DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
GASTROINTESTINAL DRUGS ADVISORY SUBCOMMITTEE
ACS Conference Room
Ronald P. Fogel, M.D., Acting Chair
Thomas H. Perez, M.P.H., R.Ph.,
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
Ralph D'Agostino, Ph.D.
Allen Mangel, M.D., Ph.D.
FEDERAL EMPLOYEE (Voting):
Maria H. Sjogren, M.D.
Robert Justice, M.D., Director, Division
of Gastrointestinal and Coagulation
Robert Prizont, M.D., Medical Officer
Garry Della'Zanna, D.O., M.Sc., Medical Officer
Julie Beitz, M.D., Deputy Director, ODE III
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
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
Eslie Dennis, M.D., Novartis Senior Medical
Director, GI Clinical Develop and Medical
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.,
Questions on Presentation 116
FDA Efficacy Presentation, Robert Prizont, M.D.,
Medical Officer, Division of Gastrointestinal
and Coagulation Drug Products 158
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
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
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
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
DR. LAMONT: I am Tom LaMont. I am a
member of the GIDAC. I work at Beth Israel
DR. LEVINE: I am Bob Levine, State
member of the GI advisory committee.
DR. METZ: David Metz, University of
DR. PEREZ: Tom Perez, Executive Secretary
to this meeting.
DR. FOGEL: Ron Fogel, Henry Ford Health
DR. SACHAR: I am David Sachar, from Mount
Sinai School of Medicine, in
voyage on the GI drug advisory committee.
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
DR. CRYER: I am Byron Cryer, from the
DR. DELLA'ZANNA: Garry Della'Zanna,
medical officer in the GI and Coagulation Drug
DR. JUSTICE: Robert Justice, Director,
Division of Gastrointestinal and
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.
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
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
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
FDA, for 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
studied representative of patients with chronic
constipation? If not, how do the populations
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
The next efficacy question is, is Zelnorm
effective for the treatment of chronic constipation
and associated symptoms?
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
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
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.
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
and it is my pleasure to share with you today the
clinical data on chronic constipation that we have
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
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
A brief introduction of the compound,
Zelnorm is tegaserod maleate. It is 5-HT
partial agonist with affinity for the 5-HT
receptor in the GI tract. For its pharmacologic
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
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
included a 4-week withdrawal period. Today what we
are going to do is show you the results of these
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
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
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
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
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
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
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
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.
An Unresolved Problem for Many
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
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
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
In my practice the most common reported
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
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
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
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
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
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
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
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 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
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
To summarize the epidemiology
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Zelnorm: Efficacy and Safety in
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
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
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
receptors is prokinetic.
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
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
Let me now walk you through the Phase 3
chronic constipation program. The study objectives
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
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
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
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
A recent state-of-the-art
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
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
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,
examination, as well as baseline ECG and laboratory
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
reflecting the time of administration of any rescue
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
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
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
history to make a diagnosis of chronic
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
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
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
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
BID dose, which you can see more clearly on this
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
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
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
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
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
What about straining, yet another
important symptom of constipation? For each bowel
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
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
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.
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
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
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
So, we looked at patients who had less
than 3 bowel movements per week at
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
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
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
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
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
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
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
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
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,
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
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
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
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
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
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.
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
vascular conductance which is a measure of vasal
activity. In addition, although tegaserod has
negligible affinity for the 5-HT
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
These data indicate that Zelnorm does not
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
Dr. Shetzline has carefully investigated
these cases and he will now discuss them in some
detail with you. Please, Dr. Shetzline?
DR. SHETZLINE: Thanks, Dr. Joelsson. I
am Michael Shetzline, an gastroenterologist and a
senior medical director at Novartis,
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
left colon. She was treated with antibiotics and
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
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
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
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
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
The cause of death was listed as bowel
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
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
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
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
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
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
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
Zelnorm-treated patients versus 0.03 percent on
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
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
are very rare reports from the postmarketing
experience. Our conclusion from these data is that
Zelnorm treatment does not increase the risk of
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.
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
I think it is particularly
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
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
This is a partial list of the commonly
used treatments for constipation. They include
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
So, what can we do about comparing
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
patients followed for 780 patient-years of
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
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
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
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
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
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
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
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
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. 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?
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
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
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
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
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
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
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
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.
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
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
DR. JOELSSON: Yes.
DR. SACHAR: And for Dr. Dennis, in slide
DR. DENNIS: I will flash it up on the
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
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
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
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.
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
DR. SACHAR: A physician or a
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
their comments brief. I am going to take the
prerogative of the chair and ask my questions of
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
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
If I could have slide AQ-58,
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
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
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
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,
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
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
efficacy is sustained throughout the entire
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
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
To address the question of why we chose a
4-week duration period, I think that was because
when physicians prescribe the drug they
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
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
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
The median use of laxatives in the placebo
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
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.
DR. FOGEL: You can present those slides
DR. DENNIS: Right, thank you.
DR. FOGEL: The next question is by Dr.