FOOD AND DRUG ADMINISTRATION

NINETY-FIFTH MEETING OF THE

CARDIOVASCULAR AND RENAL DRUGS ADVISORY COMMITTEE

8:30 a.m.

Thursday, January 17, 2002

Kennedy Ballroom

Holiday Inn

8777 Georgia Avenue, N.W.

Washington, D.C.

ATTENDEES

COMMITTEE MEMBERS:

JEFFREY BORER, M.D., Chairman

Director, Division of Pathophysiology

Weill Medical College

Cornell University

525 East 68th Street, Room F467

New York, New York 10021

JAIME HENRIQUEZ, Executive Secretary

Advisors and Consultants Staff

Center for Drug Evaluation and Research

Food and Drug Administration

5630 Fishers Lane

Rockville, Maryland 20857

MICHAEL F. ARTMAN, M.D.

Professor of Pediatrics

Pediatric Cardiology

New York University Medical Center

530 First Avenue, FPO Suite 9-V

New York, New York 10016

BLASE A. CARABELLO, M.D.

Chief, Medical Service

Veterans Affairs Medical Center

Medical Service (111)

2002 Holcombe Boulevard

Houston, Texas 77030

SUSANNA LEE CUNNINGHAM, PH.D.

Professor, Department of Biobehavioral

Nursing & Health Systems

School of Nursing, Box 357266

Seattle, Washington 98195-7286

THOMAS FLEMING, PH.D.

Professor and Chair

Department of Biostatistics

University of Washington

Box 357232

Seattle, Washington 98195-7232

ATTENDEES (Continued)

COMMITTEE MEMBERS: (Continued)

ALAN T. HIRSCH, M.D.

Associate Professor of Medicine and Radiology

Minnesota Vascular Diseases Center

University of Minnesota Medical School

420 Delaware Street, S.E., Box 508 FUMC

Minneapolis, Minnesota 55455

BEVERLY H. LORELL, M.D.

Professor of Medicine

Beth Israel Deaconess Medical Center

Cardiovascular Division

330 Brookline Avenue

Boston, Massachusetts 02215

STEVEN NISSEN, M.D., F.A.C.C.

Vice Chairman, Department of Cardiology

Professor of Medicine

Ohio State University

The Cleveland Clinic Foundation

9500 Euclid Avenue, F15

Cleveland, Ohio 44195

SPECIAL GOVERNMENT EMPLOYEES:

JEFFREY KOPP, M.D.

Kidney Disease Section

Building 10, Room 3N118

National Institute on Diabetes,

Digestive and Kidney

National Institutes of Health

Bethesda, Maryland 20892-1268

ANDREW S. BREM, M.D.

Division of Pediatric Nephrology

Rhode Island Hospital

593 Eddy Street

Providence, Rhode Island 02902

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

RAYMOND LIPICKY, M.D.

ROBERT TEMPLE, M.D.

JUAN CARLOS PELAYO, M.D.

SPONSOR REPRESENTATIVES:

MELISA COOPER, M.D., M.S.

BRIAN F. DANIELS, M.D.

LLOYD D. FISHER, PH.D.

JULIA A. BREYER LEWIS, M.D.

EDMUND J. LEWIS, M.D.

KANNAN NATARAJAN, PH.D.

HANS-HENRIK PARVING, M.D., DMSc

MARC A. PFEFFER, M.D., PH.D.

GEORGE WILLIAMS

C O N T E N T S

NDA 20-757/S-021, Avapro (irbesartan)

Sanofi-Synthelabo (c/o Bristol-Myers Squibb)

for the Treatment of Hypertensive Patients

with Type 2 Diabetic Renal Disease

\* \* \*

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

By Jaime Henriquez 6

SPONSOR PRESENTATION

Introduction

By Dr. Brian Daniels 7

Disease Background

By Dr. Edmund Lewis 10

IDNT Efficacy and Safety

By Dr. Melisa Cooper 54

IRMA 2 Efficacy and Safety

By Dr. Hans-Henrik Parving 159

Benefit/Risk Assessment

By Dr. Edmund Lewis 201

OPEN PUBLIC HEARING 134

COMMITTEE DISCUSSION OF QUESTIONS PRESENTED 212

P R O C E E D I N G S

(8:30 a.m.)

DR. BORER: I\'d like to welcome you and begin the 95th meeting of the
Cardiovascular and Renal Drugs Advisory Committee of the FDA.

Before we begin the formal presentations, we\'ll hear the conflict of
interest statement by Jaime Henriquez, the Executive Secretary of the
committee.

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

Based on the submitted agenda for the meeting and all the 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 conflict of
interest at this meeting with the following exceptions.

In accordance with 18 U.S.C. 208(b)(3), a full waiver has been granted
to Dr. JoAnne Lindenfeld for her unrelated consulting for one of the
sponsors. She received less than \$10,000 a year. And to Dr. Alan Hirsch
for unrelated speaking for the sponsor. He received between \$5,000 and
\$10,000 a year.

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 in
the Parklawn Building.

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

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

DR. BORER: Thank you.

We\'ll begin then. This morning we\'re going to consider an NDA related
to irbesartan, Avapro, for the treatment of patients with hypertension
and type 2 diabetic renal disease. I think the presentation will be
introduced by Dr. Daniels.

DR. DANIELS: Thank you and good morning, members of the advisory panel.
It\'s a pleasure to be here today to discuss information about Avapro
and its use in the treatment of type 2 diabetic renal disease. I\'m
Brian Daniels, the Vice President for the Pharmaceutical Research
Institute at Bristol-Myers Squibb.

Briefly let me review our agenda and speakers. After my introduction,
Dr. Ed Lewis, a Muehrcke Professor of Nephropathy and Director of the
Nephropathy Section at the Rush Medical College, will present important
background information on type 2 diabetic nephropathy with an emphasis
on the endpoints used in our renal studies. Dr. Lewis was a principal
investigator for the IDNT study.

Then Dr. Melisa Cooper, a nephrologist and a vice president in the
Pharmaceutical Research Institute at Bristol-Myers Squibb, will give the
efficacy and safety data for IDNT.

Then Hans-Henrik Parving, Professor and Chief Physician at the Steno
Diabetes Center, Denmark, will present the efficacy and safety data for
IRMA 2. Dr. Parving was an investigator for the IRMA 2 trial.

Finally, Dr. Lewis will then return to discuss the overall risk-benefit
profile of irbesartan in the treatment of type 2 diabetic renal disease.

We have some additional consultants that the panel can use to answer
their questions. Dr. Julia Breyer Lewis is a Professor of Medicine at
Vanderbilt University. Dr. Lloyd Fisher is a Professor Emeritus in
biostatistics at the University of Washington, and Dr. Marc Pfeffer is a
Professor of Medicine in the Cardiovascular Division at Brigham and
Women\'s Hospital. All three were involved with the conduct of the IDNT
trial.

Just to remind everyone that Avapro is an angiotensin II receptor
blocker, active at the AT1 receptor subtype. It\'s current indication is
for the treatment of hypertension. It\'s available in over 79 countries,
with over 3.6 million patient-years of experience worldwide. It\'s
recommended starting dose for hypertension is 150 milligrams daily with
a maximum dose of 300 milligrams daily.

Two complementary trials constitute the Avapro development program in
type 2 diabetic renal disease. Together they studied over 2,300 patients
along the continuum of type 2 diabetic renal disease. These trials were
designed as specific renal studies using endpoints appropriate for the
severity of renal disease being investigated.

The irbesartan diabetic nephropathy trial, or IDNT, investigated
renoprotection in 1,715 hypertensive patients with type 2 diabetic
nephropathy, defined as overt proteinuria. Irbesartan microalbuminuria
in type 2 diabetic subjects, or IRMA 2, studied 590 hypertensive
patients at an earlier point along their disease continuum, specifically
those patients with microalbuminuria.

The proposed indication for Avapro for patients with hypertension and
type 2 diabetic renal disease: Avapro is indicated for the treatment of
type 2 diabetic renal disease.

Now I would like to introduce Dr. Ed Lewis who will give important
information on the background of type 2 diabetic renal disease. Dr.
Lewis?

DR. EDMUND LEWIS: Thank you. Good morning.

Type 2 diabetic nephropathy is a growing problem worldwide. Type 2
diabetes is epidemic and approximately 40 percent of patients with type
2 diabetes will get nephropathy. Currently approximately 45 percent of
patients entering our dialysis transplantation programs in this country
are entering with the primary diagnosis of diabetic nephropathy, and the
cost of this is enormous.

The natural history of type 2 diabetic nephropathy does not differ
greatly from that of type 1, and that is that there is an inexorable
progression from early nephropathy to overt nephropathy with progressive
structural and functional changes which ultimately lead to a decrease in
the glomerular filtration rate and end-stage renal disease.

Virtually all patients with type 2 diabetic nephropathy have
hypertension. One difference between the course ‑‑ and there are many
differences in terms of the patient populations ‑‑ of the patient with
type 2 diabetic nephropathy as opposed to type 1 diabetic nephropathy is
that there is cardiovascular morbidity and mortality throughout the
course which represents a second system involved, a competing endpoint,
which has to be taken into consideration in the design of any trial.

We can define renal failure as a decrease in the ability of the kidney
to carry out its primary function of filtering impurities in the blood,
and this is measured by measuring either the glomerular filtration rate,
the creatinine clearance being one approximation of that, or evidence of
the retention of filterable molecules, particularly creatinine.

As you know, the creatinine clearance represents the estimation of the
amount of blood cleared of a molecule in a unit time, so that the
numerator in the formula is the concentration of that substance,
creatinine, in the blood and the volume of urine per unit time, and the
denominator is the serum creatinine so that when one plots the clearance
of creatinine against the serum creatinine, you have a hyperbolic
function.

Now, creatinine measures the glomerular filtration rate because it is
freely filtered and it is not reabsorbed by the kidney. However, there
is some secretion of creatinine so that it is not an ideal measure, but
it is clinically the most convenient measure of the glomerular
filtration rate. The ideal measure is a molecule that is not secreted at
all.

Given the fact that we have a hyperbolic function, it\'s important to
note that whenever the serum creatinine doubles along this curve, the
creatinine clearance halves. Early then in the course of renal disease,
a relatively large change in creatinine clearance is associated with a
relatively small change in the serum creatinine. However, doubling means
halving of the clearance. Late in the curve, relatively small changes in
clearance are associated with large changes in the serum creatinine
because it\'s a hyperbolic function.

So, in designing a trial, the goal is to have an entry criterion where
patients enter in an area where changes in the glomerular filtration
rate are reflected by readily measurable changes in the serum. Later in
the course of renal disease, small changes cause large changes in the
serum creatinine, and so again in the design of a clinical trial, we\'re
looking at the changes here being reflective of the phenomenon that we
are measuring.

A number of years ago, we, the collaborative study group, carried out
the study of ACE inhibition with captopril in type 1 diabetic
nephropathy, and we used, as an endpoint in that study, doubling of
serum creatinine, meaning halving of the glomerular filtration rate
relative to the baseline. When we compared the doubling of creatinine to
the clearances in those patients who had doubled, we looked at
iothalamate clearance and creatinine clearance. Now, iothalamate happens
to be a molecule that is ideal for measuring the glomerular filtration
rate. It is freely filtered. It is not reabsorbed and it is not
secreted. As you can see, among the patients who doubled their
creatinine in that study, there was at least a halving of the glomerular
filtration rate. So, we felt that that justified our use of doubling of
serum creatinine for that definition of halving of the glomerular
filtration rate.

End-stage renal disease is the clinical requirement for renal
replacement therapy. The Medicare definition of end-stage renal disease
for patients with diabetic nephropathy is a serum creatinine of greater
than 6 or a creatinine clearance of less than 15 mls per minute, so that
in order to use an objective definition and get away from variances in
practice of nephrology in terms of the use of dialysis in patients with
kidney disease. The objective definition of end-stage renal disease is
taken as the federal Medicare definition of serum creatinine of greater
than 6, and that again comes into the design of the study that you\'ll
be hearing today.

This relationship then between the creatinine clearance and the serum
creatinine actually defines renal function. Creatinine parameters are
not surrogates; they are not substitutes. The creatinine parameters
define the ability of the kidney to filter the blood.

To reflect further on the type 1 diabetic nephropathy trial which
preceded our type 2 diabetic nephropathy trial, when we looked at the
so-called hard endpoints of death, dialysis, or transplantation in the
captopril trial of type 1 diabetic nephropathy patients, there was a
risk reduction of 50 percent for that endpoint among the patients who
received captopril as opposed to placebo.

When we looked at the Kaplan-Meier curve for doubling of serum
creatinine, we had the same risk reduction and approximately the same
curve. And the reason for that is that the median time from a halving of
the glomerular filtration rate to end-stage renal disease was only 9
months so that a halving of the baseline glomerular filtration rate in
diabetic nephropathy, with its inexorable downhill course, is a very
important milestone. And as you will see, this is true in the type 2
patients as well. And that explains why a doubling of serum creatinine
correlated so well with the hard endpoints in the previous study.

Now, I want to remind you about the structure of the glomerular filter
because what we\'re really studying is the function of the glomerular
filter. What this graphic shows is that the glomerular capillary bed ‑‑
glomerular capillaries having three layers basically, endothelial cell,
basement membrane, and epithelial cells, so the filtration is going on
here ‑‑ and it is built on an architectural structure of connective
tissue which is known, here in pink, as the glomerular mesangium.

Now, in a normal glomerulus, the black here is silver staining of the
glomerular basement membrane, and you can see these beautiful, graceful
basement membranes of the capillary loops, and one can barely see the
architectural structure on which these glomerular capillary loops lie.

This is the face of the enemy for a nephrologist. This happens to be
from a biopsy that was taken during a pilot trial that the collaborative
study group did prior to the irbesartan diabetic nephropathy trial that
you\'ll be hearing about. In this pilot trial, we utilized entry
criteria which approximated those which are used for the IDNT, and we
did renal biopsies on these patients with type 2 diabetic nephropathy in
order to determine the nature of the glomerular lesion which we would be
studying.

This is quite typical of what we found. As you can see, typical of
diabetic nephropathy, there is a marked increase in the connective
tissue of the glomerular mesangium, and it is the progression of that
connective tissue which leads to scarring and obliteration of the
glomerular capillaries which is ultimately responsible for renal failure
in diabetic nephropathy.

In this case, as is true in the average case entering the IDNT, the
patient had already lost 50 percent of their renal function so that in
the irbesartan diabetic nephropathy trial, what we have are patients who
have this advanced abnormality and what we\'re trying to do is prevent
further progression of that abnormality.

In the design of a therapeutic program, given the goal of preventing
progression of the established lesion, it would seem appropriate to not
only try to tell doctors to try to prevent progression of that lesion,
but it would appear appropriate to tell doctors to treat a patient so
that they can prevent this advanced lesion from ever occurring. And for
that reason, it is logical to study early diabetic nephropathy to see
whether you can, in fact, tell a physician that they can treat a patient
to prevent them from going on to advanced disease.

Now, there are a number of abnormalities that can be measured in early
diabetic nephropathy. Structurally the abnormal connective tissue
metabolism which occurs in diabetic nephropathy occurs very early so
that there is marked thickening of the glomerular basement membrane in
patients who are biopsied very early with the first evidences of
diabetic nephropathy and there is expansion of the glomerular mesangium,
which you saw. If one wanted to look for the signal for connective
tissue metabolism, say, mRNA for type IV collagen, you will find an
increase in the signal very early, and I\'ll show you some data about
that.

Structurally, functionally the earliest evidence of diabetic nephropathy
is an alteration in the selective permeability characteristics of the
glomerular capillary wall, which means that the normal permeability
characteristics, which means exclusion of the filtration of
macromolecules, begins to be breached, and from a clinical point of
view, a reliable and reproducible way of measuring that is to measure
small amounts of albumin which begin to appear in the urine at the
earliest stages of diabetic nephropathy.

So, the first functional alterations are associated with increased
filtration of albumin, and some of that is reabsorbed by the renal
tubules. That which is not reabsorbed is excreted in the urine, and that
is referred to by the term microalbuminuria.

Now, microalbuminuria is defined as a urinary excretion of abnormal
quantities of urine, more than 20 micrograms per minute, which is
approximately 30 milligrams per 24 hours, and less than 200 micrograms
per minute, which is approximately 300 milligrams per day.

Now, the reason for the upper limit is it is somewhat artificial but it
is the borderline between microalbuminuria and the definition of overt
proteinuria or overt nephropathy. The reason that it\'s the borderline
is in fact that is where the routine clinical tests that doctors use for
proteinuria, the dip stick, turns positive. So, if you want to find out
whether there is an abnormality in the selective permeability
characteristics of the glomerular capillary earlier, you have to do
specific tests for albumin. The clinical dip stick is negative. So,
that\'s what defines overt nephropathy.

This is from a biopsy of a patient who has very early diabetic
nephropathy and microalbuminuria, and as you can see, there is basement
membrane thickening here, but there is a beginning of the increase in
glomerular mesangial material which ultimately leads to the florid
lesion that you\'ve already seen.

Most studies of microalbuminuria or early nephropathy have been done in
type 1 patients for a variety of reasons. I\'ll be glad to answer
questions about that later. However, it has been consistent to find
thickening of the glomerular basement membrane of the order of magnitude
similar to patients who have overt nephropathy in patients with early
nephropathy, and there is a beginning, as you saw, of mesangial
expansion in these patients.

In a study carried out by Sharon Adler, she looked at normal patients
who were living related donors, biopsies from normal patients, biopsies
from patients with diabetes who had normal albumin excretion, meaning
less than 20 micrograms per minute, patients who had microalbuminuria,
and patients with overt nephropathy. So, as you can see, among this
group the serum creatinine would naturally be normal in normals, it\'s
normal in patients with diabetes and no microalbuminuria, and it\'s
normal in patients with microalbuminuria because early in the course of
diabetes, you don\'t have changes in the ability of the filter to
function. Of course, in overt nephropathy, the creatinine is going up
because your glomerular filtration rate is going down, as you see here.
The albumin excretion rate in the microalbuminuric patients is 56 and in
overt nephropathy 4 grams.

And she measured the glomerular collagen mRNA for type IV. As you can
see, the signal in microalbuminuric patients is elevated the same as in
overt nephropathy, so that the biochemical abnormality for the
development and continuation of diabetic nephropathy is there early,
giving us good reason to intervene as early as possible.

If one were to study early diabetic nephropathy then, it is not
practical to study the structural abnormalities which occur early. It
would mean doing renal biopsies on hundreds, if not thousands, of
patients, and these are not easy patients to biopsy. They are very
obese.

The functional abnormality of altered capillary wall perm selectivity is
what we are left with in order to study early diabetic nephropathy. And
as I\'ve said, the macromolecule of clinical relevance which can be
measured and is accurately measured and reproducibly measured is
albumin.

Now, the very quantity of microalbuminuria in a study could be measured
and a conclusion made from the study, or a study can use as an endpoint
the movement from the microalbuminuric state to the overt nephropathy
state, meaning that the patient has crossed the border of 200 micrograms
per minute. So, they have progressed.

The importance of that is that in this progression of diabetic
nephropathy, that\'s what happens. Patients go from small amounts of
albuminuria to clinically overt proteinuria/albuminuria and then the
glomerular filtration rate starts going down. You cannot get a patient
having decreased glomerular filtration rate going to end-stage renal
disease without them going through the period of overt proteinuria. So,
in the design of a trial ‑‑ and the IRMA 2 trial is so designed ‑‑ what
we are looking for is an endpoint which accurately measures the movement
from microalbuminuria to overt nephropathy.

The rationale for the clinical development program then was to determine
whether inhibition of the renin-angiotensin system is renoprotective in
type 2 diabetic nephropathy just as it is in type 1 diabetic
nephropathy. And renoprotection is the term applied to the the effect of
a drug in protecting the kidney from progressive renal disease which is
independent of other systemic effects that that drug might have such as
blood pressure lowering.

Now, there are several reasons why interruption of the renin-angiotensin
system could be renoprotective in diabetic nephropathy. The glomerular
capillary tuft is an arteriole portal system, meaning that the
capillaries have an arteriole feeder and an arteriole drains the
capillary tuft, so that the pressure within the glomerular capillary
tuft is under the control of changes in the two arterioles.

In a normal kidney, there is autoregulation of the blood pressure within
the capillaries, meaning that in a normal person, if your blood pressure
goes up, there is constriction of the afferent arteriole so that the
pressure within the glomerular capillary tuft remains constant. In the
diabetic state, which has been directly measured in animals, but of
course not directly measured in humans, there is deficiency of that
autoregulation meaning that any elevation in the systemic blood pressure
is more directly transmitted to these capillaries and there is the
barotrauma opportunity there. So, any drug that lowers the systemic
blood pressure will lower glomerular capillary tuft pressure because of
this deficient autoregulation.

More importantly in the diabetic state, there is constriction of the
efferent arteriole for reasons that are not clear, and that is under the
influence of angiotensin II. So, in the diabetic state, there is an
increase in glomerular capillary tuft pressure directly measured by Dr.
Brenner and associates many years ago because of this increase in the
tone of the draining arteriole. So, inhibition of the renin-angiotensin
system at that level relieves that pressure and diminishes barotrauma.

Furthermore, abnormal matrix metabolism ‑‑ and I\'ve shown you
histologic examples of that ‑‑ is under the control of angiotensin II
modulation through TGF-beta which controls collagen type IV metabolism
in the kidney, as well as other connective tissue proteins.

Lastly, there is an issue of whether increased amounts of protein
trafficking through the kidney is nephrotoxic and angiotensin II, in
addition, does decrease glomerular filtration of macromolecules. So, it
is possible that a decrease in proteinuria traffic is also a protective
mechanism. So, there is good reason to believe that the therapeutic
interruption of the renin-angiotensin system can be renoprotective in
this disease.

So, we will be presenting studies of early diabetic nephropathy, the
IRMA 2 study, the goal of which was to show whether one could stabilize
the perm selectivity abnormality in the kidney so that the patient did
not go on to overt proteinuria and nephropathy and the irbesartan
diabetic nephropathy trial which looked at the therapy of the advanced
lesion to see whether the progression of advanced nephropathy could be
inhibited.

The goal then of the irbesartan diabetic nephropathy trial is to take
patients whose substrate glomeruli looked like this and prevent the
progression of this advanced lesion.

With that, I\'m very pleased to introduce Dr. Melisa Cooper who will
review with you the results of the irbesartan diabetic nephropathy
trial. Thank you.

DR. BORER: Thank you very much, Dr. Lewis.

Before Dr. Cooper begins, I want to determine if there are any committee
questions. We have some new people on the committee and some guests, so
I\'d like to set some early ground rules and make a statement.

One of the over-arching issues we\'re facing here ‑‑ and I think you\'ve
outlined it really extraordinarily for us ‑‑ is to determine what the
drug may do, once we hear the data, that causes clinical benefit, makes
a patient feel better or live longer, versus what are pharmacological
effects, that is, what makes the tests look better but may not have an
impact in a significant way on making the patient feel better or live
longer. So, that\'s an over-arching issue that we\'re going to have to
consider because we really need to see some evidence of clinical
benefit, which we may well.

With that in mind and with that lovely presentation having been given, I
want to ask if there are questions of Dr. Lewis, and I\'d like to
structure that just a little bit. I want to begin with the committee
reviewer, JoAnne Lindenfeld, and then we have two nephrologists who are
ad hoc members of the committee today, Dr. Kopp and Dr. Brem, Dr. Kopp
from the NIH and Dr. Brem from Rhode Island Hospital. So, after JoAnne,
I\'d like to hear from the two nephrologists and then we can ask if
anybody else has any questions about the presentation of Dr. Lewis.

DR. LINDENFELD: I\'d like to echo that was a lovely presentation. Thank
you.

Just some questions I have about clarification. One, could you tell us
something about the progression of renal disease in diabetics in blacks
and Hispanics compared to whites?

DR. EDMUND LEWIS: Yes. Well, of course, in type 1 diabetic nephropathy,
it\'s basically so few patients from those ethnic groups that we don\'t
know a lot except that the few patients who are black, African
Americans, who have type 1 diabetic nephropathy do progress faster than
whites.

In type 2 diabetic nephropathy, overall patients who are Hispanic
certainly tend to have a more rapid progression than patients who are
white, and I think that the relevant literature on this actually is
Native American literature. It\'s the Pima Indian data because I think
genetically the Hispanic problem for type 2 diabetic nephropathy is
probably based there as far as we can tell from the course of that
disease. So, it occurs earlier in patients who are Hispanic and it is
certainly inexorably progressive.

In terms of whether the absolute rate of progression is worse, that is
not entirely clear. Reflecting on the Pima Indian data, the rate of
progression of early, meaning microalbuminuria to overt proteinuria,
actually approximates the white population and the rate of progression
of the disease itself also might be a little faster, but it also
approximates the white population. So, it\'s a bigger health problem,
but in terms of what one can expect from the course, other than its
occurring earlier in the life of a patient, the courses aren\'t that
dissimilar.

Again, there\'s less information about African Americans, but I think as
a general statement one can say that kidney disease, not just diabetic
kidney disease, but hypertensive kidney disease and the like, appears to
be more progressive in the African American population and more
refractory to any therapies.

DR. LINDENFELD: So, to just follow up on that, in a study that evaluates
progression of renal disease, you would like to see those groups,
blacks, Hispanics, be equal in all treatment groups.

DR. EDMUND LEWIS: Well, I suppose that you would like to see that, but
the problem is that you have to find these patients. I think it would be
a more accurate reflection of what I would say is that in a study of
type 2 diabetic nephropathy, it would be appropriate to make every
effort to get minority groups in the sample. There\'s no doubt about
that.

To get parity I think would be extremely difficult. I think that as you
will see in the IDNT, when you start talking about multinational studies
and so forth, the representation, for example, among the blacks in the
United States in that study was certainly equivalent to the relative
population of blacks and so forth, but then when you start to get
European involvement, there are no blacks. So, it\'s harder to construct
a study where you have parity there. I don\'t know exactly how you would
come to that.

DR. LINDENFELD: I guess my question relates to whether or not one would
design the study for stratify for race, for instance, to make sure that
different races were equally represented among the groups.

DR. EDMUND LEWIS: Yes, I don\'t know. I think conceivably one of the
biostatisticians in the group might want to address that. I think that
the pre-stratification of a clinical trial such as this I think brings
in certain complexities, not the least of which is you expand your
sample size tremendously and make the study even harder to do.

There are other issues about bringing minorities into clinical trials
which also are a little difficult, and I think the AASK trial at the NIH
showed that it\'s hard sometimes to get minority populations into
clinical trials such as this.

DR. LINDENFELD: Right. I\'m not just talking about recruiting, but
rather making sure that the minority groups are equally represented
among the treatment groups.

DR. EDMUND LEWIS: Oh, yes. No, I agree with that. Absolutely.

DR. LINDENFELD: And I think that\'s going to be an important point. At
least the literature would suggest there is an increased rate of
progression of diabetic renal disease in minority groups, suggesting
that you\'d want those to be equal.

Just a second point just for my own understanding. Can you tell us if
there are any commonly used drugs ‑‑ and we use a lot more drugs in
these patients now than we did when the captopril study was done ‑‑ that
affect the secretion of creatinine or the absorption of albumin?

DR. EDMUND LEWIS: In this trial ‑‑ actually it was true in the captopril
trial too ‑‑ in order to control blood pressure, in addition to the
coded medications, at least three antihypertensives and diuretics were
used. So, the treatment of hypertension, which of course, actually both
from a cardiovascular and a renal point of view, is terribly important
in this patient population, is a polypharmacy issue and that is a very
relevant question.

None of the antihypertensives ‑‑ actually we had this data in the type 1
study because it was a much smaller study. We had iothalamate clearances
in those patients, so we were able to determine whether drugs altered
creatinine secretion better because we had both the creatinine clearance
and the iothalamate GFR. We can compare those.

The antihypertensive agents generally used, which is what was used in
the study, and the diuretics generally used would not alter
significantly the creatinine secretion course. And I think this sort of
goes back to your first question. The randomization of these patients
and the fact that all of these drugs were being used in all patients
would sort of cancel things out if there was a minor difference, but to
our knowledge there is no difference.

And in terms of albumin excretion, I think all that you can say about
that is that there is certainly a relationship between the variance in
albumin excretion and the systemic blood pressure so that if you lower
the systemic blood pressure, you will have less albumin excretion over a
very broad range of albumin excretion. Therefore, in designing a study
where one\'s endpoints are albumin excretion, you have to account for
the blood pressure lowering effect.

DR. LINDENFELD: And then just one final question. In the type of patient
that was entered in the IDNT trial, a patient with gross albuminuria and
elevated creatinine, how much would you expect the initiation of
diuretics to change the serum creatinine?

DR. EDMUND LEWIS: I wouldn\'t. I think what we found is that ‑‑ you see,
it\'s hard for me to answer this question for the trial because in a
very complex group of patients like this, physicians were using more and
less diuretics according to how much edema the patient had. We were
really all over these doctors in terms of controlling blood pressure and
stuff. So, there were variances in dosing even of diuretics.

But the only direct answer that I can give you about that is that we did
have a protocol about elevation of the serum creatinine early because
what we were concerned about was whether, using an agent like
irbesartan, something that interrupted the renin-angiotensin system, a
patient with bilateral renal artery stenosis would go into acute renal
failure.

Now, as it turned out, that didn\'t happen during the study, but there
were patients who raised their serum creatinine early in the study
because they suddenly had their blood pressure controlled, and you will
see the data on that. Most of the patients coming into the study were
way out of control relative to any standards, and once they had their
blood pressure controlled, which included diuretics, there would be a
bump in creatinine in a number of these patients, and we at the clinical
coordinating center of the collaborative study group would be advised
about these patients I think generally, usually. Certainly if they
doubled their serum creatinine, we would, but if they raised it by 25
percent, we would be advised about that, and we would talk through the
clinical problem and invariably the creatinines came back to normal once
diuretic therapy was modulated. So, these are very complex patients.

I think that we had the appropriate feedback to figure out that this was
happening, and it was not a study-long issue. It was an issue that would
occur early in the study when these patients were getting their blood
pressure controlled.

DR. BORER: Dr. Kopp?

DR. KOPP: Thank you. I\'d like to echo a second time that that was an
excellent presentation of a complicated topic.

I\'d like to get your thoughts about a topic that I\'m sure will come up
again which is the role of macroproteinuria as a surrogate endpoint for
both diabetic nephropathy and in the future nondiabetic nephropathy. We
know that the level of proteinuria represents a graded spectrum of risk
for rates of progression. Do we know quantitatively what level of
reduction in proteinuria is clinically significant, and is there data in
terms of a similar quantitative reduction in risk of progression?

DR. EDMUND LEWIS: Well, you know, I think nephrologists are on the same
wavelength on this issue, and I think that the wavelength that we\'re on
is that I think we\'re all beginning to understand that the more
proteinuria you have, the worse your course will be. I think that we can
all agree with that.

I think the other thing that we have to say for certain is that no
clinical trial has been designed to test the answer to your question.
You can tell me if I\'m wrong on this, but I think that it would require
a design where you\'re actually shooting for two different levels of
reduction of proteinuria, for example, and that hasn\'t happened. So,
all of the data that we\'re working with is post hoc.

Having said that, I think that when one looks at a given disease like
diabetic nephropathy, given the problem of constraints of how long
you\'re actually going to be able to follow these patients in a clinical
trial, I think the best that we can say is that one group did or didn\'t
progress in terms of their proteinuria more than the other, implying
that the patients who had greater progression of proteinuria are at
greater risk of continuing renal damage.

I think that almost for certain any study of kidney disease where the
patient does well, well being progression or regression of renal
disease, the proteinuria goes down. And any patient who does poorly,
that is, their GFR keeps going down, the proteinuria is likely to go up.
But it becomes a chicken and egg thing then because is the proteinuria
going up or down because you\'re treating the glomerulus or is it going
up or down because proteinuria is a determinant of nephrotoxicity let\'s
say. And I don\'t think that any of these trials, including the ones
you\'ll be hearing today, necessarily ‑‑ Dr. Parving might have
different feelings about this, but I don\'t think they necessarily help
in terms of answering your question.

DR. KOPP: So, I guess I hear you saying perhaps it\'s not quite time to
begin to use proteinuria as an endpoint in and of itself. Is that the
implication?

DR. EDMUND LEWIS: No, I\'m not saying that because what I\'m saying is
that I think that ‑‑ well, the first thing that I have to say is that ‑‑
and I think again nephrologists understand this in general together
well. When you\'re studying a filtration system, there are so many
things you can study, and it doesn\'t matter whether you\'re an
industrial engineer or a bioengineer studying dialysis membranes or a
renal physiologist. What you can study is either the capacity of the
membrane ‑‑ and in terms of the kidney, it\'s the glomerular filtration
rate ‑‑ or the selective permeability characteristics of the membrane,
which in glomerular disease is proteinuria.

So, I think that it is time for us to recognize that if one prevents
going from low amounts of protein excretion to high amounts of protein
excretion, certainly we have enough correlations there to be able to say
that that is progression of the renal disease. So, I would argue that a
study, the goal of which was to show that you didn\'t go from one stage
of the disease to the next stage of the disease, more proteinuria, is a
valid study of the intervention in the course of renal disease. But
that\'s just my opinion.

DR. KOPP: Thank you.

DR. BORER: Dr. Brem?

DR. BREM: I\'d like to ask again a question about glycemic control. One
of the things that people have stressed in the past is adequate glycemic
control for patients and that that is a major factor in progression of
disease. Yet, there wasn\'t any discussion about that in your
presentation. I was wondering if you might comment a bit about that and
perhaps how it may affect outcome.

DR. EDMUND LEWIS: Well, glycemic control in either the type 1 or type 2
patients is certainly not easy, but in the type 2 patient, it is
extremely difficult because of the fact that you can\'t just give them
insulin and get the response you want. I think we have the UK PDS, for
example, which says that a glycemic control is important.

In the IDNT, there was a tremendous range in terms of hemoglobin A1C\'s
which narrowed over the course of the disease. However, there was still
a range. These people are extremely hard to control.

One of the investigators who was on our executive committee, Dr. Rudy
Bilous of Great Britain, who\'s I think a well-respected diabetologist
worldwide, looked at our hemoglobin A1C data relative to data that they
had gotten in the United Kingdom of control of type 2 diabetes and found
that basically the distribution of our hemoglobin A1C\'s was exactly
what was the case in the general population of type 2 diabetic patients.

More important to your question is that irrespective of how difficult it
is to control hemoglobin A1C\'s, the level of hemoglobin A1C throughout
the study in all three treatment groups was equal.

DR. BREM: Right. Well, I guess the question I was asking is if the
hemoglobin A1C were in the lower range, did those patients progress more
slowly in all the different categories of treatments from these
different studies, sort of an analysis of variance.

DR. EDMUND LEWIS: I think that neither the collaborative study group nor
Bristol-Myers Squibb has looked at quartiles or quintiles of hemoglobin
A1C and the rate of progression. I think we just haven\'t looked at
that. I think that it is an interesting question, but I think that for
us the two really burning issues were: one, was our glucose control what
is seen in patients in the wild, which was true; and two, was it
equivalent in all three groups. Of the many, many analyses that we\'ve
done through, I\'m sorry to say we haven\'t done the one that would
satisfy you for that question.

DR. BREM: The other was a minor thing I guess in terms of the creatinine
doubling. That I guess is assuming that the creatinine in most people
is 1. As a pediatric nephrologist, I would point out that many children
have creatinines considerably below 1 and perhaps small adults have
creatinines that are below 1 as well, as creatinine reflects muscle
mass. If the creatinine is below 1, for instance, and doubles, it may go
into what\'s still considered a normal range and yet be doubled and, in
fact, probably represents a 50 percent reduction in renal function. Does
that 9 months apply to those patients?

DR. EDMUND LEWIS: Yes. No, I agree with that although I just want to
expand on that for non-nephrologists who don\'t think about creatinine
clearance on an hourly basis during the course of the week. The
hyperbolic curve that I showed you, that particular curve would have
been 100 over the serum creatinine. In very muscular people, the daily
creatinine production would be much higher, which would shift the entire
curve to the left, but it remains a hyperbolic curve with the same shape
and so forth. In small people, children, very elderly people and so
forth, the curve might be shifted to the left rather than the right
because they\'re making much less creatinine but it\'s still a
hyperbolic curve.

In our study ‑‑ and you\'ll be hearing more about this ‑‑ the creatinine
entry was such that you could not double your serum creatinine and
remain in the normal range. If you doubled your serum creatinine, you
were in the high 2\'s or 3\'s. I think a woman could have a lower
creatinine and come into the study, but still, when they doubled, their
creatinine was quite elevated. So, we don\'t have information about
patients who doubled their serum creatinine and it\'s still in the
normal range.

I think because of the hyperbolic curve, which would be much steeper in
a child, it would be much harder to know exactly where you\'ve doubled
and halved your creatinine clearance because you\'re really on that down
slope which is why, in the design of the clinical trial, we\'re going to
the linear part of the hyperbolic curve not up the vertical axis.

DR. BREM: So, those patients probably already had evidence of
significant renal disease or impairment at the start perhaps of their
study.

DR. EDMUND LEWIS: Yes. The mean GFR coming into our study was 50 and the
mean urine protein was 900 milligrams. The glomerulus that I showed you
was not the worst glomerulus that I picked out of 30 renal biopsies. We
really were studying advanced disease.

But I think that you hit upon the issue which we just discussed, and
that is the patient with early diabetic nephropathy, which is where you
really want to intervene, is in many ways analogous to the patient who
is a child. That is, you start to get evidence of renal disease, but you
can\'t actually measure it accurately by measuring the glomerular
filtration rate. So, all that is left for us is measuring the other
parameter of filter function which is permeability. I mean, that\'s all
that\'s left.

DR. BORER: Before we go on to other questions, let me ask Bristol-Myers
Squibb to sort of make a bookmark because you may have some data which
we haven\'t heard yet, so I don\'t want an explanation now, relevant to
Dr. Brem\'s question. My recollection is you did Cox model analyses on
these data, so you could at least tell Dr. Brem and the rest of us
whether the effect on proteinuria and the other endpoints is independent
of the effect on glycemic control or on glucose or on hemoglobin A1C
even though you may not be able to give specific data. Don\'t tell us
now but when you present the data.

Are there any other questions from people around the table about the
pathophysiology of renal disease? Ray, you had a question?

DR. LIPICKY: I guess I\'d like to just clarify something as a
non-nephrologist. I think I heard you saying two things, and maybe you
did and maybe you didn\'t. But you\'re saying, I think, that if you
understand kidney disease, the creatinine is not a surrogate measure of
anything. It is a measure of disappearance of functional glomeruli, and
consequently although patients don\'t feel anything and there is no
morbid/mortal consequence that is associated with any creatinine, it is
a direct measure of how many functional nephrons you have and that may
be just an exaggeration. So, that\'s part one.

Then part two is that although progression from microalbuminuria to
overt proteinuria again is not a symptom, that if you understand the
nature of the disease, that is a sure sign that something has happened
to the glomeruli, and if you do not see that happen, then that\'s a sign
that nothing has happened to the glomeruli. Did I say that in the right
way?

DR. EDMUND LEWIS: Let me think about it for a second.

Now, one thing you should understand, Dr. Lipicky, is that in the
profession we consider you a nephrologist.

(Laughter.)

DR. EDMUND LEWIS: So, I just want to make that clear.

In terms of the creatinine parameter, yes, I think that you state it
correctly, and that is in terms of kidney diseases, in terms of the fact
that there\'s disease going on in the kidney, not just type 2 diabetes,
but a whole variety of kidney diseases are silent. And if you are trying
to measure the progression of renal disease, you are left with measuring
the functional ability of the kidney as a filter, and creatinine is a
direct measure of that filter. That\'s why I say it\'s not a surrogate
because it is measuring the function.

And in terms of the proteinuria question, yes, once again, I think that
in proteinuria studies you have to be careful because there are, on a
day-to-day basis, many factors which can alter the excretion of protein,
including if you run up to the top floor of this hotel and run back
down, you will excrete more albumin than if you were just walking around
here. You have to be careful about that because there are alterations in
the tendency of that filter to leak protein under a variety of
conditions, chain smoking cigarettes for a while, running around,
running marathons, and so forth. But when you get fixed increases in the
level of protein excreted and you start crossing borders, like the
border into overt dip stick positive proteinuria, you are then talking
about changes which reflect the early changes in the course of disease.

DR. BORER: Any other questions? I think Alan and Steve each had a
concern. Alan?

DR. HIRSCH: My question is again a follow-up to Dr. Kopp\'s and my
nephrology colleague\'s question. When we talk about surrogate markers,
obviously, we have to place some kind of value on the surrogate, and
later today we\'ll be talking about combined endpoints and value to the
patients. I want to come back one more time.

With some surrogate markers, there\'s a percent reduction in LDL
cholesterol. I know pretty well what that does to the patient in terms
of any cardiovascular risk. There must be some threshold below which
intraocular pressure decrease will prevent blindness, some nadir wedge
pressure change which alters shortness of breath and mortality.

What I struggle with as a non-nephrologist is what level of
microalbuminuria change has any impact down the road in some time frame
on a clinical outcome. Do we have any information, or is it merely at
this point a qualitative improvement in the natural history?

DR. EDMUND LEWIS: Tell me if this is adequate or not. What I would like
to do, since Dr. Parving is probably the most logical person in the
world to discuss this topic, I really want you to hear his opinion about
this.

But to just go back to my answer to Dr. Lipicky, I think the problem is
the goal being early intervention. I think that your confidence about
measuring something that doesn\'t have a symptom and that is a point in
time during the course of a disease is dependent upon how much
information you have about the natural course of this disease. One of
the things that you can be sure of in diabetic nephropathy is that the
course is inexorable, so that when you start to see increases in urine
protein excretion, you can be certain that that will progress if there
is not an effective intervention. I think we know enough about the
course of diabetic nephropathy to be able to say that, but to a certain
extent, I\'d like to defer to Dr. Parving who\'s done I think most of
the really truly valid publishable studies in this area.

DR. BORER: Maybe we can hold that for Dr. Parving\'s presentation.

Final question, Steve?

DR. NISSEN: The cause of mortality in these patients of diabetic
hypertensive disease, if I\'m correct, isn\'t about 80 percent of the
mortality cardiovascular?

DR. EDMUND LEWIS: Yes.

DR. NISSEN: Myocardial infarction and stroke being the most common.

DR. EDMUND LEWIS: Yes.

DR. NISSEN: So, would not one test of this surrogate of doubling
creatinine be the relationship between the ability to affect the
doubling of creatinine and the ability to affect cardiovascular
mortality, death, myocardial infarction, nonfatal infarct, stroke, et
cetera?

DR. EDMUND LEWIS: See, I think it\'s not a one to one. It\'s a relative
increase. And we\'re talking about populations now.

You get into a very interesting, complex issue, and these are
interesting and complex patients let me tell you. There\'s no pleasure
to do a clinical trial with this group of patients.

Microalbuminuria in the nondiabetic population ‑‑ let\'s say the
hypertensive population ‑‑ is a marker of cardiovascular disease.
People, for example, with hypertension who have microalbuminuria have a
much worse prognosis over the next 10 years in terms of myocardial
infarction, cardiovascular death and so forth than people with
hypertension who don\'t have microalbuminuria. And we don\'t know why
that is. We don\'t know what the vascular issue is that explains that.

But I think that at this point I have to say that because there are a
number of clinical states associated with decreased perm selectivity and
microalbuminuria, it doesn\'t negate the importance of that parameter in
diabetic nephropathy just as decreased glomerular filtration rate is
seen in many diseases, it doesn\'t mean that studying that in diabetic
nephropathy is not valid.

So, the microalbuminuria means that, indeed, that is a population of
patients who have increased cardiovascular risk. Obviously, type 2
diabetic patients have increased cardiovascular risk. But I don\'t think
that one can draw the conclusion that you can use a renal parameter in
patients with overt or even latent diabetic nephropathy with a
cardiovascular index and say the cardiovascular event is the hard
endpoint even though the albumin is the renal parameters ‑‑

DR. NISSEN: But if that\'s what happens, if your renal function gets
worse, you ultimately go on and die a cardiovascular death, then
wouldn\'t one want to see that a drug that slows the development of
end-stage renal disease would have a beneficial effect on the hard
cardiovascular endpoints? What I\'m getting at is, as a way of
validating the surrogate, whether or not we ought to see such a
relationship.

DR. EDMUND LEWIS: You know, you\'re undermining my concluding
statements.

(Laughter.)

DR. EDMUND LEWIS: The thing is that if you look at the cardiovascular
course of patients with type 2 diabetic nephropathy, certainly there are
excess cardiovascular events throughout nephropathy and those patients
with type 2 diabetes who have proteinuria have many more cardiovascular
events than those who don\'t, and those who have a decrease in GFR have
more still than those who don\'t. And when they go on dialysis programs,
the cardiovascular events go way up. Of course, that is why, in terms of
preventing cardiovascular events, the one dramatic thing that we can do
is prevent them from going on to end-stage renal failure.

But I think that in this patient population, what I\'ve come to see is
that the cardiovascular disease in patients with advanced renal disease
‑‑ so, we\'re talking about the IDNT patients ‑‑ is so advanced when you
start to study those patients that I don\'t think that you can use a
cardiac endpoint to indicate that you\'ve done something as far as ‑‑
you know, that altering the progression of kidney disease can alter
that. I think that that\'s what it comes down to.

DR. BORER: I made a misstatement. We have one final question from the
far side of the table there.

DR. TEMPLE: The previous discussions are interesting. They go to the
heart of surrogacy and all kinds of things. I would say we\'ve certainly
accepted the idea that creatinine doubling is an anatomical finding that
has something to do with whether you\'re going to have renal failure.
That\'s not a big stretch in many ways for reasons you just gave.

It would be true, though, that something that had a physiologic effect
or a pharmacologic effect on creatinine might not be very persuasive
because what you\'re saying is when you see a creatinine doubling,
that\'s really an anatomic effect. You\'re describing the state of the
glomeruli. So, something that had a transient effect wouldn\'t be nearly
as persuasive. You wouldn\'t know what to make of that. JoAnn was sort
of asking about that before.

My question goes to the microalbuminuria. Do we know whether any of the
drugs being studied here might have a sort of physiologic effect ‑‑ I\'m
not sure what that would be ‑‑ that would decrease the amount of albumin
but not really reflect the state of the kidney?

Just by analogy when people wanted to say that use of ACE inhibitors at
the time of an infarction would prevent remodeling, we always said,
well, that\'s nice but just showing a change in ejection fraction while
still on drug is not very impressive because that just may be that
you\'re a vasodilator. So, that doesn\'t prove anything. Take the drug
away and show us that you still have an impact on ejection fraction.
That would be convincing.

So, my question is how, does that apply to the microalbuminuria findings
here? Is there anything these drugs might do that could be fooling us
about whether they\'re really making an anatomic change or just sort of
changing the hemodynamics in the kidney to alter protein excretion?
What\'s known about that?

DR. EDMUND LEWIS: I think that that\'s the important question for you.
It\'s the important question for us when we\'re designing trials, and in
a way it is very, very difficult to come up with a concrete answer
unless you follow these patients for 10-15 years. So, we do have the
constraint of coming up with a parameter within the period of some
reasonable clinical trial.

I think that Dr. Parving will address this because in the IRMA 2 trial,
the higher dose angiotensin receptor blocker actually was associated
with continued decrease of urine albumin excretion even after the drug
is stopped. And I think that that\'s probably the best that you can ask
for if you want to say it\'s physiological. It\'s not physiological.

I think in terms of the preamble to your question, there\'s very, very
little known about tubular reabsorption of albumin, and I think that you
will see in the IRMA 2 trial data with two doses of ARBs and so forth. I
don\'t think that there is a reason to believe that decreased albumin
excretion is because the same amount has been filtered and more is being
reabsorbed. That certainly does occur for sure with lowering the blood
pressure and that has been accounted for in this trial. So, I think my
goal here is to get off this podium.

(Laughter.)

DR. EDMUND LEWIS: After Dr. Parving\'s talk, I hope you will grill him
about this.

(Laughter.)

DR. BORER: This is really the final question. Tom?

DR. FLEMING: Well, I think my colleagues have asked a lot of the key
issues here, as I\'ve been thinking about it, but I think Dr. Temple
just got at something that I\'ve been thinking about as I\'ve been
listening to you.

You had mentioned creatinine clearance is, in essence, not a surrogate.
It is truly the clinical event of interest. And listening to your
presentation, it strikes me that what would be the truer measure would
be something that\'s fundamentally structural progression, structural
abnormality versus functional abnormality. I\'m motivated to ask the
question by Bob\'s question because it seems as though there are more
factors that could influence the functional abnormalities. Wouldn\'t we
best be served, although it may not be so achievable, to be looking at
something that is directly structural progression, structural
abnormalities?

DR. EDMUND LEWIS: Well, no. I think in an ideal world ‑‑ and I think
it\'s not unreasonable to make that demand. You know, this is coming out
of a life where my focus has not been diabetes. It\'s been lupus
actually. So, we\'re more interested in structural and functional issues
there.

First of all, I think that is to me not conceivable that one could do a
study of multiple biopsies in this patient population. This happens to
be a dangerous population for renal biopsies, and I think we were very
fortunate in many ways that we did the pilot trial and that was fine
because this is a very obese population of patients and they have
hypertension. So, their risk with renal biopsy is greater than the usual
patients whom we biopsy.

The ethics of doing multiple biopsies I am not sure that any IRB would
approve of, but I can\'t speak for IRBs in the future and so forth. And
I know that comment probably doesn\'t mean anything in terms of what\'s
going on here, but that is my opinion.

The other thing about that ‑‑ and we\'ve certainly seen this in doing
multiple biopsies in other diseases like lupus ‑‑ is that there is a
sampling issue so that if you want to find a difference between two
biopsies, certainly there are morphometric ways of measuring things, but
in the end, even though it sounds like that might be the gold standard,
the fact of the matter is that the accurate and reproducible way of
studying renal function is the functional issue which is the ability of
the kidney to filter and not the morphologic issue which in this case,
especially with the advanced disease, would mean that you would be
trying to show stability. That would become a real statistical issue in
terms of morphology.

So, in answer to your question, I think that ideally certainly at the
bench with experimental animals, that\'s what you do, but in terms of
our ability to actually study clinically patients with type 2 diabetes,
I don\'t think we could do it.

DR. FLEMING: Well, I can readily be persuaded with what you\'ve said,
that measuring these functional abnormalities may be more measurable and
even potentially more reproducible. My concern is more uncertainty about
what is the magnitude of effect, duration of effect, and other factors
that could influence those functional abnormalities that aren\'t
necessarily integral to what it is that we\'re trying to do here.

DR. EDMUND LEWIS: Well, let me just ask you, are you referring to the
perm selectivity issue, which is the proteinuria issue, or are you
referring to the filtration issue?

DR. FLEMING: Actually my concerns would apply to any of these markers.

DR. EDMUND LEWIS: I guess the key term here with type 2 diabetic
nephropathy is \"inexorable.\" As you will see, using the serum
creatinine as a direct measure of renal function, you can expect
progression, you can expect doubling, indicating having the glomerular
filtration rate. Shortly after that, you can expect the patient to get
to a level of renal function where they require dialysis and
transplantation, and that is progressive, and I think that you will see
in our data that that in fact is what happens.

So, if one uses doubling of serum creatinine, as we have, as the index
of significant loss of renal function, those patients invariably
progress to the hard endpoint, if you will, which is requiring end-stage
renal failure management. And it\'s there where it\'s undeniable that
you\'ve actually got a clinical event.

So, we are not talking about a measure. We\'re not talking about
creatinine as a surrogate any longer; we\'re talking about it as a
measure. But we\'re not talking about it as a measure that doesn\'t have
serious clinical significance; we\'re talking about it as a measure that
ultimately we can expect a hard endpoint, if in fact we were to follow
the patient long enough.

DR. BORER: JoAnn?

DR. LINDENFELD: Just one final question. You showed very nice data in
the captopril trial that creatinine clearance and iothalamate clearance
were exactly equal. Do we have any data at all like that in this type of
patients before the institution of therapy and after the institution of
therapy?

DR. EDMUND LEWIS: No. Well, I\'m not sure I get your question.

DR. LINDENFELD: To be sure that secretion is not an issue.

DR. EDMUND LEWIS: No, we don\'t have ‑‑

DR. LINDENFELD: It seems like that\'s a physiologic measure that would
help us understand that, as Dr. Temple brought up, we\'re not seeing
sort of a physiologic change that\'s not reversible. So, that kind of
measurement would be enormously helpful to show that, before and then
after treatment, those two things don\'t change.

DR. EDMUND LEWIS: Yes. Again, I want to emphasize that patients entering
the IDNT were patients who had really advanced disease. As you will see,
their blood pressures were high even on antihypertensive medication
before they got to us, and this is not a clinical situation where we can
just stop drugs and do clearances. I don\'t think that it\'s something
that is a practical thing in this patient population. I don\'t believe
that one can get the data that you\'re asking for, which is creatinine
dynamics off the drugs that these patients are going to have to be on.
So, it\'s a problem there. What I\'m saying is I don\'t think there\'s
an answer to your question.

DR. BORER: Dr. Lewis, I want to thank you very much. I must say I wish
you had been speaking about this to my class when I was in medical
school.

(Laughter.)

DR. BORER: We\'ll go on and while we\'re doing that, I want
clarification that requires only a yes or a no from Dr. Cooper or maybe
from Dr. Daniels. Is it true that the proposed indication is for the
treatment of patients with type 2 diabetic renal disease, not for the
patients with hypertension and type 2 diabetic renal disease? Is that
correct?

DR. COOPER: With hypertension.

DR. BORER: Because that\'s not what was given to us. So, we have to make
that clarification.

DR. COOPER: In both studies all the patients had hypertension.

DR. BORER: I know they did, but the proposed indication, your slide A-6,
doesn\'t say that. That\'s why I\'m asking. But now you\'ve clarified
it. You\'re asking for approval for treatment of patients who have
hypertension and type 2 diabetic renal disease.

Having clarified that, let\'s move on. Dr. Cooper?

DR. COOPER: Good morning, Chairman, members of the advisory committee
and the FDA and invited participants from the academic community. I have
been involved with the irbesartan diabetic nephropathy trial since its
inception working with Dr. Lewis and the collaborative study group to
design this trial between 1993 and 1995. I am here today to share the
results with you.

The presentation is divided into four segments: the study design and
conduct, the demographic and baseline data, the efficacy results, and
the safety.

The irbesartan diabetic nephropathy trial, or IDNT, was designed as a
single trial that tested two hypotheses. Does interruption of the
renin-angiotensin system with the angiotensin II receptor antagonist
irbesartan provide renoprotection in subjects with type 2 diabetic
nephropathy independent of blood pressure lowering? Specifically, would
irbesartan be superior to placebo in the primary comparison and would
irbesartan be superior to amlodipine in the secondary comparison?

The primary endpoint was a composite of doubling of baseline serum
creatinine, end-stage renal disease, or death. The design of the study
was carried out according to the principles that the collaborative study
group had established in the type 1 diabetic nephropathy study with
captopril. An irreversible doubling of serum creatinine is a direct
measure of the decline in the kidney\'s ability to filter blood and
corresponds to the loss of 50 percent of renal function. When a subject
reached doubling of serum creatinine as an endpoint, coded medication
was stopped to allow the study investigator to treat the subject outside
of protocol. Verification of doubling of serum creatinine as an endpoint
required submission of two consecutive samples for measurement of serum
creatinine by the central laboratory at Rush Presbyterian Hospital after
all corrective actions defined by the protocol had been undertaken to
confirm there were not reversible causes.

End-stage renal disease was defined as renal transplantation, the need
for dialysis, or a serum creatinine equal to or greater than 6.0
milligrams percent. This threshold for serum creatinine was selected
because it is the trigger for initiating dialysis in diabetics as
endorsed by Medicare.

All-cause mortality was included in the primary composite endpoint due
to the competing risk of cardiovascular disease in these type 2 diabetic
subjects.

The secondary endpoint involved cardiovascular events that affect these
subjects: cardiovascular death, nonfatal myocardial infarction,
hospitalization for heart failure, permanent neurological deficit
attributed to stroke, and amputation.

All primary and secondary outcome measures were adjudicated by the
outcome confirmation and classification committee or the mortality
committee without knowledge of coded medication assignment. These
committees were independent, non-BMS entities.

In order to qualify for study entry, subjects had to be 30 to 70 years
old with type 2 diabetes, hypertension, as defined here, and a urine
protein excretion exceeding 900 milligrams. Serum creatinine was between
1.0 and 3.0 milligrams percent in women and 1.2 and 3.0 milligrams
percent in men to assure that renal function was on the linear slope of
decline.

Subjects from 209 sites located in 27 countries were randomized to one
of three treatments: placebo, irbesartan, or the calcium channel blocker
amlodipine.

When the trial was first designed, the relative importance of blood
pressure lowering alone versus unique benefits of antihypertensives with
mechanisms of action, other than interruption of the renin-angiotensin
system, in type 2 diabetic nephropathy remained to be determined.
Published reports of studies in experimental models and in patients with
either microalbuminuric or proteinuric diabetic renal disease suggested
that administration of calcium channel blockers could be renoprotective.
Furthermore, amlodipine at that time was the most frequently prescribed
antihypertensive used in diabetics.

In order to test the two study hypotheses, aggressive management of
blood pressure control was essential. Multiple antihypertensives, with
the exception of those disallowed by the protocol, angiotensin II
receptor antagonists, ACE inhibitors, and calcium channel blockers, were
added for all subjects to ensure that the target blood pressure level,
135 over 85 millimeters of mercury, was reached. An independent
committee of physicians, the clinical management committee, reviewed
data periodically in a blinded manner to ensure a blood pressure
lowering to target levels for each subject and across the three
treatment groups.

Subjects were followed for an average of 2.9 years and were seen every 3
months until the end of the study. A data safety monitoring committee
reviewed unblinded safety and efficacy results periodically throughout
the study.

1,715 subjects were randomized to one of the three treatment groups and
all were included in the intent-to-treat analysis. 16 subjects did not
receive study drug. All of the 1,699 subjects who received at least one
dose of study drug were included in the safety analysis.

408 subjects discontinued study drug early. Of these subjects, 161
reached one of the endpoints and 121 were followed until study closure
without an endpoint. 118 subjects were missing measurement of serum
creatinine at study closure. Dialysis, transplantation and mortality
status was known in 89 of these subjects. Mortality status was known in
the remainder. 8 subjects were lost to follow-up. The remaining 1,291
subjects completed double-blind therapy as defined by the protocol.

The incidence of discontinuation of study drug was similar across the
three treatment groups.

The baseline characteristics of all randomized subjects is demonstrated
here. It was similar across the three treatment groups. Subjects were
close to 60 years of age, predominantly male and caucasian, with type 2
diabetes for an average of 15 years. In response to one of the earlier
questions, distribution of the races across the three treatment groups
was similar.

Consistent with the natural history of the disease and the duration of
known diabetes, subjects had mild to moderate renal insufficiency with a
mean serum creatinine of 1.7 milligrams percent, and notice here the
creatinine clearance at baseline was 57 to 59 milliliters per minute.
Normal creatinine clearance in this population would be considerably
higher.

The mean urine protein excretion was close to the nephrotic range.

Blood pressure measurements at baseline were also similar across all
treatment groups.

Here are the mean systolic and diastolic blood pressures plotted over
time. Reductions in systolic and diastolic blood pressure from baseline
were observed in all three treatment groups. The attained blood pressure
levels were clinically indistinguishable in the irbesartan group, which
is in yellow, and the amlodipine group in blue. There was a 3.9
millimeter of mercury and a 2.7 millimeter of mercury difference
observed between the irbesartan group and the placebo group in pink in
the mean systolic and diastolic blood pressures, respectively. While
these differences are statistically significant, analyses of the primary
efficacy endpoint, to be shared with you shortly, confirm that these
differences are not clinically meaningful in this study.

On average, two to four antihypertensives were required to achieve this
level of blood pressure control. The most frequently prescribed
antihypertensives were beta-adrenergic blockers, central adrenergic
agonists, and peripheral adrenergic blockers. The use of all classes of
agents was slightly more common in the placebo group. The majority of
subjects used either thiazide diuretics or, as renal disease progressed,
loop diuretics.

As you recall, the primary efficacy measure is the time to the composite
endpoint of doubling of serum creatinine, ESRD, or death. This slide
shares the primary results of the study. As seen here, irbesartan in
yellow significantly increased the time to the primary composite
endpoint when compared to placebo in pink, demonstrating a 20 percent
relative risk reduction, with a p value of 0.023. The treatment benefit
was apparent as early as 18 months and was maintained throughout the
study.

In the secondary comparison with amlodipine in blue, a 23 percent
relative risk reduction was observed. Again, this difference was
statistically significant with a p value of 0.006. This treatment effect
was seen in the setting of clinically indistinguishable blood pressure
levels.

To confirm that the blood pressure differences between irbesartan and
the placebo groups were not clinically meaningful, the primary analysis
was adjusted using blood pressure levels as a time dependent covariate
in the Cox regression model. The results for the primary efficacy
endpoint were similar with a relative risk reduction of 19 percent and a
p value of 0.035.

A similar analysis, adjusting for the levels of hemoglobin A1C, was also
conducted, and once again, the results for the primary composite
endpoint were similar.

Lastly, the amlodipine group behaved similarly to the placebo group with
no observed benefit in the primary composite endpoint.

This slide displays the Kaplan-Meier curves for the renal outcomes, a
predefined endpoint consisting of doubling of serum creatinine or ESRD.
Treatment with irbesartan in yellow significantly delays the progression
of diabetic nephropathy compared with placebo in pink with an observed
relative risk reduction of 26 percent. This was statistically
significant with a p value of 0.012.

For the secondary treatment comparison with respect to amlodipine in
blue, a 34 percent relative risk reduction in favor of irbesartan was
observed. This again was statistically significant with a p value less
than 0.001.

The Kaplan-Meier curves suggest that the treatment benefit was observed
as early as 18 months and was maintained for the duration of the study.
The Cox regression analysis confirmed that the observed renal benefit of
irbesartan was independent of blood pressure lowering.

Together, these results prove that blockade of the renin-angiotensin
system with irbesartan delays the progression of diabetic nephropathy
and that these benefits were in addition to blood pressure reduction
alone.

Data on the next two slides provides insight into the relationship
between doubling of serum creatinine and ESRD.

Patients with proteinuria who double their serum creatinine have
advanced to the stage of the disease characterized by progressive and
irreversible loss of renal function. This is evident in this analysis
showing the cumulative rate of reaching ESRD for subjects who have
doubled their serum creatinine. The median time to ESRD, defined as
renal transplantation or the need for dialysis or serum creatinine of at
least 6.0 milligrams percent, once halving of the GFR has occurred, was
9.8 months and is similar to that observed in the captopril trial of
type 1 diabetics, which was 9.3 months.

The relationship between serum creatinine and ESRD is further defined on
this slide showing dialysis and transplantation events that occurred in
subjects after doubling of serum creatinine or in subjects who
experienced ESRD as defined by a serum creatinine of at least 6.0
milligrams percent as a first event. Of the 322 subjects who doubled
their serum creatinine, 133, or 41 percent of subjects, underwent
dialysis or transplantation during the period of follow-up. In contrast,
only 5 percent of subjects who never experienced a serum creatinine
event reached ESRD. These results indicate that progressive decline in
renal function increases the risk of subsequent outcomes.

Of the 71 subjects whose first event was ESRD, as defined by the serum
creatinine, the overwhelming majority, 59 or 83 percent of subjects,
went on to dialysis or transplantation, and this occurred in a
relatively short time frame. The mean time until dialysis was initiated
in these subjects was only 2.5 months.

Based on these results, it is reasonable to conclude that with longer
follow-up, all subjects who doubled their serum creatinine would reach
ESRD unless death intervened. Furthermore, these results mirror practice
in the nephrology community. The standard approach to the treatment of
diabetics with advanced nephropathy is to periodically monitor serum
creatinine and initiate dialysis once the serum creatinine reaches 6.

The next series of slides portray the results for the components of the
primary composite endpoint and the secondary endpoint analysis,
cardiovascular morbidity and mortality.

This slide displays the relative risk reductions of the primary
composite endpoint and the individual components. In order to assess the
impact of treatment on the individual components, all occurrences of
that component event were included in the time-to-event analyses. When a
subject reached doubling of serum creatinine as an endpoint, coded
medication was stopped to allow the study investigator to treat the
subject outside of protocol. Thus, the intent-to-treat analyses
presented for each of the components include events which occurred in
subjects who were no longer on coded medication.

The first panel displays the risk reductions for the comparison of
irbesartan and placebo and the second panel for the comparison between
irbesartan and amlodipine. The observed benefit of irbesartan, when
compared to placebo, was driven primarily by the two renal outcomes,
doubling of serum creatinine and ESRD. The consistency of the results
are apparent in the comparison with the second control group. The
relative risk reduction of 23 percent was also driven by the renal
outcomes, doubling of serum creatinine and ESRD.

For all-cause mortality, the point estimates are close to 1 for each
comparison, suggesting that treatment with irbesartan had no adverse
effect on subject safety.

As you\'ll recall, the secondary composite measure was time to
cardiovascular morbidity and mortality and it was evaluated to assess
potential risk in the type 2 subjects given the competing risk of
cardiovascular disease and to exclude evidence of harm. There was no
difference observed between any of the treatment groups.

The sample size here, less than 600 subjects per arm, was smaller than
has been typically required to detect differences in cardiovascular
events due to blood pressure lowering using drugs with different
mechanisms of action. These results reinforce the benefits of optimizing
blood pressure control.

The next slide displays the relative risk reductions of the secondary
composite endpoint and the individual components for the comparisons
between irbesartan and placebo and irbesartan and amlodipine.
Cardiovascular events which occurred in subjects who were no longer on
coded medication were included in these intent-to-treat analyses.
Furthermore, by protocol, cardiovascular events that occurred after ESRD
was reached were not captured because the initiation of dialysis and
other therapeutic interventions are known to influence cardiovascular
risk factors.

There were no statistically significant differences in the comparisons
between irbesartan and placebo for any of the individual events,
indicating that there was no overall increased cardiovascular risk
associated with treatment with irbesartan.

In the comparisons between irbesartan and amlodipine, the result for
hospitalization for heart failure favored treatment with irbesartan. The
point estimates indicate directional trends for cardiovascular death,
nonfatal myocardial infarction, and stroke in favor of amlodipine
treatment. However, the confidence intervals for these risk reductions
overlap 1 and did not reach statistical significance.

In view of these results, a post hoc analysis combining the renal and
cardiovascular endpoints was conducted to assess the overall
benefit/risk of therapy. This combined composite endpoint provides equal
weight to both the renal and the cardiovascular events and assesses the
time to the first occurrence of any detrimental outcome, whether it be
renal, cardiovascular morbidity, or all-cause mortality. In this
analysis in which the cumulative event rate approached 80 percent,
irbesartan retains its treatment effect compared with either placebo or
amlodipine, a 19 percent relative risk reduction compared to placebo and
a 21 percent relative risk reduction compared to amlodipine, thus
suggesting that the overall benefit of treatment with irbesartan is
preserved.

The final segment of this presentation will focus on irbesartan\'s
safety profile. In general, treatment with irbesartan in this patient
population was safe and well-tolerated and resulted in few
discontinuations. This table presents the incidents of adverse events,
serious adverse events, discontinuations due to any adverse event, and
death. There were no substantial differences between any of the
treatment groups in these important safety measures.

Just to address one of the earlier questions, there were approximately
260 deaths reported in the study. Slightly greater than 50 percent of
them were due to cardiovascular events.

The next slide includes those adverse events of special interest that
are likely to occur in subjects with renal disease which resulted in
discontinuation of study drug: hyperkalemia, inability to control blood
pressure, edema, orthostatic symptoms, and the early rise in serum
creatinine.

It is well known that agents that interfere with the renin-angiotensin
system increase the risk of hyperkalemia due to hypoaldosteronism.
Although the incidence of hyperkalemia due to these agents is infrequent
in patients with normal serum creatinine, in patients with impaired
renal function that continues to worsen, the risk of hyperkalemia will
increase.

As expected, subjects treated with irbesartan experienced a higher
incidence of hyperkalemia compared with either placebo or amlodipine.
This resulted in permanent discontinuation of study medication in 12 of
the 577 subjects. Periodic monitoring and appropriate intervention
reduced the severity of this electrolyte disturbance. No subject with
documented hyperkalemia attributed to treatment with irbesartan
experienced death associated with hyperkalemia.

Inability to control blood pressure was a concern in this patient
population because of the severity of the hypertension. Discontinuation
of coded medication for this adverse event occurred more frequently in
the placebo arm.

Edema, requiring discontinuation, occurred more frequently in the
amlodipine arm.

Orthostatic symptoms were also a concern because of autonomic
neuropathy, and discontinuation of study drug due to orthostatic
symptoms was similar across all three treatment groups.

Lastly early rise in serum creatinine, a well-documented risk in
patients with bilateral renal artery stenosis treated with ACE
inhibitors, only occurred in one placebo-treated subject.

In summary, irbesartan significantly reduced the time to progression of
advanced diabetic nephropathy as demonstrated by the beneficial effects
on the composite endpoints, renal outcomes and total mortality. There
was a 20 percent reduction in the primary endpoint compared with placebo
and a 23 percent relative risk reduction with respect to amlodipine.

Importantly, renoprotective benefits of irbesartan were independent of
blood pressure reduction.

Finally, in this patient population, irbesartan was generally safe and
well-tolerated.

Before I introduce Dr. Parving, I guess I wanted to know if you had any
questions.

(Laughter.)

DR. BORER: Yes, we will, and I don\'t think we\'ll be able to complete
them all before the break that I\'m now told is mandatory for FDA
people. Other parts of the Government sometimes tough it out.

(Laughter.)

DR. BORER: But I\'m told that this group can\'t compete. In just about 5
minutes, we will take a break, so we\'ll have a few questions first.
Then we\'ll complete after we come back from a 15-minute break.

But I would like to ask you a question now so that, since you may not
have the answers readily available, during the break you can try to pull
the relevant data together.

Granted that ESRD as the first event was relatively uncommon compared
with doubling of the serum creatinine, nonetheless you show us an
evaluation with ESRD as first event that suggests that this occurred
earlier, not quite significantly earlier, but earlier, in patients who
were not on irbesartan than in patients who were on irbesartan.
Therefore, since all the patients who doubled their serum creatinine
were allowed to receive drugs that are presumed to prevent the
progression of renal disease, which I guess would in virtually all cases
have included an ACE inhibitor or an AT1 receptor blocker ‑‑ you can
correct me if I\'m wrong about that ‑‑ I\'d like to know, first of all,
what drugs were they put on.

And secondly, what happened to the rate at which ESRD developed in those
patients who went from placebo to a presumably effective drug or from
amlodipine to a presumably effective drug compared with the rate that
was seen before the cut point in the patients who were still on
randomized therapy at the time that they hit their first endpoint, being
ESRD? That may be sort of complicated and maybe I didn\'t say it quite
right, but I think you get the idea.

If you don\'t have those data right now, that\'s fine, but I\'d like to
know what those results are after the break. Do you have any idea of
that right now?

DR. COOPER: No. I\'d prefer to take a break and we will compile the
data, to the best of our ability, to address your question.

DR. BORER: Okay, that\'s great.

I\'ll tell you what. Rather than have at you here, is it okay if we
break 5 minutes earlier than you said? Yes, okay.

Tom?

DR. FLEMING: Given, Jeff, that you\'re putting on the table issues that
we might discuss after the break so they have time to get it, one thing
I\'d like to see is the numbers of people who had dialysis or
transplant, and so specifically two analyses: dialysis-free survival
analysis and dialysis/transplant-free survival analysis. I.e., the first
being events are either death or dialysis; the second events being
either death, transplantation, or dialysis.

DR. BORER: We\'ll take a break now and we will begin again precisely at
20 minutes of 11:00.

(Recess.)

DR. BORER: I assume that the requirement of the FDA that it get a break
will also mean that people who work for the FDA want to have lunch.
That\'s another thing we don\'t often do in other parts of the world.
But to be able to stop in time to do that, we\'re going to have to start
right now. So, let\'s sit down, get together, and begin the questioning
of Dr. Cooper.

Where do we want to start here? Dr. Kopp?

DR. KOPP: Dr. Cooper, I had two questions. You may have mentioned this
and I may have missed it. But were beta-blockers similarly used in all
three groups, the issue being those also have an antirenin effect.

DR. COOPER: The use of all agents was slightly more common in the
placebo group. So, the beta-blockage use in the placebo group was
approximately 50 patients of the patients; in the irbesartan group, it
was 43 percent; and it was a little bit less in the amlodipine group.
So, it was slightly more common in the placebo group.

Your second question?

DR. KOPP: The second question actually ‑‑ well, I guess I\'ll launch in
‑‑ is the issue that Tom Hostetter raised in the editorial in the New
England Journal, which was the noncomparison with ACE inhibitors. I
guess one of the issues here is that as a practitioner with a patient
with type 2 diabetes, you can look back on the type 1 diabetic study and
see that captopril had a 50 percent reduction in doubling of creatinine,
or you can look at this agent with a roughly 25 to 30 percent reduction,
and you have to choose. Do you go with an agent that might potentially
be more potent or go with the agent that has been used in the particular
subset that you\'re looking at, type 2 diabetes?

So, the question would be you must have given thought to the use of ACE
inhibitors. Any comment about why that arm was not used?

DR. COOPER: Yes. Can I please have subtalk 2.4?

There\'s no data in type 2 diabetics with renal disease as to what class
of drug, whether or not it interrupts the renin-angiotensin system,
could be effective. This was the first trial conducted in this patient
population. There was much discussion, especially because we were doing
this study in collaboration with an academic group, about the choice of
the comparator.

For using a calcium channel blocker as a comparator, there were three
points. The first was we wanted to evaluate blood pressure lowering due
to a different mechanism of action other than interruption of the
renin-angiotensin system. The second point suggested that calcium
channel blockers could possibly be renoprotective, and at the time that
the study was designed, between 1993 and 1995, there was a fair amount
of literature and much discussion about calcium antagonists in all
patients with renal disease. And lastly, because amlodipine was the
agent of choice for this patient population, we wanted to assess whether
or not this drug could be renoprotective.

Specifically addressing your question about why we did not select an ACE
inhibitor as a comparator, there were three points. The first was that
we would be testing a mechanism of action that\'s similar. It\'s similar
but it\'s not the same. With irbesartan, which is an angiotensin II
receptor antagonist, you have complete blockade of the angiotensin I
receptor. With an angiotensin converting enzyme inhibitor, you have
other pharmacological activity, and specifically you have an entire
series leading to potentiation of such things as bradykinin that were
not yet tested in this patient population. No one could make any
assumptions without data and without evidence that type 2 diabetics with
this extent of renal disease would do well with an ACE inhibitor.

And lastly, we\'re just being very pragmatic. Should we have conducted a
study with an ACE inhibitor, we would have had to conduct a
non-inferiority study, and the sample size would have been prohibitive.

DR. BORER: Let\'s keep on around this side of the table here. Bev?

DR. LORELL: I\'d like to hear a bit more information about the actual
strategies that were used in the trial when an increase in creatinine,
albeit later found to be transient, occurred. Clearly in the real world,
certainly in treating heart failure, the major reason for stopping an
ACE inhibitor and probably also ARBs in patients for whom ACE inhibitors
clearly reduce mortality is seeing transient rises in creatinine. That
will impact the use of your drug in the real world.

What strategies were actually used and what was the mean and median
absolute magnitude of transient bumps in creatinine that were addressed
and reversed?

DR. COOPER: In answer to your last point, we do not have specific data
about mean or median transient increases in serum creatinine. What I can
share with you is the protocol that was used.

There were approximately five reasons that were identified that could
lead to reversible changes in renal function. The investigators were all
instructed to first repeat serum creatinine measurements and determine
whether or not any of these five reasons could be contributing to a
transient increase in serum creatinine. They then needed to wait an
additional 4 weeks before sampling the blood again. If there was still a
transient increase, the protocol actually allowed for dose reduction of
study drug to determine if there was some dose-related effect. If the
increase in serum creatinine was sustained, then measurements from the
first aliquot and from the second aliquot were subsequently sent to the
central laboratory for confirmation of the serum creatinine. So, on
average, there were approximately 4 weeks between the first serum
creatinine being drawn and the last serum creatinine being drawn to
protect against the possibility that we weren\'t dealing with a
situation which was reversible acute renal failure.

DR. LORELL: But during those 4 weeks, did the investigators embark on
the protocol of interventions on those five potential factors?

DR. COOPER: Yes.

DR. LORELL: They did.

DR. COOPER: Yes.

DR. BORER: Blase?

DR. CARABELLO: Let me try to understand better what happened to patients
who doubled their serum creatinine. At that point, coded drug was
stopped, and they were treated openly and presumably aggressively. How
were they then treated statistically? Were they censored from the
initial group that they were in, or did they continue on in that group?
What happened to them in terms of follow-up?

DR. COOPER: In order to address that question, I\'m going to ask the
statistician responsible for the results from Bristol-Myers Squibb, Dr.
Natarajan.

DR. NATARAJAN: Hi. My name is Kannan Natarajan from Bristol-Myers
Squibb. I\'m in the Biostatistics Department.

To answer your question, we treated them as intent-to-treat, so we did
not actually discard any events that might have happened after they
stopped coded medication. All of these patients were analyzed as they
were randomized.

DR. BORER: Steve?

DR. NISSEN: Yes. I want to come back to that in a minute.

But first, I wonder if you could put up your slide C-16. Is that
possible?

DR. COOPER: Core slide C-16 please.

DR. NISSEN: There are a variety of endpoints listed there, and those of
us in cardiovascular medicine tend to think of the hard cardiovascular
endpoints as being the composite of cardiovascular death, MI, and
stroke. Now, one interpretation of the data ‑‑ and I want to see if you
concur with this ‑‑ is that in the comparison with amlodipine, you saw a
23 percent decrease in the risk of reaching your renal endpoint, but at
the cost of, at the expense of, a 36 percent increase in the risk of
cardiovascular death, a 51 percent increase in the risk of nonfatal MI,
and an 86 percent increase in the risk of stroke.

Each of those point estimates overlap a relative risk of 1, but the hard
cardiovascular endpoints, if you lump those together, my guess is ‑‑ and
I actually did some statistics here myself and Tom probably could do it
very quickly. I got a p value of around .01. So, it looks to me like
there\'s actually stronger evidence for an increased risk of hard
cardiovascular endpoints than there is evidence for a beneficial effect
on the softer endpoint of an increase in creatinine. Is that an accurate
reflection of the data?

DR. COOPER: Is Dr. Pfeffer here?

DR. JULIA LEWIS: The FDA has asked for a hold on the question. They\'re
with Dr. Pfeffer right now. Members of the FDA are with Dr. Pfeffer.

DR. COOPER: Okay. Can we come back to addressing your question when Dr.
Pfeffer returns? Thank you.

DR. BORER: I wonder if you\'ve had time to look for the data that I
asked about earlier and that Tom asked about?

DR. COOPER: I\'m going to begin with the second question that you asked
specifically about transplantation and dialysis, with the caveat that in
order to produce specific slides with time-to-event analyses, et cetera,
we\'re actually putting those together now and we can share them with
you probably after lunch. So, if we could start with subtalk 5.8.

The first slide displays the actual number of events that occurred
within end-stage renal disease. So, you have the number of dialysis,
transplant, and serum creatinine events. This is all events that
occurred, not just those that were part of the initial composite
component.

If you look at the irbesartan events, you\'ll see that 77, 73 plus 4,
events occurred in the irbesartan group, and if you look at the placebo
group, you\'ll see that 88 plus 6, or 94, events occurred in the placebo
group. So that the incidence of occurrence of transplantation or
dialysis events was less in the irbesartan group than in the placebo
group.

I do not have a risk reduction or a p value for that result, but I would
be happy to remind you that in the FDA questions, the actual risk
reduction of time to dialysis was included, and that\'s .8. Confidence
intervals do overlap 1.

Given that in this study, the progression of renal disease, you would
have needed to follow these patients for a continued length of time in
order to observe a statistically significant result. Also, the composite
endpoint was a composite, and none of the individual components were
powered in order to achieve a significant result.

The next slide. This is the total incidence of the events, dialysis,
transplantation. Of course, we include serum creatinine since it was
part of the ESRD definition for the components. So, we have 77. This is
the same slide. 77 and 94.

Let\'s move on to slide 361 which is the Kaplan-Meier curve of time to
ESRD. For the Kaplan-Meier curve here, this is ESRD. This includes serum
creatinine of 6. We\'re trying to pull together the other Kaplan-Meier
curve now. The relative risk reduction for irbesartan versus placebo was
23 percent. This was not statistically significant. It was .07, but it
trends in the appropriate direction.

Once again, if you look at irbesartan and amlodipine curves ‑‑ excuse me
‑‑ if you look at the amlodipine and placebo curves, they\'re
superimposed on each other, indicating that there\'s no difference in
the event rate in those two groups.

DR. LINDENFELD: Could I just add something here? Correct me if I\'m
wrong about this, but in the captopril trial, there was a 50 percent
reduction in end-stage renal disease, and they did not use a definition
of creatinine greater than 6.

DR. COOPER: Right.

DR. LINDENFELD: In this trial, all of the difference in end-stage renal
disease is in creatinine greater than 6. None of it is in transplants or
dialysis. So, there would be no reduction in end-stage renal disease if
one didn\'t use creatinine greater than 6. Is that correct? I believe it
is.

DR. COOPER: No, I disagree with that. As I shared with you before, the
incidence of transplant and dialysis events was lower in the irbesartan
group, and at least for time to dialysis, there appears to be a relative
risk reduction in favor of treatment with irbesartan. And that\'s your
last point.

In the comparison of the data between the captopril and the irbesartan
trials, there are a couple of points that I think are important to
communicate. The first is the relative incidence of death in the type 1
patients who, at the time of the study, were 35 years old and not 58
years old, was very, very different. We had just a handful of deaths,
and that\'s one point.

The second point is in the discussion of the captopril study, in the
communications with the FDA as we were designing the study, the feedback
that we received at that time was that we needed to have as firm a
definition of ESRD as possible.

When you consider that this trial was conducted in 27 countries and the
number of investigators, all of whom need to make a decision about when
to initiate dialysis, there is no standard in the nephrology community
on when to initiate dialysis. We felt very strongly that by including a
serum creatinine of 6 or greater as part of the definition of ESRD, we
were making that endpoint less arbitrary, and it was a clear definition.
That\'s reinforced by the results that I shared with you earlier in the
presentation where the time to dialysis following a serum creatinine of
6 was only 2.5 months.

DR. LINDENFELD: I understand the reasons that you said, and other people
may want to comment on this. But in fact if you exclude the creatinine
of 6 and use transplant or dialysis, it was 22 versus 24. So, there was
not even a trend to a change. I\'m just saying this is different.

DR. COOPER: That\'s incidence.

DR. LINDENFELD: Right.

DR. COOPER: Okay, we need to have the data for time to.

DR. LINDENFELD: Right.

DR. BORER: Tom?

DR. FLEMING: I think part of what you\'re saying, JoAnn, is my
understanding, and I think what Dr. Cooper has said is in part my
understanding as well. Let me just get that out and see if we have a
consensus here.

In the captopril trial, they did specifically look only at
transplantation, dialysis, survival. It did show a 50 percent reduction
and p was .006. I\'m still interested in knowing what the results of
that endpoint would show in this trial, specifically what does
transplant, dialysis, death, as a composite endpoint, show in this
trial.

I agree with Dr. Cooper. My understanding is the contributions of the
elements will be different. In the captopril trial, only 30 percent of
those endpoints in the composites were death, although death did show a
reduction. There was a 43 percent reduction in the death rate, although
it was less of the dominant contribution. There were proportionately
more dialysis/transplantation events. Here we would see in the composite
endpoint, which I\'m still waiting ‑‑ we still haven\'t been shown it ‑‑
we will have more dominance by death.

My understanding is where you\'re right, JoAnn, when you look at time to
the primary endpoint ‑‑ and dialysis is the first event ‑‑ there\'s no
evidence of a reduction there, 24/22. But if you continue to follow
people past creatinine increases and look at whether or not this
translates into a reduction in dialysis ‑‑ I believe it\'s what we\'re
seeing now, which is the data you\'re showing us ‑‑ there\'s evidence of
a 20 percent reduction, but it\'s not significant.

But clearly when you get this composite endpoint of transplantation,
dialysis, death, that relative risk reduction is going to be a fair
amount less than 20 percent and not at all close to the 50 percent
reduction of captopril in that corresponding analysis. So, I\'d still
like to see that analysis.

I\'d like to move on to a related point, but did you want to say any
more about this?

DR. LINDENFELD: No. Go ahead.

DR. FLEMING: Steve brings up another very key point and that is if
we\'re looking at clinical endpoints looking at the aggregation of
clinical endpoints, certainly it\'s appropriate to focus on those that
are renal related. Certainly it\'s appropriate to look at a
transplantation/dialysis-free survival endpoint separately.

But it\'s also very clinically relevant to say, especially if we\'re
going to compare to amlodipine, what is globally happening here that\'s
really clinically important? When we keep seeing these meta-analyses, we
keep seeing the creatinine changes included in those, and of course,
they continue to dominate.

There\'s no question there is a difference in time to doubling. There\'s
no question, and amlodipine doesn\'t provide that benefit. But if we
look at how that translates into true, tangible clinical outcomes,
looking first with a focus toward renal, i.e., dialysis,
transplantation, death, we haven\'t seen it yet, but my guesstimate is
it\'s going to be a reduction of 10 to 12 percent relative risk,
compared to 50 percent with captopril.

We haven\'t at all yet seen an analysis that\'s, in essence, in the
spirit of what Steve wants to see, which is let\'s look at all events
that really matter. Let\'s look at transplantation, dialysis, survival,
but then also factor in those important cardiovascular events, such as
MI and stroke, where it would appear that there\'s no longer an
advantage over amlodipine. And in fact, it\'s not clear to me whether
there\'s a disadvantage. It would certainly be important at some point
soon to see those two composite analyses.

DR. COOPER: So, if I understand you correctly, Dr. Fleming, what you\'re
requesting is the time to a combined composite endpoint, excluding the
serum creatinine events, that focus just on dialysis, transplantation,
cardiovascular events, and death.

DR. FLEMING: Indeed, because essentially what we\'re looking at here is
a continuum. What we\'re looking at in the primary endpoint is an
endpoint that is dominated by time to doubling of serum creatinine.
We\'ve seen, however, that there\'s only about a 9-month lag from that
endpoint to end-stage renal disease, and in fact a large number of
people have achieved end-stage renal disease endpoints. But those
endpoints are still heavily influenced by having serum creatinines
hitting 6. And we\'re told that that, in fact, is a trigger for
intervention, although interestingly there is some lag in when that
intervention occurs.

But if it\'s in fact a short lag, then we presumably should be fully
adequately powered to see the tangible effects. Does this translate in
tangible effects in terms of reducing the renal-focused endpoint, which
is transplantation, dialysis, death? So, let\'s look at that composite
endpoint, numbers of people that had that endpoint, relative risk
estimates.

Then looking more globally, as Steve had pointed out, let\'s look at the
more global clinical consequences, because we\'ve acknowledged that in
this setting cardiovascular events dominate what are the bad things that
happen to people. So, at least I would like to know what is the relative
outcomes in bad things. Take your secondary endpoints and add
transplantation and dialysis or take Steve\'s three endpoints, which are
stroke, MI, cardiovascular death, and add dialysis and transplantation,
and let\'s see. There\'s a lot of data here on these clinical endpoints.
Let\'s see what those results show.

DR. COOPER: Dr. Fisher, would you like to comment?

DR. FISHER: Yes, I\'d like to make a few comments. I\'m a little bit
shocked, for example, to hear Dr. Fleming think that 50 percent in type
1 diabetics, who are not required to be hypertensive, by the way, for
that trial, so that a substantial proportion were not ‑‑ so, the
concurrent therapy was very different and anything you observed could,
in part, be related to hypertension as well because it was a
placebo-controlled trial. And there were 35 and this is 58. So, I don\'t
really understand the relevance.

A second point I\'d like to make ‑‑ and I\'m not a clinician.

DR. FLEMING: Lloyd, the relevance of what?

DR. FISHER: The relevance of the captopril data in young type 1
diabetics to demonstrate nephropathy, everybody hypertensive type 2
diabetics. I mean, granted we are treating diabetes and things are
somewhat ‑‑

DR. FLEMING: You can put captopril aside if you wish. The interest in
looking at what are the direct clinical outcomes stands on its own as
being intrinsically of interest.

DR. FISHER: Just a second. We\'ve heard about the cardiovascular death,
and I think that\'s very relevant. However, the overall death rate is
essentially unity, if you take into account deaths from all causes,
total mortality. So, I personally would focus on that. I don\'t think
the patient is too concerned about why they died. Well, they\'re not
concerned about why they died actually, I think it\'s fair to say. The
patient survivors are probably not too concerned about why the patient
died but whether in fact there is an excess risk. Of course, that point
estimate, including everything, is there.

There may be analyses that haven\'t been run, but certainly the fairly
strong trend, when you look at ‑‑ and I imagine there are curves. I
can\'t remember. There are umpty-doodle backup slides. Does anybody know
if the cardiologist speaker is going to be allowed to speak?

DR. BORER: Not for a bit. There are some issues that have to be resolved
first. So, we\'ll have to hold that.

DR. FISHER: Okay, because that\'s very important. It\'s not as if nobody
thought of these issues. There\'s a very nice presentation by a person
involved in the classification of that, a card-carrying, well-known
cardiologist, who indeed could address these issues and is prepared to
address the issues.

But one of the points he makes, in case this doesn\'t get through, is he
was surprised, when they got done, that there were many more renal
endpoints than cardiovascular endpoints. Both are very important. And if
you put them together, this is a sick population.

But I don\'t know if the sponsor has every analysis Tom would desire,
but there are a number of analyses that can be presented with backup
slides looking at those endpoints.

I would only like to point out the study was not designed nor powered
for longer-term follow-up. Maybe it should have been. But I think it\'s
a little unfair to say, well, gee, if you didn\'t reach the components
that I personally like, then you know, it doesn\'t mean much. That\'s
kind of a stretch to me. You may say, well, gee, it was a great trial,
but unfortunately it didn\'t have the best endpoint for the state of the
science at this point in time, and I could understand that and that
would be somewhat defensible.

But all the additional evidence, while not totally persuasive at the
same significance level with fewer events, points that everything does
go on as you\'ve seen. You can throw things together and it looks nice
and so on and so forth.

DR. BORER: Ray?

DR. LIPICKY: Well, but I guess to my mind there is some relevance of the
captopril trial in the sense that there\'s this elegant schema for
understanding the progression of kidney disease, and that if you can
look at the captopril trial, you see that there is a clinically relevant
endpoint that is easily met, and you should accept the creatinine as not
a surrogate but a real thing. And the trouble here is, it seems to me,
that the clinically relevant stuff that was measured sort of undermines
that basic philosophy. So that although FDA has said doubling creatinine
is an endpoint that is okay, FDA may be wrong, and perhaps one
shouldn\'t accept that as a reasonable thing.

DR. COOPER: Can I just make a couple of comments?

We\'re going to do our best to collect all the data and be able to
respond. But there are a couple other comments here that are pertinent
to the conversation, and then I\'d like Dr. Lewis to be able to comment
as well.

The first comment is that, Dr. Lipicky, if you will recall the first
advisory committee on captopril, most of the cardiologists at that time
were concerned that all of the benefit for captopril was because of its
effect on heart failure, and that was driving the results of the study,
which is why we felt very much that it was critical to include heart
failure in the analysis.

The second comment ‑‑ and I think Dr. Lewis will be able to address this
‑‑ is with respect to the delay between serum creatinine of 6 and
initiating dialysis. There are clear explanations for why that, quote,
apparent delay would occur.

Dr. Lewis?

DR. EDMUND LEWIS: Well, I\'ve spent the last 8 years discussing the
captopril trial, so I don\'t see why today should be any different.

First of all, I want to make sure that we\'re all on the same page as
far as who was studied in the captopril trial and who is being studied
here because the common denominator may be diabetes, but we\'re talking
about two very different trials and two very different populations of
patients. So, let me just establish that first and then we can go on
from there.

We have slide 10-1, please.

So, as you can see, we have a population of patients that\'s 24 years
older. They are obese, whereas the type 1\'s were slim. Their blood
pressures were considerably higher, particularly the systolic. However,
I also want to emphasize that in the trial that we\'re talking about,
IDNT, 100 percent of the patients were hypertensive, and in the
captopril trial, 75 percent of the patients were hypertensive. So, 25
percent of the patients in the captopril trial had a very different
course, particularly the ones in the placebo group.

In addition, the type 2 patients that we\'re studying had a
significantly worse level of renal function with a mean serum creatinine
of 1.7 compared to the patients in the captopril trial.

So, we\'re talking about two different populations of patients here.
They\'re older. They\'re obese. They all smoke. They have an enormous
history of cardiovascular disease, as you can see, 45 percent having had
a cardiovascular event. You couldn\'t get into the captopril trial if
you had a cardiovascular event. And their blood pressure is a problem
over years. These patients have chronic hypertension compared to the
type 1 patients.

Can I have subtalk 48-6 please? Yes.

DR. LINDENFELD: Dr. Lewis, while you\'re on that subject, the levels of
proteinuria were the same, though, between the two trials.

DR. EDMUND LEWIS: Well, actually those are the geometric means. So,
we\'ve had a little interaction here because, of course, I represent BMS
today, but we are the collaborative study group, and if you look at our
paper, our actual means, not geometrical, but the actual means of urine
protein excretion in the irbesartan trial is considerably higher than it
was in the captopril trial, just meaning that we had more patients with
a lot more proteinuria which kind of evens out when you do geometric
means. So, you\'ll have to take my word for it on this. The patients in
the type 2 trial on average had higher proteinuria. We had more patients
with massive proteinuria than in the type 1 trial.

Now, in terms of doubling of serum creatinine and ESRD, one thing that I
do want to point out to the panel: times change, as well as issues about
various diseases. And the reason why our hard endpoint in the type 1
study was death, dialysis, or transplantation ‑‑ and my recollection is
there were 22 deaths in the type 1 study. It was 14 in the placebo group
and 8 in the captopril group, which was not statistically significant,
but it was that trend.

And the reason we bundled those in the type 1 study was because when we
designed the type 1 study, we included death with dialysis and
transplantation because at that time it was very difficult for a patient
with end-stage renal disease due to diabetic nephropathy to actually get
on a dialysis program. So, we saw those deaths not being as
cardiovascular deaths but as renal deaths, which is no longer an issue
because, as I say, 45 percent of patients on our dialysis programs today
have diabetes.

So, it was a different time, and that\'s why that design was put in. But
I think that it points out that you can\'t really exactly take even
definitions such as death as being identical between the two studies
because we\'re talking about the 1980s as compared to now, and things
have changed.

Now, if you look at doubling of serum creatinine, which I hope we have
established as being a very important clinical event in this course,
which presages end-stage renal disease ‑‑ I mean, this isn\'t an
episodic disease. This is a continuum here. So, if you look at that, you
can see that in fact in the two arms here, we have a substantial
decrease in the likelihood of reaching that milestone.

Now, one of the things about this and the apparently stronger results in
the captopril trial is that, first of all, we did not have
cardiovascular death as a serious competing endpoint in that trial.
People are dying during this trial before they ever have a chance to
double or go into end-stage renal disease, for that matter. And in
addition, the placebo group in the captopril trial was losing renal
function at such a rate that it was easier to show a difference between
the two groups because in those days blood pressure was not controlled
as rigidly, and that group of patients, the placebo group, certainly was
losing renal function faster.

So, in terms of comparing the two trials, from my point of view, having
been the PI for both of these trials, the only thing that I think that
really can be said about the two trials is that the results for both
trials are strongly in the same direction. To compare the numbers from
the two trials I really personally don\'t think is valid.

Now, as far as the end-stage renal disease or death issue, I think that
to a certain extent, of course, we\'ve said that we had a composite
endpoint. These people could have a renal endpoint or a cardiovascular
endpoint, and the cardiovascular endpoints were not statistically
significant. Looking at the published data in, say, just hypertensive
populations, the blood pressure trialists collaborative meta-analysis,
clearly irrespective of what agent you\'re going to use, it\'s whether
you lower the blood pressure or not that\'s going to really determine
what your cardiovascular events are. So, we\'re not too surprised about
the cardiovascular deaths really determining this.

And as far as the ESRD is concerned, I think that you can see from our
data about the way people are moving, doubling serum creatinine, getting
up to 6, going on to dialysis, that I think that we\'re really talking
about in this trial an issue of length of follow-up. I can\'t imagine
how we can be talking about end-stage renal disease ‑‑ our data not
showing that we have a serious effect in altering the course of renal
disease because we\'re altering the course in a very positive way with
irbesartan all the way up to renal disease. The only reason we don\'t
have a significant p value with that is because we didn\'t follow them
quite long enough. I think that you can assume that everybody who
doubles is ultimately going to reach 6, and then they\'ll go on dialysis
in a very short period of time.

So, in looking at the course of renal disease, not looking at the
specific p value numbers at each stage, I believe that what we\'re
showing here is not really different from the captopril trial when you
take into consideration patient population and all of that kind of
thing.

DR. BORER: Dr. Lewis, before you sit down, can you clarify something for
me? I know you didn\'t collect these data, they\'re not reported, and
it\'s not going to be a primary basis for decision making, but just so I
can understand. When somebody reaches a creatinine of 6, let\'s say he
doesn\'t get dialyzed, are there lifestyle changes that we can infer
would occur? For example, is the diet very restricted? Are there other
limitations? Can you tell us something about that?

DR. EDMUND LEWIS: Yes, I would be glad to address that.

The reason actually for the Medicare definition of a creatinine of 6 in
this population is that the goal of the nephrologist is to get the
patient on dialysis before they have uremic complications because once
they start having uremic complications, for example, just pericarditis,
the road back is a long road. So, what we\'re trying to do is to prevent
the adverse effects of uremia which are systemic by putting the patient
on dialysis before they get any of this.

One of the things that has not come up, which I would point out to the
committee, is that the Medicare criteria of a creatinine of at least 6
or a creatinine clearance of less than 15 mls per minute applies to the
population of patients with diabetic nephropathy. What that means, which
is important to the nephrologist, of course, is that Medicare has no
problem paying for dialysis when people have reached that level. They
have made the decision that that is an appropriate level. It prevents
complications, hospitalizations, nausea and vomiting, further inanition
or whatever is occurring because the patient is feeling sick, plus the
anemia and all of that. They will pay for that.

Now, if a patient does not have diabetic nephropathy and has advancing
renal disease, the Medicare definition of end-stage renal failure is not
the same. The Medicare definition of renal failure is now creatinine
equal to or greater than 8 or a creatinine clearance equal or less than
10. And the reason for that is it is recognized in the community and by
the federal government that patients with diabetic nephropathy are, in
fact, sicker than patients with chronic renal failure due to other
diseases and, therefore, deserve to be dialyzed earlier. I think that my
last statement there probably answers your question.

DR. JULIA LEWIS: Can I add a comment to that? I have an advantage as a
younger nephrologist. These are still all the patients in my clinic. At
a creatinine of 6, the patients are fatigued. They\'ve lost their sleep
cycle, and very importantly, their serum albumin as a key marker of
nutrition has begun to fall. The serum albumin is actually the single
most important predictor of survival in a dialysis patient. So, they\'ve
already begun to have signs and symptoms that they complain of. Within 2
or 3 weeks of initiating dialysis, most of my patients, both diabetic
and nondiabetic, will say I feel better than I have felt in a year. So,
they\'ve had a gradual decline in energy level, nutritional status, and
other factors.

DR. BORER: Thank you.

Bev?

DR. COOPER: May I just intercede here? One of the other observations has
to do with hospitalizations, and Dr. Pfeffer is now available and can
address some of the questions we have about the cardiovascular events.

DR. BORER: Let\'s just follow through on this idea. We\'ll come back to
that. There are several interlocking issues here.

Bev?

DR. LORELL: I\'d like to ask a question that may be a segue to Dr.
Pfeffer\'s comments. I am not a statistician, but I am a cardiologist
that deals all the time with incidents of death and interventional
cardiology trials in heart failure.

I guess I would like a comment from one of the card-carrying
statisticians either on our panel or elsewhere. If you look at the
incidence of cardiovascular death in this population, it is actually
remarkably low. It\'s about 8 percent in the placebo group. It may be in
part because they\'re being treated with antihypertensives and the
cardioprotective class of drugs of beta-blockers.

So, looking at the incidence of cardiovascular death over a 57-month
treatment period, if I were going to design a trial with the primary
endpoint of reducing cardiovascular death, I would suspect that would be
a trial that would need several thousand people in the treatment and
placebo arms. And perhaps before Dr. Pfeffer, representing the company,
speaks, we could hear a statistician\'s comment on that.

DR. BORER: Lloyd, Tom?

DR. FLEMING: If you\'re asking about whether it would take an enormous
trial if one were focusing only on cardiovascular death ‑‑

DR. LORELL: That\'s my question.

DR. FLEMING: ‑‑ it would take a very large trial, unless one were
targeting a very substantial reduction in the death rate on that.

DR. LORELL: Thank you.

DR. BORER: Lloyd, you had a comment?

DR. FISHER: Yes, you are right. It would take a larger trial. Actually,
from what I have been informed, it\'s not as large as Tom would think
probably. And the reason is that the cardiovascular event rate really
goes up when the people hit dialysis. Now, I\'m not familiar with that
literature, but everything that I\'ve been hearing, as we\'ve been
rehearsing for this meeting, assuming that\'s true ‑‑ and the
independent people brought in here could discuss that. So, if you
followed long enough, if you\'re willing to let a lot of people get to
dialysis and so on and so forth, and not feel you had to intervene to
prevent that in every way you could, then actually surprisingly not just
the death rate but the cardiovascular event rate would go up more than
you would think.

DR. COOPER: And in that situation, we would have continued coded
medication throughout the study rather than discontinuing it at the
first event.

DR. EDMUND LEWIS: If I could address that, just to finish Lloyd\'s
statement, the mortality rate, once a patient reaches dialysis, hasn\'t
changed much over the last several years, and it is much greater in
patients who have diabetic nephropathy than it is in patients with other
diagnoses on dialysis programs. The one-year mortality for these
patients is 25 percent, and the two-year mortality is 50 percent. So,
the goal is to prevent the patient from going on to dialysis as long as
possible because they\'re not dying renal deaths, they are dying
cardiovascular deaths, and whatever it is about dialysis that does this,
these patients do very badly.

DR. BORER: Steve?

DR. NISSEN: I just want to make sure I understand whether any of the
cardiovascular endpoints were censored in this trial. Am I or am I not
correct? When they reached ESRD, from then on were the cardiovascular
events included or were they censored?

DR. COOPER: They weren\'t captured.

DR. NISSEN: They were not captured.

DR. COOPER: Right.

DR. NISSEN: They were captured or captured and censored?

DR. COOPER: They were not captured. The patients were no longer on study
drug, so there\'s wasn\'t a safety effect that we were following, and
because of the interventions associated with ESRD and the change to the
patient\'s status as a result of those interventions, we did not capture
any cardiovascular events that happened once a subject reached ESRD.

DR. NISSEN: Okay. Well, maybe I\'ll have more to say in the discussion
period, but I\'d sure like to see that data.

DR. COOPER: That\'s the design.

Can we have Dr. Pfeffer now?

DR. BORER: Alan, did you have one question first here?

DR. HIRSCH: This may also just relate and maybe Dr. Pfeffer can answer
it as well.

In transition again from the balance of renal benefit to cardiovascular
benefit, I want to go back to Steve\'s point on figure C-16 where you
see a reduction in heart failure events with irbesartan, but a
relatively favorable effect on the ischemic events in the amlodipine
group. You\'ve shown us baseline data for many renal parameters. I just
want to make sure there wasn\'t any misallocation or randomization
imbalances. Do you have data on clinical coronary disease, myocardial
infarction history, heart failure in the three cohorts you can share
with us?

DR. COOPER: We didn\'t collect data at baseline to that level of degree,
but the frequency of prior cardiovascular events at the time of
randomization was similar in all three treatment groups.

DR. HIRSCH: I saw that. I was wishing to break that down a little bit.

DR. BORER: Marc?

DR. PFEFFER: I\'d like to start with an apology for some of the
confusion. I am a member of this group, but my tenure was supposed to
start after this meeting because I obviously knew I was working on this
project since 1995, and I knew this date. When I was invited to join, I
asked that my tenure start after this session. And apparently my
paperwork went through faster than anticipated. So, I apologize to ‑‑

DR. BORER: A first.

(Laughter.)

DR. PFEFFER: But my history with this trial I think is relevant because
it goes back to the design phase. Dr. Lewis and the collaborative group
had been working with the sponsor ‑‑ and this is relevant to the
difference between cardiovascular and renal ‑‑ to design a renal study
in a patient population that had never been tested with a new class of
agents that had never been evaluated.

At that time, I came in and had discussions with Dr. Lewis and the
sponsor and said how could you not look at cardiovascular events.
That\'s what will happen with these patients. And he said, Marc, you
have to understand. We\'re getting these people at the point of the
spectrum where they\'re more likely to have renal events, but why don\'t
we prospectively look at cardiovascular events too but as a clear
secondary. As a matter of fact, all the alpha in this project is on the
renal events. So, this was a renal study known in a population with a
high likelihood to have a propensity for cardiovascular events.

Now, given that, the sample size was based on the renal events. So, it
was a sample size of approximately 600 per group with three active
comparators. So, there wasn\'t a chance to talk about cardiovascular
death.

If I could have the first slide. We built a composite. Why does one
build a composite? First of all, this is a secondary endpoint. And we
built a composite knowing that with 600 people, three groups, two
comparisons, to get a signal that there was an ability to influence a
cardiovascular outcome, we would need as many what we thought were
clinically important events as possible.

So, as you\'ve heard, it\'s cardiovascular death plus nonfatal MI, and I
would say prospectively we even built in an ECG core lab where the
baseline ECG was looked at 6 months, 1 year, and approximately 6,000
electrocardiograms were looked at. Hospitalization for heart failure
required a hospitalization and an adjudication committee, as did
neurologic deficit, and the amputation was clear, above the ankle. So,
we felt this is a smorgasbord of bad news cardiovascular events, and
let\'s see, if we have a signal that in these three active comparators,
if we can see something.

To give you an idea of where we stood, we also said 600 might not be
enough. Let\'s broaden the definitions and now let\'s call this a
tertiary. That\'s clearly a definition of where we are. We\'re in the
exploratory phase, but we didn\'t want to miss something with this new
class of agents in this important population.

So, what we added to what you had seen before was nonfatal MIs called by
the site. So, if a site called it, we\'d add that. We also added
revascularization procedures. We now added heart failure that didn\'t
quite require a hospitalization, but the investigator said I\'m not
comfortable here. We\'re going to start an ACE inhibitor or an
angiotensin receptor blocker, and we also added a different level of
amputation and peripheral vascular procedures.

And the results were surprising to me that with that smorgasbord of
cardiovascular events adding all these together, in only 2.9 years ‑‑
everyone on active blood pressure control, and blood pressure levels are
going from about 160 to approximately 140 systolic ‑‑ we had a 25
percent event rate overall. Contrast that to the renal where it\'s 37.
So, Dr. Lewis was right. These people were more likely to have a renal
event.

But that didn\'t mean that we didn\'t prespecify and look at these
things. This is the actual numbers. The most common event that happened
to one of these randomized patients who was then followed for a
cardiovascular event, the most common event was the development of a
hospitalization for heart failure.

If we look at the overall composite, I think the conclusion is that this
therapy, these three arms, that there\'s no distinction in the overall
cardiovascular event rate.

Now, again, all the groups are receiving antihypertensive therapy.
There\'s a central committee blindly working with all the investigators
to try to get the pressures down, not knowing the assignment, and this
was the overall.

Now, when the investigators presented this ‑‑ and the first time that
was done was in Stockholm at the European Congress of Cardiology ‑‑ our
conclusion was that there was no difference in this prespecified
composite, lumping all cardiovascular events.

When you have a composite, I think it\'s fair to look at the components
for hypothesis-generating information, and we did that. And what that
showed was the most important line is the first dot, which is the
narrowest confidence interval, which is the overall predefined, and you
can see that that is right around the nil, which is what that
Kaplan-Meier showed.

But then when you break it down into what were the components, the only
thing that really leaves the line ‑‑ and we are not making a point of
this because it\'s one component of many ‑‑ is this hospitalization, but
it\'s counterbalanced by other factors. The event that we had the
narrowest confidence interval, of course, is the overall, and we choose
to make the statement that there\'s no influence on cardiovascular
events, some very interesting things here that will need further study.

The tertiary analysis, which is even broader, just confirms what I\'ve
just said, and once again, the components go back and forth. Really no
difference and nothing that you would say we found something here in
this one of six subanalyses in a tertiary analysis, but interesting
observations that will require larger studies, which are already
underway. There are large studies comparing ARBs to calcium channel
blockers. VALUE has approximately 15,000 patients; LIFE has 9,000
patients. That\'s what\'s going to be required.

Post hoc for the combined ‑‑ you\'ve seen this ‑‑ was let\'s add the
renal bad news to the cardiovascular bad news and see if it\'s a shallow
victory. Are we just offsetting those renal benefits by more
cardiovascular adverse events? And that wasn\'t true.

But I think an even more important analysis to some of the points that
I\'ve heard raised appropriately today, what about the patient? The
patient doesn\'t care if they\'re referred to the nephrologist, the
neurologist, or the cardiologist if they had something happen to them.
This isn\'t a \"who\'s my specialist here.\" It\'s \"how am I doing?\"

We looked at the hospitalizations. Now, this is also skewed in a way
that the data collection stopped at the development of end-stage renal
failure. So, censoring from the time of development of end-stage renal
failure means that we had slightly longer exposure in the irbesartan
group. With that slightly longer exposure, there were fewer hospital
admissions and the time in the hospital was reduced. I think that\'s a
global measure.

Now, of interest, the cardiovascular component of the hospitalizations
was not changed in these three arms with all active therapy. So, our
conclusion would be that although we did not show a measurable impact on
cardiovascular disease, we did show a measurable improvement in global
health, best measured I think by the total hospitalizations.

DR. BORER: Steve or Tom, do you have any other points you want to make?

DR. NISSEN: I tend to look at these events in more of a hierarchical
way, and I guess that\'s why I focused so narrowly on what we would
consider the hard cardiovascular endpoints of cardiovascular death,
nonfatal MI, and stroke. I would really like to see an analysis where
those hard endpoints are looked at. And the reason I say that, Marc, is
that most of the \"benefit\" on the irbesartan versus amlodipine
comparison comes from the hospitalization for heart failure, and we all
know that amlodipine tends to produce some peripheral edema and that
patients with peripheral edema are much more likely to get into a
hospital with a diagnosis of heart failure. So, what you\'re trying to
do is equate a soft endpoint like hospitalization for heart failure with
much harder endpoints.

And I really want to know what the statistical significance would be if
one looked at ‑‑ and I recognize it\'s exploratory and I recognize it\'s
not prespecified, but in terms of looking at overall benefit, I think
you have to look at cardiovascular events in that kind of hierarchical
way because they have different importance in terms of the overall
benefit to the patient. Do we have such an analysis?

DR. PFEFFER: Well, Steve, I think if we could prespecify the importance
of a nonfatal event, then give it a rank, we\'d all be in much better
shape for designing trials. Your bias is that having a nonfatal MI,
you\'ll do better than getting hospitalized for development of heart
failure. Well, there are nonfatal MIs and there are nonfatal MIs, and
there are developments of heart failure. And I think that\'s the whole
problem with once you get below death, how do you rank these things.
Even with the diagnosis of an MI, sometimes it\'s a triponin leak
versus, wow, this person is not going to get out of their chair again.
So, I think that\'s treading in an area that we can\'t do within this
study or that most studies couldn\'t do. Therefore, we chose to give you
the whole global smorgasbord and let you interpret that.

I think the hospitalizations are a very important component of this.

DR. NISSEN: One follow-up and that is ‑‑

DR. JULIA LEWIS: Could I comment?

DR. NISSEN: Sure.

DR. JULIA LEWIS: On the adjudication committee ‑‑ and Marc can speak to
this too ‑‑ we were very sensitive to that issue of peripheral edema
associated with amlodipine use that you mentioned. In fact, as we
adjudicated the heart failure hospitalizations, we required the patients
to have other manifestations such as rales, a chest x-ray that showed
pulmonary congestion, wedge pressure. I mean, there had to be more to it
than swollen ankles.

DR. NISSEN: Sure.

Let me just ask one more question, and that is I want to know the
justification for not collecting the cardiovascular event data once they
got to dialysis. I\'m very troubled by that because we don\'t have data
that I think we should have.

DR. EDMUND LEWIS: Well, once a patient goes on to dialysis, their
caregiver, their environment, everything really changes. Plus, their
clinical course changes in a highly expected way. So, that data was not
collected because of that, because in fact the way we looked at it,
requiring end-stage renal disease was the endpoint here. And the high
mortality rate of these patients, while it would be of interest to know
the exact number, I agree, but we didn\'t anticipate that it would be
any different than any other type 2 diabetic nephropathy that reached
end-stage renal disease. They, after all, had not been on coded
medication for some considerable period of time. They may have had their
blood pressure controlled better than the average patient, so maybe they
had a more benign course. But we did not feel that having detail of that
stage of the patient\'s life would actually contribute meaningful
information to what we were studying, and what we were studying was does
our intervention prevent the patient from requiring dialysis according
to what the course of things would be.

DR. NISSEN: But an intention-to-treat analysis says you continue to
collect the data as the endpoints occur. I mean, I think it\'s an
unusual approach. I can understand why you might argue that the data
might be censored, but I certainly would like to see the data.

DR. JULIA LEWIS: I just want to make two quick comments to add to the
reasons why we chose not to do that in the design committee, and that\'s
because there are two ongoing trials, one sponsored by the NIH and one
sponsored by a pharmaceutical company, looking at elements of the
dialysis membrane interaction with the patient and looking at phosphate
binders and certain things that we use to manage them once they\'re on
dialysis that are thought ‑‑ the hypothesis is that those things
actually impact on cardiovascular events. So, we really thought this was
a fairly contaminated population.

Also, recall we only start out with 1,715 patients at the beginning of
the trial. Our other feeling was that there were going to be so few
patients for a cardiovascular outcome analysis that actually reached
dialysis that it wasn\'t the appropriate setting in which to do a study
in what happens to cardiovascular events in ESRD patients.

DR. BORER: Tom and then Bob and then I have some final questions for you
before we break for the FDA-mandated lunch.

DR. FLEMING: There\'s much to say here. It\'s in a certain sense
philosophically troubling to me because we are ‑‑ and I can accept this
in a certain sense ‑‑ arguing that we need to follow patients long
enough to really be able to see the full clinical benefits achieved by
an intervention that is effectively extending the time to doubling of
creatinine. Yet, at the same time we\'re hearing, gee, when you get out
far enough, there\'s such a myriad of complicated phenomenon influencing
the outcomes of these patients, that we don\'t really want to capture
all of these events because it\'s difficult to interpret them.

In essence, what I want to understand is what are the true clinical
consequences of an intention to deliver an intervention versus not and
follow all the patients forward in time. And it may not be possible to
expect statistical significance on all the cardiovascular endpoints.
That doesn\'t mean it\'s not very informative to understand whether
there\'s a pattern here that is suggestive of benefit or lack of
benefit. So, it\'s a simple question.

Marc, you\'ve indicated that you were a bit surprised that
cardiovascular events were about two-thirds what the renal events were.
Maybe that\'s what it is. I have trouble knowing whether that\'s what it
is because we stopped systematically following the cardiovascular events
at certain points in time. So, it\'s a little difficult to understand
that.

What I would like to see, Marc, about three slides from the end, you
threw something up that is getting at, at least indirectly, what some of
us have been really struggling to see. Could you put the slide up again
that shows the actual number of documented events of each type when
we\'re looking at the secondary endpoint? And I\'d like to have this
left up for several minutes so at least we can make some notes as we go
on to other discussions.

Fundamentally, what I\'d like to see ‑‑ descriptive or inferential
isn\'t critical to me. What I want to see is what the data show about
the difference between the three intervention arms in the fraction of
patients that have the more renal endpoints here, death, dialysis,
survival. Show me what that analysis is.

And then it is relevant to be able to see more globally how those renal
and cardiovascular outcomes pool not that I have to prove statistical
significance or not. I\'d like to understand what the data show about
the actual influence of the strategies here in impacting both renal and
cardiovascular outcomes. So, at some point before we get into voting,
I\'m really hoping someone can put those specific analyses before us.

DR. JULIA LEWIS: Can I make just a quick comment? I know you\'re
cardiologists and I know that heart attacks and cardiovascular deaths
are really important outcomes for you. But again, as a nephrologist, I
have to tell you whether or not you have to go to a dialysis unit three
times a week is also a very important outcome, and if the government ran
out of money, 100 percent of those people would be dead without
dialysis. So, we don\'t have renal death because we\'re rich and
fortunate in our country. It\'s a huge factor for patients. Many of them
are more frightened of it than they are of a heart attack.

DR. BORER: Bob?

DR. TEMPLE: I guess I have a couple of observations. Maybe this should
be left for the discussion, but it seems to me the discussion is bearing
on them.

This was not a trial to describe which the best antihypertensive is. A
trial of 40,000 people is attempting to do that. We don\'t know what
success it\'s having. But you really wouldn\'t expect a trial of this
size to be able to pin down the question of whether amlodipine is better
at preventing heart attacks than irbesartan. There are mountains of data
on that question. Most of it, I admit, is ACE inhibitors not A2
blockers. But it\'s obvious that trials go every which way. I mean, a
big trial in diabetics ‑‑ not so big ‑‑ the ABCD trial sort of suggested
that calcium channel blockers are death and ACE inhibitors make you
live, and then other trials don\'t show the same thing.

It doesn\'t seem surprising to me that in people, all of whom are
treated apparently appropriately for their blood pressure, you see
twists and turns, and I\'m not sure how much you can make out of a trial
of this size on those endpoints when hundreds of thousands of patients
have not allowed anybody but certain individuals to reach a conclusion
about whether calcium channel blockers are better or worse. So, I wonder
how much one should make of this. So, that\'s one observation.

The second is ‑‑ people have said this repeatedly but I\'m not sure
whether everybody buys it ‑‑ that when you reach a creatinine of 6 or
something like that, you are on your way to dying or going on dialysis,
although this trial didn\'t follow that long enough. So, there seems to
be a minimization of that because you didn\'t die or go on dialysis yet.
I wonder about that because the contention is at least you\'re on your
way there. If we followed you another year or two, you\'d definitely be
there. But those are not counted as serious events because they didn\'t
quite happen yet. So, I wonder about that. It seems to me worth
discussing. Does any disagree with that?

Then, of course, the other observation is that there are two comparisons
here. One is against placebo which actually translates to a wide variety
of other drugs, but not including calcium channel blockers or ACE
inhibitors or something like that. And that doesn\'t show this funny
thing on cardiovascular events. So, it\'s not clear what to make of
that.

You might say that these data certainly don\'t tell you you should
always use irbesartan instead amlodipine in everybody because those
other events seemed to go the wrong way and it\'s ambiguous on that. But
does that interfere with reaching a conclusion about the effect on renal
function? And I think those are somewhat separate questions.

DR. BORER: Thank you.

I have three final questions for you before we break. No discussion,
just give me an answer if you can, and they\'ll probably come up again
as we go through the discussion of the formal questions later.

I asked you before about what happened to the people once they were
taken off their coded drug. That question had several components. First
of all, what were they put on? How were they treated after they were
taken off the coded drug, number one? And number two, what happened to
their rates of progression compared with the rate of progression in the
first portion of the trial before they were taken off the coded drug?
So, that\'s one set that I\'d like to hear an answer to.

Second, I want to know something about the exclusions beyond that point
at which people were taken off their coded drug. There were several
other people who were analyzed one way or another that I\'d like to hear
about.

And third, you made a point about blood pressure differences not being
important, and I think it\'s useful that Dr. Kopp is here because I
think that the data that exists might not support that statement and it
may be important for us to know about that.

But we\'ll go through them one at a time. First of all, what about the
patients who stopped their coded drug? How were they treated and what
happened?

DR. COOPER: Can we have the first slide on concomitant medication on
double-blind therapy please?

This slide displays the use of the different classes of
antihypertensives in this patient population during the double-blind
period. As you recall, earlier I was asked a question about
beta-blockers, and you see that the frequency of use was 52 percent in
the placebo group. In most of the classes, placebo patients by and large
received more antihypertensives.

We do not have specific information about the use of agents once
patients reached double of serum creatinine because there\'s no approved
indication and it was up to the investigator to decide what to continue
to use. Our feeling is everyone was very committed to maintaining blood
pressure control and the use of these agents most likely continued
subsequent to discontinuing coded medication.

DR. BORER: So had you replaced the coded medication to maintain the
blood pressure? By increasing the doses of these others?

DR. COOPER: I don\'t have that information. We didn\'t collect that
level of detail of information.

DR. BORER: At some point it would be important to know, because I\'d
like to know if they were put on ACE inhibitors or ARBs. If they were,
you\'d interpret subsequent data one way; if they weren\'t, you
wouldn\'t.

DR. COOPER: In the second slide that I\'d like to show ‑‑ and I believe
that this slide is on an overhead and not on a projector, so if we could
have the overhead set up. The reason why halving of GFR as measured by a
doubling of serum creatinine was considered a clinically relevant
outcome was because the study investigators felt that once you\'ve lost
half of your renal function, you needed to allow the study investigator
to treat the patient with whatever therapy, even though there\'s no
approved indication, should be used to delay the progression of renal
disease.

Interestingly enough, not all investigators put their patients on an ACE
inhibitor. I don\'t have the exact percent, but it\'s certainly not all.
And what this slide shows you is the rate of progression to end-stage
renal disease after doubling of serum creatinine in subjects with and
without ACE inhibitors following the endpoint. So, with ACE inhibitors
is on the lower curve, and there is data here suggesting that if you
treat them with an ACE inhibitor, you are going to delay their
progression of renal disease.

And subjects who did not receive an ACE inhibitor. And there could have
been many reasons for why the patients weren\'t treated with an ACE
inhibitor. These patients could have had severe hyperkalemia because of
their progression of disease as an example. The rate of progression was
more rapid.

DR. BORER: Okay. That\'s not the way I would interpret those curves, but
I can be corrected by any statistician sitting here. It looks to me like
those lines are parallel. They just have a different 0 offset. Am I
wrong about that?

DR. COOPER: If you look at the medians that were calculated until ESRD,
it is shorter for those without ACE inhibitors, 6.4 months, rather than
those with ACE inhibitors. It\'s 12.9 months.

DR. BORER: Perhaps we need a little bit more evaluation. Lloyd, can you
clarify that for me?

DR. FISHER: I agree with Dr. Borer. What he is saying is the offset are
the people who at the time they doubled already were at ESRD, according
to the creatinine criteria, reinforcing the point these are different
populations. But if you put the offset together mentally, it\'s not
nearly as impressive. So, it\'s not really clear whether there\'s
benefit or not from these data.

DR. BORER: Well, I\'m not sure how much we can infer from this, but I
would have been happier to see a real difference between the people who
actually were put on renin-angiotensin system affecting agents after the
coded drug was stopped than not, and I don\'t really see that. So, I\'m
not sure what to make of that.

MR. WILLIAMS: George Williams from Bristol-Myers Squibb.

I think we have to be careful in these kinds of interpretations of
different therapeutic events for cohorts, as described here. These are
certainly not randomized comparisons.

DR. BORER: Right, I understand.

DR. COOPER: I do have one more slide to show and that\'s the slide that
shares the rate of progression to ESRD by treatment group in subjects
who were not put on an ACE inhibitor. So, if they weren\'t treated with
an ACE inhibitor or an A2 receptor antagonist, that\'s the closest we
have to looking at whether or not there was some preserved benefit after
study drug was discontinued but they had halved their GFR.

So, you see irbesartan in yellow, placebo in pink, and amlodipine in
blue. There is no real difference here statistically, but if you look at
the trends, the rate of progression for irbesartan seems to be ‑‑ I
don\'t want to say similar because I can\'t show you the corresponding
curve before doubling of serum creatinine, but it is less than it is for
the other two groups.

DR. EDMUND LEWIS: May I add something?

DR. BORER: Yes, Dr. Lewis.

DR. EDMUND LEWIS: I just wanted to remind the panel of the hyperbolic
relationship that I showed you between creatinine clearance or GFR and
the serum creatinine because now we\'re talking about a period along
that curve that is at the tail where very small changes in glomerular
filtration rate are associated with very large changes in the serum
creatinine. So, if you actually wanted to have a valid study of
anything, ACE inhibitors or where the patient was randomized first and
so forth, those changes in GFR leading to large changes in creatinine on
your hyperbolic curve are so large that you would really need a lot of
patients to get anything other than the sort of identical curves that
we\'re showing you here.

DR. BORER: Well, perhaps it\'s just not evaluable because the study
wasn\'t designed to do this, but you\'ve shown us the data.

What about the exclusions? Now, you\'ve told us what happened or what
you know about what happened to people after they stopped coded drug
when they doubled their serum creatinine. What about the others? There
were patients who never received any treatment. There were patients who
had ESRD and creatinine doubling at the same time and were counted one
way rather than another way. Can you tell us what you did about, for
example, the patients who never received treatment? How were they
handled?

DR. COOPER: Dr. Natarajan?

There were 16 subjects who did not receive a dose of study drug even
though they had been randomized.

DR. NATARAJAN: Again, Kannan Natarajan from Bristol-Myers Squibb.

The 16 patients were analyzed as per the intent-to-treat guidelines, in
essence, actually as they were randomized.

Can I have that slide for the 16 patients please?

These are the 16 subjects who were randomized but never got a single
treatment, never treated. These 6 patients were on placebo, 2 patients
on irbesartan, and 8 patients on amlodipine. All of these patients were
treated as if they received study drug and they were analyzed by the
intent-to-treat principle.

Some of these patients did have an event very soon after the
randomization and were counted as having an event. If we were to do a
sensitivity analysis, counting in a more demonic way, the irbesartan
subject is the only one who is actually going to have the event. Still,
it does not change your conclusion.

DR. BORER: How about the people who were lost to follow-up? There were
13, as I recall, or something like that.

DR. COOPER: There were 8 subjects lost to follow-up for which we did not
have mortality status, and we have a sensitivity analysis for those 8
subjects as well.

DR. NATARAJAN: Can I have the slide for the 8 subjects?

Again, 8 subjects were lost to follow-up. We did not get any information
on these subjects at the time of the study closure. There were 2 placebo
subjects, 4 irbesartan patients, and 2 amlodipine patients. In the
sensitivity analysis, we again considered the worst possible scenario in
which all the placebo subjects, as well as the amlodipine subjects,
didn\'t have an event. However, all irbesartan subjects did have an
event. As you see, the primary composite endpoint is still very similar.

DR. BORER: Okay, that\'s great.

You also had patients who had some events known but their mortality
status wasn\'t known, and how did you deal with them?

DR. NATARAJAN: Can I have the 19-patient slide?

There were 19 subjects who had variable follow-up. There were 11
patients for whom we had the mortality status known. Most of these
subjects had withdrawn consent and the only thing that we know of is
actually whether they were dead or alive at the end of the study. One
subject died during follow-up and is included in the ITT analysis.
Assuming the other 7 subjects had a primary event, this is how ‑‑ and
again, this is in the worst case scenario which is highly unlikely to
happen in the sense that it\'s more of a demonic way of looking at it.
The placebo subjects and the amlodipine subjects didn\'t have any event.
The irbesartan subjects alone had an event, and this is how it will turn
out to be.

DR. BORER: At least we have the data in front of us, and I appreciate
that.

The final question before we break. You suggested that although there
was a 2 to 3 percent difference in blood pressure between the placebo
group and the irbesartan group ‑‑ forget for a moment the amlodipine
group because I\'m going to suggest to you that that issue may or may
not be relevant since we haven\'t considered the possibility that
amlodipine might do something bad. But if you just think about the
placebo patients versus irbesartan, there was a 2 to 3 percent
difference in blood pressure favoring irbesartan, and you suggested that
though that was statistically significant, it wasn\'t clinically
relevant.

About 6 months ago, we sat at a meeting listening to data from ALLHAT,
and there was a rather formidable presentation, suggesting something
very different from what you said, that is, that 2 to 3 millimeters of
mercury could account for a lot of difference. And I wonder if either
you or someone from the committee who\'s familiar with ALLHAT or with
the relevant data here can talk about that a little bit.

One might infer that the better results in the irbesartan group versus
the placebo group had something to do with the difference in blood
pressure control rather than some independent effect of blockade of the
renin-angiotensin system. How would you respond to that?

DR. COOPER: Well, that was the reason why we did the Cox regression
analysis using blood pressure levels during the study to adjust for the
primary composite endpoint, and in that analysis, the relative risk
reduction, 19 percent, is similar to what was observed without that
analysis. It was 20 percent.

I guess I\'m interested in your comment about comparing the amlodipine
and irbesartan group because amlodipine could have been doing harm. One
of the points is that the amlodipine event rate was similar to the
placebo event rate, and it is our interpretation that it is unlikely
that amlodipine was doing any harm with respect to this composite
endpoint.

DR. BORER: You may well be right. I\'m cognizant of the fact ‑‑ and in
fact I had come to the same conclusion that Bob stated ‑‑ we had two
different comparisons here, and we\'re asking several different
questions.

I don\'t want to lose my train of thought here before we close. Yes, I
do remember now.

I don\'t know technically how one makes adjustments with the Cox model.
I don\'t know how valid it is to say there was 20 percent and 19 percent
and whatever. What I would be willing to accept is that there is an
independent effect of treatment even when you consider blood pressure
differences, which I assume is what you found. Maybe you can expand on
that.

DR. NATARAJAN: Yes. Can I have slide 354?

What we did is basically address the issue of the differences in the
blood pressure between the treatment groups whether it\'s clinically
relevant or not. From a statistical point of view, we adjusted in a
time-dependent manner and these are the results of the analyses, both
unadjusted, as well as adjusted for time varying mean arterial pressure.
As you can see, the risk reduction change is very small, from 20 percent
to 19 percent, and the significance still exists. And with regard to
amlodipine, we did not see any difference in the blood pressure, and
thus the estimate did not differ, nor does the p value.

DR. BORER: Tom, can you comment on this?

DR. FLEMING: Well, I think what\'s been attempted here with the time
varying covariate is a reasonable approach. The question is how
interpretable or convincing is it really.

Essentially ‑‑ and I assume this is what you\'ve done, although there
are lots of variations to how you might do this ‑‑ what you\'re saying
is we know at baseline that blood pressure is predictive of risk of many
types of events, renal and cardiovascular. So, what we\'d like to do to
fully capture that influence, particularly if there\'s a difference in
the blood pressure profile over time across two different regimens, is
put a time varying covariate in that says anytime there\'s an event,
what is that person\'s blood pressure at that point and adjust for blood
pressure, not just at baseline but as it\'s varying over time.

DR. NATARAJAN: That is correct, yes.

DR. FLEMING: And that\'s a very reasonable approach to take here.

There are some pretty significant assumptions we\'re making, though, and
that is the way in which blood pressure truly is influencing outcome is
fully being captured by whatever that latest measured blood pressure was
at that point.

I\'ve attempted these kinds of adjustments in other trials in which we
have seen evolving differences in outcomes and evolving differences in
blood pressure levels, and we haven\'t also been able to explain these
differences by the time varying covariate analysis. So, I consider what
they\'ve done as a reasonable approach, but it certainly doesn\'t
reliably allow us to conclude that there are not differences in these
event rates that could well still be impacted by the difference in blood
pressure control between the arms.

DR. JULIA LEWIS: If I may add something. I\'m an investigator in the
African American study of kidney disease and hypertension, which has
been presented at the American Heart Association, and I sit on the
writing committee.

We in that NIH-sponsored trial randomized African Americans with kidney
disease and hypertension to a mean arterial blood pressure of 102 to 107
versus less than 92. We achieved between a 10 and 11 millimeter mercury
difference in mean arterial blood pressure. By any measure of renal
function, including time to event and iothalamate GFR, we were unable to
demonstrate a beneficial effect of being randomized to the lower mean
arterial blood pressure group of less than 92.

Although that\'s a different group ‑‑ it\'s African Americans with high
blood pressure and kidney disease ‑‑ I thought I would share that piece
of renal data with you, which may suggest that the renal bed is somehow
perhaps different than the cardiac bed in its response or that we\'re in
a range of the continuum where it\'s less of an impact.

DR. NATARAJAN: I would like to just add one more thing. Whether or not
we adjust and do this time-dependent analysis, the thing to keep in mind
is that there was no difference with respect to amlodipine and
irbesartan, and that would actually suggest that that is independent of
the blood pressure lowering.

DR. FLEMING: Although you\'re making assumptions there about what other
mechanisms of action could differ between the two that might offset a
difference that would be attributable to blood pressure lowering.

DR. BORER: I think that\'s been a very informative presentation. I
really want to thank you, Dr. Cooper. You\'ve been very clear and
concise and given us a lot of numbers.

DR. COOPER: I\'m a nephrologist.

(Laughter.)

DR. BORER: Yes. Well, when I was in medical school, our physiology
department was primarily skewed towards renal physiology because Robert
F. Pitts was the chairman. Knowing that I would be a cardiologist when I
grew up, I was very excited when one of the teaching fellows said that
he had a grant from the American Heart Association. So, I said, what are
you doing relative to the heart? He said, nothing of course. The only
purpose of the heart is to pump blood to the kidneys. Everybody knows
that.

(Laughter.)

DR. BORER: So, I understand what you\'re saying here.

In any case we will take a break until 1 o\'clock when public comment
will be possible, and then we\'ll finish the last two formal
presentations and go on to the questions.

(Whereupon, at 12:10 p.m., the committee was recessed, to reconvene at
1:00 p.m., this same day.)

AFTERNOON SESSION

(1:15 p.m.)

DR. BORER: We\'ll begin again.

The meeting is open for public comment. There were no applications for
public comment, but are there any individuals who have comments that
need to be made?

(No response.)

DR. BORER: If not, we\'ll go ahead. We have some additional questions
and I believe the sponsor has some responses first to Tom Fleming\'s
questions, and once you do that, we have some more questions from JoAnn
and from Tom before we get on to the next phase of the presentation.

DR. COOPER: Thank you.

What I\'m going to present now are the data to respond to the remaining
questions. Can I have the first slide please?

Part of the earlier discussion focused on the effect of treatment on
end-stage renal disease, specifically transplantation and dialysis. I
did want to share with you the results of the time-to-event analysis for
end-stage renal disease, including serum creatinine of 6.0 milligrams
percent and greater.

In this Kaplan-Meier curve in which irbesartan is displayed in yellow
and amlodipine and placebo are in blue and pink, respectively, a
treatment effect was observed with a 23 percent risk reduction in favor
of irbesartan. Once again, this is all patients who had an ESRD event
even after they discontinued study medication.

Next slide. This is the first of the analyses that was requested, time
to dialysis, transplantation, or death comparing placebo and irbesartan.
And in this analysis, the relative risk reduction was 13 percent, the
confidence interval between .7 and 1.09.

The next slide ‑‑

DR. FLEMING: Could you leave that up for a few seconds please?

DR. COOPER: Yes.

(Pause.)

DR. FLEMING: Thank you.

DR. COOPER: The next slide contains the time to event for dialysis and
death. Once again, a relative risk reduction in favor of treatment with
irbesartan was observed, 11 percent. Confidence intervals are on the
slide.

(Pause.)

DR. COOPER: Next slide please. This is the analysis of time to event of
ESRD or death. In this analysis, serum creatinine of 6 is included. The
relative risk reduction in favor of treatment with irbesartan compared
to placebo is 15 percent.

(Pause.)

DR. COOPER: And lastly, the new, redefined, combined composite endpoint,
which includes dialysis, transplantation, death, and cardiovascular
events. The relative risk reduction in favor of treatment with
irbesartan observed is 14 percent. It\'s not expected that any of these
post hoc analyses would be statistically significant. They\'re not
powered to detect differences between treatments for any of the
components.

DR. FLEMING: Do you happen to know what the amlodipine total is?

DR. COOPER: We do. That\'s slide MC-128 please.

For the same combined composite endpoint, the relative risk reduction
was 10 percent in favor of treatment with irbesartan.

DR. FLEMING: This is much of what we wanted to see. I guess the last was
this specific analysis, but only driven by the death, dialysis, and
cardiovascular. Did you happen to do that?

DR. COOPER: Death, dialysis, transplantation, cardiovascular events.
This does not include a serum creatinine of 6.

DR. FLEMING: This does not.

DR. COOPER: No.

DR. FLEMING: Okay.

DR. COOPER: Our conclusions from these results are that treatment with
irbesartan is renoprotective. When you consider this patient population
and the fact that you need anywhere between two and four
antihypertensives to optimize their blood pressure control, we feel that
these data support the use of irbesartan to protect the renal function,
but we also recognize that this does not exclude the use of another
antihypertensive to protect the heart.

DR. BORER: Thank you very much.

JoAnn, you had several additional questions.

DR. LINDENFELD: Just to make sure I understand here, when a patient was
admitted for heart failure or admitted for another event, was that
creatinine included in the events? For instance, if a patient was
admitted for heart failure in between the routine evaluations and their
creatinine had doubled, was that then evaluated as a doubling of
creatinine assuming that it was reproduced?

DR. COOPER: All events were adjudicated by the outcome confirmation
classification committee. If a patient had two events at the same time,
they would have been adjudicated independently of each other, and all of
the criteria would have had to have been fulfilled. Certainly there
could have been ‑‑ and probably were ‑‑ a number of patients who,
because of their compromised renal function due to diabetic nephropathy,
at the time of the hospitalization where there are other insults to
their system, if you will, could have been pushed over into end-stage
renal disease at that time and had incurred doubling of serum
creatinine.

DR. LINDENFELD: I guess what I\'m asking is whether or not patients who
had worsening heart failure were sampled more often and they\'re more
likely to reach the endpoint of doubling of creatinine earlier because
there was this significant excess of heart failure. That could have made
a difference of a number of endpoints.

DR. JULIA LEWIS: Let me see if I can answer the question for you. In
order for a patient to reach a doubling of serum creatinine, they had to
have a persistent doubling of their serum creatinine on two measurements
up to 4 weeks apart. During the time interval between the first
measurement of doubling of serum creatinine and the second, the
investigator would be encouraged to treat any reversible causes of the
rise in serum creatinine.

So if, for example, a patient was in the hospital with heart failure and
had a transient rise in their serum creatinine, when they came to their
next study visit, the study coordinator would be checking their serum
creatinine as part of that visit. If at that visit, the serum creatinine
was doubled, it would then fall into the usual path of confirming the
doubling.

Did that answer your question?

DR. LINDENFELD: I think so.

I\'d like to just get back to this issue of race just a little bit.
Could you show me what the doubling of creatinine was in blacks versus
whites? I recognize there was a small number of blacks in the study, but
is there a substantial difference?

The reason I ask that is there were 98 doublings of creatinines in the
irbesartan group and 135 in the placebo, so a difference of 37 patients.
There were 78 black patients in the placebo group, 63 in the irbesartan,
and 87 in the amlodipine group. This is several percentage points
difference because the total number in each group was slightly
different.

So, I\'m just concerned. If, as we\'ve heard, the progression of renal
disease is significantly different in minorities and there\'s a
difference in minorities, whether or not that\'s a significant point
here.

So, I think to just start that, could you tell me was there a difference
in the doubling of creatinine in black patients compared to white
patients?

DR. COOPER: The answer is yes. Do we have the subgroup analysis
specifically for blacks versus whites?

The subgroup analysis shows that the point estimate for doubling of
serum creatinine favors treatment with irbesartan. The effect in white
patients is greater with a relative risk reduction of 25 percent
compared to nonwhite patients with a relative risk reduction of 5
percent. This is a subgroup analysis with a very small number of
patients, and once again the results are going to be driven by the
number of patients.

DR. LINDENFELD: It doesn\'t look like there\'s enough difference in the
baseline to make a difference.

But there is an under-representation of, I think, blacks in the
irbesartan group compared to both the placebo and the amlodipine group.
There\'s under-representation in the entire trial, but I think there\'s
about a 5 percentage point difference in the number of blacks here. It
just concerns me because if blacks are likely to progress at a higher
rate, then a small difference could make an event difference of 10 or 12
in that group, which could change the total number of 37 events
substantially. Again, I think this is a problem in this kind of trial of
not stratifying for the groups that are more likely to progress.

DR. COOPER: Dr. Lewis, do you want to address the rate of progression of
renal disease in black patients?

DR. EDMUND LEWIS: Well, not any further than what I\'ve said before. I
don\'t think we have information about the rate of loss in black
patients in the study in terms of delta creatinine clearance for blacks
versus whites. So, I really can\'t expand very much on what was said
before. I think that here you have this data, and I don\'t think that
there\'s any further that I can say about that, although I will point
out that the effect of race on the outcome ‑‑ clearly patients who are
white had more irbesartan effect, if you will, than blacks. But I really
can\'t comment about your other point.

DR. JULIA LEWIS: I think I can comment a little bit more about it. Can I
have my slide 1?

This is true that if you look at the age-adjusted incidence of ESRD,
African Americans have a higher age-adjusted incidence of ESRD based on
the USRDS data.

Also, there\'s data out there that suggests that an African American
with high blood pressure and kidney disease compared to a white person
with high blood pressure and kidney disease, between the ages of 20 and
45, has a 20 times increased risk of developing kidney disease.

However, in the African American study of kidney disease and
hypertension, sponsored by the NIH that I alluded to earlier, 1,094
African Americans were randomized in a three-by-two factorial design.
I\'ve already commented on the results of the blood pressure
randomization. I will comment that the ACE inhibitors protected their
kidneys, but I would also like to comment that the average rate of
decline of renal function in this study in African Americans with high
blood pressure and kidney disease was 2 mls per minute per year, which
would mean that if you started out with a normal kidney function, a GFR
of 100, it would take you 50 years to reach end-stage renal disease. So,
some of our conceptions based on epidemiologic data on the rate of
decline of renal function in African Americans may reflect the fact that
unlike in clinical trials, their blood pressure is not under exquisite
control.

DR. LINDENFELD: I don\'t think that helps me much because it isn\'t a
diabetes trial.

Again, actually what you\'ve said concerns me just a little bit more
because if there\'s an over-representation of blacks in the amlodipine
and the placebo groups compared to irbesartan and blacks progress
faster, then to me that biases the study a bit in favor of irbesartan.

In addition, if irbesartan doesn\'t appear to work in blacks and it does
in whites, from the data you\'ve shown me, then that\'s an additional
problem more than just the fact that renal function progresses more
rapidly in blacks. So, that data actually concerns me.

I\'m really concerned because these are not very large numbers. I\'d be
interested. Maybe I\'m overdoing it here, but doubling of creatinine is
everything here, and there\'s only 37 patients difference in the
doubling of creatinine. Yet, between amlodipine and irbesartan, there
are 24 more blacks and 15 more between placebo and irbesartan. You know,
just a few patients here makes a difference between a significant and a
nonsignificant study.

DR. NATARAJAN: I agree, but I wanted to actually caution the committee
in terms of actually over-interpretation of subgroups of very small
sizes. Again, yes, actually there are very few blacks, and the
differences among the treatment groups, though numerically there, they
were not statistically significant. They were not actually any different
between any of the treatment groups.

DR. LINDENFELD: Well, I agree with that, but I\'m not talking about
that. What I\'m talking about is the fact that it seems to me from a
cardiologist\'s standpoint, if you just go back and review the reviews,
that blacks progress more rapidly and other subgroups too. Maybe
Hispanics. But it appears that the literature suggests ‑‑ you may have
some data that I don\'t have ‑‑ that the progression is more rapid.
Again, just help me with this. Maybe you can explain why that\'s not a
concern.

DR. FLEMING: I think JoAnn is talking more specifically about race in
its role as a predictor and hence a potential confounder rather than as
an effect modifier, although both are issues. But if in fact it\'s a
predictor such that blacks would have a poor outcome and they are
under-represented in the intervention group, then you would have some
level of confounding. It\'s not a serious imbalance, but her point is
the strength of evidence here is marginal at the level of significance,
so even a minor imbalance could somewhat compromise the convincingness
of results.

DR. LINDENFELD: That\'s exactly right, but it could also be an effect
modifier if in fact irbesartan ‑‑ there are not enough numbers ‑‑ but if
it\'s less effective in blacks than whites, then it becomes an effect
modifier too in a sense. They are small numbers, but the study is based
on very small differences in numbers.

DR. EDMUND LEWIS: I don\'t know about helping you. All that I can say
about the preconceptions of how much faster or how more malignant a
course patients with type 2 diabetic nephropathy have does not take into
consideration the fact that these patients do not have their blood
pressure controlled to the recommendations that are made. And I think
that in this study, we get the closest that has come actually to blood
pressure control recommendations in both the hypertensive and type 2
diabetic population.

So, I think that the assumption that because somebody is African
American, they therefore are going to have a much more malignant course
is really not exactly an accurate assumption. It\'s based on literature
where the black population, the African American population, has more
problems with blood pressure control than does the white population.

I think that once you get into the subgroup analyses, you\'re getting
into small numbers. I personally don\'t think that our outcomes are that
small of numbers. But when you get into the subgroup populations, you
are getting into small numbers, and I think that before you make certain
assumptions, you have to have the data.

And I don\'t really believe that you have data showing that the black
population ‑‑ the natural course of their diabetic nephropathy is that
much worse. The natural course of diabetic nephropathy, as we\'re
showing you, is bad and that\'s with blood pressure control. That\'s in
everybody.

So, I think there\'s a certain assumption here. I just don\'t think we
can go any further with it because I don\'t think that there\'s a number
we can put on it. I don\'t think that you can say because somebody is
African American, their chances of doubling is 1. something compared to
a white because that information really doesn\'t exist.

DR. LINDENFELD: No, I agree, and I certainly don\'t pretend to be an
expert. But if one just goes to the reviews, the reviews all strongly
suggested that progression is substantially faster without specific
data. But the reviews suggest, from studying the data, that it\'s faster
in blacks and certainly American Indians and perhaps non-white
Hispanics.

DR. EDMUND LEWIS: Well, I would be glad to go through whatever data
you\'re picking out of your reviews because I think that I will have no
problem showing you that there is a blood pressure issue.

I will say, though, that the Hispanic population and the best study
population which is relevant here is the Pima Indian population. The NIH
has supported longitudinal studies. 50 percent of the total Pima Indian
population gets type 2 diabetes and most of them get nephropathy. And
the time from birth to onset of diabetes is very well-known. From the
onset of diabetes to proteinuria is very well-known. From proteinuria to
decreasing renal function and end-stage renal disease is very well-known
in this patient population. They\'ve even had serial renal biopsies,
frankly. And I think that you will see, if you look at that population,
which genetically really represents the problem in Hispanic populations
in North America, that the curves to those various events are the same
as those reported from Germany in type 2 diabetic nephropathy.

So, when you start studying populations carefully, controlling for
things like blood pressure and so forth, you won\'t necessarily come up
with the conclusions that you get out of reviews. That\'s all that I can
say.

DR. BORER: Bev and then Dr. Kopp?

DR. LORELL: Thank you.

In a little different subgroup, I\'d like you to address the issue of
the subgroup of women. The point estimate for women for the primary
endpoint is even closer to unity than for non-whites, .98. And perhaps
you can address that for us.

DR. COOPER: Yes. Dr. Breyer Lewis?

DR. JULIA LEWIS: I\'m going to first remind you of the statistical
results, and then I\'m going to comment on putting it in some
perspective.

First, I would remind you that we were not powered for exploratory
subgroup analysis. There were, for example, nearly 900 white males in
this trial and only 91 black females.

However, as you can see from this, the common point estimate of .8
crosses all the confidence intervals, suggesting a common risk reduction
between males and females.

Similarly, the confidence intervals overlap, again suggesting that
there\'s not a statistically significant difference.

Lastly, when looking at multiple subgroup comparisons, it\'s important
that the point estimate favors irbesartan. That\'s the statistical
response to that question.

In terms of putting it in perspective of what\'s known about the impact
of gender on women in hypertension and renal disease, I would first
remind you of the hypertension studies. I\'ll remind you that when the
first studies were done, examining whether or not treating people with
hypertension with basically beta-blockers and diuretics versus placebo
was of benefit. The first three trials, the MRC done in England, the
hypertension detection and follow-up program done here in the United
States, and the Australian therapeutic trial, when the subgroup analysis
was done in women, not only did they either not find a benefit or
actually found that the women had a higher mortality rate in the treated
group.

Now, although there was concern expressed when these studies were done,
no one at that time advocated strongly that women should be withheld
from the treatment of hypertension. Subsequently, the INDANA analysis,
which has incorporated seven clinical trials looking at the treatment of
hypertension, has concluded what in fact has been I think common medical
practice, and in fact women benefitted from the treatment of their
hypertension, although not in all the categories as did men, but in key
categories, including main cardiovascular events.

In the area of renal disease, I\'ll just review only clinical trials
that have in the definition that you would accept that are randomized,
double-blind with sufficient numbers of patients enrolled to have power
to look at the group as a whole. But again, the analysis of the impact
on women is a subgroup analysis in each of these trials. I also selected
trials that have outcomes similar to the one used in IDNT.

The first, of course, is the captopril trial, which you are familiar
with, in type 1 diabetics. Males and females had equal outcomes. Males
did not have a worse rate of decline of renal function, nor was there
any difference in efficacy of the ACE inhibition for males.

A study done in nondiabetic patients with proteinuric kidney disease in
Europe found that males had a worse outcome and that there was worse
efficacy of ACE for males. Excuse me. It was better efficacy for ACE in
males.

Another study done in nondiabetic proteinuric patients in Europe. Worse
outcome for males, no. But better outcome for males.

If you look at the MDRD, which was not a study, looking at an
intervention with a specific antihypertensive agent, but at other
interventions, males had worse outcomes.

So, in fact, the subgroup analysis in the available renal studies is all
over the map, suggesting that perhaps all of these studies are not
powered for these exploratory subgroup analyses.

DR. KOPP: I just wanted to make a comment about the progression of
diabetic nephropathy in blacks versus whites. My understanding is very
close to what Dr. Lewis said, that in the setting of diabetes, blacks
are something like 2- to 3-fold more likely to develop nephropathy, but
I\'m not aware, although he may have come across something that I don\'t
know about, that once diabetic nephropathy appears, that the rate of
progression is different.

DR. BORER: Why don\'t we move ahead with the presentation, and we\'ll
get to any residual ‑‑ we have another speaker down at the end of the
table.

DR. TEMPLE: A short question. Going back to the possibility that the
greater number of blacks in one group influenced the results, isn\'t
that answered by the breakdown into the black and white populations that
we saw in which the effect was larger in the white population? That
doesn\'t seem to be compatible with the whole result being driven by the
excess of blacks. Isn\'t that right?

DR. LINDENFELD: If you think that the progression ‑‑ I don\'t want to
make a huge issue of this. I just think these are small numbers. But if
you assume that progression is greater in blacks and there are more
blacks in the non-treatment group, that group would progress faster.

DR. TEMPLE: No. I agree with that. But then they showed separate results
for the white population than the black population. The effect, if
anything, was larger in the white population.

DR. LINDENFELD: Right.

DR. FLEMING: One has to be careful, Bob, in keeping these issues of
confounding and effect modification separate. If you look at page 73,
for example, in the sponsor\'s briefing document where they present this
summary, if you look in the control arm, non-whites have a somewhat
higher event rate, 43.5 percent, from whites at 37.3 percent. And as a
result, if you end up with some excess of whites in the intervention
arm, then there would be a small level of confounding. I don\'t think
this is a very large risk of confounding. It would be very modest. But I
think JoAnn\'s point was in a setting where the significance is very
close to the border, this could have some influence.

A separate point entirely, also a relevant point, is is race also an
effect modifier, not only is it a predictor such that it appears that
non-whites have a somewhat higher rate, does treatment effect differ by
race, which is an entirely separate phenomenon from whether race is a
confounder. And it also appears here, that in addition to it being a
potential confounder because non-whites have a somewhat higher risk,
it\'s also true that the effect seems to be greater in the whites than
it is in the non-whites. Two separate issues.

DR. BORER: Without ‑‑

DR. NATARAJAN: Could I address that?

DR. BORER: No. Just one moment because I think we may have gone as far
as we need to go with this.

There may be some differential effect based on race. It seems plausible
to me. We know that renin levels are, by and large, a lot lower in the
black population with hypertension than in the white population with
hypertension, and here we\'re blocking the renin-angiotensin system.

I don\'t want to go into the realm of speculation. These are the data.
Indeed, there may be some comments, if the drug is judged to be
approvable, about labeling issues or maybe not. But let\'s deal with
that when we get to the questions, and let\'s hear the remainder of the
data that we\'re going to hear.

DR. FLEMING: Jeff, there were two quick questions that I wanted to
raise.

DR. BORER: Sure, absolutely.

DR. FLEMING: If I could go back to the sponsor\'s presentation, slide
C-13. What you had done there is you had broken out the relationship
between having had a creatinine event versus dialysis or
transplantation. Surely there is, obviously as this shows, a
relationship, as we would fully expect. It\'s interesting that 26
percent of these events of dialysis or transplantation occur in that
right-hand column, people that didn\'t have a serum creatinine event.

I guess I have two questions. One is trying to understand why a quarter
of these people would have gone on dialysis or transplantation without
having had a creatinine event is question one.

Question two is how do those 69 break out by intervention arm? Hopefully
not with more of them on the irbesartan group.

DR. COOPER: The answer to your first question is, by and large, when
patients presented requiring dialysis, it was because they either missed
visits and so we were no longer able to measure their serum creatinine
and then assess whether they had had a doubling or an ESRD event, as
determined by the serum creatinine, or the other most frequent reason
was because these were patients who were on a rapid slope of decline of
renal function, hadn\'t yet doubled, or achieved a serum creatinine of
6, were hospitalized because of an intercurrent and severe illness that
compromised whatever remaining function they had left and pushed them
over into permanent end-stage renal disease.

DR. FLEMING: So, there\'s not a fully consistent relationship, at least
in terms of documenting a doubling versus having dialysis occur. There
are a substantial number that will actually have dialysis occur before
you document.

Can you tell us how those 69 broke out in the three groups?

DR. COOPER: I honestly do not remember. Do we have that data?

DR. FLEMING: If you don\'t have it now, I can wait and we can get it at
the end of the next presentation. It would be useful to know that.

DR. BORER: Yes, let\'s try and get it.

Just a clarification in response to Tom. If I understood what you said
correctly, it\'s not that there may not have been doubling or far
greater than doubling of creatinine in many of these patients who
didn\'t have a doubling event or a 6.0 creatinine before they went on
dialysis, but that they went on dialysis in the context of a situation
which was not the time at which these events were measured and therefore
they wouldn\'t be captured that way in the data set. They may well have
had a creatinine of 6 in the context of another disease, but you didn\'t
count it that way. They just had to go on dialysis. Am I correct in
saying that?

DR. COOPER: Yes, that\'s correct.

DR. BORER: Steve?

DR. NISSEN: I don\'t want to belabor this, but we talked about other
subgroups. I was very struck by the North America versus non-North
America data, and I would really like a comment because we\'ve seen an
awful lot of studies, particularly recently, where drugs didn\'t seem to
have any effect in the North American population but did in the
out-of-U.S. population. I personally am troubled by that, and I want to
know if you have any comments or thoughts or can you help me understand
why there was only a 5 percent point estimate for the North American
population.

DR. COOPER: Part of that is driven by the fact that all of the black
patients that were enrolled and randomized were actually in North
America, so a number of those events were in that subgroup. There is no
other biological explanation for why the rates of progression would be
different or the treatment effect would be different between the
different regions. Certainly in Latin America and in the Pacific region,
the event rate that was observed ‑‑ and there are minority populations
in those regions ‑‑ was very consistent with what was seen in Europe.

Any other comments?

DR. BORER: Dr. Temple.

DR. TEMPLE: Some people have expressed some degree of nervousness about
not having a sort of ultimate endpoint on the people who got their
creatinine to 6 or doubled it or something like that. A fair amount of
time has now elapsed since you published and collected data. Would it be
of interest or a possibility to find out when all the people in the
trial went on dialysis?

DR. COOPER: We could certainly do that for all subjects who didn\'t
withdraw consent and for all subjects that didn\'t participate in a site
that was closed. Actually ascertaining dialysis or ESRD is more
difficult than mortality because with mortality you can just access a
death certificate. But yes, we can do that.

DR. TEMPLE: Even if the site is closed, they could find out when the
person went on dialysis. I\'m not saying it would be easy and I\'m not
even saying it\'s necessary. I just wondered if you could do it.

DR. COOPER: Yes, we can make an attempt to do that.

DR. FLEMING: Just a follow-up on that. Why wouldn\'t that be a
compellingly obvious thing to do in the sense that what we\'re hearing
is clearly there is a real relationship between creatinine elevation and
dialysis, the latter being an obvious clinically important endpoint, the
former being at least debatable as to the level of surrogacy that it
actually presents? But the answer is there in this database, and the
answers that we have in this database are marginal, even if you focus on
the primary endpoint, and if it\'s just a matter of time, which we keep
hearing, then wouldn\'t it be potentially very informative to know what
an updated data set would say?

DR. BORER: We could ask the sponsor to do that.

I just want to make one quick comment and then we must move on. We
shouldn\'t get into a debate here. I have no problem with recognizing
that somebody with a creatinine of 6 is sick. I\'m just a cardiologist,
but even I know that. They don\'t feel well and Dr. Lewis actually
recited the problems that are associated with creatinine at that level
left untreated by dialysis. So, I don\'t think we should spend too much
time talking about whether these people are sick or not. If they\'re not
dialyzed, they\'re real sick, and we can debate that later when we go
through the questions. But I don\'t think that\'s a key issue.

DR. JULIA LEWIS: Could I expand on that for just one second? In type 2
diabetes, there are 135 million. By the year 2025, there are going to be
325 million, a 100 percent increase in the third world, if you\'ll
forgive me for referring to it, the Asian countries. For them an
elevated creatinine is death. We wouldn\'t be able to go count them
going on dialysis later. They\'re dead because it\'s not an available
therapy.

DR. FLEMING: Then we should be able to see in those people a survival in
that as well.

DR. BORER: We should.

DR. COOPER: Right. We will make every effort to collect that data.

It is with great pleasure that I now introduce Dr. Parving ‑‑

(Laughter.)

DR. COOPER: ‑‑ who will be discussing the IRMA 2 study. You will be
hearing about the ability of irbesartan to alter the course of diabetic
nephropathy earlier in the disease so that patients do not advance from
the stage of microalbuminuria to proteinuria, the onset of which in
diabetes heralds the inevitable decline in renal function. Thank you
very much.

DR. PARVING: So, I\'m supposed to say good afternoon from Denmark.

I am pleased to give you information on the early course of diabetic
kidney disease and I\'m going to present the data from the study called
IRMA 2. It\'s dealing with irbesartan in type 2 diabetic patients who
are suffering from persistent microalbuminuria.

I will present data in two segments, one giving you some background
information and then go to the presentation of IRMA 2.

First, the background. This is actually linking up to what you have just
been told, dealing with the IDNT study. It\'s a Kaplan-Meier estimate of
the primary composite endpoint in the IDNT study in relation to
quartiles of albumin excretion rate at baseline. The message from this
baseline estimate is the following. If you have levels of albuminuria,
low 1,000 milligrams, the event rate is approximately less than 20. If
you go the very high rate, the upper quartile, then you have an event
rate of nearly four-fold higher, at least suggesting that the level of
proteinuria or albuminuria is reflecting the underlying cause of the
kidney disease as first demonstrated by Bright in 1836 in England.

This cartoon is giving you information on the different levels of
albuminuria. We have a log scale and we are dealing with the overnight
albumin excretion rate, and the reason why we are dealing with the
overnight albumin excretion rate is in an attempt to standardize the
collection. So, we are avoiding the marathon runner, we are avoiding
other special activities of standing up and lying down because we have
that phenomenon. So, we are standardizing it by using overnight
collection. So, you collect all the urine during the nighttime.

Normal albuminuria is defined as an albumin excretion rate below 20
micrograms per minute. If you have an excretion rate between 20 and 200
micrograms, we call it microalbuminuria.

This range of albuminuria is usually not depicted by the dip stick test.
You need to develop sensitive tests in order to pick it up. This was
described the first time 20 years ago by Viberti, Mogensen, and myself
as something important in relation to diabetic kidney disease. And we
actually have an anniversary this year.

(Laughter.)

DR. PARVING: Then about the 200 microgram level, we are speaking about
overt nephropathy.

You will also appreciate that while the IDNT studies carried out in
patients with overt nephropathy having an excretion rate of more than
2,000, way up here, IRMA 2 is a study carried out very early in the
course of diabetic kidney disease because, as Ed Lewis already told you,
microalbuminuria is an abnormality in the glomerular capillaries leaking
protein. So, it\'s the earliest clinical sign we have of an underlying
diabetic kidney disease. So, IRMA 2 is carried out in this range.

Very important information is that 60 percent of our type 2 patients
will never, ever develop kidney disease. Unfortunately, 40 percent of
our patients in America, in Europe, and in certain parts of Asia, even
higher, will develop this devastating kidney disease.

It\'s also true that in order to develop the disease, you are
progressing through the level of microalbuminuria, the earliest state of
diabetic kidney disease, into overt nephropathy.

Important to note is that the GFR, meaning the glomerular filtration
rate ‑‑ the drop in normal man with normal albumin excretion rate is 1
ml per minute per year. If you have microalbuminuria, the drop in kidney
function is ranging between 1 to 3 mls per minute per year and that is
based on all the available data. You\'ll appreciate later on in my
speech that the rate of decline in the IRMA 2 is 2 mls per minute per
year.

If we go to overt nephropathy, the rate of decline is increasing, and
it\'s ranging between 2 to 20, with the average rate reported in the
literature of 10 mls per minute per year. Actually the level of decline
from the IDNT study ‑‑ we haven\'t discussed that today ‑‑ was 6.5 mls
per minute per year. So, you can clearly see if you go from this level
of proteinuria to this level, you have a progressive worsening of the
kidney function. Consequently the aim of IRMA 2 is to keep the patients
within that region. We don\'t want to get them out of the box.

More background information about microalbuminuria in type 2 diabetes.
As already stressed by Ed Lewis, it is an early marker of diabetic
kidney disease. We have structural lesions too, and we have discussed
that already. That\'s the alternative. If you don\'t like the clinical
physiology, you need to do repeat biopsies. You have no other
alternative if you want to evaluate the lesions. We have biochemical
evidence suggesting abnormalities, as also seen later on in the disease.

Important to note, again based on all available literature, 5 to 10
percent of these type 2 patients with microalbuminuria will convert into
overt nephropathy every year.

As already stated, as long as you have microalbuminuria, the rate of
decline in the glomerular filtration rate is ranging between normality
and slightly elevated, but a very low rate of decline as compared to
what happens if you are running with overt nephropathy.

Then I think in all fairness it should be mentioned that the American
Diabetes Association and the International Diabetes Federation actually
are advocating that we are screening for microalbuminuria, and if we
detect it persistently, we need treatment.

The hypothesis in IRMA 2, the earliest study of irbesartan in diabetic
kidney disease, is exactly the same as in IDNT. The objective is to
evaluate the renoprotective effect of irbesartan above and beyond the
blood pressure lowering effect on the progression to overt nephropathy,
and we are comparing that with conventional antihypertensive treatment
and it\'s done in hypertensive patients who have type 2 diabetes and
persistent microalbuminuria. So, in essence, this is not a blood
pressure trial. This is a trial aiming at evaluating the blockage of
angiotensin II. Is angiotensin II nephrotoxic? Yes or no. That\'s the
answer you\'ll have from this trial.

The study design was carried out in the following way. The patient was
run in placebo for at least 4 weeks. We saw them every week at the
clinic. They were then randomized either to receive placebo, irbesartan
150 milligrams once daily, or irbesartan, the yellow one, 300 milligrams
once daily. We used 4 weeks in the titration period.

The aim of the three arms was to obtain blood pressure equivalence. So,
we were actually trying to get exactly the same blood pressure in each
and all of the arms, keeping the blood pressure below 135 over 85
millimeters of mercury.

In the placebo arm, it was not allowed to use ACE inhibitor or receptor
antagonist. Neither were you allowed to use dihydropyridine calcium
antagonists. The reason for that was that in some of the past
literature, this kind of compounds, the dihydropyridine calcium
antagonist, was reported to elevate proteinuria, and we consequently
felt that it was unfair then to use it.

The primary outcome in IRMA 2 is time to the first occurrence of an
albumin excretion rate of more than 200 micrograms per minute and an
increase of at least 30 percent in albuminuria from the baseline level,
and that had to take place at two consecutive evaluations. This endpoint
has been used for the last 10 years within trials trying to evaluate the
importance of preventing the occurrence of disease in type 2 and type 1
diabetes. So, we are using exactly the same endpoint that other
colleagues have applied in the past dealing with this question.

The secondary endpoint is the changes in the overnight urinary albumin
excretion rate, and finally, we are looking also at the changes in
estimated creatinine clearance. This is based on the so-called
Cockcroft-Gault formula, which is an old formula based on measurement of
creatinine knowing the sex of the patient, knowing the weight of the
patient, and the age, and then you can calculate this formula. Actually
the formula has been validated by ourselves in patients with diabetic
kidney disease. It works.

The baseline characteristics in the IRMA 2 study. The good news is that
the three arms are balanced dealing with demographic data, dealing with
clinical data, and dealing with laboratory data.

We have the same age, 58 years of age.

We have a male preponderance, as we should have in this disease.

We cannot discuss ethnicity in our study from the point of view we
don\'t have any other than whites because it was done in Europe. I
complained about that. Next time we have to do it around the world.

BMI was, as it should be. They\'re obese.

The known duration is identical.

Hemoglobin A1C ‑‑ we were discussing that earlier this morning ‑‑ was
also at the same level, and that level was equivalent to a mean blood
glucose of 8 millimoles per liter. I hope you know millimoles per liter,
because I\'m not able to convert it so speedily into milligrams per
deciliter. It should be all right.

Microalbuminuria, the level in micrograms per minute is also at the same
level in the three arms. Of course, there are small differences, and we
will adjust for that when we do our risk ratio measurements.

Another important issue compared to the IDNT, which you just heard about
where there was already, when they started the study, the GFR was down
to 58. So, it was in harmony already when they started the study dealing
with IDNT. In this study they had well-preserved kidney function, 109,
109, and 108.

The blood pressure was equivalent in the three arms. The same systolic,
153 in all three arms; 90 in the placebo; irbesartan 90, and 91. There
was no statistically significant differences at baseline.

So, what happened to the blood pressures during the trial? If we started
at the bottom line, you\'ll remember that there was identical blood
pressure at baseline. They went down and they stayed down during the
study. On average, the blood pressure in the three arms was identical.
It was 83, 83, and 83 millimeters of mercury. If we go to the mean blood
pressure calculated the usual way, the placebo group and the irbesartan
150 group had a mean blood pressure of 103, 103, and the irbesartan 300
group had 102. And that was significant. It was only small reduction but
there was a significant difference in blood pressure.

If we then go to the top, the systolic blood pressure. Again, you\'ll
remember that it had identical values at baseline. The values during the
2 years of observation in the placebo group was 144 millimeters of
mercury. In the group receiving irbesartan, the green one, 150, it was
143, so there was a 1 millimeter difference. And finally in the group,
the yellow one, receiving irbesartan 300 milligrams once daily, the
systolic blood pressure was 141 millimeters of mercury, and that was
definitely lower than in the placebo group. Again, we adjusted for that
in our hazard estimation.

This is the main outcome of IRMA 2. This is the cumulative event rate, a
Kaplan-Meier plot, of the development of diabetic kidney disease,
defined as earlier. First of all, I would like to tell you why this has
this bumpy appearance. It has to do with the fact that albuminuria at
these different time intervals ‑‑ it\'s not measured continuously. It\'s
measured after a certain number of month, 3 months, 6 months, 12 months,
and so on, and consequently you can only have events at these time
points.

After 3 months, you always see a separation, and the separation is
actually persistent during the 2-year study period. At the end of the 2
years, 15 percent in the group receiving placebo on top of standardized
treatment ‑‑ treatment reduced the blood pressure to nearly the
identical level as in the two other arms. There was 15 percent of these
patients who progressed to a level of more than 200 micrograms per
minute. In the group, the green one, of irbesartan 150, it was 10
percent, and finally in the group of 300 milligrams of irbesartan once
daily, it was 5 percent.

At the top you will see the relative risk reduction. The relative risk
reduction unadjusted was 70 percent for irbesartan 300 versus placebo,
with a p value equal to 0.0004.

If we adjust for the differences in albuminuria at baseline and the
blood pressure during the trial, then the relative risk reduction goes
down from 70 percent to 68 percent.

If we then look at the dose of irbesartan 150 once daily versus placebo,
we had an unadjusted relative risk reduction of 39 percent. It was not
statistically significant with a p value of 0.085.

If we adjust for baseline differences and blood pressure difference, the
relative risk reduction actually improved. It was 44 percent and the p
value was equal to 0.05.

During the study, patients who developed diabetic kidney disease were
discarded. So, when you hit the endpoint, you were out. That\'s
important to understand this slide because this is the percentage change
in albuminuria. The expectation for each and all of us would have been a
rise in albuminuria, but you have to remember that the bad guys are out.
So, when they hit more than 200 micrograms, they leave the study.

The message is then from those who received placebo treatment on top of
standardized treatment, there was no major difference in albumin
excretion rate during the 2 years of study. At the end it was 9 percent
above baseline.

If we look at irbesartan 150, the mean reduction in proteinuria was 24
percent, and this was highly statistically different from the placebo
group.

Then if we look at my favorite, irbesartan 300 milligrams once daily,
you see the reduction, and the reduction is actually continuing during
the trial period. So, at 2 years, the difference is 54 percent compared
to the placebo group.

Another important issue is that if we compare the mean reduction in
albuminuria, it was 38 percent compared to the 150 with 24. There was a
highly statistically significant difference with a p value of 0.001.

Estimated creatinine clearance. Again, remember that the patients who
developed diabetic kidney disease are leaving the study. So, what
you\'re seeing here is, in essence, what is happening in those who
remain microalbuminuric. You are seeing a picture of a so-called
biphasic response because we have the estimated creatinine clearance,
and you see the initial response from time 0 to 3 months when blood
pressure is going down. There is rather a steep drop in kidney function,
but before giving you that figure, I will just mention that the initial
value of creatinine clearance was identical in the three arms, 108, 108,
109. If we look at the initial drop, it was 5 milliliters in the group
receiving irbesartan 300 and it was 3 in the group receiving placebo or
irbesartan 150.

So, initially when blood pressure is lowered, we are losing filtration
power. That is a well-documented phenomenon when blood pressure is
lowered. From 3 months and onwards, we are dealing with a so-called
sustained rate of drop in kidney function, and the good news is that the
rate is flat.

Actually when we look from here to here, the drop in kidney function in
the irbesartan 300 milligram group and in the irbesartan 150 milligram
group was only amounting to 2 mls per minute per year. You\'ll remember
that the normal drop, just by getting older, is 1 ml per minute per
year.

In the group receiving the placebo, the drop was 1 ml per minute per
year, and if you remember that we initially started off having a GFR of
110 and you\'re only losing approximately 2 mls per minute per year, as
long as you\'re microalbuminuric, then it will take you approximately 40
to 50 years to know the states which we have discussed this morning, if
that continues. And of course, you will ask me that, so I will give you
an answer later on.

The safety profile in the IRMA 2. We are very early, so we don\'t have a
lot of concern actually. If we are looking at the most important one,
the serious adverse events, we had 22.8 percent in the placebo group. In
the group of irbesartan, it was less, 15.8, and the group of irbesartan
300, it was 15 percent. So, there were actually less severe events. The
number of deaths was equivalent.

So, in summary then, the IRMA 2 study had two messages.

The first is that by using irbesartan in patients with type 2 diabetes
and microalbuminuria, we found a 70 percent risk reduction in the
progression from microalbuminuria to overt nephropathy.

The second one is that the risk reduction was dose-dependent, meaning
that 300 milligrams was superior to 150, which of course is very
important when you treat patients, as I do every day.

Furthermore, the effect was an effect above and beyond the blood
pressure reducing effect.

And finally, as already stressed by Melisa, it\'s a safe and
well-tolerated compound in these patients.

Thank you very much.

DR. BORER: Thank you very much. Again, a really clear and lucid
presentation.

Do we have questions here? We\'ll start with our two nephrologist
members here, if you have any issues to raise. Dr. Brem?

DR. BREM: I was wondering if you could just clarify one point on the
slide D-12. The placebo group. If I understand it, the patients who met
the endpoint were not included in this slide for GFR or were they
included in the GFR?

DR. PARVING: The patients meeting the endpoint, meaning the development
of diabetic kidney disease, were excluded when they met the endpoint.
They were in the study until they met the endpoint.

DR. BREM: So, on this particular slide, D-12, were those placebo
patients demonstrating a decrease in GFR included in this slide or were
they not?

DR. PARVING: All patients, as you can see from the numbers here, were
included, but when they developed diabetic kidney disease, they were no
longer included because, by design, they had to leave the study.
Consequently, we could have no additional value on them. So, we are
following each and all of them until the time point where they developed
diabetic kidney disease and then they are left out.

DR. BREM: Do those patients have an accelerated decrease in GFR in your
particular study in the placebo group as you described in the general
population?

DR. PARVING: That\'s a very important question which cannot be answered
from this study because this study, as you see, is only running for 2
years. When you go from microalbuminuria, having a very low level of
progression, to overt nephropathy, you need a couple of years in order
to actually be able to pick up the signal that the rate of decline is
worsening.

DR. BREM: But I thought you demonstrated at the beginning ‑‑ correct me
if I\'m wrong ‑‑ that patients with overt proteinuria have a decline in
GFR of about 6 or more milliliters per minute ‑‑

DR. PARVING: That\'s correct.

DR. BREM: And these patients have a GFR decrease of approximately 2. So,
if you counted all the placebo patients who reached overt proteinuria in
this particular analysis, wouldn\'t you expect to see a more pronounced
decrease in glomerular filtration rate in that population?

DR. PARVING: It\'s completely correct, as you state, in relation to the
initial slide. The drop in kidney function in these patients is minute,
and when they go from one level of proteinuria to a next level of
proteinuria, it\'s correct that the rates start to go up. But you need a
certain time interval in order to pick up the signal. Actually most
nephrologists suggest that you have to follow the patient approximately
for 2 years in order to be pretty sure that you have that signal.

DR. BREM: So, you\'d have to follow these patients in this group for an
additional ‑‑

DR. JULIA LEWIS: The overt proteinuria patients are no longer counted.
Once they hit overt proteinuria, you\'re no longer measuring their
creatinine clearance.

DR. BREM: Right, but my thought would be, if you did, you would be able
to demonstrate efficacy in GFR much more convincingly. And I\'m
wondering why you wouldn\'t have included them in this particular
analysis because it would be more supportive of your argument.

DR. PARVING: We have data from the literature. I would like to share
them with you. I think we can show you 4-3.

This is the review of the literature available to each and all of you.
That\'s a retrospective study, the first one. All the remaining studies
are prospective.

The message from this slide is the following. First of all, the
conversion from microalbuminuria into overt nephropathy is ranging from
4 to more than 9 percent.

If we look at the drop in kidney function ‑‑ and you have to remember
that these studies were followed prospectively for 4 to 5 years, so they
had a much longer observation period than we have in IRMA 2. The rate of
decline in the study from the Pima was 1, from East Welley, it was 2,
from our study group at Steno it was 3.2 percent, from India it was 1
percent, from the ABCD trial it was 1 percent. These patients were
treated with blood pressure lowering agents here and here, while they
were untreated here because they were normotensive. So, in long-term
observational study, the rate of decline, as I depicted to you, is
between 1 to 3.

And I can expand on that because we have a follow-up of the Steno study,
and that will be 4-37.

The Steno study we published a couple of years ago. It\'s a study
dealing with type 2 diabetic patients who have microalbuminuria, the
same way as in IRMA 2. They\'re very much the same. It\'s a study where
we were looking at the potential importance of multifactorial
intervention. In this study, we were actually measuring the glomerular
filtration rate using an isotope technique initially and during the
study period. We reported the data after 4 years, and now just before
leaving Denmark, I had the possibility of looking into the data after 8
years. We have 129 patients followed now for 8 years.

Those patients who remained microalbuminuric in this prospective,
randomized trial had a rate of decline every year during the 8 years of
3.2, while those patients who developed overt nephropathy, using exactly
the same definition as I gave you earlier, had a drop in kidney function
of 4.7, again showing to you that when you pass from one category to the
next, then you start to have worsening of kidney function.

But again, the important issue in this very early state of diabetic
kidney disease is that you have to do long-term studies, and this is an
8-year study while IRMA 2 is a 2-year study and we could not pick up
that signal.

DR. BORER: JoAnn, do you have any specific questions?

DR. LINDENFELD: In the GFR substudy that\'s mentioned in the briefing
booklet ‑‑ you\'ve explained the reason for that not changing. But after
4 weeks of withdrawal of drug, certainly in the 150 group, the
proteinuria went right back up to baseline. And after 2 years, do you
find that disturbing that that doesn\'t suggest that there\'s been a
persistent change? And then again, it also went up in the 300 milligram
group, but not as much. I\'m wondering what we would make of that?

DR. PARVING: In the literature, several studies have been carried out
and after carrying out the studies, some of us, at least those of us
from Denmark, have stopped the treatment and then see what happens. That
has been done in type 1 patients, in type 2 patients, early and late.

So, in the IRMA 2 trial, we actually did the same. We followed in a
subset of patients kidney function during, of course, the 2 years of
observation, and then after 2 years, we stopped all treatment. So, at
this time point, all kind of blood pressure lowering treatment was
stopped and we are now looking at the change, after stopping treatment
for 1 month, in albuminuria. In the placebo group, the pink one,
actually the level goes back to baseline and no change. If we look
correctly at the 150 milligram irbesartan group, there\'s actually a
huge rise of 80 percent going back to normal, which may suggest that a
major part of the effect in that particular arm was hemodynamic.

The good news, however, is that in the yellow group, the irbesartan 300
group where we saw a significant reduction in development of diabetic
kidney disease, we only saw a rise of 13 percent, and this in my mind is
one of the first times ever where we have demonstrated that by stopping
this kind of treatment, we are not regaining what we expect. Actually it
seems to suggest that there is a residual effect of the irbesartan 300
milligrams, but again, that has to be proven in a larger number of
patients. So, all in all, it may suggest that the effect of our compound
in the high dose has residual renoprotection.

DR. BREM: Were those data controlled for blood pressure?

DR. PARVING: Blood pressure rose. As you may remember, the blood
pressure was identical in the three arms, more or less. The diastolic
was identical.

DR. BREM: But at the end.

DR. PARVING: All of them had a rise in blood pressure when you stopped
treatment because you stopped all kinds of medication. So, in essence, I
think if I recall correctly, the rise was less in the placebo group, was
biggest in the two groups who no longer had the treatment with
irbesartan. So, it\'s not a blood pressure phenomenon.

You\'ll also remember that despite the fact that blood pressure was
reduced to the same level in the placebo group, as in the irbesartan 150
milligram group, there was actually no difference. There was a huge 24
percent difference in albuminuria. So, even though there are minute
changes in blood pressure, this can definitely not explain that. But
there was a rise in blood pressure.

And there was also a rise in kidney function, the way it should be,
meaning that when you stopped that kind of treatment, you see a regain
in kidney function. As I said to you initially, there was a drop the
first 3 months, this biphasic pattern, and this is due to a blood
pressure drop.

Actually give me the option of mentioning something, which some of you
may remember and some of you may have forgotten, and that\'s the story
about malignant hypertension. The story about malignant hypertension is
dating back to the 1950s. When you had malignant hypertension, the
survival until end-stage renal failure was 2 years, if you didn\'t die
from stroke before that. It was a devastating condition.

However, when blood pressure lowering was initiated, we saw the
following pattern. When you lowered blood pressure, you saw a rise in
creatinine and, of course, that always indicates that you may do some
harm to the patient. However, the creatinine level then stabilized,
stabilized, and stabilized, and the patient no longer went into
end-stage renal failure.

So, this initial phenomenon is actually well described more than 50
years ago in malignant hypertension and is documented in each and all of
the major trials dealing with kidney outcome. The MDRD study, the
captopril study, all of them have this initial drop.

DR. BORER: I\'d like to go back to slide D-12 again. I don\'t want to
try to over-interpret data that have been processed in a certain way
with all the dropouts that you explained for reaching overt proteinuria.
But I\'m struck with the observation that the people who were left in
the trial in the placebo arm and the irbesartan 150 arm, even though
they more frequently had overt proteinuria, as we can see from the
numbers below, and therefore dropped out, even though there were more
dropouts, more overt proteinuria, those who are left in seem to have a
slightly better response over the 24 months than the group with
irbesartan 300. That may be an artifact of all the processing of these
data, but I\'d just like your comment about that.

DR. PARVING: I think definitely it\'s fair. From the point of view that
I stated initially, that actually the initial drop in kidney function is
the important player here because the drop in the irbesartan 300
milligram group, those who gained most in relation to avoiding
development of nephropathy, was 5.7 milliliters. So, the absolute drop
was 5.7 here and it was 3 here.

You will also appreciate that the level initially was 1 milliliter
lower. So, that\'s another issue.

At the end of the study, after 2 years of observation, the difference
between irbesartan 300 milligrams and the two other groups was 3 mls.
So, most of the difference is actually explained alone by the fact that
the initial drop in kidney function in irbesartan 300 was bigger than in
the two other arms. There was no difference in the irbesartan 300 group
and in the two arms dealing with the slope. It was identical.

DR. BORER: Should we draw any inferences from the fact that the drop was
greater in the 300 milligram group? I mean, is that a bad thing?

DR. PARVING: You could say that, unfortunately ‑‑ luckily, it\'s the
opposite. Actually it turned out that in several studies that those who
have the biggest initial drop in kidney function have the best long-term
prognosis. That has been demonstrated from our group and from the group
in Groningen in Holland and also from Italy. It actually suggests that
the initial drop in kidney function is reflecting probably the drop in
glomerular pressure which is elevated in these patients, at least in
animals, as demonstrated by Barry Brenner.

DR. BORER: Blase?

DR. CARABELLO: It\'s just that those data seem different from the table
that we have in our book, table 7, where the initial drop in the
irbesartan 300 group in GFR was 2.3 percent and then the late drop at 24
months was 12 percent. This is on page 10 for anyone that doesn\'t have
it. It seems to be the reverse of that.

DR. PARVING: This is the intention to treat. I don\'t know what you have
there.

DR. CARABELLO: This is a GFR substudy.

DR. PARVING: Oh, don\'t do that.

(Laughter.)

DR. PARVING: Because now we are mixing everything together, but it\'s
all right. I will clear it up.

This is dealing with all patients enrolled in IRMA 2. The substudy is
only dealing with a subfraction, actually approximately 130 patients,
who participated in the substudy. The substudy was not a random pick
because the substudy was dominated by Dr. Parving and his group because
we had 50 patients in the group after the 130. So, the substudy is in no
way representative or a random sample for the whole population.

Consequently, this is the important player. This is the whole group and
all the data based on the Cockcroft-Gault. It\'s not the substudy.

DR. CARABELLO: So, was the substudy done to confuse cardiologists?

(Laughter.)

DR. CARABELLO: Or was there another purpose?

DR. PARVING: I need to be honest now. We were actually asked by the FDA
to do it.

(Laughter.)

DR. PARVING: And I\'m pretty sure that the FDA did not want to confuse
anybody.

(Laughter.)

DR. PARVING: What the FDA really wanted us to look at was the effect
when stopping the drug. That was actually the aim of the FDA. They would
like to see what is the effect when you stop your treatment after 2
years. In the high group, in the group of 300 milligrams of irbesartan,
there seemed to be a persistent effect, at least the proteinuria did not
go up. And I\'m pretty sure that the FDA will be pleased to see that.

DR. PELAYO: I\'m the primary reviewer for irbesartan diabetic
nephropathy.

I think the issue for the subgroup study ‑‑ that was the wrong question
to ask because regardless how many patients you study, it doesn\'t
matter for how long you are going to follow them up after you stop the
medication, those studies have no ‑‑ you can\'t interpret them because
there are multiple scenarios that I could create. So, I would totally
disregard those studies not only as the primary reviewer but also as a
nephrologist. And I say that to confuse everybody. So, that was the
wrong question to ask because there is no answer that can be
interpreted.

DR. PARVING: Unfortunately, I happen to disagree slightly because we
made a paper a couple of years ago where we actually demonstrated in
type 1 patients with microalbuminuria, a randomized trial carried out in
Denmark for 8 years. Don\'t shake your head.

For 8 years we did the study. We published it in the British Medical
Journal, and what we did after 8 years, we measured glomerular
filtration rate during the 8 years in these type 1 patients with
microalbuminuria, and then we stopped the treatment and remeasured
glomerular filtration rate. And the outcome of this study, with the
first author as Elizabeth Mathiesen, was the following.

8 years of treatment with the drug called captopril in type 1 patients
with microalbuminuria stabilized kidney function. There was no drop
whatsoever during 8 years when we reevaluated after stopping the
treatment. So, I think actually that FDA was very smart asking us to do
that.

DR. KOPP: Just one other question about that. In the GFR substudy group,
did you drop patients out who had met the proteinuria endpoint?

DR. PARVING: Sorry. Once more.

DR. KOPP: In the substudy group that we\'re talking about ‑‑

DR. PARVING: In the substudy group, if they developed diabetic
nephropathy, they were out.

DR. KOPP: You were out in that study as well.

DR. PARVING: Yes, exactly because the aim of the substudy group was
actually to evaluate what happens when we stop the treatment. So, they
had continue until 2 years, and then we stopped the treatment.

DR. LINDENFELD: But in this substudy, without belaboring it too much,
there really wasn\'t any difference in the dropout rate.

DR. PARVING: No.

DR. LINDENFELD: So, again I think it does point up that in this study
GFR didn\'t change and you can\'t explain the substudy on the fact that
the patients that developed proteinuria dropped out.

DR. PARVING: No, no, no. The important issue dealing with the glomerular
filtration rate from IRMA 2 is the following. I will never, ever dare to
claim that there is any difference in the drop in kidney function in
these patients. The message is the opposite. The message is as long as
the patients stay microalbuminuric, you are only losing 2 mls per minute
per year. In other words, it lasts many, many years. If we calculate
this, it will take 40 to 50 years to go to the department of nephrology
asking for dialysis, and that is the message.

DR. BORER: Ray, you had a question?

DR. LIPICKY: Yes. If you could show slide 4‑197 again because I think
you said a few words, and I probably missed it.

So, in the very last end there, week 4, there are three data points, and
we were sort of led to believe at the beginning of today that you
developed proteinuria when all these things build up in the glomeruli.
So, in 4 weeks, in one of the two possible things, the green and the
yellow, all of that mass of stuff must have reversed? All of those
bluish globs that we saw early in the day went away ‑‑ or came back?
I\'m sorry. Came back.

DR. PARVING: No. I will be very pleased to answer that.

First of all, there is a rebound phenomenon. That is well demonstrated.

DR. LIPICKY: Yes.

DR. PARVING: You have to remember that the expectation is actually the
following. When you have 2 years with microalbuminuria, you\'ll assume,
if we have not treated the patient, that it will be up here. However,
there was a rebound to the baseline suggesting that a major part of the
lowering in this group was due to hemodynamic effect. I quite agree.

DR. LIPICKY: But you have the placebo group there.

DR. PARVING: Sure.

DR. LIPICKY: So, you don\'t have to refer to something way up there.

DR. PARVING: But the placebo is not a placebo group left untreated.

DR. LIPICKY: No, no. I understand.

DR. PELAYO: You know what is the problem? To interpret that, you have to
understand that the antihypertensive medication was discontinued. If it
was discontinued in the placebo, it was discontinued in in 150 and it
was discontinued in 300.

DR. LIPICKY: No, I ‑‑

DR. PELAYO: Wait. Let me finish.

Then if you discontinue the antihypertensive, the blood pressure will go
up. That in and of itself can affect glomerular permeability. If you
stop abruptly the inhibition of the angiotensin II system, that also can
modify hemodynamics and glomerular permeability. Therefore, to me the
data is not surprising.

But it still is the wrong question to ask because it doesn\'t matter
what happened after you discontinue the antihypertensive. What matters
is what happened before because all this could be due just to a
functional effect.

I think Dr. Brenner, who is sitting on my right, could explain this in a
more elegant way and without an accent. Dr. Brenner, do you care to
enlighten the audience with your knowledge about proteinuria, glomerular
hemodynamics, and antihypertensive treatment, and the wrong question and
how you can really interpret the data?

DR. BRENNER: I don\'t think I can improve on it.

DR. PARVING: Could I have a chance to answer the question?

(Laughter.)

DR. PARVING: And will you answer all the remaining questions for me?
That\'s all right.

DR. LIPICKY: Well, it\'s getting mixed up. Let me ask the question
again.

We were supposed to take the decrease in proteinuria, effect of ARBs, as
inducing a morphological change in glomeruli and that the proteinuria
occurred because of some morphological effect. And what you have there,
at least in one data point, is what looks like something morphological
happened in 4 weeks that negated 2 years of therapy. That sort of is
mysterious.

DR. PARVING: No. I think that the question raised is quite on target,
and I will definitely be very pleased to answer it.

First of all, it\'s important to realize that this kind of kidney
complication is not something which is done overnight. It takes a number
of years to develop that kind of lesion, even the early one, with
mesangial expansion as increased basement membrane. There\'s also good
reason to assume that the number of years it takes to get rid of it is
probably the same. Why should it be different?

We have one marvelous example from the literature, and that is the
beautiful biopsy study carried out by Michael Mauer from Minnesota. He
took type 1 patients, biopsied them, and then he gave them a new
pancreas. They had this new pancreas working for 10 years with
completely normal blood glucose values. No insulin, no nothing. He
rebiopsied after 5 years. There was no significant difference. But after
10 years, he saw that there was a significant reversal of the structural
damage. I think to my mind that this study demonstrates that it takes a
long time to get rid of it.

I think what we are doing here, we are only doing a short-term study. Of
course, the message from this study is that the patients are put on the
treatment. We will never, ever stop them. We\'ll continue of course.
That\'s the kind of treatment you need if you need if you want to get
reversal of the kidney structural damage. But I think, in essence, that
everybody has to realize that it\'s a very slow process and you need to
do it for many, many years in order to gain.

DR. BORER: May I ask? I\'ll try not to muddy the waters a little bit
more. It sounds to me like this is a two-component model. Number one,
the morphological changes in the kidney, and number two, superimposed
upon that, acute hemodynamic changes that can change the expression, if
you will, of the effects of the morphologic changes.

You took away drugs at week 24 and you said the blood pressure went up.
Presumably it went up relatively rapidly, and we saw here the effect of
what was sitting there with a new blood pressure level on top of it. And
it looks worse for at least two of the arms.

If you followed along further, would you have expected ‑‑ or let\'s say
you lowered the blood pressure further with some other drug. Would you
then have expected the green point to come back down a little bit again?

DR. PARVING: It depends on what kind of compounds that you\'re aiming at
because all blood pressure reduction will eventually reduce the albumin
excretion rate, each and all of them. But some of them are more potent
and those that are more potent are those that are blocking the effect of
angiotensin II. That goes for ACE inhibition and for receptor
antagonist.

DR. BORER: I understand that. I didn\'t want to get into that. I see
that the irbesartan 300 doesn\'t seem to reverse nearly so much as the
others, and that suggests that there\'s some residual effect, et cetera.

I was only asking the question if you took away the new hemodynamic load
on top of the morphological change that already existed, would you see
some tendency towards improvement. That\'s all.

DR. PARVING: Sure.

DR. BORER: And you would.

DR. PARVING: You will see that.

DR. BORER: Tom?

DR. FLEMING: I\'d like to just, one more time for my own sake, go
through the interpretation you gave to your slide D-12 just to make sure
I understand what you\'re telling us your interpretation is.

We have had explained to us today a biological progression that occurs
with microalbuminuria first, leading to proteinuria, leading to
glomerular filtration rate changes, leading to end-stage renal disease,
which in essence is dominated by dialysis, transplant, and renal death.
This is the progression.

In the IRMA 2 trial, we\'re really going back to this earlier stage.
We\'re looking at whether or not we can delay this progression to
clinical proteinuria. Often what we would want to do, from a statistical
perspective to get a sense of the validity of that as a surrogate for
ultimate clinical benefit, is to see how that translates into effects on
other tangible phenomena that are downstream in terms of clinical
consequences. Of course, the next one in line is the filtration rate.

What you\'re saying is there\'s not an apparent benefit here, but
you\'re saying be careful because it\'s going to take more years of
effects before you\'re going to get to a point where you\'re going to
expect to see effects on GFR. Is that correct? Is that a correct
interpretation you\'re giving to why one shouldn\'t be too concerned
about this?

DR. PARVING: I think you\'re right.

DR. FLEMING: And if I take that then as the interpretation, I can be ‑‑
I\'ll give my interpretation. Jeff, you can comment. Or go ahead. I\'ll
give my interpretation after you.

DR. BORER: No. I just want to ask is that really what you ‑‑ I mean, if
I\'m understanding what you said correctly, it\'s not that you were
waiting for an improvement in GFR. You were waiting to see a worsening
and it didn\'t happen.

DR. PARVING: Exactly.

DR. BORER: You want to, as you said, keep them within the box.

DR. FLEMING: Sure, but I would like to see some evidence of a net
benefit relative to placebo. And I\'m understanding that we would need
to have many more years of effect on delaying progression to increases
in proteinuria to be able to expect then, when we look at this
phenomenon downstream, we\'ll see an effect.

DR. BORER: Maybe yes, maybe no. You dropped out and didn\'t collect data
on the people who developed proteinuria.

DR. FLEMING: Yes, but my initial sense is, looking at the numbers of
dropouts ‑‑ and it\'s only a speculation. Unfortunately the trial
wasn\'t designed to truly answer this. It\'s not clear that that would
have reversed this perspective.

DR. PARVING: But could I give an answer? Because exactly what you are
saying is that if we should have picked up the signal, then of course we
should have kept the patients who developed diabetic kidney disease in
the trial. And then we should have told you that those who developed
diabetic kidney disease and were followed for 5 or more years did worse
than those who didn\'t. Unfortunately, the design of the study was so
that those who were the bad-doers were actually leaving the study.

DR. FLEMING: We understand. We understand that.

But I guess the bottom line conclusion to me is I could be persuaded
that the lack of tangible evidence of a benefit on the next phenomenon
could, in fact, be that we\'re looking too early. But at a minimum, I\'m
left without any substantive basis to say I\'ve got evidence to validate
my surrogate. I know natural history. I know the progression in natural
history, but I don\'t have any direct tangible clinical evidence to show
that when I\'ve intervened and achieved this effect in delay of
proteinuria, that this is the magnitude and duration of effect that will
reliably translate into ultimate clinical benefit downstream. It may or
it may not. But I\'m left with much less evidence of validating a
surrogate here than I would typically expect to have.

DR. JULIA LEWIS: If I could have the slide from the hyperbolic curve
from the other Dr. Lewis\' talk.

If you\'ll remember ‑‑ and I\'m sure it will be up there in a second ‑‑
the IRMA 2 trial was not intended nor anticipated nor would we ever
design a study to look at the change in rate of decline of renal
function in patients who are in this area of the curve for two reasons.

One, in order to, for example, double your serum creatinine, you have to
lose a gigantic amount of renal function to measure that.

In addition, in this area of the curve, the measurements of GFR ‑‑ the
scatter in the measurement itself is almost equal to the rate of decline
in renal function when you\'re in this area of the curve in
microalbuminuric patients.

So, in early diabetic kidney disease with microalbuminuria, you simply
can\'t reliably measure the changes in renal function in those patients,
which is why we worked in this area of the curve in IDNT. So, we didn\'t
anticipate to see changes in GFR in IRMA 2 or to be able to detect
changes in IRMA 2 in those early microalbuminuric patients over a 2-year
period.

DR. LIPICKY: I guess I wanted to follow up on what Tom said because he
said what I was trying to say much better, but I\'d like to try just one
more time to say what I meant.

And that is that the data from IRMA 2 are consistent with the hypothesis
that was forwarded. They do not prove the hypothesis that was forwarded.
In fact, they sort of don\'t help it very much.

Then secondly, the creatinine doubling is consistent with the notion
that people get into trouble in the first trial, but the actual number
of events that were observed don\'t go along with that. So, this is the
nature of the beast that you\'re evaluating.

DR. PARVING: Could I then add? I will not disagree but I would like to
say that the natural history of diabetic kidney disease, where you have
such a slow rate of progression in kidney function, which is actually
what causes the death of the patient, if you lose filtration power,
you\'re a dead man. Initially the drop is so slow ‑‑

DR. LIPICKY: The only thing I said is that if you\'re a believer, you
believe and you don\'t need data. If you\'re not a believer, you need
data, and that\'s going to be the problem that\'s discussed.

DR. PARVING: I think you have the data. I think you have the data
telling you that you only have a drop of 2 mls per minute per year in
those who are microalbuminuric. That\'s exactly what you want to know.

DR. BORER: Bev.

DR. LORELL: I think that in this study that you\'re describing, it seems
to me it would be extremely problematic to follow the patients even
longer-term to see a more rapid decline in creatinine clearance. And the
reason I say that, as a non-nephrologist, is if it is true in the
diabetic, that the development of macroalbuminuria precedes this more
rapid decline in creatinine from an ethical standpoint for the
individual physician investigators, it would have been impossible I
think, once a patient reached the point of microalbuminuria, not to use
the best data available, which would have been the captopril study, and
to have said at this point ethically ‑‑ admittedly they\'re not the same
population, but best data available ‑‑ I must move to treating with an
ACE inhibitor. So, I don\'t think even today it would be possible to do
this study to carry it out long term to look at events.

DR. LIPICKY: This was done today. What do you mean?

DR. LORELL: No. I\'m saying we have another study here now looking at
irbesartan and data from losartan.

DR. LIPICKY: So, you think it\'s ethical to do things you don\'t know
anything about rather than find out whether something works or not?

DR. LORELL: No. I would argue that from the point of view of the
physician investigators caring for individual patients ‑‑

DR. LIPICKY: But to do something where you do not know what you\'re
doing is correct.

DR. LORELL: I didn\'t say that.

DR. LIPICKY: Well, why didn\'t you say that?

DR. LORELL: I\'m sympathetic with the stopping endpoint in this trial,
given the other data that was available, albeit in type 1 diabetes. So,
I actually think it would be very problematic to keep a patient, once
they had developed macroalbuminuria, on one of these three treatment
arms.

DR. PARVING: That was actually the main reason why that was decided
because it was tested out at several of the safety committees in Europe,
and they would not allow us to go ahead. So, that was quite simple. So,
what you\'re saying is at least the notion in Europe. They may be wrong,
as Ray Lipicky is saying, but that was the notion.

DR. BORER: Steve?

DR. NISSEN: Bev, I don\'t agree with you. If it\'s ethical to take
patients at a later stage in the disease, as was done in IDNT, and give
them placebo for a long period of time, it certainly would be ethical to
do so in an earlier part of the disease curve.

This is an important question because no matter what we decide here,
clinicians have to know when in the course of the disease might an
intervention such as this be useful. So, we\'re looking for a signal
here that says, well, gee, maybe if you start this therapy very early
when you get that first microalbuminuria, you can prevent this whole
cascade. So, we\'re all kind of looking to find some evidence that
that\'s the case, and there isn\'t any evidence, unfortunately, in the
data.

DR. EDMUND LEWIS: Hopefully, I\'ll get back up there. I should be
wearing armor the next time I get back up there, but hopefully I will
get back up there to try to convince you otherwise.

There are complex issues here that involve the ethics. First of all, in
early type 2 diabetic nephropathy, microalbuminuria, the study by Ravid
from Israel using enalapril showed clearly that ACE inhibitors
absolutely stabilized microalbuminuria over a period of ‑‑ I forget. I
think it was 5 years, and that for that reason, ACE inhibitors were
appropriate therapy. So, the physician, seeing the patient with early
type 2 diabetic nephropathy using evidence base ethically should be
using an ACE inhibitor at least.

Now, in our study, the irbesartan diabetic nephropathy trial, it is not
fair to say that since they had two arms that didn\'t inhibit
renin-angiotensin, what about the ethics of that compared to this?
Because we were facing an entirely different clinical problem. The
clinical problem that we were facing was not only do type 2 patients
with diabetic nephropathy perform the same as the type 1\'s, when their
renin-angiotensin system is blocked, but also we\'re dealing with a much
older population of hypertensive patients.

So, the question was also not just benefit, but risk. That is, in this
patient population, when you use a renin-angiotensin system antagonist,
is there enough bilateral renal artery stenosis to cause serious adverse
events with acute renal failure, and do they have enough hyporeninemic,
hypoaldosteronism to cause much more severe hyperkalemia during the
course of the study than the type 1 set?

So, we had no problems with the ethics of that because before we started
the study, we had no idea. The angiotensin receptor blocker, even if it
was ‑‑ and I think it proved to be ‑‑ as effective in treating the
glomerular disease of type 2 diabetes, as captopril was in type 1, if
that effect was going to be offset by these adverse effects of severe
hyperkalemia and acute renal failure, then you had an entirely different
clinical decision to make. For that reason, there was not an ethical
problem in doing our study, but that does not mean that patients with
microalbuminuria shouldn\'t have been treated with ACE inhibitor in the
clinic at least because there was data to say that that was the case.

DR. BORER: Again, thank you for a very illuminating presentation. Maybe
we can go on to the risk/benefit summary and get to our questions.

DR. PARVING: It is my great pleasure to introduce Dr. Edmund Lewis who
will give the summary with the risk/benefit.

DR. EDMUND LEWIS: Thank you. It\'s a pleasure to be back here.

(Laughter.)

DR. EDMUND LEWIS: We propose that therapy with the receptor blocker
irbesartan alters the continuum of diabetic nephropathy throughout its
course, that the IRMA 2 study showed that, in fact, going from
microalbuminuria to overt proteinuria was significantly affected and
that phenomenon diminished by the drug, and that in the IDNT, the events
associated with decreasing glomerular filtration rate and end-stage
renal disease were significantly diminished.

Now, I want to emphasize that the endpoints that we chose were not
arbitrary endpoints. The disease is a continuum. I think there\'s
nothing in the literature or anywhere else that would suggest otherwise.
However, in designing a clinical trial, you have to identify points in
the course where you can try to tell a difference. Therefore, doubling
of serum creatinine or a creatinine of more than 6 is not arbitrary. We
chose those, I hope that you can see, and we\'ll present more evidence I
guess, to show why that was the case.

Now, I don\'t think that one can underestimate the importance of trying
to prevent end-stage renal disease, and I hope that ultimately in the
presentation of the data what you saw as cardiologists ‑‑ today I\'m
becoming much more sensitive toward the cardiologists ‑‑ is that what we
were doing, in terms of the renal system, was not putting the
cardiovascular system at greater risk, that the same drugs that one uses
to treat cardiovascular disease in these patients would be used, that
blood pressure would be managed, and that overall the mortality rate,
the endpoints that you saw were not significantly altered. So, we\'re
not saying treat these patients\' kidneys at the risk of allowing harm
to their heart. That is not the message, and I don\'t think anything
about the data indicate that.

Can you put up 1.2? There you go.

Now, the reason why we nephrologists are so concerned about that renal
endpoint ‑‑ we treat the whole patient, which includes the patient\'s
heart actually. The reason we are so concerned about this ‑‑ and this is
published annually in the U.S. Renal Data Survey. This happens to be a
publication which shows exactly the same as the USRDS. In fact, it\'s
showing you USRDS data I guess.

Here this orange curve is the survival rate of patients with type 2
diabetes on renal replacement therapy, on dialysis. As I\'ve said, here
at 12 months the survival rate is a little under 60 percent. At 24
months, the survival rate is 40 percent, which is very close to
pancreatic cancer over that period of time, and it\'s almost identical
to your consensus class IV heart failure. End-stage renal disease is a
dreadful thing to happen to a type 2 diabetic, and that\'s why we are
trying so hard to prevent it.

Up to now, there is no proven therapy. There is no data. I\'ve told
many, many doctors to treat with ACE inhibitors until the data become
available, but going back 8 years, there was no question about captopril
being approved for type 2 diabetic nephropathy on the basis of type 1
diabetic nephropathy data. This was the best you could offer. But there
is no study that ever said in the overt nephropathy patient that ACE
inhibitors were as effective, to this day.

So, what we\'re talking about here is not only the diagnosis that causes
the most patients to go on dialysis, 45 percent, but actually the
proportion of patients in end-stage renal disease programs in this
country with the diagnosis of diabetic nephropathy is increasing every
year more than any other diagnosis. So, it\'s an increasing problem, and
certainly in countries where they can\'t afford \$65,000 a year to try
to keep these patients alive on dialysis, it is death. It is death.

The IDNT, in terms of benefit, allows us to look at two active
comparators. It\'s not two trials, but it\'s more than one trial, and we
keep seeing irbesartan versus placebo, irbesartan versus amlodipine. And
at this stage of the disease where we can measure the functional
capacity, the filtration capacity of the kidney, you can see that of
course the primary composite endpoint is very positive, but the
all-cause mortality part, the cardiac part of the primary composite,
does not reveal efficacy for irbesartan. And I don\'t think we would
have expected that in this study. I think we\'ve discussed that at
length. It\'s the renal endpoints of the composite that are the
important issue: the doubling of serum creatinine and end-stage renal
disease.

I think it is clear from our data, both our renal data and our cardiac
data, that the calcium channel blocker did not have an adverse effect in
this patient population. Amlodipine appears to be a perfectly good drug
to control blood pressure in this patient population, and according to
our data, you would not get excess either cardiac events or renal events
above that using other antihypertensive agents.

The doubling of serum creatinine, then, we are putting forward as the
event that is early enough in the course of the disease where we could
say that this is a very important endpoint. But actually it has still
allowed doctors to treat patients afterwards, to try to prevent
end-stage renal disease, so that there was an ethical issue there.

However, when one looks at the doubling of serum creatinine, you see
that the median time to end-stage renal disease was 9. something months,
and these patients go on to your hard endpoint of end-stage renal
disease. Now, some of them don\'t because they doubled so late in the
study that they don\'t have time to go on to end-stage renal disease.
But it is inexorable. They are going to go on to end-stage renal
disease.

You can talk about doubling of serum creatinine as a surrogate for that.
It is not a surrogate for renal function. It is a measure of renal
function. And it\'s the renal function that is continuously going down.

So then, what we show is, relative to placebo, a 33 percent risk
reduction ‑‑ the pink is placebo ‑‑ with a p value of .002, and a 37
percent risk reduction versus amlodipine, .003, and amlodipine versus
placebo, there\'s no difference.

Now, I know that members of the panel ‑‑ in general people look at these
Kaplan-Meier curves in a vertical way. But this is a time-to-event
analysis, and from the point of view of the physician and the patient,
it\'s actually the horizontal way that counts because what we can tell
our patients, on the basis of this study, is that if they take the
irbesartan ‑‑ here\'s the average follow-up of 31 months and here is
your point of your event rate for doubling of serum creatinine, for
those who have doubled, with either placebo or amlodipine, and here\'s
the shift to the right ‑‑ you will not have your doubling event for 11
months.

This isn\'t just a point chosen nonrandomly to show you this phenomenon.
If you look at other points along the end of this curve, you see the
same, more or less, 11-month delay.

And 11 months doesn\'t sound like much perhaps, but believe me, when
you\'re on dialysis, it\'s a lot. And if your mortality rate is going to
be 25 percent during that 11 months on dialysis, then being off dialysis
sounds like a very good thing. So, I think that it is not only the
relative risk reductions, it is also this delay in the important event
that is very, very important.

And this is a very conservative issue because, remember, we\'re starting
with patients who have already lost half their renal function. I don\'t
think that it is overstating the case to say if they had only lost a
quarter of their renal function when they started, that delay might be
longer. That was certainly the case with the ACE inhibitors, that our
most conservative result was in the captopril trial. Once we really
started to use these drugs and test more potent ones and higher doses
and better blood pressure control and so forth, we got much, much more
dramatic results.

When you adjust for blood pressure, of course, irbesartan versus
amlodipine, there is no difference in terms of your renal endpoints
because blood pressure control was identical in those two groups. So,
you cannot imagine antihypertensive effect of irbesartan being the
reason why we got these risk reductions. We had to adjust against
placebo because ‑‑ not surprisingly, the hypertension of type 2 diabetic
nephropathy is very hard to treat. Anyone who has tried knows that, and
when you have to treat their blood pressure without ACE inhibitors,
without ARBs, without calcium channel blockers, you have something on
your hands. So, the fact that we had a few millimeters difference is not
surprising, but it\'s really heroic that that was all that we had as a
difference. Nevertheless, the difference between adjusted and unadjusted
for blood pressure is not significantly different.

So, in terms of the face of the enemy, please remember that patients
entering the IDNT had advanced renal disease when they started, and so
our result is in patients who are very far along.

In terms of the IRMA 2 study, you have seen this, and our evidence is in
these patients they do not enter the definition of overt proteinuria
when they\'re on the irbesartan. You\'ve had the entire discussion of
microalbuminuria, but what I want to remind you of is that in type 2
diabetic nephropathy, you do not get to the stage that we saw them in
the IDNT without going through a long stage of increasing proteinuria.
So, that is a clinical phenomenon. There are no clinical signs and
symptoms, but it\'s a clinical phenomenon that is significant. And when
you adjust for blood pressure differences for the two treatment groups,
there is no difference in the relative risk reduction of actually going
onward to a positive dip stick, which is an important clinical event.
And please note with this 300 milligram group, the relative risk is
reduced by 70 percent. 7-0 percent.

So, in terms of benefit, our conclusion is that irbesartan retards the
progression of both early and overt nephropathy in type 2 diabetes
mellitus with nephropathy by a mechanism which is independent of blood
pressure control.

Treating 15 patients with advanced diabetic nephropathy entered into the
IDNT trial for 3 years, you save one clinical event. That\'s in terms of
renal outcome. Treating 10 patients in the IRMA 2 trial for 2 years, you
save one event which is microalbuminuria going on to the positive dip
stick overt nephropathy.

I think that it is important to state ‑‑ and I\'m not presenting this as
part of the BMS irbesartan application ‑‑ that there are not two
clinical trials in the literature to which the medical profession has
been exposed to. There are three trials in the medical literature with
that exposure, and in the very least what you have to say is that on the
basis of that, there will never be an ethical trial looking at ARBs
versus placebo in the future or ARBs versus non-renin-angiotensin
inhibitor in the future because we\'ve got all of this information.

The last trial published by Dr. Brenner one page after mine in the New
England Journal ‑‑

(Laughter.)

DR. EDMUND LEWIS: The RENAAL trial was 1,500 patients. The design varied
very, very little from our trial. The outcome events were identical. The
patient population was basically identical. The baseline characteristics
of the populations were identical.

So, I just want to point out to you, just in terms of the totality of
information available as far as the prevention of progression of this
horrible disease is concerned, that if you look at the risk reductions
of that trial using losartan versus our trial using irbesartan, you see
they used the same primary composite endpoint. They got essentially the
same reduction with the same variance. If you look at the renal
endpoints, basically the same reduction. If you look at doubling of
serum creatinine, hardly any difference. If you look at the occurrence
of end-stage renal disease, about the same. If you look at all-cause
mortality, the same. So, I believe that that trial supports what we are
saying with our application, although it\'s not part of our application.

Collectively these results demonstrate that the renoprotective effects
and the benefits of irbesartan across the continuum of diabetic renal
disease, we hope you agree, has been demonstrated.

In terms of risks, you\'ve heard Dr. Cooper address the side effects and
the risks. I won\'t go on about that. Certainly the overall risks of
this drug are very well known to you. I don\'t think it was a problem
for your primary reviewer, and the specific risk, in terms of
hyperkalemia and so forth, is no different than that which the medical
community has a concern about and has to treat with ACE inhibitors. So,
the risk/benefit assessment we believe favors the use of irbesartan
across the continuum of renal disease.

Collectively the data are what they are. We hope you agree, we hope you
concur with our statement that this drug should be approved for the
treatment of type 2 diabetic nephropathy throughout its continuum. Thank
you.

And with that, I\'ll stay here for questions.

DR. BORER: Actually, I don\'t think we\'ll have many questions at this
point because we have questions that we have to go through. But I want
to thank you very much for, again, a wonderful presentation. To orient
everybody, I want to thank the sponsor for the presentation in its
totality. I certainly and I think everyone on the committee found it
very informative and enlightening.

However, at this point, we\'re going to move on to the questions put to
us by the FDA, so there\'s not going to be any more discussion and no
more comments from the sponsor unless we specifically ask for them. So,
I\'d appreciate it if you keep that in mind.

There are a number of questions here. Some of them we may be able to go
through quickly, some not. To try to be most efficient about it, what
we\'ll do, after quickly going through the preamble here, is present the
questions to our primary committee reviewer and then see if anybody
disagrees with the answers that she gives.

DR. KOPP: One question.

DR. BORER: Yes.

DR. KOPP: Dr. Pelayo described the second study IRMA as a non-IND study.
What does that mean and does that have any bearing on how we view that
data?

DR. LIPICKY: No. It has no meaning.

DR. BORER: Yes. It is important because this needs to be part of the
public record, that as we take a vote, even if we\'re all agreeing with
everything JoAnn says, we have to do that by name verbally into the
microphone, and I\'ll ask everybody to do that as we go along.

With that having been said, we\'re asked to give an opinion about the
benefits and risks of irbesartan for the treatment of nephropathy in
patients with type 2 diabetes. I assume, Ray, you may have meant
patients with hypertension and type 2 diabetes, or did you not mean
that?

DR. LIPICKY: We did not mean that. I may as well start it out. I fail to
see the distinction between having hypertension or not having
hypertension if they have diabetic nephropathy, but of course there is
an empirical difference.

DR. BORER: Okay.

Reviews of chemistry, pharmacology, toxicology, biopharmaceutics,
biometrics, and clinical safety present no apparent barriers to its
approval.

And we\'re asked to determine if the strength of evidence for a
treatment benefit, relative to the risk, supports approval.

The direct evidence comes from the studies listed.

Question number 1. There were 411 total endpoint events in the placebo
and irbesartan groups, 33 fewer in the irbesartan group than on placebo.
One of the characteristics of a none-too-small p value is that the
result is sensitive to the handling of subjects with incomplete data.

So, 1.1. 16 subjects, 8 on placebo or irbesartan, never received any
treatment. How were they handled? How should they have been handled?

JoAnn?

DR. LINDENFELD: Well, these as I understand it, were handled as
intention-to-treat, and I believe that\'s proper.

DR. BORER: Is there anybody who disagrees with that?

(No response.)

DR. BORER: Nobody disagreed.

We\'ll vote on the question at the end, I guess, with a verbal
statement.

408 subjects, 275 on placebo or irbesartan, discontinued study drug.
These were the people predominantly who reached an endpoint and came off
coded drug. How were they handled, and how should they have been
handled?

DR. LINDENFELD: These were also handled as intention-to-treat, which I
think is proper. I believe the cardiovascular endpoints were followed
only until they reached the point of end-stage renal disease.

DR. BORER: Any disagreement? Yes, Steve.

DR. NISSEN: Again, we talked about this earlier, but I\'m quite
disappointed that the other events were not collected after they reached
those endpoints. So, I think that that to me is actually an important
issue, and my feeling is that they were not handled as well as they
should have been handled.

DR. FLEMING: And just a brief added comment. I agree with both my
colleagues. I agree with JoAnn that ITT is the proper way to handle the
discontinuations, and I agree with Steve that technically speaking, ITT
doesn\'t mean including all randomized people. It also means including
the follow-up of all randomized people. So, it does compromise the
ability to at least more clearly understand the impact on those
endpoints that were censored in follow-up after end-stage renal disease
diagnosis.

DR. BORER: We\'ll put a bookmark there.

Bob?

DR. TEMPLE: Some of them were followed, though, because they have
mortality data on all of those people, and there\'s that slide that
shows which people who had an endpoint of doubling went on to end-stage
renal disease. So, I was a little foggy on what they did and what they
didn\'t follow. I guess strokes and things like that were not followed.

DR. BORER: Maybe we can have a clarification, very quick. Dr. Cooper
perhaps can tell us. You followed everyone except the ones who were lost
to a mortality endpoint. We know about ESRD because everybody was
followed to that event. We just don\'t know who had a stroke, who had a
heart attack after ESRD. Is that correct?

DR. COOPER: That\'s exactly correct. The company made every effort to
follow every patient with respect to ESRD and mortality. We have all of
the data with respect to mortality for all patients except for 8, and we
have all of the data with respect to ESRD in all patients with the
exception of 37. So, we have to go back, as indicated earlier in the
discussion, to ascertain the dialysis and transplantation status of
those patients. But that\'s correct. The only data we did not
systematically collect after ESRD were cardiovascular events that were
nonfatal.

DR. LIPICKY: Can I ask a question? Because it\'s my impression it was
after doubling of creatinine.

DR. BORER: No.

DR. COOPER: No.

DR. LIPICKY: It was ESRD. So, everyone was followed to ESRD?

DR. COOPER: Yes.

DR. LIPICKY: Even if they met the doubling of creatinine.

DR. COOPER: Yes.

DR. LIPICKY: Okay.

DR. BORER: 19 subjects, 13 on placebo or irbesartan, were lost to
follow-up. Mortal status is known for 11 of 19, 7 of 13 on placebo or
irbesartan. How were they handled and how should they have been handled?
JoAnn?

DR. LINDENFELD: Well, these were included when the outcome was known,
and as I understand the analysis, there was a specific sensitivity
analysis done to be sure that if one attributed all bad outcomes to the
irbesartan group, that this still remained, that the difference was
very, very small. So, I\'m not too worried about this small number of
patients.

DR. BORER: Any disagreement here?

(No response.)

DR. BORER: No, okay.

2 placebo group subjects were credited with endpoint events for near
doubling of serum creatinine. How were they handled? How should they
have been handled? How many other near-doubling events were not counted
as events?

DR. LINDENFELD: This is an area we didn\'t cover, and we can see if
people think we should. There were 2 placebo patients that actually were
credited with a doubling of creatinine who, when they went back and
looked at the initial, by strict criteria the first study creatinine did
not actually double. The adjudication committee, as I understand from
the briefing booklet, decided to include them in the doubling. I don\'t
believe we know how this was handled otherwise.

I guess one other question would be of the endpoint events, how many
were changed in the endpoints committee? I don\'t think we\'ve seen that
data, and perhaps you could just give us a brief answer to that.

DR. EDMUND LEWIS: Yes. With respect to those 2 patients, our protocol
design was that the central laboratory had to confirm a doubling of
serum creatinine event, which then went to our outcome committee for
adjudication.

And in the 2 patients that you\'re referring to, what had happened was
the geographic lab for that part of the world had not declared a
doubling. However, duplicate samples were sent to our central lab and we
confirmed a doubling. Now, we\'re talking about tenths of a milligram.
But we confirmed the doubling. We sent that information, along with the
information from the local labs, on to the outcomes committee and the
adjudication was that those 2 patients indeed had doubled according to
our predefined protocol determination.

DR. LINDENFELD: Maybe you can give us a quick answer to how many times
did this happen in the other groups, the irbesartan group and the
amlodipine group.

DR. EDMUND LEWIS: It didn\'t. Those were the only two cases.

DR. LINDENFELD: They were the only two cases in the entire study.

DR. EDMUND LEWIS: Yes.

DR. FLEMING: Just one refinement of JoAnn\'s answer to question number
1.3. If I\'m recollecting correctly, Jeff, you had asked this morning a
series of questions that related to these issues, and if I\'m
recollecting correctly, in the 1.3, the 19 subjects lost to follow-up,
if one did take a worst case analysis, I think the significance
technically, if you believe .05 is a magic number, was crossed. It\'s
hard to know what to make of that because a worst case analysis is
incredibly conservative.

DR. BORER: Yes. It was .055 something, as I recall.

In summary, what effect have the sponsor\'s rules for handling these
situations on the credibility of the principal finding? JoAnn?

DR. LINDENFELD: I think they\'ve been handled well, and I don\'t think
it should influence the credibility of the studies.

DR. BORER: Steve?

DR. NISSEN: Well, I sill am very troubled by the lack of cardiovascular
event data after those patients reached the end-stage renal disease time
point. And I\'m particularly troubled because prior to that point in
time, we saw point estimates for MI, cardiovascular death, and stroke
that were going rather strongly in the wrong direction. And if those
trends were to continue, they were pretty close, as individual
endpoints, to statistical significance. So, those additional events that
may have occurred later that were censored could well have led to a
statistically significant result with respect to having a worse outcome
than the amlodipine treated arm. So, I really do think it undermines my
comfort level significantly.

DR. BORER: Ray?

DR. LIPICKY: I think I feel compelled to say, because the question was
oriented so that you would, but you didn\'t, that since there was only a
delta of 33 in the two groups, that a difference makes that indeed,
depending on what you do with things and one of the conditions did make
it happen where you lost the conventional significance, and that that
was simply meant to heighten your awareness to where you were.

DR. BORER: Our awareness has been heightened.

Number 2. Of the 411 primary endpoint events on placebo or irbesartan,
58 percent were creatinine elevation and 42 percent were death or need
for dialysis. All of the apparent treatment benefit was the effect on
creatinine. And now we need to determine what we think about this.

2.1, was this a statistical anomaly, and 2.2, was this because there
were just so few clinical outcome events? Was this because effects on
clinical outcome would not be expected over 57 months of follow-up? Was
this because an effect on serum creatinine is a poor predictor of
clinical outcome?

Subjects who experienced doubling of serum creatinine could later have
end-stage renal disease and die. When these events are counted, the
relative risk of death on irbesartan was .92 and the risk of needing
dialysis was .80. Are these data supportive of an effect on clinical
outcome?

Why don\'t you try and take the whole question as one, JoAnn?

DR. LINDENFELD: I don\'t think this is a statistical anomaly.

It\'s important to say I don\'t think the study was a 57-month study.
The mean duration of study here was closer to 2. something years. So, it
wasn\'t a 57-month study. If it had been, I\'d be far more concerned
about the lack of cardiovascular events here.

I can\'t explain why there was not an increase in cardiovascular
mortality. I think when we relate this to the captopril trial, there are
several things that come up. One is that was a different population.
Those patients had much less well-controlled diabetes. These patients
are likely to have been on far better therapy at this point in time. So,
I don\'t believe it\'s just a statistical anomaly. I think the follow-up
may just have been a little bit too short to see substantial differences
in cardiovascular outcome.

I think it helps that the relative risk of death is less, but it would
be nice if it were significant. So, not strongly supportive.

DR. BORER: Can I just ask for an opinion? I think one of the key
elements here that one can infer from this question is that we\'re being
asked whether we believe that there\'s a clear relationship between
doubling of serum creatinine and a progression to ESRD within 9.8
months. And we were shown data about this. Can you comment on that,
JoAnn?

DR. LINDENFELD: I believe that there is a clear correlation between
doubling of serum creatinine and end-stage renal disease, based on this
data, yes.

DR. LIPICKY: Based on this data?

DR. LINDENFELD: I think so.

DR. LIPICKY: What do you see? What makes you say that?

DR. LINDENFELD: Well, we see a substantial difference in end-stage renal
disease, if you believe a creatinine greater than 6 as part of end-stage
renal disease. We talked about that earlier.

DR. BORER: So, the incidence of end-stage renal disease, 22 to 23,
doesn\'t mean anything.

DR. LINDENFELD: Well, that\'s if you only use dialysis or transplant. If
you use the creatinine of 6 ‑‑ and I think what I\'ve heard makes me
think that that ‑‑ and the other discussion that we heard just about the
creatinine of 6 makes me feel that that was probably a reasonable
addition.

DR. LIPICKY: But that has to be, right, because if you use creatinine as
the one thing and you also use creatinine for the other, it\'s got to be
the same? Isn\'t it? I mean, does that really convince you?

DR. LINDENFELD: No, it does not convince me, but I think it\'s
supportive data. Does it absolutely convince me? There are two
questions. Does the data absolutely convince me? No, the data doesn\'t.
Do I believe the doubling of creatinine is an important precursor for
end-stage renal disease which is important in clinical outcomes? All of
this data persuades me that that is true, in addition to other data,
yes.

DR. BORER: Any disagreement? Dr. Kopp?

DR. KOPP: No. I would say not so much disagreement. I think I agree with
what you said.

But I\'ve puzzled during the day about why the rate of dialysis and
transplant was so much higher in the captopril study, given that both
were about 3 years and the captopril study involved younger patients.
But I realized you mentioned one factor that would favor less renal
disease in this group, which is glucose control was worse in the
captopril study. Another is that blood pressure I think was not as well
controlled. And a third I realized is that some people who doubled
creatinine and therefore came off study could have then received an ACE
inhibitor and postponed the onset of their ESRD. So, I think that might
tend to unlink some of this, particularly over a 2.6‑year study.

DR. LORELL: Yes, I agree very much with that comment. I would support
that.

DR. BORER: Let\'s move on to question number 3 then.

DR. FLEMING: Another comment, Jeff, on 2 if we could.

DR. BORER: Oh, I\'m sorry. I didn\'t see you.

DR. FLEMING: It might be worth getting into just a little more depth in
2, if I could.

When I think of effect ‑‑ and it may be a simplification, but in
addition to the marker here which is looking at changes of a certain
magnitude in creatinine ‑‑ there are at least maybe three fundamental
domains of what\'s clinically important. One that I might say is a
direct obvious renal, which is dialysis/transplantation. Then there\'s
the domain of mortality, which includes renal to an extent, of course
renal-related deaths. And then there\'s the third domain which would be
the cardiovascular events. That would include the stroke and the MI,
cardiovascular death, heart failure.

My sense is what\'s happening here is when you analyze these data in
different ways, you\'re getting different weightings of these three
domains. With the first of those three domains, there\'s a signal for
benefit. The second and third domains, there\'s essentially an
indication of lack of difference or, to put it another way, to obtain
evidence that is convincing of small differences that would take a much
larger trial.

So, if I could just briefly refer to a series of five analyses that
become more inclusive as you go through them, when you look at the
primary analysis, you see the 411 events that we were asked to look at
here. If you look at a breakdown of that, when you look at the first
occurrence, what you find is there are 64 deaths in control and
irbesartan. So, there\'s no difference in first occurrence of deaths.
There\'s actually no difference in first occurrence of dialysis.
There\'s no difference in first occurrence of transplant. The entire
difference is in first occurrence of the doubling. But it\'s misleading
to look at it that way in the sense that, for example, for dialysis
you\'re truncating the follow-up there at the first occurrence of the
primary endpoint. So, we want to follow on beyond that.

And that leads to the second analysis which is looking at end-stage
renal disease. The first analysis we\'ve seen, there\'s an excess of 33.
There are 33 events prevented. And this is a relative risk of .8 and
this has the p value of .023. When you look at the end-stage renal
disease, you\'re getting almost the same relative risk reduction of .77
as the relative risk. You have 19 fewer events, and yet not quite
significant. So, if one takes the approach that end-stage renal disease
is so proximal to dialysis that it\'s a reliable surrogate, that there
isn\'t an issue about surrogacy, then for this particular endpoint,
we\'re seeing an estimate of a 23 percent reduction with not quite
statistical significance and 19 fewer events.

It\'s interesting if you look at dialysis. What we were shown is that
translates into 15 fewer events. So, in fact, it\'s sort of a
confirmation, I might say, that end-stage renal disease is close enough
to dialysis to basically refer to it as a reliable measure. But
dialysis, like end-stage renal disease, showing 15 to 19 fewer events,
is around that area that we would consider convincing. It\'s about a p
value of .07 to .1, something in that neighborhood.

When you add death, the deaths are essentially comparable. In fact, I
think most of the deaths that occur ‑‑ there were 87 versus 93 deaths.
So, there were 180 deaths. Only 36 of those were people who had had a
prior dialysis. So, a large fraction of these deaths are occurring to
people who had not had a prior dialysis.

So, basically it would be called competing risks, which points out that
at least for the duration of follow-up that we had in this population,
there is a significant myriad of health challenges these patients are
facing and the renal complications are obviously one important part, but
there are major complications outside of the renal. And it would appear
from these data ‑‑ and it may be what people would say we would expect
‑‑ is that there\'s no reduction in those particular deaths.

So, when you go to the next level of analysis, which is dialysis/death,
what you\'re seeing then is still a numerical 13 fewer events, but now
relative risk is .89. So, you\'re only reducing the relative risk by 11
percent. Obviously, very nonsignificant.

And it\'s interesting that if we compare that, that\'s the endpoint in
captopril that showed a 50 percent reduction. This particular endpoint,
we\'re showing an 11 to 13 percent reduction.

And personally I find it very acceptable to focus on the renal-related
phenomena here, death, transplantation, dialysis. But if you then go one
step further and you add in what was at least documented for the
cardiovascular events in the secondary endpoints, now you\'re looking at
209 versus 229 or 20 fewer events, corresponding to a proportion of
patients who have events, 36 versus 40, so a 4 percent absolute
reduction or about a 9 percent relative reduction.

So, my sense is when you look at this to answer this question, one
really needs to break apart these domains. And what, at least my
interpretation, these data are telling us is if you focus on end-stage
renal disease or, correspondingly, dialysis as the only measures you\'re
looking at, you\'re seeing something on the order of a 20-23 percent
reduction, but it\'s p values of .07. So, it\'s very close to whether
you would say that\'s convincing evidence.

When you then add in death ‑‑ so, you\'re looking at dialysis-free
survival ‑‑ because you\'re adding in almost as many additional events
that were not impacted at all in terms of their reduction ‑‑ that 23
percent reduction is cut in half to an 11 percent relative reduction,
very nonsignificant, although I don\'t worry about it being
nonsignificant. I\'m looking more at the magnitude. And then it\'s
reduced to 9 percent relative reduction when you bring in the other
cardiovascular events.

So, it seems as though there is ‑‑ this is an issue that we have to
decide, is there adequately convincing evidence that you\'re affecting
the clinical renal events because there\'s clearly a signal toward that.
But the other events, even if you just go to death, aren\'t being
influenced nor are the cardiovascular events being influenced.

DR. BORER: Well, we\'ll have to keep all that in mind as we move along
here.

May I ask you, Tom, just one thing? I think you\'ve really covered the
waterfront. The point is made in the questions that we don\'t see the
curves begin to separate until 18 months. And that\'s true. Of course,
we\'ve heard about the natural history of these diseases, and it\'s not
terribly surprising that we might not see an impact for a while. But
I\'m impressed with the fact that at least until you get out to 42
months, by which time the numbers become so small that the statistical
stability of point estimates would have to be of concern, the curves
seem to continue to diverge. It appears that we\'re having an increasing
effect over time. Do you accept that or can you comment on that?

DR. FLEMING: I think what you\'re referring to is this is what the
primary analysis does show when you look at ‑‑

DR. BORER: Also the end-stage renal disease analysis.

DR. FLEMING: If I go through my hierarchy of five analyses, those are a
tier 1 and tier 2. They\'re fairly close.

It\'s certainly an interesting issue. It\'s relevant. It\'s going to
mean that statistics such as the log rank test will be pretty sensitive
to those kinds of emerging effects. It means that it\'s possible,
plausible that if one had continued this for a number of additional
years, then the magnitude of the signal may have been more apparent. It
comes back to a comment just before the break I think that Dr. Temple
had asked about what ability would there be to follow up these patients
in this study to see whether there is more data than what we\'ve had
presented to us for effects of the signal on dialysis. It\'s entirely
possible that it would show more signal.

DR. BORER: Let\'s go on to question number 3. Irbesartan reduced the
composite event rate compared with amlodipine by 23 percent. Considering
the low nominal p value, is this as good as a second study? This p value
is smaller than for the comparison between irbesartan and placebo
because amlodipine did worse than placebo. How does that confirm a
benefit of irbesartan?

JoAnn?

DR. LINDENFELD: I don\'t believe that this is as good as a second study.
First, when you look at those curves, they were different. Amlodipine
was just slightly worse, not statistically significantly so from
placebo, so it\'s not a surprise that this p value is lower than when
compared to irbesartan. So, no, I don\'t think it\'s as good as a second
study.

Does it help a little bit? It helps me a little bit in that in the
amlodipine group, the blood pressure was well controlled, and I think
that\'s a helpful finding, but certainly not as good as a second study.

DR. BORER: I want to ask Tom for a clarification here again. I\'m not
sure what we can infer from the nominal p values here. The way I would
look at it, it\'s unlikely that the difference between irbesartan and
placebo was due to chance alone for the primary analysis, and unlikely
that a difference between irbesartan and amlodipine was due to chance
alone in the primary analysis. I\'m not sure what you can infer about
placebo and amlodipine and about the difference in the p values between
those two. That seems beyond what we can really draw conclusions about.
Am I right about that or am I misinterpreting here?

DR. FLEMING: Actually my sense about this is similar I believe to what I
understand JoAnn is saying. When I look at this, there is some level of
reassurance about the irbesartan effect against placebo when you look at
it against amlodipine and you track that same effect. Of course, the
extent to which I can draw that reassurance is based on the assumption
that amlodipine can really be viewed as a placebo.

Where I worry is that I don\'t know whether we can say that amlodipine
is a placebo, at least as it relates to the measures on the primary
endpoint. Certainly when we get to the cardiovascular measures, if
we\'re going to pool amlodipine with placebo, then I almost feel like,
gee, is that really fair not to pool it where it\'s going to make
irbesartan look worse, which are the cardiovascular endpoints. If we do
that pooling relative to other measures such as cerebrovascular events,
MIs, neurologic abnormalities, if you pool amlodipine and placebo and
compare it to irbesartan, it looks like irbesartan is 30 percent worse.
Well, I don\'t believe that either. I think what\'s happening is
amlodipine is better than placebo. So, to then pool amlodipine with
placebo in those measures that will make the statistical strength of
evidence look better seems to be a little bit, at best, arbitrary. So,
there is this clinical issue, can you pool this when you\'re really
having to essentially say, to strengthen your evidence, I\'m willing to
say amlodipine is a placebo. So, there is that clinical complication.

There\'s also a statistical complication. If I allowed myself to
generate a p value by essentially comparing to the placebo and comparing
to the placebo with another arm in the trial and view that whichever one
of those p values look more impressive and report that p value as being
meaningful, you\'re going to have an inflated risk of false positive
conclusions. You can\'t conditionally pool something from another arm
with my control arm if it\'s going to strengthen my evidence. It would
be interesting.

Would it have been pooled had it weakened the evidence?

Would we still have done the same pooling analysis of amlodipine against
control if it would have weakened the strength of evidence because
amlodipine itself would have carried some benefit on this endpoint?

So, bottom line is I strongly object to anybody sprinkling p values on
such ad hoc suspect analyses to, in a sense, strengthen the
interpretation of those.

On the other hand, coming back to what JoAnn said, I think there is some
level of reassurance. It\'s not remotely what I\'d call a second trial
reassurance, but there is some level of reassurance by saying that the
amlodipine arm was similar to the placebo arm and the irbesartan was
better than each of the two.

DR. BORER: Steve?

DR. NISSEN: I think I\'m agreeing with you, Tom. We can\'t have it both
ways. We can\'t say amlodipine is placebo-like for one set of endpoints,
but then ignore the others. The minute we start to do that, we\'re
creating an anomaly. It seems to me that if we look at amlodipine as
placebo, then we\'re forced to compare what happened with irbesartan and
amlodipine with all those other endpoints. Clearly, there are several of
them that go disturbingly in the wrong direction.

So, I think you have to look at the totality of the data here, and in
that sense, I don\'t find it reassuring at all because, for a patient,
you really have to ask the question. The patient enters a clinic and you
have to decide which drug you\'re going to give them, and I think if
some endpoints go in one direction and some go in the other, the net
clinical benefit is very hard to establish and certainly doesn\'t
strengthen the evidence against placebo to lump amlodipine in the same
category.

DR. BORER: Let\'s go on to number 4. Comment on other secondary
endpoints in IDNT.

4.1. There was a prespecified analysis of time to first cardiovascular
death, nonfatal MI, CHF hospitalization, disabling stroke, or
amputation. There were 416 such events with no significant difference in
the distribution among groups. Is this further evidence of a lack of
clinical benefit? Is it comforting that there\'s a lack of apparent
harm? Were there simply too few events, et cetera?

4.2. We discussed part of that here. There was a prespecified analysis
of time to first cardiovascular death, nonfatal MI, coronary
revascularization, CHF hospitalization, need for ACE inhibitor or ARB
for heart failure, disabling stroke, amputation, or peripheral
revascularization. There were 518 such events with no significant
difference in the distribution among groups. Is this further evidence of
a lack of clinical benefit? Is it comforting that there is a lack of
apparent harm? Were there simply too few events to show a meaningful
effect?

JoAnn?

DR. LINDENFELD: Once again, we have to come back. Lack of clinical
benefit. I think the primary endpoint here was renal disease and that\'s
where we really want to show the clinical benefit, and we\'ve discussed
that data. So, in this study, in this trial, I think we have a lack of a
clear-cut clinical benefit in these cardiovascular endpoints, but
certainly this doesn\'t imply a lack of clinical benefit on end-stage
renal disease.

Now, again, the point has come up over and over again. If we see this
doubling of creatinine, why is it not reflected in these other events?
But again, we\'ve discussed that, and these are two different things.
This lack of clinical benefit for cardiovascular outcomes doesn\'t
dissuade me that there\'s a clinical benefit in renal disease, which is
real.

I don\'t believe there were too few events to show a meaningful event.
Perhaps the study needed to go longer. Maybe that says that, yes, there
were too few events. But I don\'t believe there were too few events. I
can\'t explain the lack of cardiovascular outcomes here.

DR. BORER: Any other comments here? Tom?

DR. FLEMING: A very brief addition to that. The sense in which I might
argue there could have been too few events is we\'re estimating
something like an 8 percent reduction, and that\'s not significant.
It\'s informative in that it\'s suggestive that the actual effect, if
it\'s real, is very modest. I\'m not willing to say that these data
prove that there isn\'t an effect on cardiovascular events, and in that
sense it\'s too small a trial. We probably would have needed a much
bigger study. If we would have viewed, for example, that conclusively
establishing that the 8 percent is real, that would have taken a huge
study.

So, this is the third domain that I had referred to in my answer to
question 2, and my sense of that is consistent with you, JoAnn, that the
first domain is what the intention and the focus was. It\'s still
relevant to know what the third domain showed because these are very
clinically relevant endpoints. And what the data show is they suggest
that if there is an effect, it\'s very modest and it would take a much
bigger trial to sort out whether there is in fact a very modest effect
on cardiovascular events versus no effect.

DR. BORER: Now, the next question we actually have to ‑‑ I\'m sorry. Go
ahead.

DR. LORELL: I appreciate your insights on that. I think they\'re very
helpful. I think it\'s also very much worth emphasizing that the
treatment design in this appears to have had at least two potent
cardioprotective interventions that were seen in all three groups. One
was aggressive blood pressure control. A second was that a relatively
high number of patients were on profoundly cardioprotective beta
blockade. We weren\'t told about aspirin, but I\'ll assume, unless I\'m
corrected otherwise, that aspirin use was comparably distributed. So, I
would look at the way these patients were treated as having a very
powerful cardioprotective intervention that was done in all three
groups, and I think that may have partially blunted the ability to see
any difference because of the low event rate.

DR. BORER: Bob?

DR. TEMPLE: Yes, I think I had much the same comment. We keep saying
there was no difference, but there really isn\'t any hypothesized
difference. They\'re all on appropriate regimens with all kinds of
stuff. There\'s a hypothesized difference in renal events, but there
isn\'t any hypothesized difference in any of the others. I mean, there
is some disturbance about the fact that amlodipine looks a little better
on some of those. That\'s certainly something to think about. But you
wouldn\'t really have predicted an advantage in those events in this
setting unless somehow the renal events led to fewer of the other
events, and it probably wasn\'t followed long enough to see that.

DR. BORER: Steve?

DR. NISSEN: Just in response, part of the reason why you might have
hypothesized that is if progressing to doubling your creatinine and
getting renal failure is a very bad thing, leading to myocardial
infarction ‑‑ we\'ve all heard that once you get to end-stage renal
disease, you\'ve got this terrible cardiovascular morbidity and
mortality, and therefore preventing that might be expected to prevent
those secondary consequences. So, I guess I think you could hypothesize
that. Even though the sponsor didn\'t necessarily power it for that, I
think we wouldn\'t have been shocked if we saw that.

DR. BORER: The next question we have to stand up and be counted on.

Are the results of IDNT alone an adequate basis for approval of
irbesartan for the treatment of patients with type 2 diabetic
nephropathy?

JoAnn, why don\'t we start with you and then we\'ll go to that side of
the table and move around?

DR. LINDENFELD: I would say no to this question. I think that the study
shows an improvement in the doubling of creatinine, but we\'ve generally
required two studies at .05 or one study at a much lower p value than
this. In addition, there\'s a small number of endpoints. So, just as a
standalone study with no other data, I would say no.

DR. BORER: Dr. Brem?

DR. BREM: I would make one comment and it comes to the point you made
very early in the discussion and that is, is this for diabetic
nephropathy or hypertensive patients with diabetic nephropathy?

DR. BORER: I think we can define how we want to interpret that. Why
don\'t you carry through the thought?

DR. BREM: I think the way it\'s written here ‑‑ Dr. Lipicky, if I\'m
misquoting you, please interrupt ‑‑ I think he\'s trying to get at an
indication for diabetic nephropathy, yes or no, independent of the
hypertension. And I\'m not sure on one study of this nature that we have
enough information to make a blanket approval.

DR. LIPICKY: Then to make it easy, make it with hypertension. So, I\'ll
call your bluff.

(Laughter.)

DR. BREM: I think even with hypertension, I\'m not sure this study
alone, in the absence of everything else ‑‑

DR. LIPICKY: You\'ve answered my question.

DR. BORER: Dr. Kopp?

DR. KOPP: I had a question about those standards. It\'s two trials each
at .05 or one trial at .00125. Where does that second number come from?

DR. LIPICKY: Both Tom and Dr. Temple are here to amplify on what I\'ll
say. But basically if you just take the common sense view, that if
somebody finds something, well, one has arbitrarily by history defined
finding something as a p of .05. Usually you say, well, Tom found that.
I\'d like to know Harry found that too. Almost everybody says maybe Tom
is right, but I want to know someone else found it. So, that\'s another
.05.

So, if you now require for your standard of evidence ‑‑ and I\'m not
sure you should; in fact, I am advocating you should, but I\'m not sure
you should ‑‑ two trials of .05, statistically that\'s .05 squared. So,
then you have to divide by 2 because you have to end up in the same
distribution of the tails. And that comes out to .00125.

So, you have this various grading then of strength of evidence from the
convention, 1 chance in 20 of being wrong, to a really very small chance
of being wrong. One has to make the decision where you think this
strength of evidence is. And I would maintain that you ought to be
closer to the two studies at p of .05 than to one study at a p of .05
because one study at a p of .05 is just too shaky.

DR. KOPP: Clearly then my answer is, according to those standards, this
doesn\'t make it. I agree that I don\'t think we can consider this two
independent studies so we don\'t have that criteria met.

DR. BORER: Bob?

DR. TEMPLE: I just want to comment a little further. We have just been
at a workshop on this discussion.

Historically the agency always said that you need independent
substantiation of a finding, basically in the form of another controlled
study. The Food, Drug and Cosmetic Act was altered in 1997 to allow us
to reach a conclusion on the basis of a single study with what is
\"confirmatory evidence,\" whatever that means because that has never
been properly defined.

We\'ve written a lengthy document on what constitutes good enough
evidence and have generally said a couple of things. First of all, other
data from other studies, maybe with a different endpoint, can sometimes
help you believe in one study. Obviously, that\'s a matter of judgment.
And we\'ve also said that when really all you have is a single study, it
ought to be at a more extreme p value, confidence interval, whatever you
care to do. Whether that translates to .00125 or .001 or whatever is
again a matter of judgment.

But it is fairly clear that we\'re allowed to think about ‑‑ and the
document says this ‑‑ data from other sources. Now, this is anticipating
later. But you\'re entitled to take into account such things as the
other study showing a different endpoint that may or may not be
relevant. How to do that is an intense matter of judgment. I wouldn\'t
try to tell you what to do, but you\'re permitted to reach that sort of
conclusion. You even can think about related drugs, if you want to. But
how to do those things and what the precedents are is very iffy, and
there aren\'t very many. So, you\'re in substantially uncharted
territories, but you\'re allowed to think.

(Laughter.)

DR. LIPICKY: Just to add to the part of you\'re allowed to think and
nobody knows what the right answer is, it isn\'t just the p value.
Right? It\'s partly, well, yes, you made a p of .05, but if you change
one patient, and now you\'re at a p of .1, well, geez, that\'s not
really a p of .05, just as in this case, it\'s a p of .02, but if you
lose a few patients, it\'s .07. Now, that\'s a big difference. So, part
of the question is not prior knowledge or is it a p of .05, but how
robust is the data. How likely is it that if you take the numbers
you\'re looking at and act on them, you would be making a mistake? So,
it\'s another part of the whole business, and it doesn\'t come down to p
values only.

Nor is it really one study/two studies. I mean, you could have one study
that has a p of .01, let\'s say, and is so robust that you wouldn\'t
possibly think that it could turn out any other way. Or as Dr. Temple
says, you know so much that you would have predicted that, and indeed
this now turns out that way.

And so, there\'s all kinds of this. That\'s what\'s being talked about
now. Where are you on this continuum of your confidence that what the
trial found is real?

DR. BORER: So far, to summarize, we\'re at 3 to 0 against, in terms of
question number 5, and we\'ll go to Beverly Lorell.

DR. LORELL: Well, picking up on Dr. Temple\'s comment and on your
comment, Dr. Lipicky, I\'d welcome some discussion among the committee
about their interpretation of the supportive value of the RENAAL study.
Admittedly, it\'s a bit on uncharted ground, but at least to my mind,
those data in a very similar design ‑‑

DR. LIPICKY: You haven\'t seen it. I think our proceedings here should
be related to data you have seen and where you have seen a whole review
like you\'ve just seen of this, and there may be things that you know
about that haven\'t had that degree of stuff and I don\'t think you
should count that. Dr. Temple may think differently.

DR. TEMPLE: Well, I think we\'ve vetted and the committee has vetted
captopril data, so you might think that was relevant.

It is hard to take the RENAAL study into account because you haven\'t
had an opportunity to see it, although we have.

(Laughter.)

DR. LIPICKY: Well, but that is a difference.

DR. TEMPLE: Yes.

DR. LIPICKY: And we would represent to you that the captopril study is
as it was. We couldn\'t make that representation for the RENAAL.

DR. TEMPLE: We tend to be nervous about ‑‑ no offense to anybody ‑‑
presentations in journals without an opportunity to see the data, even
though everybody is trying his or her best.

DR. BORER: I think we\'ll get to the strength of supporting evidence in
the subsequent questions, but maybe we can try and deal with this one
first, which is specifically, if you look at IDNT alone, is that
adequate for approval?

DR. LORELL: Well, but in response to that explicit question, I would say
no.

DR. BORER: Do you want to state a reason?

DR. LORELL: For the same reasons that have been discussed, that it is a
single study with a modest p value.

DR. BORER: Dr. Cunningham?

DR. CUNNINGHAM: I would also say no for the same reasons.

DR. BORER: Mike?

DR. ARTMAN: I would say no. I think there are a lot of confounding
issues. We really haven\'t delved into some of the issues related to
polypharmacy and whether that was all controlled for, et cetera. I think
that the issues related to gender and ethnicity ‑‑ there was some
hand-waving.

We\'ve talked about the issues related to the black population and
we\'re told that that couldn\'t account for differences. Then we looked
at North American versus European and they said, oh, well, that\'s
because all the black people were on the North American side and that
accounts for the difference.

You know, I just am underwhelmed. And the mantra that Ray has instilled
into us has been does the intervention make you live longer or feel
better, and I don\'t see compelling evidence for either one of those.
So, I would say no.

DR. BORER: Tom?

DR. LIPICKY: You cannot blame it on me.

DR. ARTMAN: Oh, I blame everything on you.

(Laughter.)

DR. BORER: He wasn\'t blaming it on you. He was giving an explanation.

DR. ARTMAN: I\'m giving you credit. I\'m attributing it to you.

DR. BORER: Tom?

DR. FLEMING: Well, issues have been discussed, but essentially when I
look at data from a single trial and I\'m confronted with the question
should this study, at least in my own recommendation to the FDA, be
viewed as adequately convincing. We lose a little bit with the single
study of the replication concept. That is important. It\'s not just a p
of .025 squared times 2, which is what .001 is. There is that merit to
being able to see an independent set of investigators maybe in a
somewhat related setting being able to show that the results of
positivity could be confirmed.

Having said that, though, I do accept that a single trial in settings
could be adequate, and I certainly am influenced a bit by what the
strength of evidence is when you say .001, i.e., the .025 squared. There
are settings that would move me away from even saying I would need to
see that from a single trial, if I\'m looking at a mortality endpoint,
if I\'m looking at secondary measures that are strongly reinforcing
primary.

So, in this setting, I completely concur with the sponsor\'s perspective
that the first focus of this is the renal components and dialysis. And
when I look at that, I see some p values that are in the neighborhood of
.025 to .075, something lurking around .05. When I look at the secondary
measures, I don\'t see that they have to be positive in order to make me
view this as a single positive trial, but I do think that when the
primary is about .05, I do need to see those secondary measures showing
positive reinforcement for this study to be judged in its own right as a
single convincing trial. And for mortality and for the cardiovascular
endpoints, there\'s not evidence of benefit.

My view of that is I think this is just on the edge of what I would
consider adequate strength of evidence for this to be called, just
barely, a single positive trial, but I don\'t see it as meeting any of
those other factors that would bring me to a much more convincing
perspective that this study conclusively establishes benefit at the
level that I would wish to have as a standard for strength of evidence
from two independent studies.

I guess the last point is ‑‑ and I don\'t know what FDA\'s view about
this is ‑‑ I would also be persuaded if this was a setting that was a
rare setting that would be incredibly difficult to enter patients. This
is a setting where this is going to be very widely used, and I think
having a standard of being adequately convinced it\'s effective is
particularly compelling in a setting where you\'ve got an intervention
that\'s going to be so widely used.

So, I look at it as a study that just does get into the realm of
strength of evidence for being called a single positive study, but I
couldn\'t see an approval being justified based on this study alone.

DR. BORER: Blase?

DR. CARABELLO: I would vote also no. I think it was a single study. I
found the amlodipine data helpful in helping me believe that this was
not simply an effect of blood pressure lowering, but I was mostly
disturbed, despite discussion to the contrary, about its lack of effect
in women in North America. I just am bothered by the fact that that
subset analysis seemed to be so weak.

DR. BORER: Steve?

DR. NISSEN: Well, one of the questions I ask is, although it is
off-label use, almost all these patients now are getting treated with
ACE inhibitors. A recommendation to approve will cause a shift in
prescribing practices. So, what level of evidence do we want to have to
actually cause that to take place?

The p value here is really .035 for the primary endpoint, and if you\'ll
recall, the sponsor\'s analysis of the blood pressure differences
suggested that at least some of the positivity was due to that. So, now
we\'re getting perilously close to even the standard for a single study.

You add to that the confounders, as in race, gender, and location, North
America versus not, and now there are just too many confounders that
could take this on the wrong side of even being adequate as a single
study. So, I just think there\'s just not compelling evidence from IDNT
to approve. So, my vote is no.

DR. BORER: Alan?

DR. HIRSCH: The first time I think I\'ve ever gotten to speak last, and
yet I\'ve learned how to use the word opine.

(Laughter.)

DR. HIRSCH: First, I have to say to my previous instructors, Dr. Brenner
and Dr. Lewis, I also heard you and I have absolutely no doubt that ARBs
alter the structure and hemodynamics of end-stage renal disease or the
kidney proceeding to end-stage renal disease. In other words, the
paradigm I understand is important and affects a great number of
patients who will ultimately in this country and the world die of their
disease. But I opine no as well, and I should justify why.

The same issues. I\'ll repeat a few of them. Single trial, I think,
whose statistical significance is borderline. For me the supporting data
and the secondary endpoints and the use of IRMA 2, though they support
the pathophysiology, in general don\'t yet convince me that the single
has adequate power.

Like Dr. Lorell, I certainly am aware of published data from losartan
and RENAAL, and that helps me but we\'re not there yet. So, I can\'t
include that in my analysis.

A little bit like you were saying, Dr. Temple, whereas if I were a
manuscript reviewer, this is clearly an important trial and significant,
our role as advisors to the agency is different. There\'s a higher
standard of evidence because it will change practice. So, I say no now.

I\'ll go a step further to set up the discussion later I think that you
wanted, Dr. Lorell. We do change precedent by how we interpret trials,
and I fear that when we take a single trial, as you might imply, and
permit the global data to change our analysis, that we permit use of
surrogates that we\'re not all quite comfortable with, number one, that
we might permit a somewhat low sample size to be used not to understand
why there\'s no efficacy in North America when, in fact, we\'re
regulating North American use ‑‑ or I should say American use. And I
worry that then we\'ll also promulgate incomplete follow-up regarding
those cardiac events in future trials.

So, overall, looking at a large potential use with a very, very
important disease, it doesn\'t quite reach that level of significance.
So, I opine no.

DR. BORER: Opine is Ray\'s usage.

Just with regard to the strictly stated question number 5, I\'m going to
vote no as well, but I want to give some explanatory statements.

First of all, although I agree with the thrust of Ray\'s suggestion
earlier that diabetic nephropathy is diabetic nephropathy, and the
presence or absence of hypertension probably ‑‑ probably ‑‑ doesn\'t
alter the fundamental nature of the disease. Nonetheless, when we\'re
talking about approval of a drug, we have to consider the efficacy and
the safety for its intended use and the balance between the two. And I
really have no information at all that would allow me to give an opinion
about that with this drug in patients with diabetic nephropathy who
don\'t have hypertension. So, just as Dr. Brem suggested, I would limit
my consideration of this drug to patients with type 2 diabetic
nephropathy with hypertension. Those are the patients we saw where the
risk/benefit relationship may be different than in the other
populations.

Having said that, I agree that it\'s a single trial with a level of
consistency, indicated by the p value that\'s relatively close to the
margin that nominally we accept, and there are some other issues.

However, and perhaps to presage aspects of the discussion that we\'ll
get into, I really don\'t have any trouble with a creatinine of 6.0.
I\'m not a nephrologist, but my understanding of the literature and my
clinical experience is that when patients have dramatically subnormal
creatinine clearance, as people with a creatinine of 6.0 do, they
progress, and they progress relatively rapidly. And if they\'re not
dialyzed, then they will die, and before they die, they\'ll be very
uncomfortable people. I don\'t need a set of data collected by the
sponsor about the effects of pericarditis, the effects of anemia, the
number of episodes of nausea and vomiting to believe that because I
think it\'s been well documented in the literature, and I think that
nephrologists probably know that and people in other subspecialties may
not have the same feeling for it. But I do see this patients with some
frequency because of my focus on patients with valve disease who have
cardiac surgery. So, I have no problem at all with the endpoint of 6.0
or dialysis or transplant. I think the one is a short step from the
other.

And I have really no particular problem with the doubling of creatinine
as a pretty solid predictor of the progression to these bad endpoints
that we don\'t want people to get to.

Having said that, I think that I to a lesser extent and the entire
committee perhaps to a greater extent would feel more secure. We would
have a more secure view of the data and the interpretation of the data
if in fact we did have that additional information that Tom had asked
for earlier about the progression to dialysis and the progression to
transplant beyond the first event ESRD. So, I\'d like to see those.

I think if at the end of the day we don\'t come out voting in favor of
suggesting to the FDA that they approve this drug for the requested
indication, that those data should be obtained and given for review
because they might change the opinion of some of the people who are
looking at these data, specifically the kinds of things that Tom was
asking for.

I\'m really not terribly concerned about the gender and ethnicity
issues. I don\'t want to get into mechanisms. I\'m already on record as
telling Tom at an earlier discussion at another meeting that I have no
idea how any drug causes its clinical benefits, but I can talk a little
bit about pharmacologic effects.

I think that there\'s an analogy here. The gender issue, the ethnicity
issue, all the other substudies are indeed substudies. If we\'re
concerned about them, then we could suggest that the FDA say something
about that in the label and note the lack of information or the lack of
security in certain subpopulations. But they are substudies. They\'re
post hoc assessments. There was no hypothesis being tested there. So,
I\'m not terribly concerned about that.

And I\'m also a little sorry that we got into such a detailed ‑‑ I\'m
not sorry that we got into the discussion, but that the issue of the
nonfatal cardiac endpoints seems to assume such great importance because
I am convinced that when you look at the totality of major events, that
there are fewer major events on drug than without, although there does
seem to be a different distribution of some of those cardiovascular
events than the renal events which causes you to lose a little bit of
confidence in the strength of the overall conclusion.

So, again, in summary, I believe that IDNT alone isn\'t an adequate
basis for approval of irbesartan for treatment of patients who are
hypertensive with type 2 diabetic nephropathy, but I\'m not as concerned
about some of the other issues that have been raised as you\'ve heard
from some of the other committee members.

DR. TEMPLE: Jeffrey, I think not everybody who voted clearly referred to
this study alone. You just did. The question was designed to not have
you consider IRMA yet and just go on this study, but it wasn\'t clear to
me everybody was treating it that way.

DR. BORER: I think Alan didn\'t and one or two others didn\'t, but I
think most everybody focused on this alone.

DR. TEMPLE: The second observation I want to make is we\'ve been
severely criticized for putting a mention of a subset in the labeling,
referring to the MERIT trial, where we thought we had better than usual
cause. It\'s just worth observing that here the subsets are extremely
small and it would be a miracle if they all went in the same direction.
So, we\'re having some trouble for doing that at all. Just so you know,
people are threatening not to include U.S. patients in their trials
because we pay so much attention to it, but don\'t worry about that.

(Laughter.)

DR. BORER: Well, just for the record, nominally they did go in the same
direction. The magnitude of the effect was small, but as you\'ve said,
small numbers, post hoc. I don\'t know what you make of that.

DR. FLEMING: Jeff, one other quick clarification. I think there may be
more concurrence in what you were saying than you might have suggested
in handling the primary analysis. You were saying you were persuaded
that end-stage renal disease, which includes in its definition a
creatinine at level 6, would be an adequate clinical endpoint, as would
dialysis. I didn\'t hear anybody disagreeing with that.

And when you referred to my interest in seeing more data, if one accepts
that these end-stage renal disease endpoints are clinical endpoints, one
gets a p value of .07. If one uses end-stage renal disease as the
primary endpoint, and if you look at dialysis, you get a significance
level along that line as well. If you use the primary endpoint, as they
had defined it, which is a twofold increase in creatinine, then you slip
just on the other side of .05 to .023. So, when you said you would
accept that, basically, at least in my own comments, when I say you\'re
on the edge of .05, it\'s accepting end-stage renal disease as clinical
endpoints.

DR. BORER: Let\'s move on then to 6, 7, and 8. IRMA 2 randomized 611
subjects with type 2 diabetes and microalbuminuria to placebo or
irbesartan, two doses, for 2 years. The primary endpoint was time to
progression to overt proteinuria, and the analysis plan compared each
active arm to placebo. The results ordered by dose, but only the 300
milligram dose group was statistically significantly different from
placebo.

Number 6. Comment on the handling and implications of premature
withdrawal of 166 patients, 27 percent.

JoAnn?

DR. LINDENFELD: Well, patients who reached the endpoint of overt
nephropathy were withdrawn. The implication, of course, is that that
makes it difficult for us to see ultimately effects on GFR.

DR. BORER: What does that do to your level of ‑‑

DR. LINDENFELD: That\'s coming up, I think, in another question. But it
makes it difficult on the basis of the data to presume that a reduction
in proteinuria reflects a change in creatinine clearance.

DR. BORER: Any other comments on that point?

(No response.)

DR. BORER: No? Then let\'s go on to number 7.

There was a trend toward a greater increase in the rate of change in
serum creatinine on irbesartan than on placebo. Comment on the
hypothesized relationship between proteinuria and renal function as
evidenced by creatinine clearance.

DR. LINDENFELD: I think I would make the same comment again. This data
just doesn\'t allow us to make a relationship between proteinuria and
creatinine clearance.

DR. BORER: That answer certainly stands.

I think ‑‑ and perhaps you don\'t think it\'s worth doing this, but I
think the issue that Ray may be getting to us about is that the 300
milligram dose caused a greater fall in creatinine clearance than the
150 milligram dose or than placebo. And we heard that that may be a good
thing. What do you think about that?

DR. LINDENFELD: Well, as I understand the explanation, that was an early
effect and then stabilized after that early effect. I\'m not concerned
about that effect.

DR. BORER: Number 8. A 133-subject subgroup was randomized to have GFR
measured at 3 months, at the end of active treatments, and then 4 weeks
after the last dose. At 3 months and at the end of active treatment,
there were no statistically significant differences in GFR between
placebo and either dose of irbesartan. 4 weeks after the last dose, GFR
increased in all three treatment groups. Differences from placebo were
again statistically non-significant, or perhaps not statistically
significant. Comment on the hypothesized relationship between
proteinuria and renal function as evidenced by GFR.

I think it might be fair, unless Ray doesn\'t think it\'s fair, for us
to include in that discussion not just the GFR substudy, but the other
data that we saw for the entire group.

DR. LINDENFELD: I would comment here that we\'ve seen a lot of
information suggesting that the changes we would see with angiotensin
receptor blockers are likely to be permanent changes, or at least if not
reversal of the underlying disease, prevention of advancement of the
underlying disease. And when one removes the irbesartan, at least the
150 milligram dose, and sees a return right back up to placebo levels,
that makes us think that this was a hemodynamic effect of some sort
rather than perhaps a clear-cut change which we would expect to see
longer. It can\'t just be a blood pressure change, the fact that the
blood pressure was allowed to go up, because we didn\'t see that same
thing happen in the 300 milligram group. So, on the other hand, the 300
milligram irbesartan group did have a persistent lowering.

So, it doesn\'t help me. It certainly doesn\'t add to this relationship
between proteinuria and GFR, but I don\'t know that it subtracts from it
either.

DR. BORER: How about the relationship between irbesartan and ARB and
proteinuria? I think one of the thrusts of the question here may be does
the delay in any loss of apparent stabilization of proteinuria with a
300 milligram dose, after you stop the 300 milligram dose, give you any
sense of the action of irbesartan compared to placebo, for example.

DR. LINDENFELD: Maybe I\'m not quite understanding this question. Why
don\'t you repeat it or rephrase it for me.

DR. BORER: My understanding of these data are that they were shown to us
to suggest that because proteinuria didn\'t return even really towards
baseline 4 weeks after stopping the 300 milligram dose, that in fact
there was some protective effect that was maintained after stopping the
drug, as compared with placebo or the lower dose where things moved back
towards baseline. And should we draw any inferences from that finding
about the activity or presence of beneficial activity of irbesartan?

DR. LINDENFELD: Well, I think it\'s marginally helpful. I\'m concerned.
I would have liked to have not seen the 150 milligram group go right
back up to the placebo level. So, the 300 alone ‑‑ you know, if we had a
250, what would that have done? It\'s helpful but it\'s not enormously
persuasive.

DR. BORER: Dr. Kopp?

DR. KOPP: Well, I think the sponsor was careful not to speculate, but I
won\'t be so careful. So, one possibility is that the low dose is
operating purely hemodynamically and the higher dose has some additional
structural effect, even an antifibrotic, not just a stabilization
effect. So, one possibility is that during this time of suppression of
angiotensin II activity, TGF-beta, and so forth, there\'s the
possibility for some remodeling to have occurred so that structurally
you\'re better off at 24 months, even without the drug, that you were at
the beginning. Obviously, without biopsies, who knows? But it does
suggest there\'s some structural benefit, not just stabilization.

Either that, or 4 weeks wasn\'t long enough and there\'s some residual
effect that is clearly ‑‑ in that situation, I\'m not saying there are
drug levels around but some change in cellular phenotype has been
maintained that doesn\'t reverse. Of course, it would be nice to see the
same thing at 3 months. That wasn\'t done.

But I think it is favorable that 300 milligrams had a long-term effect
even in the absence of the drug for 1 month.

DR. LIPICKY: But you have answered the question I think unless you want
to discuss it some more.

DR. BORER: We do. Bev?

DR. LORELL: I think that at first, in hearing the discussion today,
there did seem to be some disconnect between the behavior of
microalbuminuria and creatinine clearance. But I think, on the other
hand, the point was made in the discussion as an hypothesis for which
there is support, that the somewhat disparate behavior of creatinine
clearance may have been related to hyperfiltration associated with
hypertension in removing that component of hyperfiltration.

But I actually did find it both interesting and supportive that, in
terms of looking at the primary endpoint of microalbuminuria, that that
benefit was not only persistent but appeared to even go in the
improvement direction with stopping the drug for 4 weeks.

DR. BORER: Well, let\'s go on to number 9 and here\'s another one where
we have to make a statement into the microphone.

Are the results of IDNT plus IRMA 2 an adequate basis for approval of
irbesartan for the treatment of ‑‑ however you want to say it ‑‑
hypertensive patients, or if you don\'t want to be hypertensive, then
any patients, who have type 2 diabetic nephropathy?

JoAnn, why don\'t you start and we\'ll go around the table again.

DR. LINDENFELD: This is obviously a difficult question. I would answer
no to this. I think that the IRMA data is supportive, but it\'s not
quite enough additional data, given the things we discussed in the IDNT
study. It\'s not yet quite enough additional data to make me feel
comfortable that all the data we have is convincing.

DR. BORER: Why don\'t we start on the other side this time. Mike?

DR. ARTMAN: I actually liked the IRMA 2 trial a lot better. I thought
the rationale, I thought the data were compelling. And, yes, there is
this disconnect between the early direction of the creatinine clearance.
That was at the same time that there was the greatest reduction in
microalbuminuria. So, I think those data are compelling. However, I
don\'t believe that they\'re robust enough for me to support the
approval. So, I would agree with JoAnn and say no on this one.

DR. BORER: Tom?

DR. ARTMAN: One more comment. I do think that if we are going to approve
an indication, it has to be for the population from which the data were
gathered. So, I agree strongly that it would have to include the word
hypertensive patients, and I\'m surprised that Ray, who has taught us
again not to stray from the study population, would try to sneak that
in.

DR. BORER: Tom?

DR. FLEMING: I think the IRMA 2 trial provides us evidence that there is
an effect on progression for microalbuminuria to proteinuria, and there
is a lot of evidence. Dr. Lewis gave a very informative presentation
about natural history and that this is an important step in the cascade
of events that lead to very significant and important clinical
consequences.

However, we have a myriad of examples and experiences to know that a
correlate does not necessarily make a surrogate, that in fact now having
a treatment-induced effect on that marker is reliable evidence of a
treatment-induced effect on the clinical events that are down the
cascade that we\'re really trying to prevent. We weren\'t even able to
directly assess the next step, which is GFR rates.

My sense is IRMA 2 is informative. It establishes an effect on an
important early phase marker that I believe does provide enhanced
plausibility of efficacy. That type of data, though, typically in my
view requires confirmation then in studies that would, in fact, more
reliably demonstrate the effect.

We have one study which, in my own view, is on the edge of what would be
strength of evidence for a single positive study. Now we\'re talking
about a study on a marker. If the first study had been much closer to
being convincing, I would have found the two together to be adequate,
but a second study that establishes an effect on a marker that does, in
fact, provide enhanced plausibility of efficacy, but falls far short of
what we would consider as strength of evidence for a single study for
establishing benefit, that doesn\'t add in adequate strength of evidence
to the first study to make it a convincing package from my perspective.
So, the two studies I believe together wouldn\'t provide an adequate
basis for approval. My vote would be no.

DR. BORER: Blase?

DR. CARABELLO: Essentially we\'ve been told that this disease is a
continuum, a trip from New York to San Francisco. And I think we clearly
have the piece from New York to Cincinnati, and I believe IRMA 2. We
have the trip from Chicago to Denver. I believe that the drug helps to
prevent the doubling in creatinine. It\'s the Cincinnati to Chicago and
Denver to San Francisco pieces that aren\'t there that I wish we had to
complete the whole story that would make this a more convincing
argument. So, I also would have to say no.

DR. BORER: Steve?

DR. NISSEN: We\'ve got lots of examples where a drug may be effective at
one phase of a disease process and not so effective in another phase,
and that\'s why it\'s hard to put the two together because they don\'t
support each other as much as they might if they were looking at a
similar population. So, that\'s the problem I have, is both studies
taken separately are useful, but I find that I can\'t combine them in
making any kind of reasonable decision because I\'m not convinced that
the process is the same early in the disease and late in the disease
without more evidence that that\'s the case. So, my vote is no.

DR. BORER: Alan?

DR. HIRSCH: It\'s not often when we all sort of come to similar
conclusions.

I think the two studies have great beauty and actually do provide great
help in advancing future care for patients with renal disease. I\'m
impressed. And the goal, of course, is to change outcomes, so I will
summarize again.

One, I do think we have a signal of efficacy in two separate trials.
Yes, I think that IRMA 2 is supportive of IDNT in the sense that we\'ve
shown a signal that\'s positive. But again, I find these are different
signals in different populations, and therefore I really have a hard
time combining them.

Again, I would emphasize the natural history continuum. There\'s been
vision in place in these things along the natural history, but I find
each of the signals along the continuum to be just weak enough that I
can\'t connect them, making the metaphor to crossing the country by
airplane. So, therefore, with two surrogates, an improvement in
proteinuria and an improvement in doubling of creatinine, they would
need to be linked yet again in my mind to a stronger clinical outcome to
achieve approvability on their basis alone.

DR. BORER: Dr. Brem?

DR. BREM: It\'s difficult to top the community summation, and I
certainly agree with it. Again, what\'s missing is the difference, the
leap between advancement of microalbuminuria and change in renal
function, which is what we all believe probably occurs, but hasn\'t been
convincingly shown.

Based on just these two studies alone, in the absence of any other
information, I would have to agree with my colleagues and vote no.

DR. KOPP: I would vote to approve. I think a couple of a points I\'d
like to make. One is that this is a continuous process histologically so
that if you do a kidney biopsy of somebody in the microalbuminuric
phase, it looks exactly like that of somebody in the later phase. So,
there\'s no reason to think that the histology is different. In fact,
there\'s reason to think that it\'s the same. It simply becomes
progressively more severe, as you saw this morning, wider glomerular
basement membranes, more mesangial matrix expansion. So, I think it is a
continuum of one disease.

Earlier I spoke against the first study, but I think I focused on the
glass being half empty. I take it that the glass for the first study is
half full. Admittedly, the p value is only .023. Although I found all
elements of the primary composite endpoint to be convincing ‑‑ I\'ll go
in the reverse order ‑‑ death, dialysis, and a creatinine of 6 I have no
problem being very hard clinical endpoints as I think most of us did.

For me a doubling in serum creatinine is very worrisome and is, as I
think Dr. Lewis was trying to make the case, more than just a surrogate
but actually a measure of renal function such that in this disease, in
particular, but really in most nephrotic conditions a certain sign that
this patient is destined to progress absent further therapy.

So, I took the composite endpoint to be quite convincing, and my only
limitation was that the p value was .023 with the caveats that if you
argue about particular situations, it might drift to a .05.

The second study with the higher dose of irbesartan had a p value of
less than .001. And I am convinced, as I say, that this is the same
disease treated at two different points. I do take the comment over here
that because we\'re studying two different points, they are not exactly
in support of one another, but I choose to focus on the other side that
it\'s the same disease process we\'re treating, and so I vote to
approve.

DR. BORER: Bev?

DR. LORELL: Thank you. I thought that the IRMA 2 study was really a very
well-done and very beautifully presented study. I would view it as a
supportive study and not as a second study of the same weight as the
IDNT trial in terms of changing practice for a very large number of
patients in the United States.

I would vote no. I think that that is very close. I would like to see
additional supportive data for some of the harder endpoints that we
discussed earlier around the table.

DR. CUNNINGHAM: Well, I think I see the glass as being maybe one-third
full. I think it\'s also supportive and somewhat convincing.

But I have to say, as a person who\'s sitting in the consumer seat, that
what I see as the real problem here is the drug that wasn\'t study, that
being the ACE inhibitors. And I think from the consumer perspective,
that\'s really what we\'d like to see the data on. So, my vote is no.

DR. BORER: Just as a point of clarification, we all would like to see
that I think, but we\'re really being asked to judge this application
not what ‑‑

DR. CUNNINGHAM: I realized that. That\'s why I said no. But I wanted to
put on the record somewhere along the way that that was my view.

DR. BORER: Okay.

I\'m right on the borderline, but not to presage any final comment here,
as we go down the question, I\'m at this point still on the minimally
negative side. I agree with everything that Dr. Kopp said. I believe
that IRMA 2 deals with the effects of this agent on the same disease at
a different point and it\'s very positive. It would be lovely if we had
the GFR data, and as a non-nephrologist, it\'s probably not appropriate
for me to make the jump from proteinuria data to GFR data, although I\'d
be willing to do it.

I\'m not concerned that we don\'t have biopsies because I don\'t think
we could get them. I think Beverly said it before, and I\'m convinced by
the information we were shown that we have enough information to be
reasonably certain what the biopsies would show if we had them.

So, I think this study is strongly supportive and I think that it gets
me right, just about, to the point where I\'d be willing to vote for
approval, but not quite. I\'d like to see just a little bit more. Maybe
those data are available or maybe that little bit more will become
clarified as we go down through these questions. So, I\'ll reluctantly,
still at this at point, vote no.

With that, let\'s go on to number 10. A drug with a related mechanism of
action, captopril, has an indication for diabetic nephropathy in
patients with type 1 diabetes. The primary basis of that approval was
the demonstration in a 409-subject 2-year study of a 51 percent
reduction, p equals .004, in risk of doubling serum creatinine, and a 50
percent reduction, p equals .006, in risk of mortality or end-stage
renal disease. Both effects were manifest in the first few months of
treatment. Captopril also reduces the progression for microalbuminuria
to overt proteinuria.

10\. Are the results with captopril germane to a discussion of
irbesartan? In particular, is nephropathy in type 1 diabetes enough like
nephropathy in type 2 diabetes? And 10.2, are the pharmacological
effects of captopril and irbesartan adequately similar?

JoAnn?

DR. LINDENFELD: I believe that we\'ve heard enough today and seen in our
background booklets that, yes, the nephropathies in these two types of
diabetes are quite similar and would be expected to respond similarly.

In terms of the second point, of course, the pharmacological effects are
not exactly the same. But I believe that we\'ve heard some data today
and there\'s some data that exists that the effect on renal function is
at least in great part an angiotensin effect. So, I think there are
enough similar mechanisms to make the data with captopril helpful.

DR. BORER: Dr. Brem?

DR. BREM: I agree. Although there are obvious differences in the first
captopril study that have been well described already in terms of age
and blood pressure normalization, I believe that the basic progression
of disease is probably similar enough in both models or both types of
diabetes that it would be expected that both should behave and respond
to treatment in a similar fashion. So, I think they are germane.

DR. BORER: Okay, that\'s a yes.

Dr. Kopp?

DR. KOPP: Yes, I think they are germane.

DR. BORER: Beverly?

DR. LORELL: I agree.

DR. BORER: Dr. Cunningham?

DR. CUNNINGHAM: I don\'t know if I\'m convinced that the pharmacological
effects are the same, but I think they\'re certainly useful.

DR. BORER: Do we need a more specific yes or no there?

DR. CUNNINGHAM: I guess yes then.

DR. BORER: Mike?

DR. ARTMAN: Well, yes, I think the results with captopril are germane,
but I take exception with the pharmacological issues. I do not think we
can equate irbesartan with an ACE inhibitor. I think there are
differences in the pharmacology. There are certainly differences in the
stimulation of AT I versus AT II receptors. Whether or not sort of this
unopposed action of AT II receptors is good, bad, or ugly, I don\'t
think we know. So, I don\'t think we can generalize the pharmacology of
ACE inhibitors to that of the AT I receptor blockers.

DR. BORER: Tom?

DR. FLEMING: I defer to my clinical colleagues in interpreting the
biological parallels. The data are confusing when one looks at them head
to head, but I think we\'ll get into that in future questions.

DR. BORER: Blase?

DR. CARABELLO: Certainly the two drugs have some similarities and also
some substantial differences, but I think the similarities probably
outweigh the differences, so I would vote yes.

DR. BORER: Steve?

DR. NISSEN: I\'m actually a little surprised by this discussion. It\'s
tough enough to look at effect of a drug when you have other drugs in
the class and say, well, an effect is a class effect. Now, we\'re
talking about two different classes of drugs, and so I\'d want to have
pretty good evidence that the effects are very, very similar before I\'d
extend that across drug classes, let alone within a class. And we\'ve
already seen in many examples where drugs in the same class don\'t have
the same biological effect. So, I think it\'s a potentially dangerous
precedent to say that two drugs that happen work through kind of similar
mechanisms would have the same effect from two different classes, and I
think we ought to be very careful here. So, my vote is no.

DR. BORER: Alan?

DR. HIRSCH: You are a strict constructionist. The words are relevant and
germane. So, I think they\'re not identical, but they\'re certainly
kissing cousins and relevant. I would say yes.

DR. BORER: I\'m going to vote yes too. I\'ve been convinced by the
discussion that the nephropathy in type 1 and type 2 diabetes is
sufficiently similar so that one should be able to draw inferences from
one and apply them to the other.

And with regard to the pharmacological effects, I agree with everything
Mike and Blase say. Steve, there are a number of differences here
between ACE inhibitors and angiotensin receptor blockers. And I\'m on
record as saying I don\'t know how drugs cause their clinical benefits.

Nonetheless, I think the fact is that both of these types of agents and
both of these agents act on the same general system, and I think that,
as Alan says, they\'re germane and relevant, though not identical. And I
vote yes.

Number 11. If the results with captopril are relevant to irbesartan, are
the results on protein excretion similar with respect to direction and
magnitude? 11.2, are the results on doubling of creatinine similar with
respect to direction and magnitude? Are the results on death or ESRD
similar with respect to direction and magnitude? And if you say no to
any of those or if you say yes, probably we ought to have an explanation
of why.

JoAnn?

DR. LINDENFELD: I guess the key word here is similar, and I would say
yes, they\'re similar. The effects are greater in the captopril trial,
at least they were certainly greater on the doubling of creatinine. I
think it was a 48 percent reduction as opposed to 33 percent, and
greater in proteinuria and end-stage renal disease, somewhat greater.
But the direction is very similar in all of these.

DR. BORER: Mike?

DR. ARTMAN: Yes. I think the directions are similar, but the magnitudes
seem to be much greater with captopril than with irbesartan.

DR. BORER: Do you draw any inferences from that observation that you\'d
like to share with us?

DR. ARTMAN: No.

DR. BORER: Tom?

DR. FLEMING: Well, we\'re comparing results from different studies.
That\'s always hazardous. Yet, I\'m not persuaded that they\'re similar
enough that I would say similar. If I chose, as best I could, a
comparable endpoint, which would be dialysis, transplantation, and
death, we\'re looking at an 11 or 12 or 13 percent reduction against a
50 percent reduction. That\'s getting to be an important difference. And
the mortality, small numbers, in the captopril setting, but there was a
40-odd percent reduction in mortality and there was more than a 50
percent or about a 50 percent reduction in dialysis, whereas here
there\'s no effect discernible in mortality; dialysis reduction is 20
percent. The setting is different to an extent, but then again, to the
extent that the setting is different, it makes me less comfortable to
extrapolate results from the other trial.

So, I\'m not as knowledgeable as my colleagues about whether the
biological phenomenon and pathways and mechanisms of action are truly
sufficiently parallel that we can really rely on a different trial and a
different agent, but at least looking statistically at the evidence, I
see a substantive difference in the magnitude of effects that are being
estimated.

DR. BORER: Blase?

DR. CARABELLO: Yes, well, certainly the ACE inhibitors appear more
effective, but there\'s been no head-to-head comparison. It\'s sort of
like saying, well, one team beat another team by 50 points and the other
one beat the other team by 20 points, and therefore the difference ought
to be 70 points. And that\'s just not the way it works. So, I don\'t
think I can draw very much from those differences.

DR. BORER: Does that mean that you think that they\'re relevant or not
relevant?

DR. CARABELLO: I think that they are relevant, but I can\'t draw any
differences between them.

DR. NISSEN: Again, I think it\'s a slippery slope here. You\'re talking
about a disease. One is a disease of insulin deficiency. Another is a
disease of insulin resistance. And how that plays out in the vascular
system leading to the kinds of events that lead to mortality and
morbidity in these patients is probably somewhat different. I think
again we\'ve got to be very careful about setting that kind of
precedent. I would not want to go on record as saying, well, something
that works in type 1 diabetics should be inferred to work in type 2
diabetics because I do think the pathophysiology of the disease, not
necessarily the kidney, but the disease overall is very different. I
think, again, we ought to be very careful about the kind of precedents
we set in these discussions because I think it sends potentially the
wrong message.

DR. BORER: Alan?

DR. HIRSCH: Well, let me reemphasize sort of what Steve just said.
Whereas I\'ve been stating that I certainly believe they\'re relevant,
we around this table can\'t ignore the similarities in directional
trends. Now I\'ll go the other direction and say although we\'ve as a
group said that the magnitude of benefit in the captopril trial might at
that time of history been due to the care given at that time or because
less cardioprotective drugs were used or glycemic control was less
intense than nowadays, all those things may be true, but I hesitate to
make too much of a comparison because it\'s also possible that the
diseases are not identical, that we really do have different molecular
entities, we have different potential pharmacodynamic effects.
Bradykinin does exist. There are known differences between what ACE
inhibitors do and A2 antagonists do in tissue and to mRNA expressions.

And finally, there\'s the dose question. It\'s really hard to know at
the end of the day how this dose of captopril in this population
compares to this dose of irbesartan in this population. It\'s very hard
to bring these together other than to say, yes, they\'re similar.

Yes, that\'s a no.

DR. BORER: I\'m going to vote yes. I think they are relevant. I think
the results are directionally generally similar, and the magnitudes
obviously are not. But these are different trials in different patients
at different times with different protocols, et cetera, and it\'s very
hard for me to get too excited about that. I think that these results
have an influence on the way I think about the results of the irbesartan
trials, and I\'m not going to quantify that.

With regard to the fact that they\'re different diseases, the patients
had different diseases, type 1 and type 2 diabetes, they did. But, of
course, we\'ve been shown data suggesting that the nephropathy in type 1
and type 2 diabetes seems to be pretty similar, and we also have in our
books data from the enalapril study in patients with type 2 diabetic
nephropathy, though not hypertensive, so I\'m going to be drawing a
parallel from a different group. But patients with type 2 diabetic
nephropathy improved in at least one measure of their renal performance
when they were on enalapril which is also an ACE inhibitor.

So, when I put all those facts together, those observations together, I
have to say that I am influenced by the captopril data. The question is
how much and how much do I have to be, but my answer is yes to 11.

Number 12. Did I miss somebody? I\'m so sorry. Go ahead.

DR. BREM: I guess this half of the table doesn\'t count. Once the
cardiologists have spoken, I guess that\'s the word.

(Laughter.)

DR. BREM: Obviously, I\'ll restate what you said. We\'re not comparing
the true efficacy of the two agents with one another. We\'re just asked
a straight question, are they in the same direction and are they
consistent with one another? I think the answer is yes, they are
consistent with one another. And I would say, for that reason, they\'re
germane and relevant.

DR. KOPP: Yes. Without belaboring it, I would say yes. I think they\'re
relevant and we\'ll come in a minute to decide are they a quarter of a
study, a half of a study, one study.

DR. LORELL: I also believe they\'re relevant, and I\'d like to comment
on the two reasons why I think they are.

I think the data presented today and, in fact, the slides that we were
shown this morning which described the effect of placebo in the
captopril trial and doubling of serum creatinine and the similar slide
that was presented for placebo in the irbesartan data are extremely
striking in that the event rate is almost identical at 48 months. So, it
suggests that although, as you pointed out, one is type 1, the other is
type 2 diabetics, that what the kidney is doing and seeing may be
remarkably similar.

I think the data are also relevant for the point that Steve Nissen
brought up earlier and that is although this may be somewhat disturbing
and not ideal, I think the reality in the United States in clinical
practice across the country is that patients who already have type 2
diabetic nephropathy are in large part being treated with off-label use
with an ACE inhibitor.

So, with those two arguments for relevance, I think it is worrisome that
the magnitude of benefit seemed to be so much stronger and more robust
in the captopril study, albeit it was type 1 diabetics and
non-hypertensives. That influences me perhaps, rightly or wrongly, in
wishing to see a more robust data set for irbesartan or any other AT I
receptor blocker since I think the impact of approval would be to
profoundly change a current, very widespread practice of use of ACE
inhibitors.

DR. BORER: Was that a yes or a no vote?

DR. LORELL: It\'s a yes for relevance. It\'s a no that I don\'t think
the results are similar in magnitude.

DR. BORER: Dr. Cunningham.

DR. CUNNINGHAM: I would agree. I think they are the same in direction,
but the magnitude is very troubling.

Actually since it\'s my first time on the committee, I\'m going to go
back and say I do not really think that they\'re pharmacology the same,
that the angiotensin receptor inhibitors are the same as the blockers. I
think we don\'t know that. That actually was two questions. So, I might
say yes to one and no to the other for 10.

DR. BORER: Number 12. Now, the key question here. Are the results of
IDNT, IRMA 2, and prior expectations derived from the captopril database
an adequate basis for approval of irbesartan for the treatment of either
hypertensive or not hypertensive patients with type 2 diabetic
nephropathy?

JoAnn?

DR. LINDENFELD: I believe they are. I would vote yes for this. It\'s
close, though. But I\'ll tell you what. The IDNT trial is not perfect
and it\'s not terribly robust, but the IRMA trial supports it. I\'m
helped a little bit by the amlodipine data which at least lowered blood
pressure, so we know this wasn\'t only a blood pressure effect in the
IDNT trial.

And I believe that, while I agree with everything that\'s been said,
that the two drugs, captopril and irbesartan, do not have entirely the
same mechanism of action, in fact, could be very different, one of the
pertinent mechanisms of action here is through angiotensin, and so they
do share an important mechanism of action.

So, I am concerned by what Bev said that by approving this drug, we
could change the standard of care, and there\'s a big concern here about
the magnitude of benefit. But I\'m not sure that can be our concern. If
the drug meets the standard of approving, I don\'t think I can let that
change my vote of yes for this.

DR. LIPICKY: Can you clarify a little bit? So, what you\'re saying is
that your priors from captopril are enough to say that when you said
no-no to the previous questions, that now you mean yes-yes. Did I say
that right?

DR. LINDENFELD: No, you didn\'t. I said I still would say no-no for the
first two questions, but what you\'ve asked here is whether or not the
data from captopril, because of at least some shared mechanisms, would
be enough to tip me over and say the totality of the data suggests that
this should be approved. Then I would say yes.

DR. LIPICKY: But that\'s because you\'re convinced from the captopril
trial that, in fact, there is class effect on the disease because this
is a different class ‑‑

DR. LINDENFELD: Right.

DR. LIPICKY: ‑‑ so it\'s not even the same class. And it\'s a different
disease.

So, I\'m just trying to make sure I understand what you\'re saying. So,
what you\'re saying is that although it\'s a different class, you\'re
willing to buy an ACE inhibitor class effect on the captopril trial.
There the delta in clinical events was 18 people I believe. Here it\'s
0, but in captopril it was 18. So, on that basis, you\'re willing to buy
this also. Is that really what you\'re saying?

DR. BORER: Ray, always does this.

(Laughter.)

DR. LINDENFELD: I think what I\'m saying is I was very, very close. I
think there\'s a lot of really good data here in two good studies, and
we\'ve seen a pathophysiologic sequence for which there\'s a lot of data
which I believe, and the fact that we have an awful lot of data with ACE
inhibitors that share a common mechanism tips me over to say that
that\'s just enough more to say that this data now becomes in my view
enough to say yes.

DR. FLEMING: Could I just ask for further clarification of this,
following up on Ray? Can you give us some insights, just in a
precedent-setting manner, of how we have done this in the past? I find
this intriguing. We\'re looking at two pivotal studies and coming to a
conclusion, and then we\'re searching for other relevant data which is
certainly relevant to do so, moving outside of the class, though.
Essentially is this then saying any agent within these two classes? How
much are we extrapolating? Any agent within these two classes then
largely would rely on the studies that had been done here, together with
some surrogate endpoint data to then be an approval? I\'d just like to
have a sense of how this is playing out.

DR. TEMPLE: Well, we don\'t keep good track. First, let\'s stay within a
class. The division pulled together the basis for approval of the
various ACE inhibitors in congestive heart failure, and quite
consistently we\'ve approved those claims with p values between .05 and
.01. Pretty consistently, usually one study. Now, that\'s because those
are all the same pharmacology. So, that\'s one precedent.

Another might be said to be the recent approvable for Valheft, for
valsartan. The committee divided closely on it. We reached a somewhat
different conclusion. I don\'t even want to blame anybody else for it. I
reached the somewhat different conclusion based on a subset analysis,
but clearly influenced, I would say, by the similar pharmacology and a
particularly persuasive subset. So, I don\'t want to over-attribute it.

But I think the answer is you are allowed to let these things ‑‑ think
of them as priors or think of them as mechanistic explanations ‑‑
influence you. The reason we bring hard questions like this to advisory
committees is that it\'s very hard to pin down exactly what you\'re
doing when you do it. They surely come into the category of what
confirmatory evidence might be under the words that the law uses,
although we\'ve certainly never pinned down what that means exactly.
What I heard JoAnn say was she was sort of here and she got pushed over
by the amlodipine comparison and these data, and I think that\'s how
people actually think. They put it all together. Obviously people can
disagree on what the right conclusion is.

DR. LIPICKY: If I might contribute to that a little bit because this is
really a very difficult issue. For a precedent, we have approved for
congestive heart failure captopril on the basis of a single trial for
exercise tolerance, a p of .0048 or something like that. So, precedent
‑‑ that is, what have you approved things for in the past ‑‑ may or may
not be useful. I don\'t think we would do that ever again at this point
for that disease because, indeed, there have been things learned.

But indeed, nephrologists, as you have heard today in very elegant
presentations, would pull all of this stuff together, including
captopril, and have it influence their thinking process. Well, are we to
say nephrologists are crazy and they don\'t think right? I\'d be happy
to say that ‑‑

DR. BORER: Remember that you were called a nephrologist earlier.

(Laughter.)

DR. LIPICKY: So, this is all a matter of judgment and I think it is not
necessary to ask the question what are the precedents because I think
the precedents only say what have you done and you may have done wrong
things. So, there\'s the logic of it.

DR. FLEMING: One does struggle, though, to see if there is a logical
consistency. Severe sepsis, a major FDA recent issue in December where
this issue went in the other direction. A study that looked pretty good,
but everything else had been negative, and FDA went ahead and approved,
more or less, saying it\'s this study even if everything else had been
negative.

Now we\'re hearing ‑‑ well, we don\'t know what we\'re hearing yet, but
I guess what we\'re being asked to discuss is if there is a study
that\'s out there that\'s positive that shows a considerably different
effect, actually more positive, which actually could pull us in the
right direction, but it looks very different and it\'s a different
class, that we should be persuaded by that. One would like to be
scientifically consistent when one thinks through the strength of
evidence you would have to see to approve an agent.

DR. TEMPLE: Sometimes a very strong result in a single study, even in
the face of past failures, is convincing. And in the sepsis case you
describe, I think that was the basis for it there and the others were
not persuasively negative. They were persuasively ‑‑

DR. FLEMING: The committee was 10 to 10 in the vote on that one study.

DR. TEMPLE: Well, I mean, obviously they\'re going to be close. The p
was .005. That\'s either strong or weak, depending on your attitude.

DR. LINDENFELD: One other thing here is we haven\'t seen any data, I
don\'t think, that suggests to us that this doesn\'t work. It may not be
strong in any single study or any single area, but we haven\'t seen
anything that suggests that it\'s unlikely to work. And that influences
me a bit.

DR. BORER: Steve, a final comment and we\'ll go on.

DR. NISSEN: Yes. I guess, JoAnn, the problem with that is that if we
make a decision to approve, it has consequences, and I think I know what
those consequences are and I think we better face that. And that is,
that some of the patients currently treated on ACE inhibitors are going
to be switched over to irbesartan. Do we think that\'s a good thing or a
bad thing? Do we think there\'s enough evidence here to tell physicians
that we\'re now going to approve this agent, the first agent to be
approved for this purpose, and the standard of care, whether it\'s right
or wrong ‑‑ I know it\'s off-label. But this drug is going to get
detailed and people are going to be told, listen, don\'t give your
patient lisinopril. Give your patient irbesartan because we have FDA
approval for this indication. Do we really want to do that? And if we
do, let\'s vote for it, but I don\'t think I want to do that.

DR. LINDENFELD: That\'s a really important issue, but that issue
wouldn\'t change if we had larger numbers with the same reduction in
creatinine doubling and the p value were stronger.

DR. NISSEN: Right.

DR. LINDENFELD: That wouldn\'t change that. The fact that you think that
an ACE inhibitor is better than this drug ‑‑ if we just had even
stronger data for this drug but it still appeared that it was less
effective than captopril, you\'d still be in the same bind.

DR. NISSEN: No, but in the presence of weak evidence, then do we really
want to change the standard of practice, which is one of the things ‑‑
that\'s one of the effects of what we do, fortunately or unfortunately.

DR. BORER: In fact, the FDA doesn\'t define standard of practice.
Guidelines committees do. And my guess is that the impact will not be
quite so great as that on patients who are being treated one way or
another way because there are biases in the minds of every nephrologist
I would guess. I think all we\'re being asked to say here is do we
believe this stuff works or do we not, as JoAnn says.

Having said that unless, Dr. Temple, you had another comment ‑‑

DR. TEMPLE: Well, if there were mountains of evidence that all the other
ACE inhibitors did what you want, you could wonder about that. But in
fact, what you\'ve got is captopril and everybody uses something else,
I\'ll bet, because they want a once-a-day drug.

DR. BORER: Dr. Brem? We\'ve had one vote yes for approval based on these
three separate sources.

DR. BREM: Well, I\'ve heard these three separate sources, but I\'ve also
heard references to outside sources, including the enalapril study. So,
if one is going to be consistent and use outside sources like the
enalapril study, then I suppose we can say we can use the outside source
that was the losartan study which is the same class of agent as this,
showing virtually the same findings as what was presented all through
today. So, I would say if you\'re going to be fair, you\'re fair for
everybody on both sides. And it would be supportive evidence, albeit it
we haven\'t gone through the same detail as what was discussed today,
but it\'s certainly consistent both in magnitude and direction. And it
is further supportive data for approval in my opinion.

DR. BORER: So, is that a yes?

DR. BREM: Yes. It would be a vote for approval.

DR. KOPP: Well, not surprisingly, I say yes again, and I\'ll stop there.

DR. LORELL: I\'m going to address question 12 very narrowly, exactly as
stated, and I view that the prior expectations from the captopril
database in fact are not an adequate basis for approval. And I\'ll
restate briefly what I said a few minutes earlier, that I think using
the terminology that Dr. Pfeffer raised earlier that observations are
hypothesis-generating, I think the remarkable difference in the
magnitude of effect, as well as the time of appearance of effect, in the
captopril studies, the benefit, the curves diverge much earlier. I think
it\'s hypothesis-generating that in fact the two drugs may not be
identical and may have quite different magnitude of effects. We don\'t
know that because that study has not been done. So, strictly answering
question number 12, the prior expectations derived from the captopril
data for me do not push over toward an adequate basis for approval.

DR. CUNNINGHAM: My answer would be no too. I think from the consumer
perspective, I really worry that if the standard of practice currently
is using angiotensin inhibitors, approval of this could actually move
people to use a drug which might be less effective for which we don\'t
have enough data. Unfortunately again, the issue is we don\'t have the
data we need really to help the people who have this. I think having
renal failure is a dreadful problem and dialysis is obviously a terrible
thing to have to endure. Just we don\'t have the information we need.
But no.

DR. ARTMAN: I\'m kind of surprised at this whole discussion, and I
wouldn\'t say no. I\'d say, hell, no.

(Laughter.)

DR. ARTMAN: I think that we\'re talking now about a different study
population with the captopril, we\'re talking about a different class of
drug. It\'s hard for me to weigh that in, in any sense, to strengthen my
decision about irbesartan.

So, if we follow this to its logical conclusion, I guess we could begin
to argue that maybe we should be recommending approval of captopril for
type 2 diabetic nephropathy. I don\'t know. It just seems over the top
to me, so I would say no.

DR. BORER: Tom?

DR. FLEMING: No. And I share your sense exactly. I do believe that it\'s
relevant, when you\'re making a judgment about the effect of an
intervention, to be aware of and take into account what is available on
efficacy of interventions that are studied in related settings. Though,
to be giving that substantial weight here, I would have wanted to have
had a much more careful discussion about the captopril data, what the
studies were, what any other studies were that would be relevant to this
decision.

Appropriately we gave a great amount of attention to these two studies,
and I believe with that tremendous information we\'ve been provided and
in an intensive day of discussion, we have absorbed an awful lot of
understanding. And even at that, there are a lot of complexities that
are still difficult to fully understand.

To now be reaching out and asking this committee ‑‑ boy, in 15 years of
being on innumerable advisory committees I can never remember being
asked to essentially say if it\'s no, but now look at external data from
other agents studied in other trials with all the complexities of
understanding differences that you see across studies, across specific
disease areas and classes of agents, that you would actually, without
having any direct presentation and discussion of those other data, be
asked to revise or reassess your assessment. It\'s very troubling to me.
But I do appreciate the need for FDA to think about this, but it\'s
troubling to me the process, that we\'re being asked to think about it
after having focused almost exclusively on these two trials.

Based on that, I\'d say no.

DR. BORER: Blase?

DR. CARABELLO: We are going to get to question 13, I assume.

DR. BORER: Yes, we will.

DR. CARABELLO: Okay. Having said that, then I will vote no on 12. I
don\'t think that ACE inhibitors ‑‑ although I think their results are
germane, I think there are still enough differences between the two
classes that they don\'t persuade me enough on top of my previous
arguments about why I thought the data wasn\'t strong enough and
compelling. So, I\'ll vote no.

DR. BORER: Steve?

DR. NISSEN: I also will say no. I want to bring up one more time the
fact that it\'s not like all the endpoints are all going in the same
direction here. I\'ve got to remind this committee that many patients
that come into this process of nephropathy have cardiovascular disease
and they tend to die of cardiovascular disease. When I see point
estimates for cardiovascular death, myocardial infarction, and stroke,
in comparison to amlodipine, go substantially in the wrong direction,
I\'m troubled. So, that takes away.

We talked about this external study kind of adding to our confidence.
Well, there are things that take away from my confidence, and that
substantially undermines my confidence in the benefit of irbesartan
here.

So, I want more data before I\'m willing to stick my neck that far out
and say that this is good for people when I know the cardiovascular
endpoints are such a prominent problem in this patient population.

DR. BORER: Alan?

DR. HIRSCH: I\'ll start off with my no, but I\'ll try to add something
new as we as a panel face these decisions in the future.

I think we\'re all feeling uncomfortable because there are three things
we\'re weighing. We\'re weighing this intrinsic data set for this
particular ARB. You\'ve heard our opinions about that. We\'re obviously
weighing this need to consider precedent-setting if we want or don\'t
want to do that. And then the third thing is how we think it will affect
the market.

So, I\'ll just add, though I care a lot about how standards are set for
clinical practice, I very well trust the renal community to make its
guidelines. I think guideline committees are where the market and the
practice standards will be set. That\'s not our role, though I care a
lot.

Vis-a-vis precedent, I actually do care very much. I think Tom was
getting to this, that we think as a group how we look at data and how we
set precedent. Ray, we can ignore some bad past ones and maybe make
better current ones.

So, with those two things in mind, looking at the first thing we usually
do, which is this data set, I\'ll stay with no.

DR. BORER: I\'m going to vote yes. I want to point out to everybody that
there\'s nothing in the label of this drug as it now exists, because
it\'s an approved drug, that would preclude anyone from using it in a
patient with hypertension who happens to have diabetic nephropathy.
It\'s a drug for people with high blood pressure.

The issue of whether it actually is beneficial for the kidney disease,
over and above that, is what we\'re talking about here. I\'m convinced
that it probably is, and I\'m sufficiently convinced both by the two
trials that we saw, taken in tandem, plus what inferences I\'m going to
draw from drugs of a different class, it\'s true. So that I think that
in total these data are sufficient to allow me to believe that it\'s
reasonable to treat patients for prevention of progression of their
diabetic nephropathy, as well as for their hypertension. So, I\'m going
to vote yes.

I think that if, at the end of the day, because we have a couple more
votes here, we still have a net no, as we do right at this moment,
perhaps it would be useful to cite what other kinds of information we
might want to see so the FDA could think about that. Maybe some of those
data can be drawn from the existing database.

Having said that, let\'s go on to number 13. It doesn\'t require a
stated vote for everyone. Are there results from other development
programs that impact on approval of irbesartan for the treatment of type
2 diabetic nephropathy?

JoAnn?

DR. LINDENFELD: Well, the RENAAL study certainly, although we\'ve said
that it\'s difficult for us to talk about that too much because we have
not actually seen the data and what\'s published sometimes, it\'s been
brought up, is not always the data, once we see an FDA analysis.

But again, there are other enalapril trials, other ACE inhibitor trials.
While, again, these are different mechanisms, I think that there\'s a
weight of data from a number of other things that there are shared
mechanisms of benefit here in other trials. So, this would push me a
little bit more, but I\'m probably not the one to say too much here
because I said yes already.

DR. BORER: Does anyone else want to add to that? Blase?

DR. CARABELLO: Yes. I think the RENAAL trial is compelling. I remember
reading it in the New England Journal and saying, gee, isn\'t this
interesting. A sartan works in type 2 diabetes, and thinking, gee, if I
saw a second study that said that sartans worked, that I would probably
be convinced. I realize the depth of plumbing of the data is different,
but I do think it has an impact here and it has an impact on me.

DR. BORER: Steve?

DR. NISSEN: I really have to take exception to that. Again, I\'m worried
about precedent, and I\'m worried about the slippery slope. We don\'t
have the RENAAL data in front of us. One of the things I\'ve learned in
the last year or so on this committee is the data isn\'t always what it
seems to be, and until you get a real look up close and personal at the
data, you ought to be very careful. I don\'t know if that trial will
ever be presented to this committee, but when it is, we ought to look at
it with the same scrutiny and the same microscope we looked at the IDNT
and the IRMA 2 data. In the absence of that kind of scrutiny, we ought
to be very, very careful about the precedent of making decisions
regarding data that is not on the table.

DR. FLEMING: One more comment? One more question?

DR. BORER: Tom?

DR. FLEMING: A question for Bob and Ray. You have said you\'ve seen this
data. We haven\'t had the data presented to us. Do you really want to go
around the table and get our vote? You\'re certainly at liberty, since
you\'ve seen the data, to factor it in however you choose. Do you really
want to go around the table and get our views on data that you didn\'t
share with us?

DR. LIPICKY: Well, we have not seen the data. It exists but you haven\'t
seen a review.

DR. TEMPLE: No.

DR. LIPICKY: You haven\'t seen a table. You haven\'t seen a figure. I
haven\'t see a table. I haven\'t seen a figure. I haven\'t seen any
pros. I haven\'t talked to anybody who has actually opened the volume.
So, we don\'t know any more about RENAAL than is in the New England
Journal.

DR. TEMPLE: Right. You could tell us what you would think, for example,
if after review, that was thought to be a solid study. We can\'t tell
you that we know that. But you could say that. Obviously that might not
affect your conclusion because you wouldn\'t know.

But it raises the whole question of what, which is absolutely not
settled, except I did tell you that we have behaved as if ACE inhibitors
share common properties when we deal with congestive heart failure. And
I would go further and say the beta-blocker approvals probably all
reflect the fact that other drugs of the same class have had that
effect.

So, you can tell us how you\'re thinking of it. I don\'t know that fits
into a vote exactly.

DR. FLEMING: Well, in fact, you have asked us this structured set of
questions. We have gone through question 12, which basically is based on
the two trials and prior expectations from the captopril study, what was
our judgment. Now in question 13, you\'re saying is there other relevant
information. I don\'t have a problem with your asking the committee. I
understand why you might want to ask the committee are there other
sources of data that we would advise you should look at when you think
about your final judgment.

But I don\'t understand why you\'re going to press to question 14 and
then say, now I want you folks to vote on that. That\'s an entirely
different perspective. Why are you asking us to do any more now than
suggest additional sources of information that you should think about?

DR. TEMPLE: First of all, some people have, without thinking about those
other studies, reached the conclusion that the answer is one way or
another. So, you don\'t necessarily have to incorporate that. But you
might want to tell us I\'m at the edge. I\'d be convinced if you looked
at that study and found it satisfactory. You can tell us whatever you
want. It isn\'t only the vote. We listen to the text also. It would be
of considerable interest to me to know if you thought that a favorable
finding in a closely related drug should be taken as the priors or the
other evidence or whatever. And we can worry about getting access to
other data, and then we can also worry about whether we\'re violating a
company\'s proprietary interest and a wide variety of other interesting
questions that we\'re not ready to talk about here.

DR. LIPICKY: There are people within the agency who tell us not to ask
questions where the answer is obvious, and to me the obvious answer to
this question would be, of course, not. You\'re insulting my
intelligence by asking me. Sometimes it\'s useful to ask questions like
that so that we can get your reaction. But here we\'re being told now,
because we asked questions we probably shouldn\'t have asked, that you
know, well, the captopril study tips me over. Well, then it\'s fair to
say, what else would tip you over?

DR. BORER: As the hour is moving on here, question 14 ‑‑ 15 is going to
require some discussion I think. But 14 says, should irbesartan be
approved for treatment of nephropathy in type 2 diabetes? Prior to 13,
there were 4 yes votes already. So, just to deal with the time issue, I
think I understood Blase to say that at 14 he would change his previous
vote, but for the record, what\'s your vote now, Blase?

DR. CARABELLO: That is correct. Yes.

DR. BORER: So, now we have 5.

There are six other committee members who have not been convinced by
these data, and so I\'m going to ask to go through each of those six.
Should irbesartan be approved for the treatment of nephropathy in
hypertensive or non-hypertensive patients with type 2 diabetes? Beverly?

DR. LORELL: For the issue of diabetic nephropathy in hypertensive
patients, my answer would still be no.

DR. CUNNINGHAM: No.

DR. BORER: Mike?

DR. ARTMAN: No.

DR. BORER: Tom?

DR. FLEMING: I encourage the FDA to look at all information that they
would have access to that they judge to be relevant.

I can\'t go beyond question 12 without specific data put before us with
a judgment and with a good insight that we have a level of understanding
of that data comparable to our level of understanding of the two trials
here. My answer is no.

DR. BORER: Steve?

DR. NISSEN: My answer is also no. And I really do need to say something
here, and that is the reason that I don\'t want us to consider the
RENAAL data is there were things that came out in the discussion of the
IDNT data that I didn\'t know from reading the publication. For example,
the cardiovascular endpoints are not in the New England Journal of
Medicine publication. Those individual endpoints were very persuasive to
me. I don\'t know as a fact that there aren\'t things in the RENAAL data
that we haven\'t seen yet that would be very negative in my view. So, my
answer is still no. I can\'t consider a study that isn\'t before us.

DR. BORER: Alan?

DR. HIRSCH: Well, no surprise based on my prior comments. No. But I
would, since the text is read, strongly encourage the FDA to gain
whatever access to data sets that exist that would permit us to look at
this issue again, if that\'s possible.

DR. TEMPLE: I just want to be sure I understand the last couple of
comments, and perhaps other people have the same sense. We have no idea
whether we can get the two companies on the same stage or sort of steal
one\'s data to use in the other. Let\'s leave all that aside.

What I guess I hear you saying is that some of you are not so convinced
by information about captopril in a different population, but you might
find independent studies of the same drug class in a very similar
population more persuasive.

DR. HIRSCH: Yes, and I\'ll just try to summarize my feelings and maybe
speak for others here. This is a very major national clinical problem.
We\'re all seeing a signal of efficacy. We are all very close to the
edge, but we\'re not quite there. So, whatever we can get that brings us
closer to a decision would be great.

DR. BORER: Before we go on to number 15, which is the last question, can
I ask if anyone has any comments about data that could be perhaps
presented to the FDA and if they were presented to you would be useful
over and above issues about other drugs and what have you. What, for
example, would you think if the company was able now retrospectively to
go back and determine cardiovascular events in the patients after
cardiovascular events were no longer being counted? And what if the
differences sort of evaporated? Would that be compelling to anyone?
Would you like to see that?

DR. LORELL: Yes.

DR. BORER: Okay. So, that\'s one type of information that might be
useful if the FDA is not convinced by the data that exists.

There may be others. For example, although Tom suggested that he accepts
the creatinine of 6.0, as I do, perhaps if we asked the company to come
back with the actual numbers of people who went on to dialysis or
transplant and the time at which they did that to confirm the importance
of the creatinine level, would that be useful to anyone?

DR. LORELL: Yes.

DR. BORER: Okay, so that would be too. So, there may be some additional
data that exists that might be helpful to the FDA in its final
deliberations.

Having said that, do the results of the irbesartan development program
in type 2 diabetic nephropathy support the use of proteinuria as a
surrogate for clinical benefit? And we need everybody to say something
about that. JoAnn?

DR. LINDENFELD: I don\'t think the data quite support the use of
proteinuria at this point for a couple of reasons. One, I think that we
don\'t have any idea of how much reduction in proteinuria is clinically
important. I mean, if you saw a 10 percent reduction, would that really
lead to some sort of realistic clinical change? I don\'t know the answer
to that. So, I\'m not ready to say that yet.

DR. BORER: Let\'s start on this side of the table with the nephrology
contingent. Dr. Brem, what do you think of that? Do the results of the
irbesartan development program in type 2 diabetic nephropathy support
the use of proteinuria as a surrogate for clinical benefit?

DR. BREM: I was just talking to Dr. Temple about the very same issue.
For a nephrologist, I believe that it does. And I read the FDA
commentary, and I suppose by itself, in the absence of changes in GFR to
correlate, it wouldn\'t. But I believe that it does. So, as a
nephrologist I think it does, and if they looked at it correctly, it
would correlate with a change in GFR. One thing that would be very
helpful and supportive is if the company had similar data or would be
able to retrieve that information to demonstrate the connection between
development of proteinuria and change in GFR; that would be a very
strong selling point.

DR. BORER: I\'m sorry, Tom. Go ahead.

DR. FLEMING: I just wanted to clarify to make sure that at least I\'m
understanding the question. There are at least two different questions
you could ask. One is, is proteinuria a correlate for subsequent
clinical endpoints? Or there is the much more complicated question, is a
treatment-induced effect on proteinuria an adequately reliable predictor
of a treatment-induced effect on long-term clinical endpoints, that
simply the demonstration of the effect on proteinuria is adequate
evidence of an effect on the clinical endpoint? Which is what I would
typically think of as the surrogate. Are you asking the first question
or the second or both?

DR. LIPICKY: We\'re asking the second question only. Is it a surrogate?
That is, proteinuria would be good enough. You see that proteinuria goes
away and you say that people aren\'t going to get transplanted or have
dialysis.

DR. TEMPLE: We believe a lot of nephrologists, as you\'ve just heard,
believe that proteinuria is an indicator of the fundamental structure of
the kidney going down the tubes, and we have a lot of people who are
asking us to use that as an endpoint because it\'s a very accessible
endpoint and it occurs early and you don\'t do harm to people. So,
that\'s a very important question.

DR. FLEMING: And that\'s the first issue. And there\'s a myriad of
natural history data, and Dr. Lewis and others have clearly discussed
the relationship that is establishing this as an important biological
step along the cascade of events, such that in natural history, it\'s a
correlate.

But we have a myriad of correlates across all disease areas, the vast
majority of which are not established to be surrogates, and those that
are typically are done so after extensive clinical experience where one
is looking at the relationships of treatment-induced effects on the
marker and the predictiveness of those effects on the clinical endpoint.

We didn\'t even get from this study evidence of whether there was a
relationship with effects on proteinuria to effects on filtration rate,
much less the ultimate clinical endpoint. So, how does this study begin
to provide us evidence as to whether we don\'t just have a correlate but
we truly have a replacement endpoint surrogate?

DR. TEMPLE: Well, don\'t yell. Just say no.

(Laughter.)

DR. BORER: We have his vote now.

Dr. Kopp.

DR. KOPP: You specifically asked about diabetes, but I\'ll make the
first point that if you were looking at other diseases, a complete
remission I think would be acceptable, that is, somebody with a disease
like minimal change that you had an agent that could put people into
complete remission, I think most nephrologists would be convinced that a
sustained remission, as defined by no proteinuria, would be evidence of
benefit.

How about in diabetes? I guess if you had an agent that put somebody
into complete remission, no proteinuria, who previously had proteinuria
and that was sustained, I would find that pretty convincing.

The problem comes from what you mentioned, JoAnn, which is how about a
50 percent decrement, which is the typical effect of ACE inhibitors.
Then how about a 30 percent? Then how about a 25 percent? And as we said
earlier, we don\'t have a graded spectrum of risk table that allows us
to evaluate that. So, I think that\'s where you\'re coming from.

And I have to say by itself, I don\'t find it adequate. Now, I did find
it adequate in the second study, IRMA 2, because I had another study
that had a GFR measure, and in that setting, it\'s supportive. But by
itself as the only measure, short of a complete remission, I have
trouble accepting it.

DR. LORELL: I agree with that. I think the evidence is very compelling
that proteinuria is both a measure and may even play a role in the
progression of diabetic nephropathy. I don\'t think that that is
sufficient to use it as an endpoint for approval or disapproval of a
drug.

I think a very poignant example in the recent cardiovascular and even
perhaps cardiovascular-renal world is the use of estrogen replacement
therapy where it was argued for a long time that the improvement in
lipid profiles that were seen demographically and in trials could be
used as a surrogate marker to indicate expected improvement in major
cardiovascular events. And actual trials that asked that question have
given a striking answer in the other direction.

DR. BORER: Dr. Cunningham.

DR. CUNNINGHAM: I think I don\'t actually know, so I cannot say yes, but
I don\'t know if I can no either. So, you\'ll have to deal with that.

DR. BORER: It\'s an abstain.

Mike?

DR. ARTMAN: I would say no and leave it at that.

DR. BORER: Tom, I think you already said no.

Blase?

DR. CARABELLO: I think I also would like to be fair and simply say I
don\'t know.

DR. NISSEN: No question that proteinuria is a bad thing, but the
question being asked is do we know that a drug that reduces proteinuria
is going to have a consistent, reproducible effect on hard endpoints. I
would want to see several trials, maybe even with different classes of
drugs, showing that we know what the relationship is between the
reduction in proteinuria and the reduction in end-stage renal disease,
dialysis, transplant, death, and a lot of other hard endpoints. And we
haven\'t come even to the first step. Validating a new surrogate is like
hitting an inside-the-park home run, and we haven\'t even gotten to
first base yet. So, I think we\'ve got a long way to go here.

DR. BORER: Particularly in Cleveland where the stadium is now smaller
than it used to be.

DR. NISSEN: But the team is good.

(Laughter.)

DR. BORER: Alan?

DR. HIRSCH: I probably don\'t know either. Not to disrespect my renal
colleagues, I also would like my protein in my urine to go away with
treatment anecdotally, but when it comes to data and approval, my
problem with surrogates is that we\'ve been burned too often as
clinicians, whether it\'s left ventricular hypertrophy as a surrogate
marker ‑‑ I can go on and on ‑‑ VPBs with dysrhythmic drugs. So, if I
was going to use proteinuria as a marker, I need some specific clinical
outcomes and some kind of a dose response where I know, like with blood
pressure, these many millimeters down affects these many cardiovascular
risks, this LDL change affects this clinical outcome. I need some better
handle on the dose response, I think as you said Dr. Kopp.

DR. BORER: I\'m going to vote no also. With Dr. Kopp, I thought that the
proteinuria data were very compelling as supportive evidence with
another trial with harder endpoints, but by itself, the issues that
everybody has mentioned, the relation of the magnitude of the effect to
the outcome of interest to us just is too poorly known to allow us to
accept as a surrogate at this point.

Bob?

DR. TEMPLE: Well, I was very struck by the observation that at least one
dose of irbesartan was able to produce a dramatic decrease in
proteinuria that obviously had nothing to do with anything anatomical at
all. So, maybe the other dose did something anatomical I don\'t know.
But that was impressive, I thought, that it could go away so quickly,
and it certainly seems reason for pause.

DR. LIPICKY: Jeff, I think you said that IRMA supported IDNT, and now
you say that proteinuria is not a surrogate. Can you explain how you
came to those what I think are disparate decisions?

DR. BORER: Yes, I can. I don\'t think they\'re disparate at all.

IRMA I believe gives me some information about the pathophysiology of
disease and convinces me that the drug has an impact that\'s positive on
the pathophysiology of the disease. That was supportive of hard body
count data from another trial. Absent the hard body count data from the
other trial, I would not have been in favor of ‑‑

DR. LIPICKY: But the body count was 22 and 24.

DR. BORER: Well, in my judgment the data in their totality, for all the
reasons that I stated that are going to be on the record when you read
it, I thought were sufficient.

DR. LIPICKY: I withdraw my question.

DR. FLEMING: If I could, I\'d like to, even though I voted against it
being a surrogate, defend that there\'s logic to what Jeff has said.
When I argue it\'s not established to be a surrogate, my belief is we
have not come close to establishing the scientific evidence to be
confident that when you simply show an effect on proteinuria, that we
know that it\'s of the duration, magnitude, and all the other things we
have to understand to know that it\'s reliably going to predict an
effect on clinical endpoints.

Nevertheless, there\'s still a level of plausibility of efficacy that
you gain from such an insight. Even if you have a marker that\'s not an
established surrogate, you understand natural history, and if you can
impact that marker, it provides some level of sense of plausibility. So,
if in fact you believed that the first trial was close enough or was
quite close, then something that\'s not a surrogate, but establishes a
level of plausibility, could tip you over. I don\'t know if that\'s
where you were, but it\'s logically consistent you could have that
opinion.

DR. BORER: You said it better than I could.

I think we\'ve completed the questions, but Bob has another.

DR. TEMPLE: No. I just want to say one thing and it\'s not tooting my
horn because they were written by someone else. I think this was a
terrific set of questions, and I want to compliment Norm Stockbridge and
Ray who did them. It led to what I think is one of the more fascinating
discussions I ever remember at an advisory committee that brought out
all kinds of stuff.

DR. LIPICKY: Just Norman. I had nothing to do with it.

DR. TEMPLE: Okay, even better.

(Laughter.)

DR. BORER: Okay. With those disclaimers having been made, we\'ll adjourn
and meet again tomorrow morning.

(Whereupon, at 5:50 p.m., the committee was recessed, to reconvene at
8:30 a.m., Friday, January 18, 2002.)