference, we can see that we
show a
statistically significant benefit on
three out of
these eight domains for quality of life,
and we see
an improvement in all of the domains,
albeit small,
I give you that, but we are certainly
seeing an
improvement in quality of life as well.
Discussion of Questions
DR. FOGEL: Thank you.
I am going to stop
the discussion now and we are going to
deal with
the questions. the ground rules that we are going
to follow are that every member of the
committee
who is voting is going to be asked for a
yes or no
296
on each question. If you have a comment to make at
that time, you can make it. In the interest of
time, please try not to repeat what others
have
said.
Question number one with regard
to
efficacy, discuss the appropriateness of
a primary
efficacy endpoint of an increase of
greater than 1
complete spontaneous bowel movement per
week versus
a
total of 3 or greater complete spontaneous bowel
movements per week. We will start with Dr. Cryer.
DR. CRYER: Well, that is not a yes or no
question.
[Laughter]
DR. FOGEL: Good point!
DR. CRYER: We have had a lot of
discussion about these various
endpoints. You
know, I have gone back and forth on this
to reach
my conclusion that ultimately,
irrespective of
which subgroup you look at or how you do
an
analysis and how it is defined, there was
some
improvement in constipation in the people
who
received Zelnorm.
297
What I am more concerned with
actually
than the quantitative description of
number of
bowel movements which define this
endpoint is the
duration of therapy. It is the more durable
response of 12 weeks rather than their
prespecified
endpoint of 4 weeks because this is
ultimately
going to be a chronic treatment.
So, my answer in brief is that
I believe
that they have demonstrated in a
subpopulation that
there is an improvement in constipation,
albeit by
some people's definition they remain
constipated.
DR. FOGEL: Do you think this is an
appropriate endpoint? Yes or no?
DR. CRYER: Yes.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: Greater than 3 is obviously a
more robust endpoint than greater than
1. I
believe greater than 1 is a suitable
endpoint.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: In reality, actually the
difference between the Zelnorm group
responders and
placebo is actually only 0.6. So, it is actually
298
less than 1 if we look at the responders
only. But
if it was greater than 1, I don't think
that that
is clinically significant at all because
that is
subject to variation. If we look at the Rome II
criteria, the definition was less than
3. Of
course, we can't turn that around and
say, in terms
of treatment, if you get over 3 you are
not
constipated but my personal opinion is
simply
having 1 more bowel movement a week is
not
sufficient on its own to eliminate
constipation so
my answer is no.
DR. FOGEL: Dr. Sachar?
DR. SACHAR: If we chose a total of equal
or more than 3, I think the sponsor could
say that
Zelnorm relieved chronic
constipation. If we
choose equal to or greater than 1, I
think the
sponsor can say patients with chronic
constipation
who take Zelnorm will still be
constipated but it
won't be as bad. I would say it is not adequate.
DR. FOGEL: My vote is that it isn't an
appropriate endpoint. I think it is far from the
optimal endpoint. I would like to make a
299
suggestion to the FDA, since this is a
huge market
and I am sure you are going to see many
more
functional bowel disease studies in the
next months
and years, that you consider making the
appropriate
primary endpoint being subjective global
assessment. Dr. Metz?
DR. METZ: I would agree entirely with
those statements. I am happy with 1; happy with 3.
I like global assessment.
DR. FOGEL: Dr. Levine?
DR. LEVINE: I agree with Dr. Sachar. I
am not happy with 1 and I would be
happier with
greater than 3.
DR. FOGEL:
Dr. LaMont?
DR. LAMONT: I agree with that this is an
adequate and appropriate endpoint,
especially since
it was discussed and apparently approved
by the
FDA.
DR. D'AGOSTINO: My comment is similar.
It seems to have been prespecified. It also does
correlate fairly well with these other
measures. I
also agree that the subjective global
would have
300
been a much better endpoint.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: Inappropriate. I don't
think it is fully standardized and its
clinical
relevance has been questioned.
DR. FOGEL: Dr. Strom?
DR. STROM: I am going to abstain, and the
reason is I don't think it is a relevant
question.
I think, no matter how you look at it, we
are
seeing the same consistent results that
the drug
works and I think this was agreed upon
beforehand
and the criteria shouldn't be changed
along the
way.
I think it is an important general broader
question, not to this regulatory
decision, and we
haven't seen the data to be able to
answer that,
but I think relevant to this regulatory
question it
is really a non-issue.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: I do believe these patients
met the Rome criteria. Actually, in some of the
parameters they were stricter to enroll the
patients in the study, and to evaluate
the efficacy
301
point they followed the guidelines of the
protocol.
I do believe that one complete
spontaneous bowel
movement in patients with this type of
very severe
constipation adds to their quality of
life. So, I
do vote yes to the question.
DR. FOGEL: Thank you.
Dr. Levin?
DR. LEVIN: I would agree with Dr. Strom's
answers.
I will pass on this or abstain. I
also I
think look more favorably on the global
assessment.
DR. FOGEL: Thank you.
Yes?
DR. BEITZ: Just a clarification on the
recommendation for future studies to have
as a
primary endpoint a global satisfaction
score, how
would you also factor in the number of
bowel
movements? We that be composite two co-primary
endpoints or a secondary endpoint? Could you say
anything at this point?
DR. FOGEL: That is a very tricky question
that take more thought than I can give it
right
now, but I would probably consider it a
secondary
endpoint.
DR. STROM: I think there needs to be
302
formal work developing that as a
scale. I also
think global assessment or some
equivalent category
makes more sense, but I think there needs
to be
formal development like you would develop
other
things.
I don't have a problem that SF-36 or SF-12
weren't used because they are not
responsive
instruments in this kind of
situation. You need a
responsive constipation-based instrument and
there
needs to be the basic underlying quality
of life
work done to develop and validate it
accordingly.
DR. FOGEL: Question 1(b), is the
population studied representative of
patients with
chronic constipation? If not, how do the
populations differ? We will start with Dr. Levin.
DR. LEVIN: I sort of half pass, but I
think I would be remiss not to speak to
the fact
that in 2004 I am sort of dismayed that
the
participation by minorities as to race
and
ethnicity is not much larger in this
study. I
think sensitivity to the inclusion of
ethnic and
racial majorities in research is critical
and I
think it is sort of dismaying, as I said,
that
303
there is so little participation by
ethnic and
racial minorities.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: During the discussion the
point was made that people with IBS and
constipation were not excluded from the
study, and
I think that was a point of
contention. However, I
do know that it is very difficult
sometimes to make
the distinction because some people with
IBS may
not have the symptoms all along and may
present
with constipation, like functional
constipation.
Therefore, although I agree and I would
like to see
more men in the study and more
minorities, I do
vote yes to the question.
DR. FOGEL: Dr. Strom?
DR. STROM: I think the population is not
representative of those with chronic
constipation
but that is always the case with a
premarketing
clinical trial so I wouldn't expect the
company
could have done anything differently from
that
perspective. I do think there is a major issue in
terms of missing--I think it is important
to sort
304
of change the question slightly and
emphasize that
it is patients with chronic constipation,
that is,
people who are going to be coming for
medical care
with chronic constipation and they are
mostly going
to be elderly, and there clearly was a
dearth of
elderly here but we will talk about that
more in
the next question.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: I agree with Brian, the
population is not representative. I think, in
addition, it is not really well defined;
it is a
mixed bag.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: I am leaving for the next
couple of responses the age and gender,
and also
the racial discussion, so I am taking
this as being
the type of constipation was the chronic
constipation. They did remove the IBS and it still
seemed to be significant. So, I think they have at
least a subpopulation that corresponds to
chronic
constipation.
DR. FOGEL: Dr. LaMont?
305
DR. LAMONT: yes, I think that this does
represent the type of patients that I see
with
chronic constipation.
DR. FOGEL: Dr. Levine?
DR. LEVIN: I too am waiting for the other
questions on the elderly and on
males. I would say
this does represent a large sub-cohort of
patients.
DR. FOGEL: Dr. Metz?
DR. METZ: Yes, age and gender not
withstanding, plus potential confounding
with
irritable bowel, I think this is the kind
of
patient that walks in the door and ends
up in these
studies.
I have no problem.
DR. FOGEL: I would agree with Dr. Metz.
Dr. Sachar?
DR. SACHAR: I would have said no on the
basis of age and gender and confounding
with IBS,
but I think it is a duplicative question
and I am
going to roll (c) and (d) into (b) and
say no.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: I am younger than Dr. Sachar
so I would say--
306
DR. SACHAR: Everybody is younger than me!
DR. BUCHMAN: It actually does fit with
the patients that I would certainly see,
but I want
to
add a caveat and I think this is much more
important than the rest of the
question. That is,
there is--if any--efficacy for 12 weeks,
not for
treatment of chronic constipation in any
of these
groups regardless of age, sex, gender,
ethnic group
or the planet that they are from.
DR. FOGEL: Dr. Mangel?/
DR. MANGEL: I agree with Dr. Prather's
comment this morning that symptoms don't
distinguish constipation subtypes, and Dr.
Schoenfeld's comment that treatments are
the same
regardless, but I don't think this
represents
chronic constipation. I think the population which
was included was a subtype of chronic
constipation.
The have a functional constipation. So, I say no.
DR. FOGEL: Thank you.
Dr. Cryer?
DR. CRYER: I also say no. When you look
at the demographic profile of the
population that
was studied here and then if you were to
compare it
307
to the Pare study, the Canadian study
that Dr.
Prather showed us earlier, the
percentages were
quite similar. Fifteen percent of the people were
older than 65. However, the thing that really
caught my attention was when Dr. Prather
spoke
about her recent experience of
self-reported
constipation in older populations. If I remember
correctly, it was 40-50 percent of the
people in
that older population who were
self-reporting
constipation. So, my suspicion is that if these
observations were generalized in clinical
practice
ultimately, that would be the target
population
that would frequently request this drug.
DR. FOGEL: Thank you.
The next
question, only 9 to 16 percent of
subjects were
greater than 65 years of age and the
treatment
effect was significantly smaller in older
populations. Are these data adequate for an
indication that is common in the
elderly? Yes or
no, Dr. Cryer?
DR. CRYER: Following up on my recent
comments, no, and I reached my conclusion
when I
308
saw Dr. Prizont's statistical evaluation
of the
data in which he concluded that in
subjects greater
than 65 there was no statistical or
numerical
difference seen.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: Yes, I need a clarification
of the question, if I could. I could read this
question one of two ways. The first is that those
greater than 65 should be excluded,
contraindicated, whatever, in the label. The
second interpretation of the question is
because
there is inadequate number of patients
who were
greater than 65 should, therefore, the
drug not be
approved for this indication? And, I just can't
tell which way the question is intended.
DR. FOGEL: Dr. Justice?
DR. JUSTICE: It is the former.
DR. MANGEL: I believe individuals greater
than age 65 should be excluded. So, I guess the
answer is no.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: I would agree with that.
309
The incidence of diarrhea as a side
effect was
actually greater than the efficacy in
these
patients, at 10.5 percent. So, I would actually
exclude the elderly from the indication.
DR. FOGEL: Dr. Sachar?
DR. SACHAR: I vote no, which means yes,
exclude them.
DR. FOGEL:
I believe that the elderly
should be excluded. Dr. Metz?
DR. METZ: No.
DR. FOGEL: Dr. Levine?
DR. LEVINE: I would say no, but I would
like to point out that over 65 is maybe
the elderly
but there are a few of us here that don't
really
want to be called the old-old rather than
the
early-old.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: I vote no.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: No.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: No, and there is nothing
310
magic about 65. I think you should run further
analyses.
If you do your quartile analyses the
cut-off maybe should be 55 or 60.
DR. FOGEL: Dr. Strom?
DR. STROM: I think the data are certainly
not adequate to prove safety in those
aged 65, and
they are strongly suggestive of, in fact,
safety
problems there and lack of efficacy. So, I would
support that it should not be used in
those over
age 65, especially given that they are
most of the
market.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: I think Novartis should
expand their studies to people that are
over 65
before they are given the green light so
the answer
is no.
DR. FOGEL: And Dr. Levin?
DR. LEVIN: No.
DR. FOGEL: The next question, only 9 to
14 percent of the subjects were male and
the
treatment effect was smaller in males
than females.
Are these data adequate to support
approval of
311
Zelnorm for use in the treatment of
chronic
constipation in males? Dr. Levin?
DR. LEVIN: Pass.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: This is a touch one because
it was a small number, 220-plus men. However, when
they showed us the data this afternoon
there was a
statistical significance. Actually, it was pointed
out that there were more percentage
points for the
men than the women. I would certainly hate to deny
anything to my male counterparts--
[Laughter]
--that women would get. But I do think
they need to expand those numbers so I
will say the
answer is no.
DR. FOGEL: Dr. Strom?
DR. STROM: I agree completely. I think
the results are very different than in
the elderly.
There wasn't evidence of an increased
risk. There
wasn't evidence of an affirmative
difference in
efficacy, in contrast to the
elderly. On the other
hand, the numbers are still small in
order to
312
ensure safety so I too wouldn't want to
deny access
to men but I would prefer to see more
data before
affirmatively saying yes.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: No.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: No.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: No.
DR. FOGEL: Dr. Levine?
DR. LEVINE: No.
DR. FOGEL: Dr. Metz?
DR. METZ: I would include men but I think
more data are required. It is very interesting to
me that in the subgroup analyses we did
see
differences amongst men but in a regional
presentation the odds ratio was
absolutely 1 and
the confidence intervals went in both
directions.
So, I think we need more information
here. I don't
think it is going to be dangerous and,
therefore, I
would be quite willing to accept it.
DR. FOGEL: I vote no for men. The data
313
that was presented this afternoon showed
a
significant effect in the 200 or so
patients. The
placebo effect was only 6 percent, which
is much
lower than anything else we have
seen. At this
moment I would say no but I think that
with
additional data the answer could be a
yes. Dr.
Sachar?
DR. SACHAR: As long as we are excluding
people over 65, I would say yes for the
males
because the data looked pretty good for
the young
men.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: I agree with Dr. Sachar on
that.
I thought that there was actually some
efficacy in the young males. Obviously, the effect
we saw in the subgroups this afternoon
was a little
bit different from the overall effect
this morning
but that included the elderly males which
may have
watered down the effect seen in the young
males.
So, I think young males would be
appropriate.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: No.
314
DR. FOGEL: Dr. Cryer?
DR. CRYER: The data aren't there but the
trends certainly are. I didn't see a safety signal
of concern in young men and so my sense
is yes,
consistent with what has been commented
before.
DR. FOGEL: The next question, are the
clinical trial data adequate with respect
to the
population of non-IBS patients with
chronic
constipation that is likely to be treated
with
Zelnorm?
Dr. Cryer?
DR. CRYER: In brief, yes.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: I would say yes with chronic
constipation being substituted by
functional
constipation-predominant.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: I would say yes, although I
still have some concern that 15 percent
of the
patients that entered and completed the
trial
didn't even have constipation. So, I am not sure
how representative everything is.
DR. FOGEL:
Dr. Sachar?
315
DR. SACHAR: Strictly by the numbers,
things didn't look bad when the IBS
patients were
subtracted, but this question specifies a
population that is likely to be treated
with
Zelnorm and, because I think that the
people who
are going to get treated with Zelnorm are
not going
to be well distinguished between those
with IBS and
those without, I would have to say no.
DR. FOGEL: I would say yes. Dr. Metz?
DR. METZ: I have a concern and perhaps I
need a clarification of the
question. If we are
talking about what is really going to go
on in the
big, wide world when people get their
hands on this
drug, I have a concern that it may
potentially be
given to people with other types of
disease states
and, therefore, I think that the answer
would be
no.
On the other hand, if I look at what the data
is as was presented, if you just take the
IBS-like
patients out, I am quite happy that the
drug worked
within the definition of the study
parameters. So,
I think I need a clarification on the
question.
DR. FOGEL: FDA?
316
DR. JUSTICE: It is the population that is
likely to be treated that we are
concerned about.
DR. BUCHMAN: You mean including secondary
causes of constipation?
DR. JUSTICE: Yes.
DR. BUCHMAN: You would be including
secondary causes of constipation in that
question
then?
Is that correct?
DR. JUSTICE: Well, any off-label use
would be considered--we are specifically
concerned
about the labeled indication.
DR. BUCHMAN: A lot of people with
secondary constipation probably would be
treated if
it was approved for primary constipation.
DR. FOGEL: Let me just ask the FDA, I
assume the assumption is made that if the
patient
is evaluated and diagnosed appropriately
is the
drug indicated? You are not taking ownership of
medical care across the country, are you?
DR. JUSTICE: That is correct. No, we are
not.
DR. FOGEL: Dr. Metz?
317
DR. METZ: Well, that still doesn't
clarify it for me. The bottom line is I can accept
this label. I think the safety side is going to
have to be well strengthened.
DR. FOGEL: Dr. Levine?
DR. LEVINE: I certainly agree about
safety.
I also have a concern about the robust
amount--how robust this is and I am very
disappointed in the figures. So, I am going to
abstain.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: I vote yes.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: Yes.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: Well, I am struggling. I
think for use over 12 weeks--is it 12
weeks?
DR. FOGEL: Yes.
DR. BUCHMAN: That is not correct. It is
chronic; it is not limited to 12 weeks.
DR. FURBERG: That affects my answer.
They have data for 12 weeks.
318
DR. BUCHMAN: It was the statistician from
North Carolina that said 12 weeks; he is
the only
one.
DR. FOGEL: Clarification from the FDA,
please.
DR. JUSTICE: Well, I think the sponsor is
proposing to limit treatment to 12 weeks.
DR. BUCHMAN: So, the label indication
will be 12 weeks?
DR. JUSTICE: Well, in the dosage and
administration. In the indication section it will
say for chronic constipation, and then in
the
dosage and administration section they
are
proposing to say for 12 weeks of
treatment.
DR. BUCHMAN: The indication slide
actually didn't say 12 weeks. It just said chronic
constipation. That needs to be changed.
DR. FOGEL: No, no, no, the indication for
the drug is chronic constipation. The duration of
treatment is 12 weeks. So, the drug is only being
approved for a 12-week course of
therapy. I
believe that is correct.
319
DR. CUTT: That is correct because the
indication usually addresses the
population and the
dosage and administration section in the
label
addresses how you administer the drug.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: Yes, for use over 12 weeks
but I am concerned. It should be pointed out that
they have no data on long-term efficacy
and safety.
DR. FOGEL: Dr. Strom?
DR. STROM: My answer is no and it is
really for three reasons. One is that those likely
to be treated with Zelnorm are likely to
be mostly
elderly and we haven't seen that. Second, most of
the use I still think is going to be
long-term use,
regardless of what the label says, and we
haven't
seen the data on that. The third is the issue of
direct-to-consumer ads which are going to
have all
sorts of people coming out of the
woodwork who are
not now coming for medical attention for
treatment
for constipation and would not have been
included
in the clinical trials.
DR. FOGEL: Dr. Sjogren?
320
DR. SJOGREN: My answer is going to be yes
if, indeed, the FDA is going to limit the
age group
of
the patients to a population that is represented
by the clinical trial.
DR. FOGEL: Dr. Levin?
DR. LEVIN: No for all the reasons that
Brian stated.
DR. FOGEL: The next question is as
follows, is Zelnorm effective for the
treatment of
chronic constipation and associated
symptoms? Why
don't we start with Dr. Metz this time?
DR. METZ: Yes.
DR. FOGEL: Dr. Levine?
DR. LEVINE: As I said, I didn't think it
was sufficiently robust but I am going to
vote yes
if we limit it to the kind of populations
that we
are all targeting.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: Yes.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: You know, we said we
don't have data on the elderly and we
talked about
321
the males, and so forth, but all of those
put
aside, yes.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: I abstain.
DR. FOGEL: Dr. Strom?
DR. STROM: Yes, excluding the elderly.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: Yes.
DR. FOGEL: Dr. Levin?
DR. LEVIN: I abstain.
DR. FOGEL: Dr. Cryer?
DR. CRYER: It is a yes with a strong
exclusion, and I think we really need to
look very
carefully at the exclusion of the elderly
population because of lack of efficacy
and of
safety signal.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: Yes.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: I think there is a
suggestion about some efficacy but not
sufficient
for me to vote yes. I disagreed with the primary
322
endpoints. I wasn't involved when that was
designed, but that is not my
problem. So, that is
a no.
DR. FOGEL: Dr. Sachar?
DR. SACHAR: Well, coming from New York, I
think I live in the real world and I am
going to
say no.
DR. FOGEL: I say yes, with the caveats of
age and male gender. Dr. Levine?
DR. LEVINE: I am switching my vote from
yes to no.
DR. FURBERG: And so do I.
DR. FOGEL: Why don't we re-vote on this
just to make sure. You got it?
Okay.
The next set of questions deal
with
safety.
Question number one, postmarketing cases
of ischemic colitis and serious
complications of
diarrhea were not limited to patients
with
irritable bowel syndrome. What are the
implications of these adverse events for
patients
with chronic constipation? Dr. Sachar?
DR. SACHAR: Is that a yes/no?
323
[Laughter]
I think the implications are
that safety
is not adequately established, especially
in view
of the lack of estimate with the population
at
highest risk being placed in the
denominator. So,
I am going to say I don't think it is
safe.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: Given the fact that new
onset of diarrhea in an elderly person
who was
previously constipated could actually be
the only
sign of ischemic bowel disease or
ischemic colitis,
I would have significant concern with
that and
would have to say no.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: I am sorry, I don't really
see where this is a yes/no answer.
DR. FOGEL: It is not a yes/no.
DR. BUCHMAN: Then just strike my last
sentence.
DR. MANGEL: Where we are right now, I am
not quite sure we could answer this
question one
way or another, forgetting about the
yes/no. I
324
think we are still going to discuss
today, and
obviously it won't be resolved today, is
there an
increased incidence of ischemic colitis
in
irritable bowel syndrome. The bulk of the events
of ischemic colitis were in the IBS
patients. I am
sure that we have a good handle from the
postmarketing data on how many of the
constipated
patients--I think there were two
constipated
patients with ischemic colitis but we
don't know
how many patients received the drug for
constipation. I think it is just too early to
comment on it.
DR. FOGEL: Thank you.
Dr. Cryer?
DR. CRYER: I think we all acknowledge
that there is clearly under-reporting in
the
postmarketing experience, and what I learned
from
this is that there is clearly a great
amount of
off-label use, based on the demographics
of the
prescribing that we saw today and what we
know from
other therapeutic categories. So, I do not think
that 11,600 patients in the clinical
trial
experience to date are going to be
representative
325
of the older population and their risk
for these
adverse events. I also was concerned with the very
high, 12 percent, incidence of diarrhea
in the
population that was greater than 65, from
these
trials.
So, the implication for these events as it
relates to chronic constipation is that I
do have
some concern, particularly in these who
are greater
than 65 years of age.
DR. FOGEL: Dr. Levin?
DR. LEVIN: I would say based on what we
heard today there are still serious
concerns about
the safety profile of the drug.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: I think the sponsor has done
a very good job in presenting to us the
results of
the clinical trial and emphasizing that
is young
person in the placebo group that
developed ischemic
colitis.
So, it is a very serious diagnosis but I
do feel that if we don't address the over
65, we
don't lump them into this, they have done
a pretty
decent job and I don't have as many
concerns as
with other drugs in terms of ischemic
colitis.
326
DR. FOGEL: Dr. Strom?
DR. STROM: I vote against ischemic
colitis and severe diarrhea.
[Laughter]
DR. FOGEL: Okay, thank you. Dr. Furberg?
DR. FURBERG: Those problems represent a
serious concern and there should be
warning
included in the labeling.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: I think there are still
concerns.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: Yes, it is serious and I
think we are going to come to the warning
versus
precautions but these are serious
complications and
the implications are that we have to deal
with
them.
DR. FOGEL: Dr. Levine?
DR. LEVINE: I agree.
DR. FOGEL: Dr. Metz?
DR. METZ: Yes, implications of these
issues--I am very comfortable that this
drug works
327
in the selected population that has been
targeted
and I don't want to see it denied. So, I would
vote to approve but the implications of
these
issues are that I think we have to be
very careful
about having the drug get over-used in
populations
where efficacy hasn't been shown and
there might be
concerns, primarily the elderly, and I am
not sure
in my mind what to do about the males but
I think
the younger males should be getting the
drug. So,
the implication is that I would limit the
access or
make people aware of the fact that this
isn't
something you can just dish out like
M&Ms.
DR. FOGEL: I think that the adverse
events are something that require
additional
attention, and I think a proactive
postmarketing
effort needs to be made to make sure that
we
actually quantify these adverse
events. So, I
think it is an issue.
Before we go on to the next
questions, we
are actually just going to quickly review
what we
already decided. Tom?
DR. PEREZ: I feel like I am on a runaway
328
train here. As far as the questions where we have
taken clear votes, the first one was
1(c), for
which we had a unanimous 13 no's. For 1(d), we had
8 no and 5 yes. Number 1(e), we had 9 yes with
caveats in many of them, 3 no, 1
abstained. For
1(f), we had 7 yes, 3 no and 1 abstained.
DR. FOGEL: We are going to move on.
DR. BEITZ: Excuse me, I thought we had
two abstentions.
DR. PEREZ: For what?
DR. BEITZ: For 1(f).
DR. PEREZ: One changed so we have one
abstention, Furberg changed from an
abstention to a
no vote.
DR. SACHAR: What about 1(b), did we ever
vote?
DR. PEREZ: We didn't have a clear vote on
that.
Let's see, we had a lot of comments but
there was no clear indication of a yes or
no.
DR. SACHAR: That is like the last
election.
DR. PEREZ: If you would like to take a
329
vote on that--
DR. FOGEL: Would the committee like to
take a vote on question 1(b)? The question that we
are going to vote on is, is the
population studied
representative of patients with chronic
constipation? Yes or no?
Dr. Levin?
DR. LEVIN: Abstain.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: Yes.
DR. FOGEL: Dr. Strom?
DR. STROM: No because of the elderly
issues.
DR. FURBERG: No.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: We went through this in
terms of saying that in answering this we
were
anticipating also (c) and (d). So, excluding the
(c) and (d) part in the IBS I said yes.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: Yes.
DR. FOGEL: Dr. Levine?
DR. LEVINE: Yes.
330
DR. FOGEL: Dr. Metz?
DR. METZ: Abstain.
DR. FOGEL: Yes.
Dr. Sachar?
DR. SACHAR: No.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: Yes.
DR. FOGEL: Dr. Mangel?
DR. MANGEL:
No, I think it is functional
constipation.
DR. FOGEL: Dr. Cryer?
DR. CRYER: No.
DR. FOGEL: Thank you.
We are going to
move on now--
DR. PEREZ: Wait a minute. We have 5 no,
6 yes and 2 abstentions.
DR. FOGEL: Safety question 2(b), the
incidence of diarrhea and
discontinuations due to
diarrhea was higher in patients greater
than 65
years of age. Is there sufficient information that
Zelnorm is safe for use in this age
group? Dr.
Levin?
DR. LEVIN: Resoundingly no.
331
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: No.
DR. FOGEL: Dr. Strom?
DR. STROM: No, and I am also worried
about incidence of diarrhea but that
diarrhea will
have worse implications in the elderly.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: No.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: No.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: No.
DR. FOGEL: Dr. Levine?
DR. LEVINE: No.
DR. FOGEL: Dr. Metz?
DR. METZ: No.
DR. FOGEL: No.
Dr. Sachar?
DR. SACHAR: No.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: No.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: No.
332
DR. FOGEL: Dr. Cryer?
DR. CRYER: No.
DR. PEREZ: Thirteen no.
DR. FOGEL: Question 2(c), do the adverse
event data from the clinical trials and
post
surveillance provide adequate evidence of
safety of
Zelnorm for the treatment of chronic
constipation?
Dr. Cryer?
DR. CRYER: I was just reading the
question.
My answer is no.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: Well, once again, excluding
the subgroups which have been spoken
about I would
say yes.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: I am going to abstain
because although in essence it is
insufficient but
what else can you do, besides get the
data from
clinical trials and postmarketing
surveillance? We
don't live in a communistic society or in
a society
where there is a registry for everybody
with
constipation.
333
DR. FOGEL: Dr. Sachar?
DR. SACHAR: In the grand scheme of the
world, yes.
DR. FOGEL: For the population under age
65, I think that there is adequate
evidence of
safety of Zelnorm. But we know from other drugs
that with increased use of the drug we
will see
increased incidence of
complications. Dr. Metz?
DR. METZ: Yes, for people under 60, 65,
70, wherever the cut-off ultimately ends
up.
DR. FOGEL: Dr. Levine?
DR. LEVINE: yes, if we look at a cut-off
of 55, 60, 65 etc. and find a good
cut-off.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: yes.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: Yes, with the same
comment about the age cut-off.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: No because of the long-term
safety.
DR. FOGEL: Dr. Strom?
334
DR. STROM: Yes for short-term use in
young women.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: Yes, with the same caveats
for age.
DR. FOGEL: Dr. levin?
DR. LEVIN: No because of the lack of
long-term data.
DR. PEREZ: Let's see, question 2(c) had 9
yes responses, 3 no and 1 abstention.
DR. FOGEL: Question 2(d) should the
information on the postmarketing cases of
ischemic
colitis and intestinal ischemia be moved
from the
precautions section to the warning
section of the
package insert?
The labeling regulations state
that the
precautions section of the labeling
"shall contain
information regarding any special care to
be
exercised by the practitioner for safe
and
effective use of the drug." The warnings section
"shall describe serious adverse
reactions and
potential safety hazards, limitations in
use
335
imposed by them, and steps that should be
taken if
they occur. The labeling shall be revised to
include a warning as soon as there is
reasonable
evidence of an association of a serious
hazard with
a drug; a causal relationship need not
have been
proved." In addition, the warnings section should
include any potentially fatal adverse
reactions.
So, to re-read the question,
should the
information on the postmarketing cases of
ischemic
colitis and intestinal ischemia be moved
from the
precautions section to the warnings
section of the
package insert?
DR. LEVINE: Clarification.
DR. FOGEL: Yes?
DR. LEVINE: Is age considered here? In
other words, are you going to say a
warning for
over 65 and no warning for under 65?
DR. FOGEL: FDA?
DR. JUSTICE: No, we are not proposing to
separate by age.
DR. BUCHMAN: Actually, I want to ask the
FDA one other question for another choice
in this.
336
Because there is no way to prevent
ischemic colitis
in a patient who you are not suspecting
has
underlying SMA disease for example, or
IMA disease,
the only way to prevent it is not to give
the drug.
That would actually not make it a warning;
that
would make it a contraindication. So, is the
choice actually between a precaution and
a
contraindication with warning actually
not even an
issue?
Are we actually being asked to choose make
the correct choice here?
DR. FOGEL: Hang on one second.
DR. SCHOENFELD: I just wanted to note
that the revised labeling, the revised
labeling
that went into effect in April,
specifically says
that if a patient develops ischemic
colitis they
shouldn't get the drug. So, if I understand Alan
correctly, if a patient has ischemic
colitis it
specifically says that you should not
prescribe it
and that is now in the labeling.
DR. FOGEL: Can we get a clarification
from the FDA?
DR. JUSTICE: We are only asking whether
337
it should be moved from precautions to
warnings.
We are not proposing a contraindication.
DR. BUCHMAN: But I am asking you whether
you should because the thing is that if
you have a
patient who doesn't have a history of
ischemic
colitis, because it clearly would be
contraindicated in that individual and I
think that
is probably adequate as it is stated, the
question
is if there is a risk of ischemic colitis
in a
patient who is not known to have ischemic
colitis,
is the drug contraindicated in that
individual? If
they are on birth control pills for
example, should
they not receive Zelnorm? That would be a
contraindication for example.
DR. FOGEL: We don't have any data to
support that.
DR. BUCHMAN: We don't, but then maybe it
should stay as a precaution. Because the warning
is in between. It means you don't know what
decision you should make. If it truly is linked to
ischemic colitis, for example, then clearly,
in my
mind, a young woman who is receiving
birth control
338
pills should not get Zelnorm. If we don't think
that it is, then we could leave it safely
as a
precaution because there is nothing you
can do
about it, other than not give it.
MS. DINGEMANSE: May I comment? We have
done a study in 45 women of childbearing
age
receiving oral contraceptives, and we
also looked
at the progesterone levels to assess the
lack of
ovulation. This was proven. This study has been
submitted with the IBS application. So, there is
no increased risk of ovulation and also
the
pharmacokinetics have not changed the
ethinyl
estradiol and level of norgestrel to a
significant
level.
They are a little lower for the level of
norgestrel but there is no change in
ethinyl
estradiol.
DR. MANGEL: I am reading the question
different from Dr. Buchman. Your different
severities of regulatory statements,
regulatory
advice where a warning is more severe
than a
precaution and where actually a
contraindication is
a different family of material in the
label than
339
either a precaution or a warning. In reading the
question, is the threshold met that this
is more
severe than a precaution and warrants a
warning,
rather than starting to evoke whether or
not there
is additivity or synergism with other
populations.
DR. FOGEL: Let me ask the FDA a question.
What is the specific issue that you want
us to
address here?
DR. BEITZ: Well, before we get to that, I
want to read you the regulation on
contraindications. Under that heading, the
labeling would describe situations in
which a drug
should not be used because the risk of use
clearly
outweighs any possible benefit. So, it is pretty
strong language. Then, further on the regulations
say known hazards and not theoretical
possibilities
shall be listed.
DR. JUSTICE: What we are asking is
whether the language that is currently in
the
precautions section regarding ischemic
colitis and
intestinal ischemia should be upgraded
from a
precaution to a warning. We don't think we have
340
sufficient information to propose a
contraindication.
DR. FOGEL: Thank you.
Is that clear to
the committee? Dr. Levin?
DR. LEVIN:
We also had some discussion
about the wording of the precaution. Is that
appropriate to address? There was some feeling
that it was a little too positive a
precaution, if
such a thing is possible. Forgive my ignorance, is
there a medication guide required with
Zelnorm? Is
that an issue to be discussed today?
DR. JUSTICE: No.
DR. MANGEL: Before the vote, could I just
also get a clarification. For me, when I look on
the surface it looks like perhaps two and
a half
months after a label change when, at
least my
understanding from what I heard today, is
that
there is not a new signal; there is not a
concern
to upgrade the safety information within
the label,
I am concerned about alarming the
prescribing
community for another "dear
doctor" letter to go
out saying it goes from a precaution to a
warning
341
when perhaps at one level it is a
clarification
from your previous conversations with the
sponsor.
I am curious if it is upgraded to a
warning if you
have a plan or even a preliminary plan of
what the
roll-out would be. Would there be a medication
guide?
Would there be a "dear doctor" letter? You
know, what would be the nature of the
explanation
for the prescribing community?
DR. JUSTICE: The answer to the first
question is that one of the reasons we are
asking
now, after having made these changes, is
that if
Zelnorm is approved for chronic
constipation it
would be expanded to a larger population
with a
potentially different risk/benefit
ratio. So, I
think it is a new question now.
I think as far as would we
request a "dear
doctor" letter or med guide, we have
not discussed
that internally so we are not prepared to
give you
the answer right now.
DR. FOGEL: Dr. Cryer?
DR. CRYER: I just want to echo comments
which Dr. Justice just made which caught
my
342
attention, that is that the approval of
Zelnorm for
a different indication will clearly lead
to an
expansion to different populations and a
change in
the risk/benefit ratio which we have seen
to date,
and principally younger women.
So, as I read this, what the
warnings
allow that differ from what the
precautions would
provide is a mechanism to alert the
prescribing
physician of what those concerns might be
in brief
and what we have summarized in our
discussions
today.
The specific mechanisms that I see here in
the warnings section suggest a potential
safety
concern, potential safety hazards and,
specifically, limitations imposed by
them. So, if
there is not going to be any specific
differentiation of a warning or a
precaution based
upon an age of 65, I think that that
specific
limitation should be implemented using
the warning
mechanism, specifically age.
DR. FOGEL: Dr. Mangel?
DR. MANGEL: I think the answer is
still
unknown with respect to IBS versus
Zelnorm. I
343
don't see a signal for chronic
constipation but, by
the same token, based on the IBS data we
wouldn't
have seen it yet, not enough
patients. I am
concerned about upgrading the label with
no new
information. If this was the original label and
you asked should it be a warning for IBS,
I would
have been comfortable with yes at that
point. To
change it now, I would say no.
DR. DELLA'ZANNA: I am just going to make
a statement. Without knowing the results of
whether or not this gets approved or not
approved
for the chronic constipation, we may be
looking at
a recent labeling change either way.
DR. MANGEL: And my answer would still be
the same.
It would be no based upon no new signal.
For me, it would have been on the fence
but it
would have been certainly credible for
IBS for
there to be a warning versus a
precaution. It
could have gone either way since there
were no
cases in 11,000 individuals in clinical
trials,
which gives us a degree of comfort in
terms of the
relative rate. To make the change now with no new
344
data, I would say no.
DR. SACHAR: Even though it says, "in
addition, the warnings section should
include any
potentially fatal adverse reaction?"
DR. MANGEL: Yes. I
understand that and,
once again, if a drug is given to three
million
people some people will die. You know, that is
where I don't think we have robust enough
data to
say you have four deaths out of three
million and
for each of the deaths they were
difficult,
confounded cases--is that reasonable;
unreasonable?
Where we sit now, I would say it is not a
clear
association.
DR. FOGEL: Dr. Buchman?
DR. BUCHMAN: I would leave it as a
precaution but with a significant
caveat. We don't
actually even know what the incidence of
ischemic
bowel disease is in the general
population. I
don't believe the data that it is
increased in
irritable bowel syndrome because that is
an
oxymoron statement because they wouldn't
have
irritable bowel syndrome if they had
ischemic bowel
345
disease.
But I think that the precaution should be
substantially more robust, including not
only what
we discussed this morning, to make them
equal
length, but to actually make it
longer. I think it
specifically should list in precautions
that it
should be used with precaution in
individuals that
are taking concomitant oral
contraceptives, and who
smoke, and who have coexistent or known
thrombotic
disorders, and I think there needs to be
postmarketing surveillance in those
particular
individuals because those would be at the
highest
risk for developing ischemic disease and
could
easily change to a warning or a
contraindication,
depending on what the results of that
postmarketing
surveillance would be.
DR. FOGEL: I just want to make sure your
answer is yes, it stays as a precaution?
DR. BUCHMAN: No, my answer is no, it
stays as a precaution.
DR. FOGEL: Dr. Sachar?
DR. SACHAR: I think the best way to
achieve Dr. Buchman's aims is to move it
to the
346
warnings section. I would say yes.
DR. FOGEL: If we exclude those people
over the age of 65, I would recommend
that it stay
as a precaution, and I agree with the comments
of
Dr. Buchman. Dr. Metz?
DR. METZ: I would say no, I would leave
it as a precaution. I think that we have no real
data to suggest that the drug has this
negative
impact.
We are all worried about it but there is
nothing that is a strong warning to
me. I do,
however, think it is very important that
an
additional precaution go into this label,
and that
is that idiopathic constipation is what
it is
indicated for. It is not indicated for secondary
causes of constipation, and there is
potentially
concern about efficacy and risk/benefit
in people
over 65.
So, that would be an expansion, I
suppose, of the precautions section but
that
doesn't mean that people won't be able to
use it
for those specific indications.
On the other hand, I would feel
uncomfortable if you took a long laundry
list of
347
all the potential risk factors of
thrombotic events
because then you are going to be
frightening the
very people who are going to be using
these drugs,
and there is no data in my opinion to
suggest that
smoking has an effect on this particular
population, that hypocholesteremia,
hypotension,
diabetes and other things you might put
in. So, I
don't think it should be so restrictive.
I am concerned about secondary
causes and
I am concerned about the risk/benefit
ratio in the
elderly, but they may well ultimately be
people to
benefit from this drug.
DR. FOGEL: Dr. Levine?
DR. LEVINE: I would say yes, I would put
it in the warnings because in the real
world what
is going to happen is that this is going
to be used
much more frequently in non-indicated
patients.
Number two, I predict, as with Rezulin
and a few
other drugs, as more patients use it you will
begin
to see, very likely, signs of ischemic
colitis or
vasculitis or other types of things that
we don't
know yet.
I would say if you can make a very
348
strong precautionary note at this point
and then
change it to a warning when you see the
rise in the
postmarketing--I think one and a half
years is
nothing for these figures in
postmarketing. You
are going to see a huge change, I
predict. So, I
would vote yes, move it to a warning.
DR. FOGEL: Dr. LaMont?
DR. LAMONT: Yes, I think that there is
reasonable evidence of an association
although it
is not causal, and it is potentially
fatal. So, I
vote yes, to move it to the warnings
section.
DR. FOGEL: Dr. D'Agostino?
DR. D'AGOSTINO: No, I don't see the data
justifying it.
DR. FURBERG: I do, yes.
DR. FOGEL:
Dr. Furberg is yes. Dr.
D'Agostino is no. Dr. Strom?
DR. STROM: I vote yes.
I think there are
no data; since the "dear
doctor" letter came out
there is a wave of new adverse
reactions. I think
there isn't a strong association when you have
rates of reported adverse reactions,
spontaneous
349
reports, which are on the same order as
the
background rate of disease, given the
available
data.
The only argument against that are the data
suggesting that maybe people with IBS
have a higher
rate of ischemic colitis and I don't find
that
credible but I haven't seen those studies
in enough
detail to be able to comment on them.
I am
skeptical.
I feel even more strongly that
wording
changes that need to be made that were
suggested
before so that we don't give a
quantitative summary
of only the absence of an effect and
don't provide
the quantitative summary where there is
an effect.
I think the other reason to put
it into
warnings is the issue of the elderly, and
that this
will be overused and shouldn't be used in
the
elderly, and that needs to be made loud
and clear.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: Well, I feel at odds with
some of my colleagues but the sponsor
presented
very good data in primates and in humans
in
coronary-arteries and mesenteric arteries
that
350
there is no effect of the drug. So, I am puzzles
by so much fear that I sense from some of
my
colleagues.
And, we are forgetting the thousands
of patients in the clinical trials where
there is
no evidence of ischemia.
I think the agency and we,
ourselves, need
to remain credible because if we are
going to put
in warnings for things that we are just
fearful of,
I think we are going in a very
treacherous way.
So, I would say to remain as a precaution
rather
than a warning.
DR. FOGEL: Thank you.
Dr. Levin?
DR. LEVIN: I would move it to warnings
and, obviously since I talked about it, I
would
strengthen the wording to at least be
equitable in
describing non-events and events.
I would also urge the agency to
think
seriously about a medication guide
requirement
because we are relying on patients, and
this will
be in the package labeling, to report
immediately
to their physicians certain symptoms that
are
indicative of serious adverse reactions
and I think
351
patients need to have that information
given to
them at the time of dispensing. So, I really
think, if you haven't thought about it,
FDA, you
ought to think about requiring a
medication guide
for this product.
DR. PEREZ: Dr. Levin, you said, yes, move
it?
DR. LEVIN: Move it.
DR. FOGEL: Do you want to give us a
summary of question two?
DR. PEREZ: Yes, 7 yes, 6 no.
DR. FOGEL: The last question, I will read
it and I have a quick clarification
question for
FDA.
The question as written is as follows: Should
Zelnorm be approved for the proposed
indication of
the treatment of patients with chronic
constipation
and relief of the associated symptoms of
straining,
hard or lumpy stools, and infrequent
defecation?
My question for clarification
is as
follows, we have had discussion about
gender and
age exclusions. Is this just a question of what
the indication would be, and the
modifiers of
352
gender and age will be added at a later date?
DR. JUSTICE: We can do that of, if the
committee wants to revise the question to
reflect
the discussion about age and gender, they
can do
so.
DR. FURBERG: Can we also get in duration
of treatment?
DR. FOGEL: Can we do that?
DR. BUCHMAN: To be short-term
constipation?
DR. FOGEL: No, no, short-term treatment;
long-term constipation is the indication.
DR. STROM: Ron, can I suggest two votes?
One would be on the unqualified
indication, the way
it is worded. The second would be an indication
for short-term use in young women.
DR. FOGEL: Actually, we have a number of
different clauses to consider. Why don't we vote
on the main question and we will vote on
each one
of these special cases.
So, excluding gender, age,
duration of
therapy, should Zelnorm be approved for
the
353
proposed indication of the treatment of
patients
with chronic constipation and relief of
the
associated symptoms of straining, hard or
lumpy
stools, and infrequent defecation? Yes or no, Dr.
Levin?
DR. STROM: Can I just clarify the
question again? When you say excluding those--
DR. FOGEL: We will come to all those.
Those will be separate votes.
DR. STROM: So, we are voting as written.
You are asking for vote on an
unrestricted
indication.
DR. FOGEL: We are going to vote on the
recommendation as written and we are
going to add a
number of different questions.
DR. STROM: I am still confused.
DR. FOGEL: We are going to vote on the
question as written, and then we are
going to vote
on whether it should be used in people
over the age
of 65; whether it should be used for
males.
DR. LEVIN: That is what the sponsor asked
for so we are voting on what the sponsor
asked for.
354
No.
DR. SJOGREN: I am confused. If I vote
yes, that means that the sponsor will
have no
restrictions?
DR. FOGEL: Is that correct, FDA?
DR. JUSTICE: That is correct.
DR. SJOGREN: Then the vote is no.
DR. FOGEL: Dr. Strom?
DR. STROM: No.
DR. FURBERG: No.
DR. D'AGOSTINO: No.
DR. LAMONT: No.
DR. LEVINE: No.
DR. FOGEL: Dr. Metz?
DR. METZ: I am also still confused. If I
vote yes, the precautions and warnings
and issues
are all jacked up--
DR. FOGEL: No, we are voting on what it
says.
DR. METZ: Then I have to vote no.
DR. FOGEL: No.
DR. SACHAR: No.
355
DR. BUCHMAN: No.
DR. MANGEL: No.
DR. CRYER: No.
DR. PEREZ: Unanimous, 13 no.
DR. FOGEL: What I would like to do is
start by adding on a number of
clauses. Should
Zelnorm be approved for the proposed
indication of
the
treatment of patients with chronic constipation
and relief of the associated symptoms for
females
only, for treatment of female patients
only?
DR. BUCHMAN: That is excluding age?
DR. FOGEL: We will get to age next. For
female patients only?
DR. STROM: You are saying of any age and
any duration?
DR. FOGEL: Correct.
Dr. Cryer?
DR. CRYER: You asked should Zelnorm be
approved for females only?
DR. FOGEL: Right.
The question is should
we exclude males? Let's phrase it that way, the
indication would exclude males from
treatment.
[Multi-member discussion]
356
DR. JUSTICE: Could I just offer a
suggestion? Maybe you could just go one by one and
say what the exclusion should be.
DR. FOGEL: Okay, I think that is a better
suggestion.
Dr. Cryer, what exclusions would you
like to place on this?
DR. CRYER: Sixty-five or older; no gender
exclusion.
DR. MANGEL: Sixty-five or older. I would
exclude males and I would change the
nomenclature
for chronic constipation to either
functional or
idiopathic constipation,
DR. BUCHMAN: I say no, actually, to
anything because we are looking at a
completely
benign disorder, despite the fact that it
affects
lifestyle. So, I think that really almost any
adverse events are unacceptable, unless
the data
was really quite robust, and a 10 percent
benefit
over placebo is not sufficient for me to
waive the
adverse events. I don't agree, actually, with the
primary outcome variable of one bowel
movement, and
I looked at the three bowel movements
which was
357
statistically significant but not
clinically
significant. So the bottom line is it is no for me
under any circumstance.
DR. FOGEL: Dr. Sachar?
DR. SACHAR: I am with Dr. Buchman on
this.
We have been here for eight hours and I am
convinced that we can squeeze some
statistical
significance out of these data but, when
all is
said and done, knowing how this drug is
going to be
marketed, advertised, prescribed,
renewed,
continued, passed around and consumed,
for me it
just doesn't cut it. I vote no approval under any
circumstance.
DR. FOGEL: I vote for approval of the
drug.
I would exclude all individuals over the age
65.
I would exclude males and I would vote for a
12-week course of therapy. Dr. Metz?
DR. METZ: I would vote for approval. I
would exclude patients over 65. I would have a
precaution for males, that the
risk/benefit ratio
has not been shown. I would suggest that there
also is comment on the fact that the
studies were
358
only done for 12 weeks but I don't think
it should
be restricted to only 12 weeks.
DR. FOGEL: Dr. Levine?
DR. LEVINE: I was going to support what
Dr. Buchman said about specific diseases,
etc. to
exclude.
I think the risk is so great that it will
be over-utilized, I vote no.
DR. METZ: Forgive me for going back. I
feel very strongly that secondary causes
of
constipation should be considered before
people
start this drug and I would put that in.
DR. FOGEL: Thank you.
Dr. LaMont?
DR. LAMONT: Yes, I vote yes for 12 weeks
of therapy in chronic idiopathic
constipation,
females only, less than 65.
DR. FOGEL: Thank you.
Dr. D'Agostino?
DR. D'AGOSTINO: The same.
DR. FOGEL: Dr. Furberg?
DR. FURBERG: The same.
DR. FOGEL: Dr. Strom?
DR. STROM: The same, but only if there
was a risk management plan to ensure
that, in fact,
359
it was used that way.
DR. FOGEL: Dr. Sjogren?
DR. SJOGREN: Actually, I would like to
say that it is not a benign
condition. I have
several patients that have undergone
surgeries.
Some others have contemplated
suicide. It is a
very serious condition for patients with
constipation. We are blessed, I guess, at this
table, especially my male colleagues that
are not
being recruited into these studies--
DR. BUCHMAN: The drug didn't prevent
surgery though.
DR. SJOGREN: No, no, but it is a very
serious condition. If you can treat it and there
is hope with some kind of medical therapy
I don't
think we should deny it. I vote yes for people
that are 65 or younger. I would not like to see
men because the data, although very
provocative,
still needs to be expanded. I think I would not
restrict the length of the therapy.
DR. FOGEL: Dr. Levin?
DR. LEVIN: I would vote yes under 65;
360
women only; 12 weeks of therapy. I would add that
there be a medication guide, and I agree
with Brian
that there be some sort of proactive risk
management program, that we do not rely
on what the
studies tell us isn't very effective,
that is,
product labeling to do the job of
preventing the
use of this drug inappropriately in the
general
population.
DR. FOGEL: Thank you.
Any additional
information that the FDA would like? Any
clarifications that they would like?
DR. BEITZ: Yes, since you brought it up,
could you elaborate on the risk
management plan
that you are thinking about?
DR. STROM: The answer is easy--no. It
would not be an easy risk management plan
because,
obviously, use for IBS is very different
and I am
not suggesting it get stricter for
IBS. How you
differentiate that, it is not clear. We need a lot
more thought than I have given it, and a
lot more
creativity I think.
I think my point is I would
only be
361
comfortable with it being available in
this way if
there was a way of being sure it wasn't
going to be
overused.
I don't know that I can come up with
such a way without impairing its use for
IBS, which
I am not suggesting that we do. I guess one way
would be just to look at things like, you
know, a
medication guide plus a close marketing
survey
about how the drug is being used, with
the idea
that if it is being used substantially in
people
over age 65 or long-term use, which are
easy things
to measure, that the company has to take
major
proactive action in order to limit use or
risk
losing the indication.
Certainly the things we are
concerned
about--gender, age, duration--are easy
things to
measure in a postmarketing surveillance
study, and
I would want to make sure it is not
happening, as
well as to have the company very, very
actively
market, plus a med guide in order to
prevent that.
DR. FURBERG: Discourage off-label use.
DR. LEVIN: I would agree, med guide,
tracking to see how the drug is being
used, and
362
perhaps educational detailing is another
method
that the company could use to deal with
off-label
use and to deal with inappropriate use of
the drug.
DR. FOGEL: Is there any other--
DR. METZ: I don't want to rush to a
defense of the sponsor but a very
important point
is that the more you make these things
restrictive,
the more you chase the prescribing doc
away and you
deny drugs to patients when they
certainly work for
indications. I think another drug that works
exactly opposite to this one has
essentially died
because of that kind of
intervention. So, I would
be wary about going overboard here and
making it
such a big spiel that it is just not
going to
happen.
DR. FOGEL: Well, I think the other drug
died because it was over-prescribed and I
think we
are trying to save this drug from a
potentially
similar fate.
DR. LEVIN: The patients also died with
the other drug, not just the drug.
DR. SACHAR: I need one comment on the
363
record because I am taking to heart the
comments of
Dr. Sjogren and of the patient
representative who
spoke to us, and I just want to make it
clear that
when I said I am with Dr. Buchman on this
I exclude
any implication that this is not a
serious
condition.
DR. FOGEL: Does the FDA have any other
questions, clarifications that they want?
DR. BUCHMAN: I will modify my statement.
The word benign is a relative term, and
it is
benign when compared to ischemic bowel;
it is
benign when compared to cancer. I, myself, have
never had a suicidal patient but it
obviously is a
problem or we wouldn't be here
today. But benign
is a relative term only; so is efficacy.
DR. STROM: But I think it is also
important to point out that the degree of
efficacy
we are dealing with here is very
marginal. I guess
the other thing I would like to add is if
we can
see analyses of predictors of responders
that look
in much more detail at some of the kind
of things I
was asking about before, I would feel
much more
364
comfortable with it being more freely
available to
people who fit that requirement. My concern is
broad use of the drug for a condition
where there
will be a very high placebo response rate
and
people are going to think the drug is
working--patients and docs are going to
think it is
working when it is just placebo effect.
DR. SACHAR: you have stated well the
basis of my no vote.
DR. FOGEL: Thank you all for your
clarifications. At this juncture, I would like to
thank the members of the committee. I would like
to thank the representatives of the
sponsor,
Novartis.
I would like to thank the FDA.
And, we
will close the meeting at this time. Thank you,
all.
[Whereupon, at 4:45 p.m., the
proceedings
were adjourned.]
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