us food and drug administration: 3423t2

8/14/2019 US Food and Drug Administration: 3423t2

http://slidepdf.com/reader/full/us-food-and-drug-administration-3423t2 1/216



ajh

AT&.—

–-

- -.

1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

GASTROINTESTINAL DRUGS ADVISORY COMMITTEE

DISCUSSION OF GUIDANCE

FOR THE CLINICAL DEVELOPMENT

OF DRUGS AND BIOLOGICS FOR CROHN’S DISEASE

VOLUME II

Friday, May 29, 1998

9:00 a.m.

Holiday Inn Bethesda8120 Wisconsin AvenueBethesda, Maryland

MILLER REPORTING COMPANY, INC.507 C Street, N.E.

Washingtonr D.C. 20002

(202) 546-6666



aj h

—>.

m.

2

PARTICIPANTS

Stephen Hanauer, M.D., ChairpersonJoan Standaert, Executive Secretary

MEMBERS

Rosemary R. Berardi, pharm. D., (ConsumerRepresentative)

Janet Elashoff, Ph.D.Barbara Frank, M.D.Loren Laine, M.D.William M. Steinberg, M.D.Christina M. Surawicz, M.D.

INVITED GUESTS

Brian Feagan, M.D.

Barbara S. Kirschner, M.D.Paul Rutgeerts, M.D.David Sachar, M.D.Lee S. Simon, M.D.

FDA

Barbara Matthews, M.D.Terry Neeman, Ph.D.John Senior, M.D.Jay P. Siegel, M.D.Lilia Talarico, M.D.Karen Weiss, M.D.

MILLER REPORTING COMPANY, INC.

507 C Street, N.E.Washington, D.c. 20002(202) 546-6666



ajh

.8-.

.—-.—

3

Call to Order: Stephen Hanauer, M.D.

Statement of Conflict of Interest: Joan

Introductory Remarks

Stephen Hanauer, M.D.Karen Weiss, M.D.

General Discussion of Questions

Standaert


Washington, D.C. 20002(202) 546-6666

PAGE NO.

4

4

56

22



ajh

1@ -–

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

4

Call to Order

DR. HANAUER: It is 9 o’clock approximately and I

would like to bring this meeting to order. To begin with,

Joan Standaert has some introductory comments.

Conflict of Interest

MS. STANDAERT: The following announcement

addresses the issue of conflict of

this meeting and is made a part of

interest with regard to

the record to preclude

even the appearance of such at this meeting.

Based on the submitted agenda for the meeting and

all financial interests reported by the committee

participants, it has been determined that all interests in

firms regulated by the Center for Drug Evaluation and

Research present no potential for an

conflict of interest at this meeting

exceptions .

appearance of a

with the following

In accordance with 18 U.S.C. 208, general matter

tiaivers have been granted to all committee participants who

have interests in companies or organizations which could be

affected by the committee’s general discussion on guidance

for the study of drugs to treat Crohn’s disease.

A copy of these waiver statements may be obtained

Oy submitting a written request to the Agency’s Freedom of

Information Office, Room 12A of the Parklawn Building.


507 C Street, N.E.Washington, D.C. 20002(202) 546-6666



ajh

———

—-.

__—_

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

5

In the event that the discussions involve any

other products or firms not already on the agenda for which

an FDA participant has

participants are aware

from such involvement,

the record.

With respect

a financial interest, the

of the need to exclude themselves

and their exclusion will be noted for

to all other participants, we ask in

the interest of fairness that they address any current or

previous financial involvement with any firm whose products

they may wish to comment upon.

That concludes the conflict of interest statement

for May 29, 1998.

Introductory Remarks

DR. HANAUER: This meeting is going to be somewhat

~ifferent than yesterday’s meeting, and I want to thank the

~Ponsors yesterday for introducing the important topic

:oday, which is the real importance of this two-day meeting,

tihich is to discuss the future of the guidelines for drug

development for inflammatory bowel disease, and we are going

jo focus on Crohn’s disease today.

Also, a little different from yesterday’s meeting,

it is not an adversarial type of arrangement. I want it to

>e much more of an open meeting and encourage discussion

=rom outside of the table. We all recognize that industry

md individual members, not necessarily at this table, have


507 C Street, N.E.Washington, D.C. 20002

(202) 546-6666



ajh

-A..— .

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

6

given a great deal of time and consideration, consultative

support to the development of clinical trials in

inflammatory bowel disease, and we certainly want to utilize

the resources that are available to improve the draft

guidelines and basically put this on a reasonable playing

field for everybody.

Before I introduce today’s panel members, I would

like Karen Weiss to introduce the purpose of the meeting and

then we will proceed. Before she starts I want to give her

and the Biologics a great deal of credit. They have rapidly

come up to speed with inflammatory bowel disease over a

short period of time, and I am incredibly impressed by the

amount of

diseases,

of credit.

work and effort and insight they have into these

and Karen, as one of the leaders, deserves a lot

Karen.

DR. WEISS: Thank you.

I wanted also to extend my welcome to the members

md guests for today’s session, and just to take a minute to

say why we are here and how we got here.

Yesterday, there was some mention to

iocument which was called Draft Guidelines for

the published

Therapies for

:rohn’s Disease and Ulcerative Colitis. That was a document

:hat was published in the Journal of Inflammatory Bowel

lisease in 1995 with Stephen Fredd as the author. But that


507 C Streetr N.E.Washington, D.C. 20002(202) 546-6666



ajh

.-.

..—-=

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

7

document wasn’t a formal FDA guidance document. In fact,

that document

1990s largely

really had its roots I think in the early

due to the efforts of Mr. Hanauer to try to

put down on paper some guidance because there wasn’t any

such thing prior to that time.

As people are probably aware, the agency is very

actively involved in the development of guidance for many,

many different areas, and this particular draft publication

was developed in the days before we had something called

Good Guidance Practices,

standard procedures that

developing guidance, and

and Good Guidance Practices is the

we are to follow whenever we are

one part of that procedure is

exactly what we are doing right now, to at the very early

stages, see input from advisory committees, from the public

to get a broad input as we do the first step, which is to

develop a guidance document, so that is really the purpose

of today’s meeting.

We have some questions that are directed

questions, but they are not intended to limit discussion so

much as to stimulate and facilitate discussion. Our plan is

to take those comments that we receive today, also to allow

additional time to put these specific questions out on an

FDA web, so that others can respond that are not here today,

others can respond to those questions.

We will take all of that input together with the


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

existing

guidance

comment.

guidance

disease.

8

draft document and develop a first draft of the

document, which will then go out again for further

The ultimate goal would be then to develop an FDA

document on development of therapies for Crohn’s

Again, thank you, and I look forward to these

discussions,

DR. HANAUER: Thank you. Now, here is my intended

format .

DR. WEISS: Excuse me. I would also mention that

this effort was a joint effort between Center for Biologics,

the Center for Drugs, Dr. Hanauerr and so I would also like

to then just turn it over to Dr. Talarico, my counterpart in

:enter for Drugs, to make a comment.

DR. TALARICO: I just wanted to say that I concur

tiith Dr. Weiss’ comments completely, and our hope is that

me of the results of this meeting is to stimulate

development of new drugs for Crohn’s disease. We have heard

~esterday how desperate the need is. We have seen now a

]iologic compound, very promising, and we hope to see drugs

.n the future that will come up because there is really a

~eed for such things.

DR. HANAUER: At this point, I want to introduce

:everal of the guest panelists who we have invited today.

leginning on my left is Dr. Sachar. David is the Chairman


507 C Street, N.E.Washington, D.c. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

9

of Gastroenterology at The Mt. Sinai Hospital, as we heard

yesterday. You were introduced in absentia, so to speak,

Dr. Present. Dr. Sachar has been very much involved on a

worldwide basis in many clinical aspects of inflammatory

bowel disease, and particularly is leading an effort, a

joint effort between United States and international

organizations on the classification of inflammatory bowel

by

disease. As we are moving on toward genetic insights, Dr.

Sachar has been prominent in trying to develop clinical

phenotypes that will correlate with the genetic background.

Paul Rutgeerts, who we met yesterday, is a

consultant we have asked to join the panel. Dr. Rutgeerts

is a Professor of Medicine at the Catholic University in

Leuven, Belgium, and has been very prominent in the

development of endoscopic monitoring and endpoints for

specifically Crohn’s disease, and led information regarding

the recurrence of Crohn’s disease after surgical

intervention, and has been very prominent as a worldwide

leader in clinical development and particularly as it

reflects on endoscopic changes.

Welcoming back Barbara Kirschner, who is a

Professor of Pediatrics at the University of Chicago, has

~een involved in pediatric aspects of inflammatory bowel

Iisease, has been a committee member on this panel, has been

~ major advocate of development of guidelines particularly

MILLER REPORTING COMPANY, INC.507 c Street, N.E.

Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

10

related to pediatric interests inflammatory bowel disease,

and after I give a brief overview, I am going to ask you to

make some comments when it is appropriate regarding specific

needs to the pediatric population, so I want you to think

about a few comments. I know you have done that.

Dr. Simon was introduced yesterday. Dr. Brian

Feagan from the University of Western Ontario has been a

major play in the development of clinical trials in

inflammatory bowel disease. He is an expert trialist in

general. He has a broad perspective of clinical trial

techniques and also an interest in quality life assessments

in inflammatory bowel disease, and I think will help round

out that discussion.

Dr. Berardir we met; Dr. Laine and Frank, we have

net; John Senior is joining’ the panel as a member from CDER.

1 think everyone else has been introduced.

My plan today is to work for approximately two to

two and a half hours, take a 30-minute not lunch break, and

then come back and complete the session, so that we should

be hopefully finished by between 1:30 and 2 o’clock, so

people

here.

things

who have to leave for the weekend can get out of

That is my initial plan and we will try and move

accordingly.

Now , to being with I just want to set the scene

Eor where we are heading with a series of slides and


507 C Street, N.E.”Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

hopefully limit, if it is possible, to

introduction of where

Most Of yOU

slides, and they also

minute lecture.

[Slide.]

we have been and

know me, know we

know there is no

11

about a 5-minute

where we need to go.

can’t speak without

such thing as a 5-

To set the scene, we heard about Crohn’s disease

yesterday and I think the issues related to drug development

md to this disease were very much highlighted yesterday.

On the other hand, I am also very pleased that we

were able to at least as a committee approve a drug based

~pon the draft guidelines that haven’t been published to

iate.

Now , the importance of classifying Crohn’s ,

iisease, which is probably a series of inflammatory bowel

~iseases, we are coming to the concept that this is probably

lot one disease, and as I mentioned to Dr. Simon yesterday,

:he rheumatologists have been quite fortunate in that they

lave a series of serologic criteria that can help classify

>atients with previously unclassifiable or indeterminate

~eatures of rheumatologic diseases. We have lacked those

:hus far in inflammatory bowel disease and Crohn’s disease,

md yet as we have seen, the classification

)f diseases is going to be important from a

standpoints, from the diagnostic standpoint


507 C Street, N.E.Washingtonr D.c. 20002(202) 546-6666

for this series

variety of

and



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

understanding

disease, from

the

the

12

underlying genetic underpinnings of the.

therapeutic standpoint which is critical

from this body’s standpoint, and from the patient’s

standpoint and from a prognostic and actuarial standpoint we

need to understand a better classification of Crohn’s

disease from the prognostic standpoint.

[Slide.]

Now , these inflammatory

colitis and Crohn’s disease, have

diseases, both ulcerative

begun to appear as a

heterogeneous series of illnesses, and that heterogeneity

comes in a variety of different presentations -

heterogeneity by disease location, by disease complications,

and also by the different response to therapies. As an

example, yesterday, we heard that infliximab was effective

by certain criteria in approximately two-thirds of patients,

but one-third of the patients did not respond, and that may

predict a pathophysiologic relationship or underpinning of

the disease that may impact on future trials.

[Slide.]

We didn’t get much into it yesterday, and

appropriately so, but we also think that there are a number

of genetic factors that may influence response, perhaps on

=he immune and immunoinflammatory compounds, perhaps the

ability to produce factors or cytokines, such as TNF, the

Level of regulation of these may be important.


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

13

We do have some serologic findings, and Dr.

Targan, who spoke yesterday on behalf of Centocor,

emphasized that there are some serologic factors, such as

they carry nuclear ANCA, that is not yet totally defined,

that may be a predictor of some subgroups, but leave it at

the moment that there appear to be a series of subgroups of

inflammatory bowel disease that may be defined on a variety

of different clinical disease location, complication, and

hopefully, eventually, genetic bases that will better

classify these diseases. At the moment we do not have such

an available classification.

[Slide.]

So, how do we define Crohn’s disease and its

~isease activity? Well, we recognize that Crohn’s disease

produces a variety of different symptoms in individual

patients, and they are not all the same as was emphasized in

yesterday’s discussion.

From a subjective standpoint, patients may present

with a variety of symptoms including diarrhea, ‘abdominal

pain, rectal bleeding, nausea, vomiting from a symptomatic

standpoint, and this is by no means a total list.

From an objective criteria, they can present with

a series of findings including weight loss, fever. In

children, as was emphasized yesterday, growth is a very

important factor. They may present with an inflammatory

MILLER REPORTINGCOMPANY, INC.

507 C Street,N.E.Washington, D.c. 20002(202) 546-6666



ajh

__—-. 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

I 15

Iinflammatory activity. Diminished albumin may be related, to

Imalabsorption or protein losing enteropathy. Signs of

protein losing include fecal or clearance of alpha-l

antitrypsin, and other laboratory features may replicate or

identify the exudation or presentation of leukocytes in the

inflamed bowel via leukocyte scanning or leukocyte

excretion, and this is by no means an inclusive list of the

laboratory features.

[Slide.]

The endoscopic features of Crohn’s disease are

also quite variable, and they can be the typical of

classical linear ulceration and focal ulceration that tends

to be transmural, but there is a clinical overlap, and

Crohn’s disease may absolutely mimic the endoscopic and

pathologic features of ulcerative colitis in a group of

patients that we consider as having indeterminate colitis.

These endoscopic features do not, to our current

therapies, and current meaning preceding the infliximab

therapy, have not altered dramatically according to therapy

particularly as response to steroids, and that has led to

some of the previous draft guidelines that we are going to

review.

[Slide.]

When one looks at the histologic features of

Crohn’s disease that are also focal and can be quite


Washington, D.C. 20002(202) 546-6666



ajh

.—-.

—_

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

16

variable, they do not necessarily, neither the microscopic

score, on the left, according to histology, or endoscopic

appearance, in general, have not correlated with disease

activity, although with a drug such as infliximab that may

be changing and we need to be cognizant that we are seeking

drugs that will affect both the clinical, laboratory,

endoscopic, histologic, and eventually cytokine features of

these diseases.

[Slide.]

Correlates between endoscopic activity and

clinical activity seem to be related to the severity of the

lesions, but there are many other lesions including what are

thought to be primary lesions, such as aphthous ulcerations,

that do not correlate at all with symptoms or other

laboratory features.

[Slide.]

So, when we are measuring Crohn’s disease, we need

to be aware that the level of inflammatory mediators does

not correlate very well with symptoms, that sfiptoms do not

correlate very well with endoscopic features, and endoscopic

features do not correlate very well with the need for

surgical resection, and this has been a major problem.

[Slide.]

so, in the past and up until this date, we have

used a number of different therapeutic endpoints for Crohn’s


Washington, D.C. 20002(202) 546-6666

.--. =.. . .



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

17

disease. These include clinical indices, and indices such

as the Crohn’s Disease Activity Index, such as exemplified

yesterday, are components of subjective

disease, as well as objective features,

components of

and they have

criticized because they do not necessarily correlate

the wellness, how the patient feels, with the degree

inflammation.

the

been

tiith

3f

They are not primary indicators of inflammatory

disease, and as an example, we have many patients who have

irritable bowel syndrome, who according to the Crohn’s

Disease Activity Index, would have very severe Crohn’s

disease demonstrating the lack of specificity of indices

such as that.

Indices have been used by some investigators,

primarily in Europe, as predictors of relapse, and according

to composites of laboratory features of inflammation, we

could at least begin to predict the likelihood of clinical

relapse in patients who are quiescent, and we need to learn

better how to use the endoscopic response in particularly

defined therapies that have endoscopic correlates to

subjective and objective components of the disease.

[Slide.]

So, what have been the

guidelines for Crohn’s disease?

lot have a pathognomonic measure

problems in developing

Well, the first is we do

or label for this disease.


Washington, D.C. 20002(202.)546-6666



ajh

..-.1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

18

The diseases are quite heterogeneous and vary in sYmptoms.

between site of disease, in patient who have rectal Crohn’s

disease are going to have different components of symptoms

than patients who have esophageal or duodenal Crohn’s

disease, the symptoms are going to be different.

Many of these patients are going to undergo

surgery, and after surgical resection, their baseline non-

disease state is different. Many of them will have more

bowel movements than they would otherwise, and that will

impact upon non-inflammatory components of the disease.

We need to distinguish between inflammatory and

non-inflammatory symptoms. We are confronted by the poor

endoscopic symptom correlation, and we need to define what

is remission of these diseases. You heard yesterday how the

Crohn’s Disease Activity Index, at a level of 150, often

correlates with disease well-being,

point out, what happens to patients

but as our statisticians

when the CDAI, Crohn’s

Disease Activity Index, actually goes below 150, and some

patients with a level of 150 do have active disease, and

frankly, some patients with disease activity indices above

150 are in clinical remission by all other criteria.

[Slide.]

We tried to come up with some solutions in this

draft guideline proposal that have already been published.

We suggested comparison of homogeneous subgroups of

MILLER REPORTINGCOMPANY, INC.507 C Street , N.E.

Washington, D.C. 20002

(202) 546-6666



I

.—.=

1,

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

20

homogeneous subgroups of patients with predefined endpoints,

which I think were met to

degree, with the approval

[Slide.]

some degree, to a considerable

process yesterday.

From a remission standpoint we have still not

successfully defined a drug therapy related to this because

of difficulties in defining remission based on the clinical

aspects, as well as the

suggest that a clinical

endoscopic aspects, although we did

remission could be defined based

upon symptoms, signs, and a composite index if they were

predefine in advance and were acceptable to the agency,

we still need to come up with endoscopic criteria for

remission.

[Slide.]

and

As far as maintenance of remission, we suggested

both clinical and the postoperative recurrence model as

potential maintenance means of gaining approval for

maintenance, but still obviously this needs additional

clarification as I have discussed.

[Slide.]

Quality of life is something that has been

=mphasized by our patients who presented before the formal

neeting yesterday. Patients wish to be free of pain and

?erform their regular activities. Yet, in the setting of a

uhronic disease, it leads invariably to disappointment in

MILLER REPOR~INGCOMPANY, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

21

physicians and in therapy because of the chronicity and lack

of curability.

[Slide.]

Quality of life is a very complicated determinant,

but in inflammatory bowel disease, at least we do have some

invalidated indices that were discussed yesterday, the

Inflammatory Bowel Disease Questionnaire, that has been

validated against the Crohn’s Disease Activity Index.

[Slide.]

And we do have means of assessing quality of life

either by these indices, but need to consider many other

aspects of quality of life as we continue with the drug

development process.

[Slide.]

So, with that very brief overview, we need to

consider additional therapeutic goals in the future. From

the scientific standpoint we need to identify pathognomonic

marker of disease. In the future, we hope to identify

patients who are going to be at risk of this d“isease, to

look at it in its actual preclinical or genetic stages, and

identify the factors that are actually causing and

triggering this disease, but, that is more from the

scientific standpoint, not necessarily from the regulatory

standpoint, but as these features come into play, it will

obviously modify these guidelines as we proceed.


Washington, D.C. 20002(202) 546-6666



_&=.

,-_r

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

David, do

22

With that brief introduction, I open this up.

you want to comment on that?

General Discussion of Questions

DR. SACHAR: Steve, let me lead off first by

congratulating you for such a clear and succinct

encapsulation of the most salient problems and questions in

dealing with evaluation of Crohn’s disease, and second, let

me point out that not having been here yesterday, I have the

great advantage of not being encumbered in anything I say by

any facts, knowledge, information, or data.

But if we want to start off by looking at

indications, and particularly defining the first two

sections that you have under Sections for the Committee, it

is probably a mark of my own simple mindedness that I find

it easier to think of the indications on two broad

~ategories rather than three.

DR. HANAUER: Let me just read the first paragraph

oecause the members in the audience may not have this.

The first question that was posed to” the committee

Ls that one purpose of the indication statements (the

ulaims) in a product label is to inform prescribers and

?atients about the beneficial effects from use of the

?roduct. The existing draft guidance discusses three

?otential indications for therapies, as I describe: (a) the

;reatment of acute disease; (b) induction of remission; and


Washington, D.C. 20002(202) 546-6666

.



ajh

.n1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

23

(c) maintenance of remission.

DR. SACHAR:’ I like to think of indications in two

rather than

disease and

three broad

maintenance

categories: the treatment of active

of remission. I rather prefer the

term “active” to acute since often if we are trying to

ameliorate diarrhea, fevers, pain, fistulae, these symptoms

may have been very chronic, they may have

years or decades. I don’t know that this

acute disease, but it is certainly active

When we talk about induction of

been there for

is necessarily

symptoms.

remission as a

separate indication, I know that the definition there refers

specifically to mucosal healing, and I sometimes find it a

little confusing to refer to induction of remission and then

assume that people must understand that that is different

from the treatment of active disease, simply because we are

setting up a particular outcome measure or response

variable, namely, endoscopic evidence of mucosal healing.

We could say that mucosal healing is, in fact, one

>f the response variables or one of the potential outcome

neasures of the success of the first indication, treatment

of active disease, just as when we go on to Section 2 here

#here you are asking should we look at other indications,

such as fistula healing, steroid sparing, abscess treatment,

obstruction treatment, or quality of life.

All of those, can really, in a sense, be subsumed


Washington, D.C. 20002(202) 546-6666



aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

24

as response variables or outcome measures of either the

treatment of active disease or maintenance of remission.

With regard to maintenance of remission, while we

talk about it as surgical remission, medical remission, I

think there is an important subdivision of maintenance of

remission that is often overlooked, and that is the

difference between the new introduction of a new therapy in

a patient who is already in remission, spontaneously or

postoperatively or without medication, as opposed to

continued active therapy. That is to say, a patient is in

remission on a given therapy, and that remission is either

maintained as the therapy is continued or not maintained if

the therapy is discontinued.

I will just give you two quick examples of that,

if I may. There are in the literature several randomized

placebo-controlled trials of maintenance of remission by

antimetabolites, 6-MP or azathioprine. The design, however,

of the most effective studies on that regard are really

continued active therapy.

They are the taking of people in whom those

particular agents have already proved their success by

having maintained a remission, and then patients are

randomize either to continue on that active therapy or to be

transferred to a placebo, and there are differences in the

relapse rates.


Washingtonr D.C. 2QQQ2(202) 546-6666



aj h

.4-%1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

25

That is rather different from a design in the

studies, let’s say, of steroids. There are three

randomized, controlled trial studies of steroids in the late

seventies and early eighties, where steroids are shown to be

ineffective for the maintenance of remission in Crohn’s

disease as defined in part by the new introduction of

steroids in patients who are already in remission.

But if we look at subgroups of those studies, we

all have the experience of patients who are what we call

steroid dependent. They are on remission on steroids, and

when you try to reduce the steroids, they relapse. That is,

in fact, the majority. of our steroid-treated patients.

Do we say, on the one hand, that the steroids are

ineffective for maintenance of remission because when you

introduce them newly

any better than when

are effective in the

in untreated patients, they don’t do

you don’t? Or do we say that steroids

maintenance of remission because as

long as a steroid-treated patient stays in remission on the

steroid, and doesn’t relapse until they come off, then, the

steroids are effective in maintenance of remission.

So, my comment there is, just to summarize, I

think we are really talking about active disease rather than. .

necessarily acute disease. I think that an issue of mucosal

healing rather than being a broad category of one of three

categories, should be included together with fistula healing

MILLER REPORTINGCOMPANY, INC.507 C Street,N.E.

Washington, D.C. 20002(202) 546-6666



ajh

p%

.-.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

or abscess healing as a goal of treatment of active disease

rather than as a whole separate category; and third, that

when we think of maintenance of remission, we need to draw

distinction between what I call out-of-the-blue therapy,

coming in with something new in a patient already in

remission, and continued active therapy and continuing a

patient on a drug that has already induced remission.

a

DR. HANAUER: Dr. Sachar has always been a master

of metaphors, but you are mixing some.

precise

perfect

purpose

DR. SACHAR: It’s called the “mixmaster.”

[Laughter.]

DR. HANAUER: Yes . I think we need to be very

when we discuss this because I think you show

examples of different definitions of remission. The

of the guidelines, as they were stated, and dividing

treatment of active disease versus induction

was actually to stimulate drug development.

of remission

We recognize that there may be drugs out there

that impact upon the level of active disease, that can

actually improve it without inducing remission, and we did

not want to halt drug development, did not make a home run

of inducing complete endoscopic healing, complete

symptomatic resolution, et cetera.

So, your example of steroid-induced remission,

most of us would think is not a remission because those


Washington, D.C. 20002(202) 546-6666



ajh

..-=

27

1 patients continue to have endoscopic lesions et cetera, and

2 they do have a clinical remission, their symptoms are

3 IIameliorated, but as we know, they continue to have activeI

4 endoscopic lesions.

5 so, the original concept -- and it can certainly

6 be modified -- of remission was really the home run of I

7 getting everything.

8 DR. SACHAR: Just to respond to that, Steve, I

9 IIthink that in a sense you may be mixing a couple of things I

10 there, too. You have talked about the difference between

11 treatment of active disease and induction of remission as

12 though we were talking about complete versus incomplete

13 remission versus a criterion of improvement in the CDAI by

14 100 points as opposed to improving below the level of 150,

15 but the way the guidelines are written now, we are not

16 talking about complete versus incomplete, we are talking

17 about all together different definitions. We are talking

18 about mucosal healing as a different definition of

19 remission.

20 II Alsor with regard to the steroid sparing issue, I I21 think that comes in under Section 2 when we talk about

22 11steroid sparing or discontinuation as an indication. That III I

23 is, in fact, sort of part of what you have here as

24 indication of (c) the maintenance of remission. It is one

25 of the ways in which you show that you are effectively



(202) 546-6666



—_

———.-

aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

maintaining

point is to

flare.

28

the remission. Anybody can stop steroids. The

stop the steroids and not have the disease

DR. HANAUER: Dr. Simon, from the rheumatologic

perspective.

DR. SIMON: Not as a gastroenterologist, I have to

ask a question here. I have always lived with the

assumption that anyone that has Crohn’s disease has some

structural abnormality. It may not be visualizable based on

technology, but nonetheless, it exists, so that you don’t

have Crohn’s disease without having mucosal disease, and the

converse is you don’t have symptoms of fever or other

constitutional issues that are measurable based on quality

of life scores and other measurable components without

having structural abnormalities.

Is that true?

DR. HANAUER: I don’t want to consume the

committee. It is not” totally true because we have a

condition called irritable bowel syndrome that” the digestive

tract produces many symptoms in what appears to be

anatomically and pathologically normal individuals that can

replicate the symptoms. So, patients can have diarrhea,

abdominal pain without having Crohn’s disease - nausea,

vomiting, et cetera.

DR. SIMON: Right, but my point is that the

MILLER REPORTINGCOMPANY, INC.507 C SCreet, N.E.

Washington,D.C. 20002

(202)546-6666



n

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

29

response elements that we were just talking about were

multifactorial and there have to be a composite score system

to be able to include all of

discussion that just ensued,

those issues, and the

mixing and matching metaphors,

actually includes all of those particular issues, so it

seems that from an outsider’s perspective, that if one is to

create a system of response indicators, that one has to

include both invariably a response from structure, as well

as invariably a response to symptoms and signs, and that

they cannot be separated, and that somebody who is going

into complete remission is well, they are better. They are

not better, they are not sick any longer, and not being sick

any longer means not having any of the symptoms and signs of

being sick or having structure abnormalities of being sick.

DR. SACHAR: There may be extra enteric

manifestations,though, independent of structural

abnormalities .

DR. SIMON: That would also be structural, if it

is arthritis or uveitis, that would still be measurable and

definable.

DR. SACHAR: They are objective, but they may not

be structural, things like fever, for example, or some of

the cytokine effects on bone marrow production and anemia

nay be metabolic, and not actually defined as structure.

DR. SIMON: That’s true, constitutional .


Washington, D.C. 20002(202)546-6666



.—=.

__-..

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

30

DR. HANAUER: Dr. Sachar has suggested that the

three current indications should be modified to treatment of

active disease, still with induction of remission or no?

DR. SACHAR: I think to make induction of

remission a separate indication is confusing. I think what

you have defined in induction of remission is just one

possible response variable or outcome measure of treatment

of active disease, what is the goal of therapy, and among

those goals may be improvement of endoscopic mucosal score

or

or

complete mucosal healing or complete closure of a fistula

complete resolution of an abscess.

These are all potential definitions under one

category, the treatment of active disease, and I don’t see

why the mucosal healing indication is sort of elevated to a

full separate category

DR. HANAUER:

out there and each one

that they could get an

of indication.

There are two dozen drug companies

you are suggesting a laundry list

indication for fistula healing, one

company; another company, endoscopic healing; “another

company - you are suggesting a laundry list of potential

indications within the realm of Crohn’s disease.

DR. LAINE: We haven’t defined that. Right now we

are only talking about acute - I think the

about what makes up remission. We haven’t

I would agree.


Washington, D.C. 20002(202) 546-6666

later ones talk

done that yet, so



aj h

.--.=1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

31

DR. HANAUER: Christine.

DR. SURAWICZ: I think the problem that I have

with the term “reduction of remission” is that to me, it

immediately connotes leukemia where you have cancer cells

that you can measure and they are either in the blood or

they are not, and that is remission.

so, if I look at (a) treatment of acute disease,

or I look at (c) maintenance of remission, but I change

maintenance of remission to prevention of relapse, I don’t

have a problem with those, but I think I don’t understand

tihat maintenance of remission is, I mean what induction of

remission is. What is that, how is that different than

treatment of acute disease?

DR. HANAUER: Very simply.

3et from the statistician standpoint,

One would be you could

we could define

~reatment of acute disease as a reduction in the Crohn’s

lisease Activity score, and you could define induction of

remission as a proportion of patients, would they score

~elow an acceptable level, but that is one example.

DR. SACHAR: But that is not what is in the

?ublished guideline. The published guideline defines

induction of remission as mucosal healing specifically.

DR. HANAUER: Right, and there are several

iifferent means of doing that. That is open. That is for

discussion.


Washington, D.C. 20002(202) 546-6666



ajh

..:—-

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

32

Barbara.

DR. FRANK: Well, it seems to me that yesterday,

well, first

rather than

of all, yesterday, we did talk about active

acute disease, so I don’t think anyone disagrees

with what Dr. Sachar said about this is clearly active

disease that can be chronic if it has been there for a long

time.

The other thing is” that we had a specific

Definition that the company could recognize as a response

that was a specified change in the Crohn’s Disease Activity

Index whereas some patients who fell below the 150 mark were

~onsidered in clinical remission. I don’t think anyone was

particularly concerned about complete remission in terms of

symptomatic, as well as mucosal healing for the simple

reason that that is very difficult to achieve in Crohn’s

3isease.

On the other hand, perhaps with our new drugs, we

~eed a specific definition of complete remission because

~ome of these drugs may be capable of providing us with

Zomplete healing. So, I think there has got to be

difference between a clinical remission versus a complete

remission in terms of healing and symptomatic relief.

DR. HANAUER:

DR. FEAGAN:

:roubling because here

Dr. Feagan.

I find this whole discussion really

we are trying to set standards and I


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

. .53

guess, in the guidelines, the draft guidelines and some of

the discussion around the table, there are a lot of problems

in the sense that we are talking about the matrix that are

preferable, yet, there are definition problems which granted

that is the purpose of this conference, but there has been

very little attention paid to the operating properties of

the matrix that we are talking about - are they valid, are

they responsive, are they reliable, and a quantitative

approach to that whole

For example,

mucosal healing really

suspect that if we ask

process.

the issue of mucosal healing, what is

in terms of validity? I would

gastroenterologists around the room,

we would even get different definitions of that, you know,

which just seem to be very basic and robust measure, and

then when you get into the operating properties of the

definitions of things like remission, in terms of

symptomatic remission, you are going to get even more

heterogeneity.

I guess I am making an appeal for sort of a

broader process in an attempt to bring the process in line

with what the rheumatologists manage to do or over the

course of many years, is to try to bring this to a

quantitative rather than qualitative level of discussion.

DR. HANAUER’: Dr. Fries, did you want to comment

cm that, on the process?


Washingtonr D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

34

DR. FRIES: Thanks, Steve, at the risk of wearing

out rheumatologists, we are down to two rheumatologists, I

think. I think that we still take up a lot of the

discussion time.

I thought it might be just useful to give you a

couple of minutes of discussion of what has happened in

rheumatology. I am Jim Fries from Stanford. I directed the

National Arthritis Data Resource, which is called ARAMIS,

for the NIH for I guess this is the 23rd year, and we have

done a lot of work in

defining conceptually

outcome in rheumatoid

It has been

developing outcome instruments and in

what we are trying to do in terms of

arthritis in many other ways.

a long evolution because as is

apparent in this discussion, there aren’t any absolutely pat

kinds of things that you can say, but there are some general

things that you could say about what has

time, and I think that people are pretty

happened over the

gratified, both in

the agency side and the industry side and the academic side

with regard where we have come in rheumatology” over the

years, and these have been positive and there is a sense in

which they can serve as models, and some of the same things

are happening here.

For example, we have moved in treatment, if I use

rheumatoid arthritis as an example, we have moved from

thinking of it as an acute process to an active process, to

MILILERREPORTING COMPANY, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666

. .. ..



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

an outcome process, a

measured chronically,

35

chronic disease in which it is

in which the ideal outcomes that you

would like for an individual and measured over the entire

course of the illness, be it 20 years or whatever it is, the

ultimate goals go a long, long time out, much farther than

the clinical trials can, but you have to keep in mind when

you are making the treatment decisions about steroids or

whatever, what is the cumulative aspect of these as you get

on the long way.

Partly there, we

discussing activity versus

cumulative things, whether

have gotten into areas of

damage, because there are

they are related to steroids or

to the ever shortened bowel, which represent

which may be resulted from the activity over

time, but in a chronic illness patient, move

damage aspects,

a period of

from the

activity phase dominating in, say, rheumatoid arthritis, to

where the damage phase of the disease is really dominating.

We have movement

and we have really grown a

Measurements of disability

toward more humanistic outcomes,

lot more comfortable with those.

which are based on patient self-

report, for example, have moved into being probably the most

dominant accepted thing. We have moved away from little

process measures like walking times and buttoning things or

changes in sedimentation rates are things which might be

similar to your synovitis per se, and into the things that


Washington, D.C. 20002(202) 546-6666

—..



aj h

.=-.1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

36

affect the patients.

In this, you have tried to define outcomes, long-

term outcomes in terms of dimensions which are

exclusive and collectively exhaustive, so that

somehow in the outcomes everything the patient

the system to do for them with that disease.

mutually

you include

could want

In our area and in some other areas -- this is

going way back to Carl White’s things -- those dimensions

have fallen out different ways for different investigators,

but in general, into mortality measures, death, disability

measures, symptom measures, pain, drug side effect measures,

toxicity of the treatments, and economic impact.

If you define thing appropriately, you can get all

of the desirable outcomes into a relatively small number of

dimensions, and then you work at your indexes to have

indexes which reliably and validly, as we were hearing here,

quantitative, you can actually discuss these.

So, it is some of these areas that gradual

evolution and acceptance and comfort of scientists really

moving toward softer measures, which actually have better

measuring characteristics than the harder measures, and I

think here, your amount of exposed mucosa, for example, is

very, very difficult, a nice scientific measure, very hard

to. quantitate and probably reflected from the patient’s view

better by some other things that are actually experienced by


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

37

the patients.

Finally, to just sort of close, there is the

question of to get this intellectual move toward conceiving

what you are trying to do a little bit differently, then,

you can begin to build consensus, and what has happened in

rheumatology over the last really five years, has been the

development, first, of the international group called

OMERACT, which is

trials, which set

thought should be

outcomes in rheumatoid arthritis clinical

out and agreed upon six items which they

common endpoints to be used in all

clinical trials, and then these came to the American College

of Rheumatology, which again reflected on what endpoints

should be present as a core set of outcome variables to be

included in all clinical trials, and they added to the list

of generally soft things that, in fact, it would be a good

idea to get acute phase reactive like sedimentation rate,

and any trials that were a year or more, you ought to have

x-rays of the hands to be able to count erosions, so they

got those eight items.

There now is international consensus, and it

relatively easy for both industry or the agency, which has

been very involved in this consensus development process,

very actively involved, but now there is at least a core set

which is internationally agreed, and so I think that is the

shift that I would sort of hope that this group would be,

MILLIER REPORTING COMPANY, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666



ajh

E===.-.1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

we are going to try to set out to

and I think that is a good way to

39

achieve with our study,

think about things.

We were hung up -- I think there is a lot of

confusion, and I appreciate the discussion on the

differences between active versus acute, and induction

versus maintenance. Those things are all similar terms that

are being used in the RA document. Dr. Simon I know is

heavily involved with all these discussions going on at the

Arthritis Advisory Committee, because there was something

that could be used to reduce the signs and symptoms, a study

that should go on for at least six months to show the

reduction in the acute signs and symptoms.

There is a specific section on remission, and I

can’t remember exactly. It is like the index. There is the

ACR-20 that is used for that, and there are some specifics

about whether or not we have to be on or off various types

of rheumatology drugs to be declared in remission.

Then, there is structural changes to occur years

later. Then, there is quality of life. It is”very, vary

~arallel and that document has been extremely helpful. That

is what I hope we can get at as a start with these

~iscussions.

DR. HANAUER:, Is the ACR-20 more valuable than the

2DAI in their respective diseases?

DR. FEAGAN: Is blue a nicer color than yellow? I


Washington, D.C. 20002(202) 546-6666



ajh

_—-

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

40

mean they are different things. I don’t think the issue is

the parallels between rheumatoid arthritis and Crohn’s

disease. I think the issue is as far as the

measures. The parallels are in the process.

outcome

The process is

exactly parallel. You had a very heterogeneic diversity of

opinion, but what was important, there was a process that

was set up in which that was resolved through a scientific

and logical method in which there was a broad input and

consensus was reached. I think that is they key.

DR. SIEGEL: There is probably more diversity of

physiological processes in the CDAI than the ACR. It is

hard to compare. I know some of the criticisms we have

heard about how CDAI can and can’t be

comparing and scoring together things

numbers of bowel movements, pain, how

used when you are

like fistulae, anemia,

you weight them and

what their implications are to different subset of patients

can be more variable. In that regard, I think the ACR-20 is

-- it is hard to compare what they are intended to do and

what they actually do’.

DR. HANAUER: Dr. Elashoff.

DR. ELASHOFF: I just

of the difficulties with making

and defining that as remission,

of 150, a third of the patients

would have been “in remission, ”

MILLER REPORTING

wanted to comment that one

some cut point in the CDAI

specifically, the cut point

in the fistula T20 trial

at the beginning of that

COMPANY,INC.507 C Street, N.E.”

Washington, D.C. 20002(202)546-6666

-.



aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

DR. KIRSCHNER: I guess one of

have, I can see the necessity perhaps of

42

the problems we

endoscopic scoring

if we are talking about -- I guess I think of the way we

talked about treatment of active disease in terms of partial

and complete responses, and that is where induction of

remission and remission occurred, because otherwise it

didn’t make sense, but we have problems with the CDAI, which

doesn’t really

underestimates

issues are not

respond to pediatrics at all.

the degree of activity because

applicable.

But also the fact that we need some

I really

many of the

kind of

measure that can be used continuously over the long course

of disease, and requiring radiologic or endoscopic methods

to assess how a patient feels, their response to activity,

isn’t going to satisfy the long-term response to patients.

DR. HA.NAUER: Dr. Rutgeerts.

DR. RUTGEERTS: I would like to state on the

relationship between the clinical remission and endoscopic

remission. The status for the moment as follows, that, in

fact, not one drug is able or was able up to the present to

induce mucosal healing. If you give or the French studies

gave seven weeks long very high dose of corticosteroids, 1

rig/kg body weight, and they achieved 92 percent of clinical

remission, and they had only 29 percent of endoscopic

improvement .

MILLER REPORTINGCOMPANY, INC.507 C street, N.E.

Washington, D.C. 20002(202) 546-6666

,..



aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

Other

corticosteroids

43

Swedish studies have shown that You can give

for months, and ileal disease will not heal

at all. So it is only now with infliximab that we see for

the first time that we can have quick healing of endoscopic

lesions within four weeks and that it correlates with

clinical improvement.

On the other hand, the French have done also a

very interesting study that in the patients who improved

endoscopically or they continued monitoring those patients,

and they saw that patients who improved their lesions

endoscopically, did no better in the long term. They did

not maintain their remission longer than patients who had no

endoscopic remission.

So, the relationship between both parameters,

clinical remission and endoscopic remission, remains a

puzzle. Nobody knows how to handle it for the moment. So,

if you put mucosal healing as an endpoint, it is an endpoint

that is difficult to reach and maybe is not completely

relevant.

DR. HANAUER: Dr. Simon.

DR. SIMON: Just as another comparison, we do not

include in the ACR responder index structural healing or

actually even inhibition of erosions. That is a separate

measure and it then can be looked at later on. So, we do

not even consider response acutely or chronically within


Washington, D.C. 20002(202) 546-6666

.. .



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

44

that particular index of functional response of disease

modification.

intervention,

it relates to

feels.

DR.

We consider it a response to therapeutic

signs and symptoms of activity of disease as

activities of the patient and how the patient

HANAUER : Personally, I have problems with

that. Basically, your expectations of novel drug therapies

are very low because if you had a therapy that healed the

lesions and improved them, I would suspect that there would

be a better indication. It is similar to mucosal healing to

us, just because you can’t do it doesn’t mean it shouldn’t

be a goal of therapy.

DR. SIMON: I don’t mean to suggest that it is not

a goal of therapy. I am just suggesting that --

DR. HA.NAUER: That it is not an indication.

DR. SIMON:No, no, (a) it would be great to be

able to measure it. We

free. We know who that

criteria, but to have a

can see a person who is disease-

person is based on lots of different

scientific approach to” understanding

healing of erosions, change of erosions, progression of

erosions at the time is limited by the technology. Perhaps

MRI will help that, but right now the x-ray evidence of that

is not perfect, so therefore, it is not our expectation of

bad drugs, it is our expectation of bad technology.

DR. LAINE: It seems to me you have got to


Washington, D.C. 20002(202) 546-6666



ajh

_——___1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

document that

into clinical

can’t do that,

45

endoscopic or histologic healing translates.

benefit, and at the present time, since one

I wouldn’t even bother necessarily including

those as primary endpoints.

If you can prove to me that endoscopic healing

will make the patient do better, then, I would agree it

would be a reasonable endpoint, but at this point from

everything we have heard, we don’t have any clear evidence

of that.

DR. SIEGEL: In the article that was published in

’95, it is not taken out as a separate endpoint, and I think

for clarity, I should note that the definition of remission

there is not the same and not related to the definition of

remission based on a CDAI of 150, which I think was

correctly noted not necessarily to reflect remission given

that patient’s fistulae were under that.

The claim for remission, induction of remission in

the draft guidance required, as opposed to treatment of

acute disease which required a reduction in inflammatory

symptoms, it required resolution of clinical symptoms and

signs, resolution as opposed to reduction, in addition,

documentation of mucosal healing, so that goes to the point

you just made, that documentation of mucosal healing per se,

without full resolution of clinical symptoms, would not make

that claim of remission. That is what is proposed there,

MILLER REPORTINGCOMPANY,INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666

.



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

endoscopically. We might catch

3 centimeters where the disease

47

a glimpse of the TI for 2 or

might be raging 20, 30

centimeters more proximal to that.

That is the point I would like to bring out in

terms of endoscopy and radiology. Another point that has

~een cross-referenced back and forth is the utility of CDAI

for different clinical indications for the drug.

Take,

in terms of the

3ill Tremaine’s

for example, the discussion we had yesterday

CDAI scores in patients with fistula and

referenced this briefly. For instance, you

lad a patient who started out in the T20 trial, the fistula

=rial . If a patient with a single draining perianal fistula

mtered the trial with a score of 300, and managed to close

=hat fistula, but still opened up two new fistulas during

:he trial, and the CDAI score went from 300 to 310, and

night have developed a new abscess, that patient would still

~e considered a success in that trial.

DR. SIEGEL: That is incorrect.

DR. NEEMAN: That is incorrect.

DR. KORNBLUTH: In what way?

DR. MATTHEWS: If they had just one, they always

had to have them

that new fistula

two , they always

of the number at

closed, but it was interesting in the fact

could be assessed, so if the patient had

had to have greater than or equal to half

baseline reduced. So, new ones could


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

48. .

count.

DR. KORNBLUTH: Not more than they had closed.

DR. MATTHEWS: Right.

DR. KORNBLUTH: So, in other words, if you had

three and you closed two --

DR. MATTHEWS: You were a responder.

DR. NEEW: You had to have one.

DR. KORNBLUTH: After forming a new fistula, you

needed to have greater than 50 percent reduction?

DR. NEEMAN: If you had three, you had to have

one.

DR. KORNBLUTH: But you could have formed a new

abscess, and your CDAI could have stayed at 300.

DR. MATTHEWS: That is true, yes.

DR. KORNBLUTH: And there is an index out there,

the present correlates index,that basically looked at each

patient for each indication and used again to go back to the

patient’s own endpoints. If a patient had a

fistula, you don’t need to look at the CDAI.

you say we need closure of this fistula, and

as +1, +2, +3, -1, -2; -3 fbi that

If another patient has a

inflammatory activity, and you are

patient’s

rip-roaring

Prospectively,

we grade that

endpoint.

great deal of

going to make that an

endpoint, you score according to that basis.

Nowhere did we hear yesterday about closure of


Washington, D.C. 20002(202) 546-6666

. .



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

49

fistula vis-a-vis continued use of steroids or reduction. ,

We don’t know that some of those patients didn’t go down on

their penicillin at all. In a drug like Crohn’s disease,

very often a measure of success or maybe the sole indication

for the use of a drug is steroid sparing, and that can be

measured as the sole indication, as well.

DR. HANAUER: David, last comment on this.

DR. SACHAR: In fact, we have sort of moved on in

part this morning to discussing Section B, the response

variables, and we are starting to get into details about

CDAI scores, endoscopic findings, radiologic findings,

histologic assessment.

Before we move on to B, I would

like to return to a proposal for settling

proposal would be about indications would

just sort of would

Question A. My

be to talk about,

first, treatment of active disease, and to divide that into

categories : symptoms, symptomatic, partial or complete.

Partial has traditionally been defined as reduction of CDAI

Oy 100 points and complete to getting below 150. We can

iiscuss those details when we get to Part B.

Mucosal ulceration. Partial is sometimes defined

as a decrease in the Rutgeerts score of two points, or

:omplete, getting a Rutgeerts score down to zero. Fistulae

~as been defined in the Centocor trial as either partial, 50

?ercent closed, or complete, 100 percent closed, and quality

MILLER REPORTING C!OMPANY, INC507 C Street, N.E.

Washingtonr D.C. ZOO02(202) 546-6666

. ,. ”. .



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

50

of life, either partial or complete, and that can be defined

by whatever we choose here, whether it is IBDQ or SF-35 or

HLQOL or SIP or whatever.

That would be my proposal for Indication 1,

treatment of active disease. Indication 2 would be

prevention of relapse as you propose, and that would be

prevention or relapse following surgical remission, which is

the whole post-op prophylaxis issue, of following medical

remission. Within that category we would have steroid

sparing.

DR. HANAUER: Were there other comments?

DR. SURAWICZ: I like it. I understand it. It

makes sense.

DR. SIEGEL: That differs in some ways from the

article in a number of important ways. One that I would

like to highlight specifically, just to make sure that is

the sense and what you think, is that the difference between

partial and complete is where there is a difference between

treating active disease and inducing remission; but then the

logic that went into that piece -- and I am not promoting or

defending this, I was”not involved at all in writing this, I

am just trying to clarify the issue -- the logic that went

into that piece, well, we don’t want to say it is complete

if there is still inflammation in the mucosa.

I have heard people say you can have a lot of


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

aL

disease and not have inflammation in the mucosa, but this.is

really what was addressed there is the opposite question,

If you have no disease and the mucosa is inflamed, you want

to give a claim that says there is a complete whatever you

call it - complete response, complete remission, or

whatever, or do you want to show also that you have

of inflammation in addition to a loss of symptoms.

the loss

DR. SURAWICZ: But this is a focal disease, so it

depends where you biopsy. You can have one area that is

inflamed and

becomes very

DR.

You can have

another area that is not inflamed, so it

subjective.

HANAUER : And the converse becomes true also.

a lot of disease

on a very frequent basis, but

it into 12 categories or such

an acceptable type of process

Please.

DR. GRAFFNER: Hans

and no symptoms, which we see

industry standpoint, dividing

as that, is that going to be

or goal for you?

Graffner, Molndal, Sweden.

I like the idea of treatment of active disease,

symptoms of active disease, and prevention of relapse.

rhose are the things that the patient wants. It is easy for

the pharmaceutical industry, I would say.

I am having difficulty with things like endoscopic

criteria because patients, they do not care about. We don’t

treat endoscopic picture, we treat the patient. So, if we

MILL”ER REPORTING COMPANY, INC.507 C Street, N.E.”

Washington, D.C. 20002(202) 546-6666



ajh

,_.!_

& .

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

can have those two things, treatment

versus

on the

we can

global

prevention or relapse, and we

52

of active disease

will be able to decide

definitions of these things, and particularly also if

have a phenotypic kind of thing like I think on a

setting, that would be a way of categorizing the

different kinds of patients.

DR. WEISMAN: I am Harlan Weisman. I am from

Centocor. Not necessarily from an industry standpoint, but

from a more simplistic physician’s standpoint, I don’t know

what remission is in Crohn’s disease, I don’t want to

pretend to, but remission to me means no disease. That is

certainly a laudable goal. It is the goal of cancer

therapy, it is a goal of a lot of things, but, you know, you

would like to think that there may be a therapy in which

there is

with any

no evidence of the disease.

Whether we can measure that or not, or know it

degree of certainty or not is a different question,

but it is something that I understand. I understand the

words. If you had a therapy that could achieve that, that

would be desirable I think.

Also, control of symptoms is desirable. I think

controlling the activity of disease is something I

understand, I am sure patients understand it. That is

desirable. And I understand the differences between those.

I am not sure I know how to measure them, but I know how to

MILLER REPORTINGCOMPANY, INC.S07 C Street,N.E.

Washington,D.C. 20002(202)546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

54

maybe for the wrong reasons, is that it is a continuous

variable. ACR-20 is an index in which you are dealing with

proportions of things, and I have just conceptually

difficulty understanding the ACR-20 or the Paulus 20 for

that reason, whereas, the CDAI, because it is

continuous index, is something I understand.

it is valid is a different question.

DR. HANAUER: Dr. Sands.

DR. SANDS: Bruce Sands, Boston.

measured as a

Whether or not

I think I would like to amplify what Brian Feagan

has already said, which is that there has been a lot of

discussion about how we describe responses, but very little

discussion about the yardsticks that we are using, and the

CDAI for sure has brought the field forward by providing a

common yardstick, but I don’t believe that is necessarily

the best yardstick, and I would argue that the IBDQ or

quality of life instrument is better.

I think the problem with the CDAI is that it

straddles the line between measuring elements of quality of

life and elements of biologic activity, if you will, and it

Sees neither particularly well. The IBDQ really focuses

very well on how the patient feels, which arguably is what

is most important in the end for a drug effect.

It is a very reliable measurement, very well

characterized in different populations, and it correlates


Washington, D.C. 20002(202) 546-6666



ajh

-—.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

56

felt was a major goal in view of the toxicity of the

disease, but the most important thing that we also put in

was duration, and I am always disturbed by studies in which

someone gets the CDAI to 140 for a goal, and that is the end

of the study, because that is not what the patient really

cares about. What the patient cares about, is that going to

go on for a month or two or three, and I think somewhere in

the criteria for

some durability,

improvement for a drug, one has to show

whether that is a month or a week or six

months, I think it is something that has to be put in the

indications because steroids may be a good drug for six or

eight weeks, but it may not be a good drug for a year.

You heard what Dr. Fries said, carrying it out on

a long-term duration, so I think there can be indications

for a drug for a period of time, but I think symptomatology,

and I have come to the conclusion, as Dr. Sands says, that

the IBDQ should be included in the goals, in other words,

make goals of therapy, but IBDQ rather than CDAI is probably

better because that is how the patient feels, and that is

what we all want to do.

DR. HANAUER’: Dr.” Goldstein.

DR. GOLDSTEIN: George Goldstein, Medera.

Steve, this is one of those rare moments. As the

father of a Crohn’s patient, as a pediatrician, and not

officially representing but as a member of the Executive


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

al

Committee of the Crohn’s and Colitis Foundation, I think we

ought to seize this rare moment.

I support David’s proposals. There is a crying

need for simplicity and clarity in this. From the point of

view of industry, simple, clear, easily understood

definitions, as Harlan Weisman and my Swedish colleague have

mentioned, with a phenotype, are something that I think we

can support and would make the job and the understanding of

the practicing physician,

points out, the patient’s

and, indeed, ultimately, as Dan

life a lot easier.

DR. HANAUER: Yes.

DR. LAINE: I was just going to reiterate my

opposition actually to including the endoscopic or

histologic parameters given the sense that my understanding

is the agency does not actually give indications for things

that don’t have clinical or physiologic correlates, and to

use the H. pylori area, which I am more interested in, you

know, H. pylori causes inflammation in all people who have

H. pylori, but H. pylori, healing of H. pylori” infection and

H. pylori gastritis cannot be considered by the agency as an

indication unless it is associated with ulcer, cancer, some

sort of clinical or physiologic endpoint, so I would say if

we don’t have any evidence that these endoscopic or

histologic features clearly correlate with clinical

~ndpoints, that we shouldn’t be including that as an

MILLERREPORTINGCOMPANY, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

indication for a sponsor.

DR. SIEGEL: There

58

are certain types of approval

based on surrogate endpoints, however, it is also correct

that we have outcome measures that are involved in approval

that require resolution of radiologic -- in other words, if

a drug improves survival in cancer patients, and the

patients were living longer without any symptoms, but had

nodules growing in their chest, we wouldn’t call that a

complete response. If the symptoms are completely resolved,

we wouldn’t call it a complete response.

DR. LAINE: But it is just it is felt to be an

association with the presence of cancer -- I mean there is a

fairly good correlation between the presence of cancer and

iioing badly, and there may not be that association between

H. pylori and gastritis and doing badly or histologic

inflammation in Crohn’s disease and doing badly, that is all

I am suggesting.

DR. SIEGEL: But this committee is suggesting --

what I hear this committee suggesting is that we talk about

treatment of active disease, and we say if the symptoms

~ompletely go away, we should call

m complete something that was the

that complete resolution

proposal even if the

=ndoscopy shows that the balance are completely inflamed

oecause we can’t rely on endoscopy, and that is not terribly

5issimilar to saying that you have a complete response in


Washington, D.C. 20002(202) 546-6666



aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

59

cancer while there is nodules growing.

DR. FEAGAN: How do you define complete

symptomatic response? I think this comes down to the cut

point versus where does the noise start, and you start

measuring signal.

DR. SIEGEL: No, I don’t think you want

CDAI under 150 a remission. I wouldn’t think you

to call

would want

to if people are unable to sit down because of fistulae,

that is not my idea of a complete remission.

DR. FEAGAN: I think the idea of fistulous

disease, I mean one proposal would be

is heterogeneic enough that we really

about it in a different set of metric

seems reasonable. I don’t think that

discussion.

that that population

should be talking

score, I mean that

that should color this

DR. FRANK: It disturbs me to completely throw out

nucosal hearing. I mean there is no question in the fact

that when the patient has severe mucosal disease, they are

Yoing to bleed, and that is symptomatic. They” are clearly

setter if they have complete

On the other hand,

can be totally irrelevant to

healing.

mucosal healing in the bowel

the presence or absence of

fistulas. The other thing is that if the patient has severe

~lcers in their colon, they are probably more susceptible to

perforation, and so they may be at higher risk of getting

I MILLER REPORTING COMPANY, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

60

sick even if at the moment they may not have symptoms.

so, I wouldn’t want to completely get rid of

mucosal healing.

DR. HANAUER: Dr. Rutgeerts.

DR. RUTGEERTS: Yes, I agree. I said that there

is no good correlation between endoscopic healing and

symptomatic improvement, but that does not mean that

endoscopic healing is not important.

I think in the studies, endoscopic endpoint should

be included because we will learn a lot from these

endoscopic studies, For instance, in the infliximab study,

if also the American centers had performed endoscopies, we

would have known much more about the relationship endoscopic

healing and symptomatic

DR. HA.NAUER:

improvement.

Should it be a regulatory requisite

to have endoscopic demonstration for every drug?

DR. RUTGEERTS: Well, it depends if you have a

drug --

DR. HANAUER: Or biologic.

DR. RUTGEERTS: If you have

known that it does not induce healing,

a drug for which it is

that endpoint is not

important. If you look at 5-ASA or corticosteroids, you

know you will not induce mucosal healing, so to include an

mdoscopic endpoint

lot of importance.

in a study you do with these drugs is

MILLER REPORTING COMP~Y, INC.507 c Street, N.E.

Washington, D.C. 20002(202) 546-6666



ajh

.P%1

2

3

4

5

6

i’

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

61

DR. HANAUER: So, this should be a separate

entity, a separate indication?

DR. RUTGEERTS: I think so.

DR. HANAUER: An extension.

DR. NEEMAN: In rheumatoid arthritis, there is a

claim structure, so you can get a claim for signs and

symptoms and then you get additional claims for additional

things that promote --

DR. HANAUER: Moving on to some additional things,

we talked about general, and I am trying to get everything

moving in a movement forward direction, and we talked about

general claims, and hear some consensus regarding that, but

what about these individual specific areas, should there be

separate criteria for fistula healing, steroid sparing?

Yes? Within those or additional? Are we adding on or

incorporating?

DR. LAINE: Separate.

DR. HANAUER: Separate.

DR. LAINE: And inclusive.

DR. SACHAR: They are subcategories, in my view,

of either treating active disease or preventing relapse. If

you treat a fistula that is there, and make it go away, that

is treatment of active disease. If the fistula has gone

sway, and you want to prevent it from coming back, that is

still fistulous disease, but that is prevention of relapse.

MILLER REPORTING COMPANY, INC.507 C Street, N.E,

Washingtonr D.C. 20002(202) 546-6666



----

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

,.62

DR. LAINE: The question is could those be

individual claims on their own, and yesterday we said yes,

because

I think

steroid

achieve

worth a

we said fistula closing is an individual claim, and

it is different enough that I would favor that, and

sparing alone, it would seem to me, if you could

the same effect with no steroids, that would be

claim I think to most patients and physicians.

DR. SACHAR: Although steroid sparing is then a

category of prevention of relapse. The patient could come

off steroids and not relapse. So, I think it is possible to

take all of these separate categories and classify them

either as treatment of active disease or prevention of

relapse. And what is it you are trying to prevent or what

is it you are trying to treat, it is symptoms, it is

ulcerations, it’s fistulae.

DR. SIEGEL: But the question really we need an

answer to is if somebody does a study successfully, which

shows which shows that fistulae closed or that shows that

you can taper steroids in the patients who get’ the drug, but

not in those who didn’t, you say you could classify those as

treatment of active disease, but would you want the labeled

indication to say this is indicated to treat active disease

or should there be an

closure of fistula or

DR. SACHAR:

indication that specifically says

sparing of steroids?

That is what we are here to discuss.


Washington, D.C. 20002(202) 546-6666



#=e

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

63

I would vote with those who say the closure of fistula is,

worthwhile as a specific indication, and that when we talk

about steroid sparing, that by itself doesn’t mean anything,

it is steroid sparing and what? I mean all you have to do

is just stop taking steroids, and you are not taking

steroids, but it is steroid sparing without what then

happening, and it is either without getting symptoms back

again or without having

DR. HANAUER:

now, B, steroid sparing

a fistula open.

A, you are trying to simplify, but

is going to be prevention of relapse

but with withdrawal, how would you define steroid sparing,

is it a subcategory of treatment of active disease, a

subcategory of prevention of relapse, or an individual n

number indication?

DR. SACHAR: In my view, by definition, it is a

subcategory of prevention of relapse, because that is what

You are trying to do, you are trying to get the patient off

the steroid and not relapse, so however you define

~revention of relapse, steroid sparing is one of the

categories of that, just as prevention of postoperative

relapse is another category within prevention of relapse.

DR. HANAUER: So, additional verbiage, words in

the indications, they can be easily modified and extended

~eyond even what we are anticipating.

DR. SIEGEL: Absolutely, and steroid sparing,


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

64

designs have been attempted in a number of diseases, and the

basic approach I think is consistent with what you are

suggesting.

You take patients not necessarily in full

remission, but at any given stage, in a defined clinical

status, as you would for any clinical trial, that are on

steroids, you give them a new drug or placebo, and then you

attempt -- blinded usually -- then you define failure

points, so a new fistula, increase in CBAI, whatever you

want to define as a failure point, and you attempt to taper

the steroids, and you measure, not improvement in disease --

and that is why the indication is a little different from

treatment of acute disease, they are not getting better, but

you are showing that you can maintain where they are and

more successfully decrease steroids while --

DR. SACHAR: A failure point is a synonym for

relapse.

DR. HANAUER: In the absence of other indications.

DR. SIEGEL: Well, relapse implies remission. You.,

may have people with active disease, and that may be a

synonym for flare.

DR. SACHAR: Relapse or flare.

DR. KIRSCHNER: Or even initial active disease.

DR. LAINE: It is staying the same level or better

is really what it is. I mean no matter where you start, it


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

.—.= 13

14

15

16

17

18

19

20

21

22

23

24

.-=25

65

is staying at the same level or better.

DR. HANAUER: Is prevention of worsening disease

an indication?

DR. SIEGEL: Well, it is.

DR. HANAUER”: IN RA it is, but we don’t accept it.

DR. SIEGEL: In another chronic disease, I should

say, in multiple sclerosis, for example, we have given two

different indications, one for preventing the flares, which

is essentially a symptomatic one, if it is a recurring

relapsing disease, and

iiisability. Sor there

DR. HANAUER:

another for preventing progression of

are certain parallels there.

This was mentioned. Is improvement

in quality of life sufficient as an individual indication

for therapy without other evidence? Dr. Sands says it is.

Dr. Feagan is somewhat in favor of that.

DR. FEAGAN: I didn’t say that.

DR. HANAUER: He is not in favor. He didn’t say

sither way. He is on the border, so to speak.

DR. FRANK: If you reconstruct a CDAI, what is a

7DAI ? It is a quality of life measure essentially with a

few biological thrown in. So, I don’t think it is a

quantum leap, but there is a considerable body of knowledge

that suggests it is a useful measure, so I think the issue

of whether you accept or reject it is -- again, a wider

~onsensus and you don.”t make those decisions without a


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

2.0

21

22

23

24

25

,, 66

considered review of the operating properties.

The point was made about the operating properties

of the CDAI being superior. That is not really true. The

responsiveness is a little less in the CDAI when it is

measured against external gold standards, such as patient

globals, so again, I think these terms, definitions, and a

considered overview of operating properties before these

decisions are made.

DR. SAC!HAR: As a predictor of a need for steroids

or as a predictor of need for surgery, and I think the IBDQ

did a little better than the CBAI.

DR. FEAGAN: Well, talking about responsiveness, I

was really looking at external criteria, patient globals and

physician globals. I think the point you are raising,

David, is what endpoint do you use for externality. It

huge problem. If we had a wonderful gold standard like

angiogram, we wouldn’t be sitting here being perplexed.

is a

an

DR. LAINE: It would seem to me that given a good

instrument, there is no doubt the quality of life should be

an indication on its own personally.

DR. SURAWICZ: Since the correlation is so good

between IBDQ and CDAI, why have this as a separate outcome?

I think that IBDQ would be very useful if it would pick up

also side effects of drugs, and it doesn’t do that, and that

is a major drawback I think.


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

., 68

attainable, because the surgeons can get a complete

resolution of disease from a surgical standpoint to leave

you at baseline. The durability of that is in question.

DR. SENIOR: Well, they haven’t gotten rid of the

disease because the disease is still there in the tissue

that remains.

DR. HANAUER: No, it is not, not measurable by any

criteria.

DR. SENIOR: Not measurable, but I am just

concerned about complete response, that’s all.

DR. HANAUER: Janet had some comments about -- you

~anted to discuss the measurability?

DR. ELASHOFF: It probably comes under B(2) best

~hen we talk about the issue of doing a mean change versus

~hat sort of thing, but I do want to discuss that when we

3et to that.

DR. HANAUER: Okay. To move on to hopefully some

=impler aspects of this, is what is the durability. The

iraft guidance suggest a study duration of 8 to 26 weeks to

~stablish an effect on active disease or remission -- I will

~xtend that -- and from 12 to 24 months to justify

?revention of relapse to modify our current terminology that

we are using.

What should the study duration be for an active

iisease, is 8 to 26 weeks?


Washington, D.C. 20002(202) 546-6666



.—=

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

69

DR. SACHAR: To compete with steroids, you could

even do it in 4 weeks.

DR. HANAUER: Is that sufficient?

DR. FEAGAN: It was yesterday.

DR. HANAUER’: Are’you satisfied with that? Are

you satisfied with what you saw from yesterday’s response?

DR. FEAGAN: Yes.

DR. HANAUER: Okay.

DR. KIRSCHNER: No.

DR. HANAUER: Dr. Kirschner?

DR. KIRSCHNER: I wasn’t here yesterday, so I

missed that discussion, but I

6-MP, which we feel can treat

would be insufficient, unless

high-dose intravenous; but we

mean if we are talking about

active disease, then, 4 weeks

we are talking about possibly

consider that to be an

effective drug. That is not within 4 weeks.

DR. HANAUER: We are talking a minimum, not

maximum.

DR. SIEGEL: The question here, as I-read it, is

about not where the endpoint is measured, but the study

duration. I would note that neither of the studies we heard

about last week only had 4 weeks to follow up, if the

committee is saying that it would be okay to just study a

patient for 4 weeks and report those results, that is a very

different thing from saying j.t would be okay to measure at 4


Washington, D.C. 20002(202) 546-6666



.-.

aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

71

DR. HANAUER: Let me state it a different way.

What is the minimal durability for treatment of active

disease? How is that?

DR. LAINE: It really does totally depend on the

drug, though. It is a little hard --

DR. HANAUER: But what is the minimum that the

government should insist on? They don’t want you feeling

better for a day, and the patients would like to feel better

for a day, and then they will leave it to the rest of us.

DR. LAINE: Let’s say a drug that makes you

totally better in one day --

DR. HANAUER: For one day.

DR. LAINE: No, in one

Weeks, and for 4 weeks with that

and every index is down to zero,

incredible drug. Would that not

day -- and it lasts for 4

drug you are feeling great,

let’s make up some

be acceptable?

I mean we don’t have anything like that, and we

nay not see anything in the future, but I think it is very

~ard to predict, when you are doing guideline documents, it

is very hard to predict without knowing the nature of the

~rug. Then, you would normally want

follow up based on the initial Phase

tiould think.

to make the length of

I studies of the drug I

DR. HANA~R; They. are asking clinical guidance

Erom. us What is the minimal clinical durability of an


Washington, D.C. 20002(202) 546-6666



ajh

__& _-=

L-.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

acceptance for an acute drug,

it 4 weeks? Is that too much

DR. WEISS: I guess

72

is it a day, is it a week, is

to ask?

there are two things that

maybe we are confusing here, or maybe it’s just me, but

there is giving -- like we saw yesterday, it’s a good

example -- giving an agent in a single dose and seeing how

long the response lasts, the durability of response, but the

other thing is guidance on how long

should go on and whether or not you

one point or look at the area under

particular period of time. Perhaps

would be better.

these initial studies

measure the response at

the curve over that

nearer to the curve

But what we are talking about what is the minimal

duration a study should be designed, the length of time for

that particular study?

DR. LAINE: This has to establish remission, so

really all you are asking is, what Steve said, how long does

a patient have to have a remission before you are willing to

accept that as a remission.

DR. HANAUER: A response.

DR. LAINE: A response.

DR. HANAUER:Not necessarily remission, response.

Dr. Simon.

DR. SIMON: The only way you can do that is if you

define the remission, so if you are going to say signs and


Washington, D.C. zoooz(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

73

symptoms of the patient feeling better by certain measurable

criteria, you may be able to say 8 weeks or 12 weeks. If

you are going to say, in fact, that you are expecting X

other parts of the disease to be gone for a period of time,

that may be 26 weeks. In rheumatology, we said signs and

symptoms of disease for 6 months, structural abnormalities

of disease in a year, and that is mainly because we can’t

measure it in less than a year.

so, it just depends on one’s considerations of

what you are really asking the response to be measured by,

and how you are going to distinguish that and what is the

validity of it, what is the internal characteristics of the

measurement, and are there differences between point A and

point B.

DR. WEISS: Dr. Simon, when you have 6 months, is

it a landmark right at 6 months, did you look at time points

all along and do an area under the curve?

DR. SIMON: You do time points all along and do

area under the curve, and that is really the critical issue,

but I haven’t heard us define what you are measuring and

then whatever you are using to measure that with the

validity of it from point A to point B.

DR. LAINE: Yesterday, as Steve said, we accepted

that 4 weeks of a remission was good enough response.

Admittedly, the study went longer, but you are asking how


Washington, D.C. 20002(202) 546-6666



aj h

1

2

3

4

5

6

7

8

9

10

11

12

_—_ 13

14

15

16

17

18

19

20

21

22

23

24

25&’— .

74

long, so I mean in a sense we have already said that this

drug works for 4 weeks in length, that it is acceptable to

us .

DR. HANAUER: Basically, for RA, to look at your

guidelines to give us a guideline for our guidance, they

said for new drugs the trials must go on for 6 months. It

is not to say the effect must last, but the trials are of 6

months with a defined response unless the drug is well

classified and already available.

so, in RA, they are proposing that a study must go

on for 6 months.

DR. NEEMAN: And that is true and we have also

accepted a 6-month landmark analysis although we have been

encouraging sponsors to look at duration and measure things

over time.

DR. HANAUER: Do potential sponsors want to

comment on the necessity of a 6-month trial for a new drug?

DR. WEISS: I think that is what we would like. .

know. Is there a minimum duration? In RA, it”has been

recommended that there should be a minimum of at least 6

to

months on study, and there is trials, you know, many of them

-. there is cross-overs and other things, 6 months is the

end of the trial. We heard yesterday 4 weeks was, for all

intents and purposes sort of the end of that --

DR. HANAUER: To be fair to the company, they did


Washington, D.C. 20002(202) 546-6666

. . -.



aj h

(-

,.=-

[..

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

75

have follow-up for 6 months. That is not to criticize the

company.

to detect

DR. FRANK: It seems

safety issues beyond

to me you need the 6 months

the efficacy issues also.

DR. ZELDIS: I am Jerry Zeldis from Celgene

I am just looking at your draft guidelines, and

getou are defining two types of treatments, those which

rid of symptoms of acute disease and those which maintain

remission. There may be categories of drugs which are

superb for inducing or stopping active disease, but they

will not work for maintaining remission and vice versa, and

I would go back to a point that Loren made five minutes ago,

that it really is dependent on the drug. I will use

thalidomide in leprosy as an example. In ENL, steroids

would take about a month before you saw an effect. When you

came in with thalidomide, you saw a very excellent effect, a

superb effect within 3 days.

It turns out that thalidomide is good to maintain

remission, as well, but the point is that I could see drugs

where you knock down the active inflammation, then, you come

in with some other drug to maintain the remission.

I think at this point it is too arbitrary to say 6

months, a month, or whatever, until you know what you are

dealing with.

DR. HANAUER: Dr. Weisman.



(202) 546-6666



ajh

.-..

.-..

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

weeks for

RA, it is

76

DR. WEISMAN: Just historically, why we chose 4.

Crohn’s disease, when we have a clinical trial in

almost completed, and it will have an endpoint of

a little more than 6 months, and it goes somewhat to what

Dan was saying, and other people were saying, and I tried to

say earlier, it does to some extent depend also what the

patients needs and want, and we heard that yesterday from

the patient on the committee, as well as some of the other

patients, RA and Crohn’s disease are fundamentally

iifferent.

What we were told by our experts who are

rheumatologists is that a therapy that is only for 6 months

ioesn’t mean very much to the doctors, it doesn’t mean very

nuch for patients. That is the nature of R-A. RAisa

uhronic, gnawing disease that goes on and is thought of over

course of the

Crohn’ s

long term.

disease is a disease which can be

devastating over a very short period of time, and the relief

>f those devastating symptoms is very meaningful to the

?atients, whereas in RA, I think under most circumstances

:hat is not the case.

so, I would say it is

iisease to another. We chose 4

>ecause we were told in talking

ire on the panel, that that was

MILLER REPORTING

exactly translatable, one

weeks for Crohn’s disease

to our experts, some of whom

meaningful, that that meant

COMPANY, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666

--.”— .



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

something to

think it was

We

patients,

validated

were told

77

it meant something to doctors, and, I

yesterday.

in RA, anything less than 6 months

isn’t very meaningful” to us’.” That is why we chose 6 months.

DR. HANAUER: We brain-wash our patients

differently.

DR. PORTER: Steve Porter, Therapeutic Antibodies.

I would like to amplify the concept that we not

get ourselves into another conundrum of 28-day all-cause

nortality scenarios

an agent that would

very actively remit

Eor a long period of time. Reset the rheostat would be a

Very important paradigm in this disease state, and things

that work that rapidly, acutely, and have benefit ought to

~e examined and not be held to a 4- or an 8-week or some

arbitrary endpoint if they have real net term benefit of

resetting a rheostat

Iormative process of

?atient population.


DR. SIMON: However, if you are resetting the

rheostat, then, you would expect that rheostat would have

~een reset for that .6;month..period or 3-month period or

and I would be deliciously happy to have

do something very fast, very rapidly,

something, and maintain that remission

and allowing other drugs and the

natural healing be eviden’t in that

whatever you are talking about.


Washington, D.C. 20002(2o2) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

_.-. 13

14

15

16

17

18

19

20

21

22

23

24

25

79

DR. HANAUER: I wish I had you quoted elsewhere

where Dr. Present’s previous lifetime, whatever he was then,

used to say this is a’ disease of a lifetime, I don’t care

about 6 months, I want to know about 6 years.

DR. PRESENT: I do want to know about 6 years, but

the patients want to know, they want to know about 6 months.

DR. SACHAR: Actually, it was only 2 years ago

that Dr. Present was decrying the use of any quality of life

measurements at all, so he really has come a long way.

On the point of the 6 months, then, the

cyclosporine works for 6 months, but needs take-over therapy

with 6-MP, therefore, it seems to me that you would not be

calling cyclosporine an adequate drug for maintenance of

remission, that 6 months would still be within sort of the

treatment of the active disease. If it is not acting beyond

6 months, you are really not thinking of it, are you, as a

remission-maintaining drug?

DR. PRESENT: I believe cyclosporine can maintain

remission. The problem is toxicity, and that is why we

discontinued cyclosporine in ulcerative colitis, not in

Crohn’s disease.

DR. HANAUER: Let’s not get into specifics.

DR. PRESENT: SO,

drug for some diseases, not

DR. HANAUER: Dr.

I think that it is a maintenance

for all.

Goldstein.


Washington, D.C. 20002(2o2) 546-6666



ajh

—=-1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

DR. GOLDSTEIN:

same point. At the front

80

TWO points. Well, basically, the

end was the kick-in time that

David mentioned, but let us not forget the back end, the

restoration of responsiveness where it had, so to speak,

gone, and the fact that the measurement of time in which one

is remitted by a drug, whether it be 2 weeks or 6 weeks or 6

months, may in fact allow time for other drugs to be used.

We heard this yesterday and we will doubtless hear

it again.


DR. SIMON: But isn’t there a sense of time

inherent to the term remission? Remission has to mean no

disease, however you are going to measure that, and that it

is meaningless to say somebody has no disease for 3 months

or 6 months. There has to be some inherent sense, because

you are looking for indication meaning that if a drug some

up and says it has demonstrated that it remits disease, it

remits it for how long? That is important.

DR. HANAUER: I think we will duly state that the

committee feels 12 to 24 months is appropriate, but with

respect to Dr. Present who says 6 months is okay for chronic

disease. We will get that on the record.

DR. MATTHEWS: I am sorry, I just need some

clarification because now I am getting confused between

remission and treatment of active disease.


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

82

DR. GmFFNER: And one year. I think it is fair

to state that you don’t teach a drowning man how to swim,

you drag him ashore, and that is what you do in the Crohn

community

treatment

being

would

where

put

because they are kind of drowning, and that is

of active disease.

Then, the patients need to learn how to swim by

on something else, another kind of agent which

prevent relapse. From an industry viewpoint, that is

the line is, so you don’t need to worry about that,

because we all want to have good drugs for preventing

relapse.

DR. SACHAR: This” is indeed a chronic disease, but

it is one characterized by exacerbations and remissions,

flare-ups, so what we are really talking about is the

treatment of an exacerbation.

DR. MATTHEWS: So is rheumatoid arthritis, so that

is why I am getting a little confused, because, yes, it is

an exacerbation, and you get a product, and you quiet it

down, and I can understand -- and that can be One

indication, but then the question comes in -- I guess this

is where it goes back to the definition of remission,

because it seems like there can be some sort of a stage in

between where patients may not be so severe that they are

borderline on surgery, but they can be quiescent, although

not in remission, but are able to cope with life, because


Washington,D.C. 20002(202)546-6666



ajh

..-=1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

83

not all products are going to be as remarkable about what,

you heard yesterday. I mean we have to keep that in mind

and we don’t want to prevent that development from going on,

because not all patients responded to infliximab.

DR. SACHAR: Thinking not just of the product, but

of the disease, you touched on the important implication of

surgery. There are flare of Crohn’s disease that can have a

life-threatening implication within a month if the fire

isn’t put out, and can lead to some kind of need of major

surgery if the fire is not put out within a month, and that

is why we are talking about certain situations in Crohn’s

disease as opposed to RA where putting the fire out for a ;

month isn’t a

DR.

there is some

worthwhile goal.

MATTHEWS: But my concern is the fact that if

statement that says unless it

there won’t be an incentive for development

will study further. That is my concern.

is fine, that

of drugs that we

DR. SIEGEL: There is a difference between

indications we discussed yesterday for short term or even

for one-time use to control acute symptoms. Whether or not

it is induction of complete remission, it has quieted down,

it is induction at some level, it is treating an acute flare

versus chronic -- 1 think the indication in the RA document

for treatment of signs and symptoms, that 6 months is not so

much focused on the ability to show effect on a flare, but

MILLER REPORTINGCOMPANY, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

84

rather on a drug intended to be taken on a chronic basis,

and if a drug is intended to be given on a chronic basis,

the idea was, in that disease at least, that 6 months of

therapy would be -- in fact, in the initial attempts, in

yesterday’s study, to look at chronic use, it was very small

numbers in the retreatment phase, that went out 48 weeks.

DR. NEEW: Patients were dosed up to 36 weeks.

DR. SIEGEL: That is really something somewhat

distinct from I think what you are talking about in terms of

treating a flare, an acute flare.

DR. HANAUER: The last point on this issue. Dr.

Kirschner.

DR. KIRSCHNER:

probably hundreds of kids

As a pediatrician who has seen

with JRA, as well as the same with

inflammatory bowel disease, I think we are giving kind of a

misperception, at least from my point of view, about what

grohn’s Disease is. There may be 50 percent or so that have

active disease and they have exacerbations and remissions,

and there are at least 50 percent you are dealing with all

the time that have essentially chronic active disease.

I think our patients’ expectation, particularly

for having new drugs that we don’t know their safety, we

don’t know their

duration, that a

who have already

side effects, we don’t know

four-week period of time in

failed other therapies, are



the long-term

these patients

expecting more

(202) 546-6666- .



ajh

.——..1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

85

than a 4-week response to a drug.

I guess we can say they then get it every month,

so that they would have to have it at 4-week intervals, but

they are expecting as are their physicians, more than a 4-

week control of disease. These are chronically active

patients.

DR. HANAUER: We heard yesterday -- and I agree

with you, expecting and accepting are different conditions,

they expect more, but they will accept we heard yesterday a

shorter response. They would like more, but they will

accept a new drug if it only gave them 4 to 8 weeks of

improvement . We heard that they would accept that. But we

Want more. It is not an issue, We, of course, want more,

and we will give them more from an indication standpoint if

they can prove durability in this.

DR. KIRSCHNER: If they accept 4 weeks, does that

nean that they are assuming that they can then get it 4

weeks again and prolong

happy with only 4 weeks

DR. HANAUER:

the remission, or they would be

if it loses its efficacy?

We are not talking about how we

treat the patients here. We are talking about how we

approve new drugs for patients, and we have

issue. We are keeping them in mind, but we

they would accept, and this committee would

ninimum response of 4 weeks. We would like


Washington, D.C. 20002(202) 546-6666

to divorce that

did hear that

accept, a

more for you and



ajh

,#—

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

88

Centocor put together last night, which for their two

studies shows the relationship between baseline CDAI and 4-

week CDAI for the T16 study, a plot or scatterplot where the

first plot distinguishes between placebo and all of the

active treatments, the second plot distinguishes the

different doses of the active treatment.

The additional plots are for the T20 trial at the

2-week and at the 6-week point. I would simply say that

looking at that kind of information in some detail helps

with exactly how you are going to decide to look at it, mean

change or whether one wants analysis of covariance or

something like that.

Specifically for CDAI, it appear that the linear

relationship between pre- and post is much the same in the

T20 trial as it was in the T16 trial even though much lower

down the scale. There doesn’t seem to be a lot of bend

which would make one a little unhappy with that sort of

thing.

The spread around the curve is reasonably

in the T16 trial as it is in the T20 trial although

similar

it does

narrow a bit in the lower doses, and the placebo group

pre/post relationship versus

relationship do appear to be

would support an analysis of

that I would argue for using

the active treatment pre/post

reasonably parallel, which

covariance or a mean change, so

the more continuous measurement

MILLER REPORTING COMPAm, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666



.-.

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

89

or examining if one, for example, went to the IBDQ instead

to examine that in a similar way to see what is really going

on with the characteristics before one finalizes exactly how

one

are

cut

the

the

wants to look at it because the underlying assumptions

always important here.

DR. HANAUER: Stated another way, if you take a

Off of remission at 150, for instance, for an example of

CDAI versus a

problems that

mean change of drug versus placebo, one of

we are going to be confronted with is what

is a clinically relevant difference, and if you show a 10-

?oint reduction in CDAI with drug versus placebo, that may

be a statistical difference, but most of us would agree that

it is not a relevant difference.

Should we then have two criteria, do you need a

ninimal change in addition to a mean change?

DR. ELASHOFF: I would like to make two points

about that from a statistical point of view.

First of all, when you power the study, when you

figure out how many people you are going to need, you power

it for detecting a particular size of mean change, and you

uould obviously, if you feel that

important, that is what you would

DR. HANAUER: Does that

ninimal criteria?

a change of 70 is

power the study for.

mean that should be the

DR. ELASHOFF: Let me make an additional comment


Washington, D.C. 20002(202) 546-6666



.-p=+

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

90

before we get to that.

The second is that you don’t entirely get away

from that issue in doing things the way they were done in

T16, because although you said 70 was the important cut

point, first of all,

somebody who changed

is pretty arbitrary,

you distinguish in a big way between

69 and somebody who changed 71, which

but secondly, only about 50 to 60

percent of the treated patients met that cut point.

In addition to making the cut point, you need to

say how many patients ought to be making that, and we could

have insisted it was 70 or 80 percent, we might have, if the

study was big enough, seen a distinction between the drug

and the placebo, but even if it was only 35 percent of

people who made whatever cut point that was, so you don’t

entirety get away from that issue even when you are using

cut points.

Definitely, I would say that you should always

address the clinical importance issue, as well, but you

don’t have that as a hard-to-deal-with leftove”r doing mean,

and not have it the other way. You have it in both

instances because both

define how many people

DR. SACHAR:

you define the cut point and you

have to reach it.

I like to be collegial and flexible,

but I am really unalterably and emphatically opposed to the

use of an overall group effect. It is clinically


Washington, D.C. 20002(202) 546-6666

...—



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

91

meaningless. You can deal with a sigmoidoscopy score going

from 3.4 to 2.2 as a mean. You deal with reducing steroids

from a mean of 45 to a mean of 30, you can get your CDAI

from a mean of 350 down to a mean of 250.

You can prove anything with a mean overall score

that is worthless, worthless information when to comes to

whether the drug is any good for treating the patients,

worthless.

DR. SIEGEL: Why would not cutting the mean

steroid use or improving the mean score by 100 points, why

would that be worthless?

DR. SACHAR: Because it would give you no

information as to what proportion of patients are going to

improve on the drug. You can’t calculate it.

DR. SIEGEL: I guess if you define the only

information of worth is the proportion of patients who

improve on the drug --

DR. SACHAR: That to me is the only information of

worth. It is a self-fulfilling prophesy because I am

starting a priori only wanting to know what proportion of

patients are going to benefit from this drug, not what is

going to happen to the group mean score. I can’t conceive

of a situation where that would be useful to me.


DR. SIMON: I would point out two things.



(202) 546-6666... ......,..,_ .

One is



-._-

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

the issue of expectation bias and the movement toward the

mean under big, large populations, number one, and number

two , we grappled with this whole issue as it related to

rheumatoid arthritis, and the concept was that we decided

create consensus of what it meant to have a clinically

92

to

significant response, whatever that was, and we decided --

again a little embarrassed about the fact that it is partly

related to technology and what is measurable -- but we

decided that a 20 percent response, in whatever the variable

was, was the minimal variable that we would accept as a

change of importance as it related to what the patient also

thought was important.

so, that might be joint counts, that might

VAS scale, that might be something else, and we also

the idea of a damage scale, the idea that either the

could cause damage or the disease could cause damage,

be a

created

drug

and

there would be activities that you would measure that would

be incorporated or parallel measurements to look at those

issues, and again would require some percentage association

for change that was valid, reliable, and show a difference

between point A and point B.

DR. SACHAR: Did you measure proportion of

patients or overall group scores?

DR. SIMON: Proportion of patients. It would have

to be on an individualized patient basis. It would have to


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

94

size calculations many different times, it just isn’t there

actually. It is actually more efficient to continue to

dichotomize at that 150.

That is an issue and then the issue of treating it

as a continuous variable, the interpretation of a delta CDAI

in sicker patient populations, when the variance is much

larger, 100 to 150 for the change scores versus, at the

lower end of the curve again creates a problem that I don’t

think they mean the same thing.

DR. SIEGEL: SO, if somebody did a study in very

severe disease where the baselines were all 400 to 600, and

all the patients wound up clustered around 200, we would

call that a failed drug --

DR. FEAGAN: If you move 100 points from 400 to

300, I don’t think that is clinically meaningful, and I am

not sure it is even -- from a measurement standpoint,

because it is not efficient from a measurement standpoint

because of the variance.

DR. SACHAR: It is excessively driven by counting

bowel movements, which is a highly invariable count.

DR. SIEGEL: I would suggest that what is reliable

and reproducible in an individual may not be in a

population, which is to say it may

goes from 8 bloody bowel movements

individual, and one of the reasons

not matter if somebody

to 4 or 6 as an

it may not matter is the



(202) 546-6666,....



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

next day

in fact,

95

they may be as likely to have 8 as to have 4, but,

if you do hundreds of individuals, and you move an

average from 8 to 4,

level of statistical

you may well be demonstrating some

certainty that people are on this drug

having this many bowel movements.

What you are saying is that knowing cutting bowel

movements in half doesn’t matter, really, you have to get it

below a cut point, that if you are not below 1, you haven’t

done anything, that is one thing, but if what you are saying

is that smaller changes, you are not comfortable with

because of other factors, such as particularly variability

of the response or weighing them against toxicity, which is

another issue than cost, that needs to be dealt with

differently.

DR. HANAUER: Are there clinicians, clinical

investigators who feel differently than what you have heard

from Dr. Sachar, myself, Dr. l?eagan, that some percentage

reduction is valuable?

DR. FEAGAN: I don’t have

means. I think it is just means in

a problem with using

this specific

application of CDAI scores. I am not sure what means mean

at the top end of very high CDAI scores.

DR. ELASHOFF: I would like to comment on that

specifically. That is partly a matter of the score itself

which a small kind of resealing of the score would take care

MILI~ERREPORTINGCOMPANY, lNC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666

....



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

96

of, and you could make it uniformly variable at the

beginning and at the end.

That is a specific statistical

could be taken care of. In fact, if the

kind of thing which

scores are

reasonably uniformly distributed around that sort of thing,

proportion making a certain amount of change is directly

calculatable from the mean change and from the standard

deviation. They are not completely separate things. They

are completely related from a statistical point of view, and

they could be

DR.

DR.

defined in a related way.

HANAUER : Last comment. Dr. Kirschner.

KIRSCHNER: From a pediatric point of view, we

have much less data, but since the CDAI really doesn’t fit,

it seems to underestimate severity of disease, we have been

talking among our

Research Group of

pediatric CDAI as

North American Society of Pediatric

taking 30 percent reduction in the

a modifier because 188 could indicate a

Very severe disease for us, way below what is published in

the literature for adults.

DR. SACHAR: Are you looking at overall group

affect or proportions of

DR. KIRSCHNER:

patients achieving that goal?

Each individual patient reducing

their score by 30 percent.

DR. ELASHOFF: If you do a proportion on each

?atient, it is essentially just the same as taking a change


Washington, D.C. 20002(202) 546-6666



_A=

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

98

You take are of that, and that is a question that

everybody wants to know through secondary analyses. I was

just talking to Kevan Anderson, who is the head of

statistics at Centocor, and he pointed out that the

committee didn’t just look at our primary endpoint. The

primary endpoint was important, that was our primary

hypothesis that was being tested, it was judged to be

meaningful, but if we had a primary endpoint that was

meaningful at 4 weeks, and everybody was sicker at 8 weeks,

I bet the outcome of yesterday’s committee meeting would

have been different.

DR. HANAUER: But you would have selected a

primary endpoint of being at mean reduction and CDAI

compared to placebo and came in with a 30-point

statistically significant, well-powered study.

DR. WEISMAN: And it goes to the point that you

can overpower things, and the reality is that you judge what

a meaningful difference is. There are statistically

significant differences that may not be clinically

significant, so if you do a 10,000-patient study and show a

Very small change, it may not have clinical significance,

Out that is one of the reasons we have advisory committees,

oecause

?rimary

the advisory committee didn’t just look at our

endpoint.

They looked at our secondary analyses, in fact, we


Washington, D.C. 20002(202) 546-6666



. n .

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

99

ranked our secondary analyses of ones of importance. Some

of them had to do with the duration of effect, some of them

had to do with consistency of the effect. Some of them had

to do with magnitude of the effect.

Those kinds of things

them go into the judgment about

clinically meaningful to render

are important and all of

whether what you saw was

an opinion, and I would say,

Dr. Sachar, this is really an issue of what are the best

analytical techniques available to us to make judgments, but

you clearly want to guard against what you are concerned

about, but I think people know how to do that.

DR. SACHAR: I am not concerned about just what

happened with some of the TA studies where you have tens of

thousands of records, and you can show a difference of a

tenth of a point in hemoglobin or something and get

tremendous statistical significance. I think we are all

sophisticated enough to be able to dismiss statistically

significant changes

trivial.

But there

that are biological or clinically

are measures like the CDAI where you

~ould have many patients going from 20 bowel movements to 10

Dowel movements or something, which has an enormous impact

m the CDAI, multiply by factors of 7, all that. It is

really going to be clinically meaningless although the

softly clamped modification of collapsing some of these


Washington, D.C. 20002(202) 546-6666

,,. .....-



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

101

guidance document. It is very important issue in Crohn’s

disease from a clinical standpoint and also from

pharmaceutical development standpoint because I know that

many in industry have tried to tackle this issue.

That is related to steroids. Also, it pertains to

the statistical issue. The question is -- there are

actually two questions related to steroid therapy and

steroid dependence -- the first is, is a reduction in

steroid use an acceptable indication or is complete

elimination of steroids the desirable indication, and the

second question is what is the durability of that response,

is just getting them off for a day okay or in order to

achieve the indication, is some life span off of steroids

necessary?

Dr. Kirschner.

DR. KIRSCHNER: For the same reasons we talked

about before, we view this for many of the kids chronic

active disease, and there are a number of studies in the

pediatric literature suggesting that steroids can have some

benefit in those that have

relapsing disease, so from

it in the same way we have

chronically active disease or

out point of view, I guess I see

talked about some other things as

complete withdrawal and partial withdrawal.

If we could get the steroids down from 50 mg a day

to less than 10 mg a day or every other day, that would be


Washington, D.C. 2000Z(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

102

of benefit. Now , it would be ideal to have discontinuation

of therapy, but we wouldn’t view

15 mg a day to less than 10 mg a

chose or every other day.

it as a failure going from

day or some amount that we

DR. HANAUER: SO, in your laundry list of

indications, this would go under the heading of prevention

of relapse, steroid withdrawal, partial reduction or

complete reduction?

DR. SACHAR: Right, and there are ample precedence

to help answer your questions because if we are talking

about prevention of relapse, we have already said it should

be for about 12 months minimum getting a patient off

steroids for 3 months and then relapsing or 4 months and

then relapsing, would not for some of us be a worthwhile

goal .

DR. HANAUER: SO, for duration you

one year off steroids? That also requires a

are proposing

one-year,

minimum one-year trial for approval of that indication. Can

Rheumatology just give us your guidance on guidelines?

DR. SIMON: We have incorporated the knowledge

base that it is believed it is less than 7 1/2 mg prednisone

a day is far less toxic than more than that, so therefore,

we have aimed to get patients on a dose of less than 7 1/2

mg a day.

Howeverr we have also agreed that if you think


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24-——..

25

103

about remission of disease, it would be nice to be off of

all drugs and cured, because that is an ultimate goal that

we are trying to reach, so it is a continuum, like a

continual variable. It is going all the way down, instead

of making cuts, and we accept the achievement of less than 7

1/2 mg as a laudable goal.

DR. HANAUER: For what time period?

DR. SIMON: I don’t think we actually added a time

period to that as an indication, did we? No.

DR. HANAUER: So, you get them down to 7 1/2 mg a

day and it’s okay.

DR. SIMON: Since that never happens, that didn’t

come up.

DR. NEEMAN: I think probably the way steroid

reduction would be measured would be as area under the curve

over a period of time, so we are not talking about a single

day reduction, but over the course of the trial what would

be the average steroid use, maybe not starting from day one,

but say starting from week 16 to week 48.

DR. HANAUER: The average dose area under the

curve is 7.5 or less, that the AUC averaged out to 7 1/2 mg?

DR. NEEMAN: We haven’t seen any steroid sparing

trials in RA.

DR. HANAUER: Okay. So, it is a goal.

DR. SIEGEL: There was a steroid sparing trial in


Washington, D.C. 20002(202) 546-6666



_n.

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

104

lupus . Yesterday, somebody commented there were a lot of

patients on steroids that are not responding to them, which

led me to wonder why they are on the steroids, but, in fact,

there was a trial, as I

sparing, where patients

drug, and steroids were

failed because tapering

the placebo arm without

DR. HANAUER:

but you guys haven’t --

understand in lupus, of steroid

received either placebo or a study

tapered, and the trial in part

steroids was highly successful in

flare .

So steroid sparing is a worthy goal,

DR. SIMON: We discovered three things. The first

is that a lot of the patients shouldn’t have been on the

glucocorticoid to begin with and therefore they were better

anyway, so tapering them didn’t help us understand better.

Number two, that was actually a primary outcome which was

the tapering of the glucocorticoid, and that was

difficult primary outcome plus the variable dose

a very

of

glucocorticoid even in systemic lupus, it is a very

heterogeneous disease, so therefore, depending-what you are

using the glucocorticoids for, that changed what you were

using the primary comparative drug for, and it made people

uncomfortable based on what was being measured.

So, we are not very good at this,

under the curve that one is thinking about,

think that most people would think it would


Washington, D.C. 20002(202) 546-6666

“...

but it is area

and I would

have to be at



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

105

least for 3 months that area under the curve although I

don’t think we really addressed that issue. Did we?

DR. WEISS: I

it, but I mean there is

to put into this.

DR. HANAUER:

proportion of patients

and sustain a clinical

DR. SACHAR:

don’t think the document addressed

obviously some common sense you have

Wouldn’t you rather see the

who are able

response for

You actually

important questions and perhaps not

The important question of duration.

to taper below 7 1/2 mg

3 to 6 months?

have identified two

identified the third.

Again, we looked at the

budesonide trial where maybe at 3 or 6 months it was no

better than placebo, but at 9 or 12 months it was not.

I would be looking to go longer than 6 months, and

ny thoughts would still be at about 12 months.

The second question you have raised has to do with

the threshold issue again. How much is enough to qualify?

In every other category, whether we were talking about

symptoms, mucosal ulceration, fistulae, we had a two-step

thing, what was enough to call it significant improvement,

and then what is enough to call it complete improvement, and

I don’t see why the same thing couldn’t be done with

steroids saying a significant improvement is to get to 7 1/2

ng a day or less and the complete improvement is to get


Washington, D.C. 20002(202) 546-6666

.



r

<-—.

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

106

completely off.

DR. HANAUER: Also, from another standpoint in RA,

I believe there is data that low dose steroids do sustain a

clinical response.

DR. SIMON: That was a paper by Kerwin in The New

England Journal of Medicine a couple of years ago based on

some earlier observations. The problem is that has not been

sustainable in other prospective clinical analysis.

DR. SACHAR: We all have clinical experience,

which is going to bring me to the third point that you

didn’t address, which has something to do with the so-called

steroid-dependent patient.

By definition, if there is such a thing as a

steroid-dependent patient population, by definition, that

means that there is a patient population for whom continuing

steroids prevent relapse.

So, the question

It is sort of by definition.

we would have to ask is the third

question that you didn’t raiser Steve, is how do we define

the steroid dependent population to whom steroid-sparing

therapy is applied, because if you have a patient that has a

flare for the first time, you put them on 40 mg and you

start to take them off and they are down to 20, they haven’t

yet declared themselves as being steroid dependent, so you

put them on a drug and you get them off the steroids. You

don’t know if you have done anything because you didn’t know

MILLER REPORTINGCOMPANY, INC.SOT C Street,N.E.

Washington,D.C. 20002(202)546-6666

...-..



g--

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

109

disease on the two populations, whether they both start with

inactive disease or active disease is going to be

essentially the same.

The difference you are going to see is one got

less steroids, so it is a different question. How long of

that is it going to take to convince you that you are

looking at clinical benefit?

DR. HANAUER: How long? How long? Simple

question. One month? Two months?

DR. SURAWICZ: Many months.

DR. HANAUER: Six months?

DR. SACHAR: I think you are still mixing two

things together. You spoke about the patient who is still

symptomatic on steroids, so you are adding something. That

is the treatment of active

who you may want to define

having disease although on

The other we are

disease, and that is a patient

as steroid resistant, who is

steroids.

talking about is not incurring a

relapse in a patient who is controlled on steroids. That

patient is steroid responsive, steroid dependent.

DR. HANAUER: While you are on that, would you

mind defining those for us?

DR. SACHAR: I am coming to that. Now, YOU

asked the third question, which you hadn’t before.

On the issue of duration, I think that when


Washington, D.C. 20002(202) 546-6666

have

we are



aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

111

of the effects on bone, the effects on growth.

DR. HANAUER: Just to get Dr. Rutgeerts and

Feagan’s notion, in many countries they set 5 mg as a

threshold dose.

DR. RUTGEERTS: This dose is not very well

defined. We set 5 mg, others 10. Personally, I think that

it is best to achieve discontinuation of steroids, that that

should be the aim, and not decrease.

DR. SACHAR: Is 7 1/2 the same as 15 every other

day?

DR. KIRSCHNER: No, it is probably more.

DR. FEAGAN: I would just like to revisit the

issue of activity. Again, I think there are logical

inconsistencies into the attitude of 6 months versus as

little as 4 weeks.

We heard yesterday that patients find

change in their delta CDAI score over 4 weeks.

you ask patients the same thing, is it of value,

meaningful a

I think if

of benefit

to remove steroids over a period of one month, “two months,

three months, you would achieve an affirmative answer.

There is a down side to being on steroids. It is

not activity, it’s side effect activity.

DR. HANAUER: Dr. Present.

DR. PRESENT: I agree with the last statement.

don’t thing patients would consider being off for 4 weeks


Washington, D.C. 20002(202) 546-6666

.

I



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

112

significant. I think being off completely they would

consider significant. I think at least a year or more, but

I agree with you, I think steroids fall into a totally

different category for evaluation because of the potential

of long-term toxicity, and I think it is a worthy goal, as

much as suppressing pyoderma or something like that. I

think being off steroids will be meaningful to patients’

health over a long period of time.

I agree with Paul, discontinuing steroids has

always been my criteria,

criteria, it doesn’t let

for that criteria. They

that is good enough when

and I think when you set lesser

physicians do it. They don’t go

are willing to stop and say, well,

we have learned that a lot

people are on steroids who really don’t need them.

haven’t needed them for a long time.

DR. SIMON: I just want to make a comment

have asked several times about the threshold issue,

problem is that science doesn’t give us the answer.

of

They

that you

and the

It is

somewhere between 5 and 10, and most people feel 7 1/2 is

the dose that they have chosen.

You can see data on both sides of the street.

Certainly zero is better than S,and certainly 5 is better

than 10, and that is all you can say.

DR. HANAUER: Should there be in a separate segue,

should there be an indication for treatment of refractory


Washingtonr D.C. 20002(202) 546-6666

.



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

114

that they really thought was a salvage drug?

DR. WEISS: We do that all the time in the

oncology setting, which is what I know best. Certainly, in

Oncology, almost all drugs are started in the setting of

refractory disease, because, you know, we are lucky to take

away something, even if it is not great, at least it had

some sort of track record, and so many of these things are

first started, first explored, sometimes first approved in

the refractory setting, and then they gradually move on to

nore front-line therapy.

Is that something that should be part of drug

development for Crohn’s disease?


DR. SIMON: We actually thought that that was

appropriate in the considerations regarding the new

Formulation of cyclosporine,

uoxicity issues, and so that

but that was driven mostly by

clearly was limited to only

=hose patients that had failed both approved and not

approved therapies as the standard of care. Basically, that

is what the statement was.

If you did not respond to standard of care, then,

you might be a patient that would be appropriate for this,

md then it got a big black box warning, so under those

circumstances you may always have that choice to add on top


Washington, D.C. 20002(202) 546-6666

,..



aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

115

DR. SACHAR: Everything then that I have heard

that reflects what went on yesterday seems quite acceptable

to talk about approving a drug for Crohn’s disease that has

been refractory to conventional therapy without defining it

further.

The only circumstance it does need something to be

defined further, if you are going to hav a specific

indication for steroid refractory disease and steroid

dependent disease, because once you are talking about a

specific drug to which the disease does not respond or on

which the disease is dependent for maintenance of remission,

then, you do have to define it with respect to that drug,

and we wrestled with this a bit with the clinical

phenotyping committees and we proposed, as I recall, that

the definition for steroid refractory was unresponsive to 40

mg of prednisone or more of four

~ould argue and so the Europeans

md Modigliani would say no, it

that was sort of the principle,

above for about a month, and if

weeks duration, and people

may say it has to be 60,

has got to be 1 mg/kg, but

that it was somewhere 40 or

they hadn’t responded by

Lhat time, that was not responsive to steroids.

The definition for steroid dependent -- Dan can

~omment on that, too -- is I believe we had said that if

there had been two efforts within the space of one year to

remove the patient from steroids, and if a relapse had


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

a

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

116

occurred within two months of something like that, or three

months, that that was steroid dependent.

DR. HANAUER: Dr. Weisman is actually looking for

guidance as he plans his next clinical trial with the goal o

steroid sparing. What are the entry criteria?

DR. WEISMAN: Some methodological issues. First

of all, who does the tapering and how is that decision made,

because you are talking about a randomized clinical trial,

patients randomized to one treatment versus another, let’s

say, placebo-controlled, or active treatment-controlled, and

then if you don’t randomize to steroid withdrawal, you are

dealing with post-randomization events, things that are

happening after you have randomized that are dictating what

is happening in the trial, and you start seeing imbalances,

and one of the things -- and Steve knows this has haunted me

-- whatever goes into the decision to start a taper, may be

different in the placebo group than it is in the active

treatment group.

For example, if the active treatment actually

works better, those patients might be more likely to go

through a tapering, and therefore, you may see imbalances on

your primary endpoint if you are making steroid tapering an

important secondary endpoint.

so, that is one set of issues. The other one is

one the dependents are in. I was actually hoping that Dr.


Washington, D.C. 20002(202) 546-6666



-__—_.

__

_&

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

117

Sachar would talk about what the definitions are, but there

is the steroid dependency maintaining the benefit of

response to treatment, but another thing that Dr. Hanauer

knows that I have worried about is the issue of inducing

Addisonian symptoms in a patient who you are tapering, and

distinguishing the Addisonian driving of an increase in

CDAI, because Addisonian symptoms will mimic in some fashion

an acute flare, and how do you deal with that.

There is all kinds of methodologic issues here,

and one of the issues of randomization, in other words,

doing a factorial design in which half the patients in each

of the groups get tapered and half don’t, which is a

reasonable thing to consider, is I have been told is that

people are unwilling not to taper.

If you have a patient, for example, on infliximab,

and they are doing perfectly well, is it reasonable to

demand that that patient stay on steroids for a year, just

so you can do the statistical test? If it is not, then, you

run into the issues of post-randomization bias” that are

going into the decisionmaking. This is not straightforward.

I have a lot of trepidation of stepping into this, and I

would love to have some guidance on these particular issues

on how to design the trial.

DR. HANAUER: One of the problems I think you are

having is, frankly, you are trying to design the trial that


Washington, D.C. 20002(202) 546-6666

.-.,



.-..

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

will answer all

trial might not

are left to you

agent.

118

the questions, and as we have emphasized, .a

answer the multiplicity of questions that

guys to answer regarding your therapeutic

DR. SIEGEL: I think that is particularly true

vis-a-vis the issue of measuring steroid withdrawal as a

secondary endpoint where you are trying to measure clinical

benefit in which you get that confounding effect, because

the better drug will allow more steroid withdrawal, which

then may obliterate the

steroid withdrawal as a

DR. WEISW:

trial, it is implicitly

clinical benefit versus measuring

primary goal of a product.

If you are doing a maintenance

confounding whether you explicitly

recognize it, and it has to do with that fact that I

mentioned. If you are dealing with a one-year trial in

which a certain proportion of the patients are responding,

you are going to start seeing steroid tapering probably.

That is going to be the inclination for both the patient and

the physician. The question is do you try to understand

that and looking at the confounding in some type of

systematic way or do you just ignore it and just do a large

enough trial so it all just works out in the noise.

What I am hearing is that

important question in the treatment

you probably want to systematically

this is enough of an

of Crohn’s disease that

approach it in a long-


Washington, D.C. 20002(202) 546-6666

..



-=

ajh

1

2

3

4

5

6

7

8

9

10

11

12

14

15

16

17

18

19

20

21

22

23

24

25

119

term trial. A four-week trial, it doesn’t bother you.

DR. SIEGEL: If you start with a population as I

think Dr. Sachar talked about before, of patients who are

actually in remission, but steroid dependent and on

steroids, and you taper on both arms, but then on either arm

you reinstitute steroids at the initiation of new

symptomatology, you shouldn’t get confounding because all

patients are being maintained below a certain level of

symptomatology.

You are looking at a primary endpoint of steroid

sparing. It is when you try to do it all together and

steroid sparing at the same time --

DR. WEISMAN: Let’s just say you don’t care about

it, clinical benefit is your goal. You still have to deal

with the confounding factor of steroid tapering. We can

just ignore it and say you are trying to do too much or

don’t do it, but I still think it would be useful for the

committee to at least provide guidance on how you deal with

chronic steroid use in a clinical trial looking for long-

term benefit.

What I have heard is everybody wants clinical

trials that last a year, so you have to cope with steroids

in that context, either implicitly or explicitly.

DR. GRAFFNER: In ongoing trials in steroid-

dependent patients, defined the way Dr. Sachar defined it,


Washington, D.C. 20002(202) 546-6666



\

_-..

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

120

they are being conducted in a way that you suggested, having

one primary aim, and that is to withdraw steroids and still

having to the patients in remission.

I think most clinicians think that is a very good.

primary variable, that is what you want, to get them off of

steroids, and if you do that slowly, you have no great risk

of reducing Addisonian crisis.

Sor having one arm leading off with placebo, one

arm on steroids, you will also get the answers that you

asked about earlier, that quite a few patients are steroid-

dependent, actually are not that, they are being weaned off

on placebo, so one primary variable, get off steroids.

DR. SACHAR: I would like to second that. I would

like to cast my vote for the ability to spare steroids

without relapse in steroid-dependent patients, which is a

primary indication.

DR. HANAUER: Dr. Feagan?

DR. FEAGAN: I guess the issue of whether it is a

confounder or not depends on whether the effects on activity

and steroid reduction are actually discordant, and that is a

gamble. I think the sponsor should be allowed to take that

gamble if they feel that the compound -- if you have

patients that are active on steroids, and they choose to

withdraw steroids, and they are able to discern an effect on

steroid use and effect on activity, and those two effects


Washington, D.C. 20002(202) 546-6666



ajh

_@-%

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

are in

into a

121

concordance, it is a win/win.

It is only if there is discordance that one gets

problem of interpretation and confounding. So, I

wouldn’t necessarily dissuade a sponsor from conducting a

design of that, but let the buyer beware if it turns out

that is the effect. It is going to be uninterpretable.

DR. HANAUER: Dr. Kirschner.

exception

DR. KIRSCHNER: I would just like to take a little

with the definition that dependent disease is that

you have tried twice and failed.I mean that is probably

the tip of the iceberg, are the most serious ones. There

are lots that are going to be in the range of 10 or 15 mg a

day that are steroid-dependent, that you have been able to

wean down several times, and yet they are in for potential

toxicity. Since we showed that intraocular pressure is

elevated and it becomes normal when their prednisone dose is

under 10 mg a day, so maintaining somebody at 10 mg a year

is potentially putting them at risk.

DR. SACHAR: That is part of my definition.

DR. KIRSCHNER: I know, but we were just

discussing he was having trouble with should we be able to

require that people stay on prednisone for 10 mg a day.

DR.

#here that is

that was just

SACHAR : I can’t conceive of any study design

part of the design. The issue is the design

proposed here is either -- everybody gets

MILLER REPORTING COMPAIJY, INC.507 c Street, N.E.

Washington, D.C. 20002(202) 546-6666



ajh

.4-%1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

122

withdrawn, but one is on the putative agent, and the other

is on a placebo. But the effort is to look at steroid

withdrawal in the steroid-dependent person as a primary

indication, as a primary endpoint. We are just trying to

define what is the steroid-dependent patient.

DR. KIRSCHNER: That is what I was referring to.

DR. SACHAR: Right, and I thought that we were

actually agreeing with each other that if you have not been

able to lower the patient below 10 without a flare, that is

a steroid-dependent patient.

DR. KIRSCHNER: I agree with that. I thought yOU

had said if two attempts at tapering below 40 --

tapering.

different

DR. SACHAR: Not below 40, no, no, two attempts at

The 40 came up with steroid refractory, a totally

question of a patient who doesn’t respond to 40

acutely within a month isn’t going to respond.

DR. SU~WICZ: I think it is very difficult. I

wish there were an easy answer to it, and I can’t come up

with them, but I think Crohn’s patients often are very

attached to their steroids even if when they reduce them,

they don’t have a flare of their disease, but they feel

miserable or there is .a psychological attachment, they are

very independent, they like to -- at least in my experience

-- they like to decide themselves what dose of steroids they

take, not what dose of steroids I recommend.

MILLER REPORTINGCOMPANY, INC.507 c Street, N.E.

Washington, D.C. 20002(202) 546-6666

..”-



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

sparing agent, a perfectly good design and a

endpoint.

DR. HANAUER: That is one subgroup

124

perfectly good

of patients.

The next subgroup that I would like to discuss is

pediatrics, and this came up yesterday. The infliximab was

recommended for approval for Crohn’s disease based on data

with the youngest patient treated being 12 years old.

It was an agent that was not in the clinical

trials, but in the open-label trial, the youngest

patient. It was dosed on a 5 mg/kg dosing, so it

treated

was not at

a fixed dose. I would like Dr. Kirschner to begin the

discussion by telling. us why kids are different than adults

with Crohn’s.

DR. WEISS: Maybe in fairness, just to maybe start

off by addressing a question. Actually, I have it marked 3,

it is supposed to be Question 4, which is I think the

fundamental question that I have is can you extrapolate

sfficacy as defined in adults to pediatric populations, and

that goes to whether or not

adults with this disease.

DR. KIRSCHNER: I

children behave the same as

think one of the intuitive

thoughts, and it is

tempo of disease in

actually don’t even

know, for instance,

not data, and that is whether or not the

children is the same in adults, and we

know that. In ulcerative colitis, we

the progression of limited disease is


Washington, D.C, 20002(202) 546-6666

. .. ..---.. —



a-jh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

125

much more likely to occur in children than adults. They

don’t act the same way.

We know that the risk of -- well, it appeared at

least prior to the immunomodulatory agents -- the risk of

surgery in children with Crohn’s disease was very high,

something like 70 percent in five years.

We also know that when we talk about a term that I

really don’t like at all, reagent grade patients, because I

don’t think there is such a thing. I really think that

these are evolving processes, ”and Joyce Grabowsky, for

instance, has a paper of Crohn’s disease in children under

the age of 10, in which at the onset, 2 percent of the

children had fistulas, and five years later, 25 percent had

fistulas, so if we want to talk about inflammatory versus

stenosing versus inflammatory disease, it depends at what

time in the child’s life

they may be inflammatory

you are talking about, and that

when we first see them, and five

years later they are stenosing.

It may be that many of the adult physicians who

are here, who have done most of the studies, are getting

referral patients five years into the course of their

iisease, and so they assume their disease has more stenosing

md fibrosing because they are seeing them maybe later and

lot at the same onset.

I think kids have a really aggressive course, and


Washington, D.C. 20002(202) 546-6666



A.=

aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

126

whether it is the same or worse in children, I don’t know,

but there are some indications to suggest that it is pretty

severe, and the effects of puberty and what that may do, for

whatever reason, when we plot the number of the mean age in

kids when they develop Crohn’s, the years between 11 and 12

are just incredible in terms of diagnosis of disease.

I have a huge database, and every time I put in 11

or 12, it is like 80 percent of them, so there is something

about that particular point in time that seems to be

affecting the

disease.

so,

kids, and our

immune response for getting a lot of Crohn’s

there are clues that maybe it is different in

doses are different. I mean we go everything

on a mg/kg dose, you go on set doses, and so that our doses

of prednisone are probably much higher for a child than they

would be in an adult. Adults , you are talking about 40 mg a

day, and those are 70 kg people, we are giving 40 mg to a 40

kg person. So, I have no idea how to

what you are using to what we can use

essentially looked at our own studies

and keep looking back at mg/kg to get

extrapolate back from

in kids,” and so we

and our own results

our guidelines.

DR. HANAUER: As the question is posed, if the

pharmacokinetics are similar, in other words, if the sponsor

performed a study demonstrating similar pharmacokinetics in

children and adults, would it be necessary, in your opinion,


Washington, D.C. 20002(202) 546-6666

. .



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

127

to do a separate efficacy trial in children?

DR. KIRSCHNER: From my point of view, it is. I

am not sure that we can tell anything about pharmacodynamic

effects necessarily from the pharmacokinetic effects, that

we don’t know that the response rate will be similar.

DR. HANAUER: In your view -- 1 don’t want to put

words in your mouth, but is it necessary for every new drug

to be tested in children, and then the next question is

going to be, if so, what age groups need to be tested

specifically for Crohn’s, and just as a background,

yesterday, one of the sponsor’s consultants got up and said

that it was going to be impossible to do trials on Crohn’s

disease in children, to get sufficient size, sample size and

efficacy data on all these drugs.

DR. KIRSCHNER: I can tell you that the CCFA has

estimated there are 200,000 children with Crohn’s disease,

so I don’t know how difficult it is going to be studied.

DR. HANAUER: The sponsor yesterday

400,000 patients overall.

DR. KIRSCHNER: But I mean the fact

are certain age ranges that are highly likely

estimated

is that there

to be a

problem, and that would be those that are probably 6 years

of age and up. We are not going to be studying infants and

we are probably not going to be studying children much under

the age of 6, but around 5 to 7 we start seeing a fair

MILILERREPORTINGCOMPANY, INC.507 C Street, N.E.

Washington,D.C. 20002(202)546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

128

number of children with Crohn’s, and we certainly see a lot

in the 10 to 12-year-old range.

DR. HANAUER: 1s it then necessary to do studies,

as defined here -- we have definitions of four pediatric

subgroups, neonates, infant up to 2 years, children 2 to 12,

and then adolescents -- so, is it necessary to do studies in

children 1 to 12 with Crohn’s, and subsequently in

adolescents?

Dr. Present said that adolescents were the same as

adults . Do they need to do two separate

~hildren?

DR. KIRSCHNER: I can tell you

age groups in

when people are

looking at the IBDQ for children, that we find we have to do

~ different one for adolescents than we have to do for

~hildren. I don’t think many of us would consider a 13- or

~ 14-year-old an adult who is essentially an adolescent.

We would say that

~hildren, and we would want

DR. HANAUER: SO,

approval, you would like to

?ediatric age groups.

we want to see studies in

to see studies in adolescents.

for a sponsor to g’et pediatric

see studies in two separate

DR. KIRSCHNER: Yes.

DR. HANAUER: Clinical and pharmacokinetic.

DR. KIRSCHNER: Yes.

DR. SACHAR: Steve, I am not sure when the


Washington, D.C. 20002(202) 546-6666



___

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

appropriate

doesn’t get

of patients

point is to

overlooked,

129

bring this UP, but just so it

I am concerned that there is a group

who are being discriminated against in all

studies by being systematically excluded from any study for

an artificial reason, and I am referring to patients with

stomas. Virtually every sponsored study will exclude

patients with colostomies or ileostomies, because you can’t

do CDAIS.

That is something I would just like the committee

to think about because this does become an issue of

discrimination, as I see it, that they are being

systematically excluded from the opportunity to participate

in clinical trials.

DR. HANAUER: I think in future studies that have

been suggested, I think that there probably are ways to

modify that. Some committee members and other consultants

have recommended modifications off of the CDAI which have

not been validated, nor reproduced for Dr. Feagan’s benefit,

but he has even signed on, too, agreeing to include

modifications.

so, I think we are beyond that hopefully.

DR. SACHAR: But a lot of the modifications,

whether it’s Harvey Bradshaw or [Softky Clamp] or Oxford or

Capetown, and so forth, still are going to be excluding

patients with stomas. Even the IBDQ, I am not quite as

MILLER REPORTING COMPANy, INC.507 C Street, N.E.

Washington, D.C. 20002(202)546-6666

. . . . .



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

130

familiar with it, but the kinds of questions that YOU ask.

about quality of life are again different than the stoma

patients.

I don’t have any answer here at all, I have no

proposal. I just want to bring it to the committee’s

attention that some thought has to be given how not

systematically to be discriminating against that population

of patients.

DR. HANAUER: Dr. Goldstein.

DR. GOLDSTEIN: I would like to offer some

Uontext. I don’t know whether you all read the material in

svery sense that the agency provided, but the FDA

!lodernization Act, known in Washington parlance as FDAMA,

became law late last year. It mandates improvement in

?ediatric labeling and “the study” of drugs heretofore

approved in adults, but utilized significantly in children.

rhat certainly applies to the drugs we use.

~ords, no

iiagnosed

There should be, in Harry Shirkey’s immortal

more therapeutic orphans. My daughter was

at age 7 and has been on virtually everything you

uan imagine plus two surgeries plus TPN, so I learned a lot

~f pharmacology that way.

I also happen to chair the American Academy of

Pediatrics section on clinical pharmacology, so I think

studies, at least in two age groups, children and


Washington, D.c. 20002(202) 546-6666



.-

25

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

131

adolescents, is applicable, and as Barbara can confirm,

children as young as one years old have been diagnosed with

Crohn’s. The Act itself that provides for incentives

pharmaceutical manufacturers to invest in additional

for

development work, principally in the form of exclusivity and

six months exclusivity or under certain circumstances 12

months exclusivity can make a substantial difference in

terms of manufacturers’ and researchers’ incentives to do

these studies.

The original rule published -- and by the way,

children, in case anybody is uncertain, are not just small

adults. There is no such thing, ladies and gentlemen, as

midget medicine.

FDA has been coming at this for some time, and I

can only applaud them for doing so, for approved drugs and

biologics.

supporting

similarity

Originally, you could submit some literature

pediatric use. FDA must conclude sufficient

to permit the extrapolation, which was your

question, Steve, about efficacy data to pediatrics, but that

didn’t really raise much, and I think some 25 or 30 percent

of manufacturers at most submitted data.

This new law, which has now been signed, will

require studies in pediatrics, Barbara, as you know, allows

for the deferred submission of some or all data until the

application -- unless FDA specifically defers or waives it,

MIIJLERREPORTINGCOMPANY, INC.507 C Street, N.E.

Washington,D.C. 20002(202)546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

- 13

14

15

16

17

18

19

20

21

22

23

24

25

132 Iand how do you get a waiver? Well, no meaningful benefit. to

children, studies are impossible or extremely impractical.

Thirdly, it is likely. to be unsafe or ineffective, and

lastly, reasonable formulation efforts being made to get a

reasonable formulation, if needed, have failed. Those are

four criteria for getting such a waiver.

FDA has been mandated to develop, prioritize, and

publish a list of approved drugs for which additional

pediatric information may be produce -- in the words of the

law -- health benefits in pediatric populations.

There are, I believe, since I was asked to comment Ion lists somewhere along the line, some IBD drugs on that

lists. What is the impact of all of this? Well, there is

likely to be a surge in the number of studies in pediatrics.

Certainly, there is a surge in the development in pediatric

formulations development, and in thinking about pediatric

trial design, and the extrapolation across all ages is what

this committee is currently looking at.

DR. HANAUER: Let me break for one second there

and get your and Dr. Kirschner’s opinions specifically on

what Dr. Weiss asked. Should the approval, not our

approval, not this committee’s approval, but the agency’s

approval for the drug that was recommended for approval

tomorrow be withheld until the sponsor has data that Dr.

Kirschner and you are requesting in children?

MILLER REPORTING COMPANy, INC.S07 C Street, N.E.

Washington, D.C. 20002(202) 546-6666

. . . . ... . .



-.

-

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

133

DR. GOLDSTEIN: Emphatically not for all the

reasons that were brought forward yesterday, and in addition

to the fact that there are safety considerations, as Dr.

Simon noted, which can be answered by the use in adult and

developing a greater safety base.

DR. HANAUER: Are you ready to see this drug used

in children now, applied and studied in children?

for 15

safety

DR. GOLDSTEIN: Am I ready?

DR. HANAUER: Yes.

DR. GOLDSTEIN: Well, I am not in practice. I was

years.

DR. HANAUER: You observed the discussions on

and efficacy.

DR. GOLDSTEIN: If I were faced with a patient

significantly having failed a number of drugs and in a

sufficient clinical state to require it, the answer is yes,

I would use it.

DR. HANAUER: And you would put a 5-year-old into

a trial?

DR. GOLDSTEIN: Depending on the circumstances.

Obviously, Steve, the devil is in the details.

DR. WEISS:There is a difference between when

something is approved and on the market, also using it in a

particular patient who you think might benefit, and then

systematically studying it in the course of clinical trials.


Washington, D.C. 20002(202) 546-6666

. ..



____

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

134

Part of the new pediatric proposal that Dr. Goldstein is

referring to talks about the fact that it is going to be

requirement that pediatric data will have to be generated,

and it may be that as get more input, as well, that what Dr.

Kirschner has said is pretty much going to be the gold

standard, that for pediatrics, one cannot extrapolate, that

you have to do separate efficacy trials, not just small PK

trials, but separate efficacy trails in pediatric

populations.

Given that point, then the next question is when

in the course of development, which is sort of the second

part to this question, when in the course of a drug’s

development would it be appropriate to systematically start

studies in pediatric populations.

DR. HANAUER: The other question that I would like

a little clarification on is that pediatric claims can

include studies when the agency concludes that the course of

the disease and drug’s effects are sufficient -- the course

of the disease is different, and we have heard- some data and

speculation that the course of the disease is different.

Aside from growth, which is certainly an important

issue, what data is the agency going to require that the

course really is different? Does that fall upon the

scientific community to demonstrate a difference in the

course or is that a judgment?


Washington, D.C. 20002(202) 546-6666

. ... --—



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

should be

135

DR. GOLDSTEIN: There are some elements that

common to all pediatric applications. Basically,

I have thought about six. The use of functional disease-

related endpoints. The availability of a pediatric

formulation with supporting PK data. An appropriate trial

design, adequately powered. Certainly prospective data

collection. What I would like to call the sequestration or

isolation of a new agent’s contribution to efficacy.

Finally, particularly important in pediatrics, the use of a

well-tolerate regimen.

That is a little short on specifics, but if you

want a broad overview, I think that is it. Companies have

done it. A Swiss firm with an anticonvulsant not too long

ago with some plus-minus studies, supported it with a rather

effective discussion of the comparative pathophysiology in

adult versus child, et cetera. It can be done, and it is a

question now of not only the substance data, but fleshing it

out , and there are lots of ways of fleshing that out, which

the agency can call for, and which industry is”prepared to

submit.

DR. WEISS: Steve, also to address your question

how you decide whether or not the disease is similar enough,

so you can reasonably extrapolate, I mean I think there are

a lot of things that go into it. There are large amounts of

natural history databases, workshops, and various types of

MILLER REPO~TINGCOMPANY, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666

. ~....,-...



ajh

1

2

3

4

5

6

7

8

9

10

11

12

.[—-= 13

14

15

16

17

18

19

20

21

22

23

24

25

137

particularly multi-dose approach like is being done in

adults, where we have different doses, because we can’t

extrapolate what the dose is going to be, what the frequency

is going to be.

We really don’t know what to recommend what the

use is going to be.

DR. HANAUER: I think Paul is not suggesting

concurrent, but he is suggesting lowering the inclusion age-

in the initial trials from what is normally 18 to what?

DR. RUTGEERTS: To 12. I think in centers who

have good GI departments and who have good pediatric

departments, such studies can be done in cooperation, and

then you don’t need to design separate studies for children.

You can adjust doses, of course, but that is feasible, I

think.

DR. GOLDSTEIN: Let me pent something out. Some

months ago I did some research on the issue in a different

therapeutic area, but it applies here, relative to the

developmental, the size and weight of children; and it turns

out if you take -- and I have spoken to NIH experts and

Cornell growth and development experts on this, so this is

where it is coming from -- it turns out that some

indications are from, for example, from zero to 10 years

old, and from 11 to 1.9, but if you look at the percentile

growth tables, from 10th to the 90th percentile, just to


Washington, D.C. 20002(202) 546-6666



_—_—

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

138

leave out the two extremes, that a 66-pound child can be 8

years old, 9 years old, 10 years old,

need to get a little bit creative and

point of view of not age, but weight,

11, 12, so maybe we

look at it from the

and not weight alone,

but basically the percentile tables that allow you, because

in many respects, an 8- or 9- or 10-year-old will fit within

that 10th to 90 percentile as easily as a 12-year-old. So,

you are extending this

DR. HANAUER:

DR. FEAGAN:

age downward that way.

Dr. Feagan.

As, Paul, you suggested the composite

trial, which is attractive from the feasibility issue, I

guess the only down side is that from the measurement tool

standpoint, as Barbara suggested earlier, some of the

instruments just aren’t probably valid in children, so you

have to get around that issue if you are going to combine

the data.

DR. WEISS: Many of us were at the conference in

Philadelphia sponsored by CCFA, that specifically discussed

pediatric studies, and the consensus that I he’ard at that

neeting was that it doesn’t work just to take an adult

protocol and use the word processor and change the age down,

that you actually need to have some differences in the

study, and those are probably best down in pediatric

senters. I mean that is a bit of a separate issue about

just the mechanics of how it is done, whether or not a


Washington,D.C. 20002(’202)546-6666



ajh

&-%1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

139

separate study. There are groups that are really geared to

doing specifically pediatric trials.

DR. KIRSCHNER: There is a pediatric collaborative

research group specifically for IBD, which includes centers,

many of us could work together within our institutions.

DR. GOLDSTEIN: Not only is the group that Barbara

mentioned, but the National Institutes of Child Health and

Human Development have set up a series of 7 -- this is three

or four years ago -- 7 PPRUS, or Pediatric Pharmacology

Research Units, it is about to become 10 very shortly, which

takes studies from industry, from academia, from anywhere

and basically does that in major pediatric centers.

so, I am sure it can be done.

DR. SIEGEL: I have a question for Dr. Kirschner,

Dr. Goldstein or anybody, but regarding if, in fact, it is

the case, as you said -- and I have

-- it would be risky to extrapolate

no reason to doubt that

efficacy data, that the

disease is different in children, say, in adolescents or in

children, one wouldn’t want to assume that a drug that works

in adults would work there.

One would expect

this temporally sequential

first developed in adults,

often seems to happen, and

it also to follow then that if

approach is taken, if a drug is

which may not be optimal, but

a drug were found in adults to be

safe, highly effective in important ways, one would not find

MILLER REPORTING COMPANy, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666



.——.

aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

140

problems with children or pediatricians enrolling in

randomizing trials for placebo-controlled trials, because

presumably, since one couldn’t extrapolate efficacy, there

would be substantial data as to whether it would work in

adolescents. Do you think that is the case?

DR. KIRSCHNER: I think it would probably work.

The question is what is the dose, what do we use. I mean

there may be a question that children require a higher dose.

DR. SIEGEL: The question that Dr. Hanauer had

proposed before is do you need pharmacokinetic

data to apply to children, or do you also need

randomized or other efficacy studies, and I am

and safety

additional

not sure now

exactly what you are answering to that question.

DR. KIRSC!HNER: I think we would want efficacy

studies, as well as pharmacokinetic studies. We have

discussed this actually at Centocor when we had a meeting of

people who were setting up the pediatric trial. We had a

meeting at the CCFA when they were 50 people there, many of

them pediatric gastroenterologists. I am speaking for the

group, not only for myself. We felt that pharmacodynamic

and efficacy studies in children were essential.

DR. SIEGEL: But it is probably easier to get

those before you have definitive efficacy data in adults I

would think.

DR. KIRSCHNER: The way this document reads, and

MILLER REPORTINGCOMPN, INC.507 C Street,N.E.

Washington,D.C. 20002(202)546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

141

what Harlan wrote in his letter, and what the consensus was

in inflammatory bowel disease issue that we had to approach

this problem, was at the conclusion of Phase II, where the

FDA is meeting with the sponsor, the pediatric efficacy

trials would be initiated. I guess we would like to see

some efficacy information

DR. HANAUER: I

here of regulatory power,

in adults.

guess there

and I guess

is an undercurrent

the bottom line issue

is should the agency withhold approval of a drug before --

Sponsor A could take decades to generate that data.

DR. WEISS: Under the new proposals, the feeling

was it would not be a good idea if you let something that is

safe and effective as proven in adults to withhold approval

in getting that product out on the market. Under new

?roposals now under consideration is the idea that if

?ediatric data were not available under the marketing

application, and you had reached agreements with the

~ponsor, that those studies could be deferred until sometime

in the postmarketing period, there would be very specific

time lines that would have to be honored whereby those

additional pediatric data would have to come in, and there

could be some type of court sanctions, et cetera.

It wouldn’t be like accelerated approval where the

product would be withdrawn from the market, but there would

have to be --


Washington, D.C. 2000z(202) 546-6666



.——.

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

142

DR. HANAUER: It is my opinion that this really

needs to be done on a case-by-case basis with a pediatric

review of the available adult data, because for a total

novel drug, such as this, such as the one that was

recommended for approval yesterday, there may be some

potential risks that the pediatricians foresee, whereas,

another agent there may not be, and the rapidity of the

requisites for pediatric trials may vary at those points.

I don’t know that this can be guided on a local

basis.

DR. WEISS: I think that is a fair statement.

DR. KIRSCHNER: I think the CCFA is trying to

sxpedite the ease with which these studies can be performed,

and certainly that is the whole point of our pediatric

collaborative research group. I mean we want these drugs

out quickly, too. SO, it wouldn’t take a lot of information

if efficacy to get pediatric trials started fairy early, so

that we can use this information to recommend

?atients.

DR. HANAUER: But you have to watch

them for our

what you are

saying. You are saying it is efficacy, but again, if it

were my child, I would be more concerned about safety.

DR. KIRSCHNER: I don’t now more. I am certainly

concerned.

DR. PRESENT’: Just to be a nay-sayer and assume


Washington,D.C. 20002(2.02)546-6666

.......—.



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

143

Brian Feagan role at this moment, are there any control

trials to show that pediatric patients behave differently

that adult patients? Is there a single control trial in IBD

to show that, because again, my clinical experience in

adolescents is the exact same behavior, no experience in

under 12 because I don’t take care of them, and a

pediatrician has recently completed a control trial with 6-

MP, which is exactly the same data as we found in adults, ,SO.

I am much more in favor of Paul Rutgeerts’ comment including

patients down to age 12 and let them enter studies depending

upon the drug. If it doesn’t seem appropriate, don’t let

them enter. I think that would increase the collaboration

between the pediatric gastroenterologists and the adult

gastroenterologists, and we might find out the answers if

there are really differences.

DR. HANAUER: But as Dr. Feagan points out, you

have to have an adequate instrument to measure that age

group.

DR. GOLDSTEIN: Dan said he was going to make a

comment that would rile me up.

DR. HANAUER: Make a quick one to un-rile him.

DR. GOLDSTEIN: No. Basically, we have to keep in

mind that clinicians deal one on one. An agency like the

FDA deals with hundreds of thousands, and the issue of

safety is a paramount issue, and to get safety data from


Washington, D.C. 20002(202) 546-6666

..-



L’--

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

144

adults at least to a point is I think important. The

parent, you are quite right is going to say I am not

submitting my kid to be a guinea pig, the child is

interested in only the tastiest formulation, and you go from

there, but safety is important, but I am saying that we need

not be so safe to the point of waiting months or years to

start some of the studies. We can start them earlier than

historically they have been started.

DR. HANAUER: Before Dr. Present leaves, I just

want to address the issue of geriatrics.

DR. PRESENT: I wouldn’t know about that at all.

[Laughter.]

DR. HANAUER: Gain some experience. The corollary

.- and we can come back to your question -- but is there a

5ifference in the geriatric population? Does anyone want to

address that? Dr. Kirschner, is there a need to do

iifferent studies in Crohn’s disease in geriatrics and kids?

I would argue, frankly, the exact same that you

io, that we have experience that the disease does behave

differently, but I can’t substantiate that with good

>vidence–based data.

Dr. Kornbluth.

DR. KORNBLUTH:

?utgeerts’ model in terms

?rotocol, if we lower” the

A quick follow-up question.

of methodology designing the

age, say, from 18 to 12, and


Washington, D.C. 20002(202) 546-6666

Dr.

then



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

145

we want to extrapolate the data from the group as a whole, to

the subgroup of, say, age 12 to 18, do we need to do a

subgroup analysis and then do we run into problems with

sample size and power of

looking at the age group

DR. ELASHOFF:

that conclusion if we are just

of 12 to 18?

Yes.

DR. SIEGEL: Let me clarify that question. We are

not specifically asking about this disease and don’t

specifically ask about diseases, whether they behave

differently in the elderly. We presume, and the

Internationally Harmonized guidance presumes that for drugs

that are used

=x erience inP

is a lot more

interactions.

significantly in the elderly, one needs

the elderly, for any numbe-r of reasons. There

likely to be specific concomitant drug

There is more likely to be concomitant liver,

Kidney, or circulatory problems which impact use of many

~ifferent drugs for a variety of other reasons.

The policy in terms of the geriatric data,

:herefore, it is not so much dependent on whether the

~isease is different, but dependent, as it is with pediatric

also, but here more so on how significant geriatric usage

is. There are some diseases which are predominantly in the

Jeriatric population, some which are significantly in the

3eriatric population, and some which are relatively rarely

seen in the geriatric population. I think that is more what


Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

146

we are trying to get some input on.

DR. HANAUER: Dr. Elashoff, is it significant in

the geriatric population? I am just kidding.

DR. KIRSCHNER: I have a question. When we talk

about prospective studies in children, what about

prospective studies, for instance, of the safety of

azathioprine and 6-MP in the elderly, over 65, over 75?

mean you hear anecdotal reports, you know, bone marrow

suppression may be worse. Is that known?

DR. HANAUER: No.

DR. SACHAR: Point of information just for

definition, are we talking about older patients who have

I

had

disease for a long time

about people with onset

that may be an entirely

DR. HANAUER:

specifically talk about

and are now older, are we talking

of disease at an older age, because

phenotypically different disease.

I would leave out and just

Crohn’s disease in patients over 65.

DR. SIEGEL: Either way.

DR. HANAUER: I think either is an a~propriate

question.

DR. SACHAR: It is just that there might

conceivably be a rationale for excluding patients whose

disease began over age 65, because it may represent a

phenotypically different entity, but there would perhaps not

be such a rationale for excluding people who had th disease


Washington,D.C. 20002(2.02)546-6666

..— ..



..&=%

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

147

for a long time and now just happened to be old, because

that might be discriminatory.

DR. HANAUER: The bottom line may be that there

are relatively so few patients with Crohn’s disease over the

age of 65 that you are not going to end up seeing -- you are

not going to do clinical trials in patients over 65

exclusively.

DR.

include. One

age of cutoff,

WEISS : I think the question was more to just

side is there has almost always been a lower

but there usually is not an upper age. At

one time I think it was up to the age of 70 in many studies,

but I think that has gone now and there usually is not an

upper age limit in studies.

We almost always do subgroup analyses after

studies are done to try to get a sense, even though the

studies are usually not powered to show it, but we usually

do some type of subgroup comparisons by age, other important

type of features to try to get a sense about a differential

type of response or something, important safety signals to

maybe look at or to study further later on, or to be on the

lookout for.

I think the question was are there enough patients

65 years and older that we should just seek to include a

sufficient

whether or

number, so that you can try to get an idea about

not there are important differences because of


Washington, D.C. 20002(202) 546-6666



1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

149

different. I think we should have it. I don’t know if you

are going to get it, but I think as an advocate of the

elderly -- and I want

had a geriatrician on

same.

that on the record -- I think if we

this panel, they would insist on the

DR. KIRSCHNER: I was going to say the same thing.

With the numbers of Crohn’s disease patients increasing and

age going up, there is going to be more and more elderly

people, and we should be collecting data on them.

DR. SIEGEL: What is the age

not for onset of Crohn’s, but patients

DR. HA.NAUER: At the moment,

job, they are gradually aging, but the

distribution like,

with Crohn’s?

if we are doing our

peak

second and third decade, and I would say --

prevalence?

onset is in the

do you know the

DR. FEAGAN: If you look at the clinical trials,

it is very stereotypic, you know, there are issues about

inclusion, but it is 33 plus or minus 10. So, I don’t know

what happens to those people. They are out there, but --

than the

there.

DR. HANAUER: And they are not dying much more

general population, so they are about to be out

DR. WEISS: Usually, when you look

trial, you want to have the trial be broadly

of the people that are going to be receiving

at a clinical

representative

the drug, and

MILLER REPORTING COMPANY, INC.507 C street, N.E.

Washington, D.C. 20002(202) 546-6666



-,

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

so

is

150

you look at things like ethnic breakdown after the trial

completed. It is not that you necessarily seek to have

certain

but the

specific numbers of different types of categories,

idea is basically when the trial is over, you have a

broad representation of the types of people unless you

specifically excluded, for instance, like pediatrics.

DR. HANAUER: I believe you are getting that

the trials to date because we are not excluding a

in

significant number of elderly patients. I am looking for

~ome concurrence on that. We have been excluding

significant proportions of pediatric patients.

DR. SACHAR: I think there is a selection issue

Iere. If you are talking about people, say, age 60 and

>ver, they have had the disease for 25 or 30 years. NOW, by

:hat time, they have either sort of settled down on whatever

regimen they are on, they are not shopping for experimental

irugs, or they have had operations to the point that they

me not no perhaps candidates for the drugs.

But the people who are having these active

diseases, and so forth, generally aren’t the people who have

already carried the disease 25 or 30 years. It is a

selection issue.

DR. HANAUER: Segueing into safety, as our

penultimate topic --

DR. WEISS: “Can I just go back? Somebody asked


Washington, D.C. 20002(202] 546-6666



.-——=.

aj h

1&--—=

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

151

from the audience, I believe, a question about subgroup

analysis -- this goes back to pediatrics, but it is

applicable to others -- if you include children down to age

12, and then look at the overall population, and then try to

make some kind of extrapolation or comparison with very

small, for instance, subgroup that is from 12 to 18, your

statistician started to address that.

We always look at various

analyses afterwards to try to get a

types of subgroup

sense of things, but

knowing very well that the subgroups are frequently

underpowered.

DR. ELASHOFF: I think what I would say on that,

if you are in a situation where there is no real reason to

believe that the subgroups are different and you are just

kind of checking to make sure there is no strong evidence,

then, it is reasonable to simply include people and hope for

the best.

If you are in a situation where it has been stated

that they believe there are going to be real differences,

then, you are in a situation where you need to make sure

there is enough power for that younger age group, in which

case you are really, from the sounds of it, might as well

have two separate trials since there is enough reason to

deal with the children separately.

DR. WEISMAN: One of the things that frightens me

MILLER REPORTINGCOMPANY, INC.




ajh 152

1 about the discussion is we are already dealing with this,A-.

2 and what Dr. Simon was bringing up yesterday, I think

3 everyone agrees that you would like to know as much about

4 TNF suppression as possible, particularly on the safety

5 side, and I think the issues are really more safety.

6 I remember having a conversation with Dr. Weiss

7 about this earlier in the year, that my concern about the

8 pediatric studies were more on the safety side than they

9 were on the efficacy side.

10 I do believe fundamentally that the data would

11 suggest that certainly down to the adolescent age, we are

12 going to see similar efficacy, and it comes down to safety.

-. 13 The safety risks we are talking about are fairly low

14 incidence rates probably, although we probably in small,

15 reasonably-sized trials, be able to exclude disaster. The

16 thing that you are really looking for in terms of looking at

17 whether there are age–related differences, you are already

18 dealing in pretty small numbers in a population which is

19 already pretty small.

20 The other thing I would like to point out, at

21

IIleast is the case of the product we are talking about,

I22 infliximab, it is a biological, that isn’t usually where

23 liver impairment or renal impairment is going to make all

24 that much difference, and really what you are talking about

25 is molecular pharmacology, you know, sort of the basic


507 c Street, N.E.Washington, D.C. 20002(202) 546-6666



,,.-’--

a-jh

1

A--2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

153

molecular mechanisms of disease along the lines that Dr.

Simon was talking about.

I just really think it is going to be very tough

to get the kind of data that you are saying that you want in

pediatrics in a feasible fashion, in a believable fashion in

a randomized population within way that

discouraging to the industry to even get

indication to begin with.

DR. HANAUER: I wanted to hear

would not be

involved in the

that, I wanted to

bring that up as a reality check for what we are doing here.

DR. KIRSCHNER: But that has always been the

excuse why pediatric trials have never been done. I mean

our problem is we agree that safety is an issue, but for

many of the drugs that we have, we need doses that are

efficacious .

For instance, the S-ASA drugs, I mean we still go

back on a mg/kg basis if something is 3.6 or 4.8 or 2.4.

DR. WEISMAN: I can’t even find adult

gastroenterologists to agree that those drugs work in

adults. As you know, because you are one of the

investigators, we are studying infliximab in a pediatric

population. I agree with the need that you are talking

about, but I think the certainty that you are saying that

you require in pediatrics or, you know, if you say

pediatrics, well, look, you know, only s percent of the


Washington,D.C. 20002(202)546-6666



aj h

1_.-—–

2

3

4

5

6

7

8

9

10

11

12

-–.

13

14

15

16

17

19

20

21

22

23

24

25

154

patients in the infliximab studies were black, I just

referred a black Crohn’s disease patient to Mr. Sinai. I

think the drug works there. The evidence suggests it works

there. You can use subgroup analyses, but you are not

talking about subgroup analyses, you are not talking about

trends, I heard you talking about definitive information,

and definitive information in small subgroups of particular

interest is going to be difficult when you are dealing with

small --

DR. KIRSCHNER: I don’t know how small these

populations are. I mean I have several hundred patients

with Crohn’s, so how small -- I mean I am not the only one,

there is Boston, there is New York, there are a lot of these

patients around.

DR. WEISMAN:

population is small.

DR. SIMON: I

That isn’t the point. The overall

wonder whether or not we could

distinguish between what might be an idiosyncratic, very

care event, and something that may be, in fact; in biologic

~odification, may be actually inherent to the mechanism of

~ction, or the inhibition of the target.

That might be actually a very common event, and

:hat might be very different in a developmental way in

:hildren than in adults. I tried to get that across

~esterday with biologic modifiers. I clearly did not get it

MILLER REPORTINGCOMPANY, INC.507 C!street, N.E.

Washington,D.C. 20002(202)546-6666



ee.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

155

across appropriately, that in the case of agents that

inhibit a target that may have a lot to do with development,

and it may be very different in a child than in an adult,

because it may not be important for development in the

adult, therefore, we might see a very consistent event

taking place in children that is not hard to see. It would

not require huge numbers.

It did seem to me that the numbers yesterday were

quite small even for adults, so one could imagine that one

could create trials that are quite targeted to children.

DR. WEISMAN: The problem is that the way you

~hrase that and the way the questions are being asked are

open-ended questions - is it possible that something, and,

of course, the answer to that is always yes.

I guess if you had biological plausibility

questions, if you had a question of biological plausibility

:hat was really focused, then, I think, yes, you should do

:hat, but if you ask the question is it possible that agent

{ will be dangerous in a certain subpopulationj the answer

is invariably yes, of

DR. SIMON:

:hat up, because that

course, it is possible.

It is very interesting that you bring

is, in fact, why we design randomized

:linical trials. We don’t go in to a drug X and know in any

>opulation that it is going to do YZ.

DR. WEISMAN: The point I was making is that you


Washington, D.C, 2oo02(202) 546-6666



aj h

&-1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

do have evidence of efficacy and safety broadly.

have, we are -- Dr. Kirschner knows this because

156

you do

she is

participating in the trial -- we will have pharmacokinetic,

and, in fact, because these response rates are so high with

infliximab, it is relatively easy, at least on a per-patient

basis, even in a small population of children to see that a

relevant index is going to go down, no question about that.

What I was getting at is the amount of buffer that

you want around that to rule out is it possible that

something bad

that.

DR.

that is large

is going to

SIMON : But

happen. You are not going to know

if you have a patient population

enough to

on what the product is,

:hat group of patients,

demonstrate adequate efficacy based

and what the target is, and within

they do not have unique toxicities,

=hen, that’s fine, because the issue is, if it is a

developmental issue, it should be seen very frequently if

IOU inhibit that target.

If it is not, then, you are talking about

idiosyncratic events.

DR. WEISMAN: What is that? You are talking about

~ fishing expedition, and fishing expeditions you usually

ion’t find anything, and how many patients do you have to

lote to know that you didn’t find something that you didn’t

mow what you were looking for?


Washington, D.C. 20002(202) 546-6666



a jh

[---

[’-

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

DR. SIMON:

bit and think about a

157

Could we turn the clock back a little

nonbiologic response modifier and talk

about cyclooxygenase-2 inhibitors, which there is

speculation that this is up-regulated in growth in children,

cyclooxygenase-2,

to bone growth.

We have

and that it might be important as relates

no idea that that is true. There is

actually even no science that applies to that except for one

experiment taking a piece of bone, subjecting it to

stressors, and observing that in that piece of bone in

vitro, COX-2 was up-regulated.

DR. WEISMAN”: I am fine with that. In fact, you

just stated an hypothesis based on observation that was

generated, that was then testable. I guess what I was

saying is -- that wasn’t a fishing expedition. That is

looking at data that has been generated, that has resulted

in an hypothesis that is then going to be tested. That is

fine, and I have no issue with that.

That is what I meant by biological plausibility.

If you have a plausible hypothesis based on something, even

if it is intuition, that you are then focusing on, then, you

can probably know how” to design the trial with the right

sample size to try to answer that, but if you are asking an

open-ended question, can something go wrong, I think you are

probably talking about low-incidence things --


Washington,D.C. 20002(202)S46-6666



ajh

r–1

2

3

4

!5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

DR. SIMON:

potentially about low

158

My point is that I am not talking

incidence --

DR. WEISMAN: What are you talking about?

DR. SIMON: I am talking about potential

developmental anomalies that are based on inhibiting

cytokine interactions that we have no idea about, because

they have not been studied.

We have rapidly jumped over the science of

development of understanding interactions with cytokines,

and because you have a product that may alter a specific

~ytokine target, because the science has not caught up to

your observations doesn’t mean we should ignore the

possibility they may be involved in development.

As a result, you have a tool to answer the

question. Because of that, it is worthwhile knowing that in

~hildren because they. are a unique population of people that

ieserve to have that question answered. That is not a

Eishing expedition.

DR. WEISMAN: It is for the following reason, and

:hat is, let’s say that there is, let’s say that the

qq?othesis that you just stated is the case.If it is not

>ased on anything, in fact, you don’t know what pathway or

vhat mechanism you are looking at, you are basically fishing

>ecause let’s say there is, in fact, something that would be

)f concern or worry, when you don’t observe it, you don’t





J?=.

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

know whether you didn’t observe it

it, you didn’t have adequate power

because it doesn’t exist, and that

It is untargeted examination.

159

because YOU didn’t find

or you didn’t observe it

is the point I am making.

DR. ELASHOFF: I think there is another thing that

would help here. If you can’t say on what developmental

parameter, you can’t make sure you have been measuring those

parameters in your trial. You don’t know what your trial

ought to be measuring in order to find it.

DR. KIRSCHNER: But I think you are holding

pediatrics to a different standard. I mean you are saying

for efficacy in adults, we only need to do this, but for

children we had better have a very specific hypothesis that

we are testing in terms of toxicity, and it makes no sense

because we don’t know in advance what these toxicities are

going to be, and we don’t want to avoid them, plus we also

want to find out what the efficacious dose in children is.

it may be metabolized differently, and we can’t extrapolate

back. There is nobody in pediatrics who I think feels

differently than I do.

DR. GOLDSTEIN: There is no way I can top that

dialogue. I won’t even try. There are a couple of points

to be made. Earlier, a question was asked about

pharmacokinetics, pharmacodynamics, and safety, and what is

more important. Obviously, in children, safety is probably


Washington, D.C. 2(Jo02(202) 546-6666



#-*-_

.&----

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

160

primary, they are the most vulnerable population, but the.

signal-generating aspects of adult studies should not be

overlooked.

Now , industry has, we all have in point of fact,

but certainly industry has issues involving liability and

the like, which to some extent color our judgments, but if

you look at the adult experience -- and remember, folks, the

life of a drug premarketing is far shorter than the life of

a drug postmarketing -- and every single interaction between

a patient and a physician is an epidemiologic event.

Those events in the adult community certainly can

be, many times and many diseases, and probably including

this one, captured and used to signal, to generate signals

for studies on safety or efficacy, to make better labeling,

to provide research initiatives, and a whole host of other

things, and I think a“ lot of information, directly relevant

to the pediatric and indeed adult community can be gained

thereby, and ought to be gained thereby.

That might cut this down to a bit more manageable

sizer and I suspect it is probably behind some of the

agency’s initiatives in bringing us better pediatric studies

and better pediatric labeling.

DR. HANAUER:

hesitations .

Moving on as

You stated that well despite your

an appropriate segue on safety, to


Washington, D.C. 20002(202) 546-6666



aj h

(-=

=k-

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

almost conclude, the ICH

specifically address the

161

guidelines on safety evaluations,

long-term treatment of chronic or

repeated intermittent use for longer than six months for

nonlife-threatening conditions.

The guideline calls for a minimum of 300 patients

treated at the maximum recommended dose and who are the

intended patient population for at least six months, 100

subjects treated for at least one year, and a total safety

database of 1,500 patients treated.

This is directly relevant to yesterday.

Does the committee generally agree with these

recommendations for products for Crohn’s disease? Is this

number of 300 patients, at the recommended dose for six

months, 100 patients for one year, and a total safety

database of 1,500 patients, is that acceptable for Crohn’s?

DR. ELASHOFF: For long-term use.

DR. HANAUER: Well, both short- and long-term.

this the standard we should use for Crohn’s, is this

acceptable? I don’t know how this applies to orphans.

Is

DR. SIEGEL:

treatment and it has a

DR. HANAUER”:

as an orphan by virtue

The guidance is for long-term

specific --

By the way, you have labeled Crohn’s

of this, so I don’t know how you need

to apply this to orphan --

DR. SIEGEL: The guidance specifically notes in



(202) 546-6666



ajh

1

2

3

4

!5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

some cases a

for example,

162

smaller number of patients may be acceptable,

where the intended treatment population is

small. So, it is not specifically linked to the orphan,

which has its own definitions, however, there is a definite

acknowledgment that in

be reasonable.

DR. HANAUER:

some

Dr.

representative, not labeled,

:omments?

DR. FEAGAN: Well,

diseases, these numbers may not

Feagan, you are a

but you are from Canada.

Canada is smaller than the

J.S., and I think the flexibility, as you pointed out

~esterday, it is a guideline, I think it is not an

mreasonable guideline. In this case, the situation might

>e that it may not be met.

DR. HANAUER: For example, you now have a

)recedent from yesterday, which was 200 patients treated for

mywhere from six to 12 months. Is that going to be

:ufficient for the next agent?

DR. SIEGEL: You did not recommend long-term

,reatment.

DR. HANAUER: Right. So, are we only asking for

.OW many patients for long-term treatment and short term is

p for grabs? What kind of guidance do you want from us?

DR. WEISS: I guess what we struggled with are

hose diseases for which we are talking about chronic


507 c Street, N.E.Washington, D.C. 20002(202) 546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

163

treatment, and that is generally at least six months. I

mean the idea is we are talking about things like Crohn’s,

inflammatory bowel disease. Rheumatoid arthritis I think I

think is the classic example where your studies go on for a

certain number of months, but you are really talking about

perhaps lifetime therapy for a chronic disease.

The guidance that is written is just the sort of

general minimal numbers that were felt to be reasonable to

have in hand at the time that you are reviewing a marketing

application.

Where there is concern

instance, you are certainly able

about more toxicity, for

to, and should be asking

for more than that, but this is the minimum that we are

:alking about.

In Biologics in the past, many of our therapies

~ave been for very serious life-threatening diseases,

relatively short therapies, and now we are emerging on this

~ge where we are talking about chronic therapies.

I think we would just like the guidance. If we

Ire talking about chronic treatment for Crohn’s disease, and

i.t is obviously difficult in the abstract without actually

laving a specific application and getting a signal in terms

>f the particular types of events that are observed, it is

~omewhat difficult, but we were just asking for general

>stimates about the kinds of numbers people would be


Washing ton, D.C. 20002

(202)546-6666



ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

164

comfortable seeing.

DR. HANAUER: Is this a general number that is

reasonable for Crohn’s?

DR. SACHAR: Is it practical? Look at the size of

clinical studies, the overall size of all the patients in

the studies. And then you are not talking about the placebo

patients. You are only talking about the active patients.

DR. ELASHOFF: I would like to make a comment that

I am not going to address the specific question of 300 or

400 or 200, but I would like to see in these discussions

estimates of the kind of event rates that one rules out if

one doesn’t see them. If you see zero in 300 patients,

then, the 95 percent confidence interval for the event rates

goes up to something, so in a discussion, you have those

figures next to these numbers to give more meaning to the

discussion.

DR. SIEGEL: That, by the way, was precisely the

logic that went into the guideline, and the numbers of 300

to 600 for six months were based on determinations that for

most drug used chronically, most events that will occur,

will occur in the first six months, not all, but there are

only uncommon events that occur only after six months that

don’t also occur in the first six months.

Observing nothing in 300 patients gives one a

fairly high confidence, about a 95 percent confidence, that

MILLER REPORTING COMPANY, INC.507 C Stree t, N.E.


(202) 546-6666



aj h

____1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

167

There are certain types of nondisease-specific

toxicities, you know, idiosyncratic bone marrow suppression,

that it may not matter what disease you give a drug in, if

it has an incidence of that, it may be very pertinent. I

think it tends to be the case with biological response

modifiers, perhaps because we don’t understand biological

responses very well, that many of the safety issues that we

raise often involve exacerbating certain aspects of the

disease, and it is harder to get good safety data from other

diseases.

DR. HANAUER:

question we were asked

Along those lines, and the final

to address, 80 percent of the

patients who were treated for Crohn’s disease yesterday were

on concurrent therapies with either an immunosalicylate,

corticosteroid, antibiotic, or another immunomodulatory

agent.

The committee is asked to discuss specifically

which drugs commonly used in Crohn’s disease would be most

useful to evaluate with the next test agent for formal

interaction studies.

I will bring

to the panel yesterday

out a question that wasn’t addressed

related to the biologic. We saw

long-term data with infliximab yesterday, despite the

committee’s not examining or not recommending for approval

on a long-term use, many of those patients were on


Washington, D.C. 20002(202) 546-6666



ajh

L’m.

&,.-

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

168

immunomodulatory agent, and data that was not exposed

yesterday is that there may have been a concurrent effect of

the immunomodulatory agent on a long-term response.

those long-term responders may have been on what we

Some of

consider

a current maintenance drug, such as 6-MP or azathioprine, so

do we need to look at drug interactions as far as efficacy

is concerned ala rheumatoid arthritis, where methotrexate is

almost incorporated into every clinical trial.

DR. SIMON: We have actually gone so far to

suggest that we don’t feel compelled to use placebo response

any longer as compared to the active comparator, and the

active comparator almost always right now is the gold

standard of methotrexate.

But the implication from that is that it is also

unethical to look at this without comparing it to active

drugs, that if you take

DR. HANAUER:

somebody without that, it --

Let’s ask the committee, is there a

gold standard comparator yet? Dr. Feagan.

DR. FEAGA.N: I would say no, and I think it

becomes the problem. I mean if you look at what is out

there in the community, I think the trial reflects that.

When we looked at the antimetabolite use, first of all, not

all patients were on antimetabolites. When one looked at

the dose, the dose

recommending, so I

was not reflective of what experts are

think that the people entering the trial


Washington, D.C. 20002(202) 546-6666



/-—.,r

g-=

,+–—.

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

proved that, that there isn’t

therapy.

concordance

169

of the standard

DR. HANAUER: Dr. Rutgeerts, any comments on this?

DR. RUTGEERTS: No, it is the same point, that, in

fact, the number of drugs that were used were suboptimally

used, and then another point is I think the drug to compare

it with is with corticosteroids.

DR. HANAUER: It’s a

DR. RUTGEERTS: It’s

DR. HANAUER: Let me

head-to-head trial.

a head-to-head trial.

just take that, because in

many European trials, we have seen other drugs or regimens

compared to regimens of corticosteroids. Is there a

generally acceptable steroid regimen to be employed in

clinical trials to compare it to?

DR. FEAGAN: I think you will get an argument

about that, but I don’t think the argument is well founded

in data, that if one looks at the response rates and the

durations, the differences are small, and I really think the

challenge to the FDA would be to accept that conceptually,

that we are getting into an era of active comparator

therapies as far as induction of remission.

The question of refractory patients --

DR. HANAUER: So, what would be --

DR. FEAGAN: Anti-metabolites, I think is the more

difficult one.


Washington, D.C. 20002(202) 546-6666



ajh

r1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

170

DR. HANAUER: So, from an induction of remission,

the rheumatologists have a standardized regimen for baseline

therapy or comparator. What would you recommend to the

agency to be the standard corticosteroid regimen to be

compared with? Is that a question you want or no?

DR. SIMON: Steve, could I ask you one more

question? What is the rate of response to azathioprine and

6-MP in inflammatory bowel disease?

DR. HANAUER: Dr. Feagan?

DR. FEAGAN: Well, 1 hate to echo the discussion

this morning about what the definition of response it, and I

don’t think anyone in this room can answer that question,

because it would mean defining

and the studies have been very

outcome measure actually was.

what the primary outcome was,

heterogeneic about what the

DR. SACHAR: But

there? It is slow. About

responding.

there is some consensus, isn’t

two-thirds of patients are

DR. FEAGAN: What outcome is that, David, two-

thirds of what? What happens to the two-thirds?

DR. SACHAR: That is the point at which steroids

taper without a flare when they start to feel better, when

the extraintestinal manifestations are not as common, when

the fistulae start to heal.

DR. FEAGAN: Show me the trial that it shows that



(202) 546-6666.



aj h

1-.

2

3

4

5

6

7

8

9

10

11

12

.--% 13

14

15

16

17

18

19

20

21

22

23

24

25

171

two-thirds of the patients have a well-defined, clinically

relevant outcome.

DR. HANAUER: Dr.

DR. KIRSCHNER: I

studies in children are not

Kirschner, you had a comment?

was just going to say the

prospective, they are

retrospective, but the number is approximately 70 to 80

percent were able to substantially or reduce steroids once

azathioprine and 6-MP are added, which is exactly very

similar to what he says for methotrexate, and we are saying

that is the gold standard -- which he probably might now say

-— but it is an effective active agent for rheumatoid

arthritis.

DR. HANAUER”: Do you have a specified dose?

DR. SIMON: Unfortunately, no.

DR. HANAUER: Do you have a specified dose?

DR. SACHAR: Of what?

DR. HANAUER: For the efficacy of

immunosuppressive that you can compare with.

DR. KIRSCHNER: If we were to use steroids, at

least in children, we

DR. NEEMAN:

only a statistician.

DR. SIMON:

would say at least 1 mg/kg.

Could I go back just a second? I am

But a good one.

DR. HANAUER: That is significant.

DR. NEEMAN: But I have reviewed protocols for


Washington, D.C. 20002(202) 546-6666



ajh

L_——-_r

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

172

rheumatoid arthritis, and I should say that the community,is

still doing placebo-controlled trials in patients who have

failed DMARDS in particular, methotrexate, and they do 4-

week withdrawals.

DR. SIMON: But they failed it.

DR. NEEM?iN: Right. What I am saying is that that

population, the so-called refractory population, is probably

the population, at least for the agents I have seen, that is

most likely to be studied for new agents. So, I think there

still is a place for placebo-controlled studies, at least in

R.A.

DR. SENIOR: In children, though, particularly

those under 12, given that the pediatric community and

parents want to see some efficacy and some safety in adults

first, would they accept a placebo-controlled trial when

there may be what is essentially a proved therapy for adults

already out there?

DR. NEEMAN: There is a pediatric trial in

rheumatoid arthritis, and it is in some sense ~- I don’t

know if I would call it a placebo-controlled trial, it is a

randomized withdrawal trial.

DR. SIEGEL: In the interest of concluding, I

Would like to get back to the safety questions, but I

nesitate to leave this issue, which I don’t think was in the

questions, without a couple of cautions, particularly for


Washingtonr D.C. 20002(202) 546-6666



.*=

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

173

those of you out there doing research.

It is very difficult to prove that a drug works in

an active control trial depending on a number of conditions,

but if you are intending to do this, first of all, if your

goal and result is to show superiority to an active control,

and you are pretty sure that the active control isn’t

harmful, that is pretty good. If your goal is to show

efficacy on the basis of equivalence to active control, you

need to have a pretty solid, sound estimate, quantitative

estimate of the amount of active control benefit.That has

to be based on historically controlled comparisons to trials

of the active control generally compared to placebo.

You have to look at that benefit. You have to

look at the confidence interval around that benefit. You

have to determine what is the smallest benefit that you are

pretty sure the drug has, not the best estimate of the

benefit it has, and then, as with all historical

comparisons, you have to extrapolate that benefit from a

population that that active control was studied in, into the

population which is being studied in your planned trial,

which may be very different in its baseline characteristics.

It may have different use. It may have anti-TNF therapies

given alongside that weren’~. available in the historical

data, and so forth. It is a very difficult thing to do.

We are working on some guidance regarding that,

MILIJER REPORTING COMPANY, INC.507 C Street, N.E.


(202) 546-6666



e-.

.—.-= ..

aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

and the ICH process,

very difficult thing

174

and writing that guidance has been a

to do, but there is a guidance on

choice of control groups.

Suffice to say that -- and this is not a

commentary on when you can or can’t use a placebo, and

whether it is possible to use a placebo, and whether you

should use a placebo -- but if you are going to try to show

efficacy through equivalent in an active control trial, that

is an extremely difficult thing to do from a scientific

perspective.

I would like to move back, though. We got into

this as a little tangent from drug interactions, which I

would like to discuss, but we also moved on a little bit

from the numbers, perhaps because I created some confusion

about what we are looking for.

But one of

we are interested in

the issues that

hearing from is

get too confused with where you were

I think fundamentally

-- and I don’t want to

yesterday -- each drug

has its own factors, safety”concerns, its historical

development, its level of efficacy, but we deal -- and these

guidelines will go to a lot of companies manufacturing

drugs, you know, working. They may now only be in the pre-

IND phase. They may be early on.

Should we be telling a company that they ought

anticipate, if they are coming to us with an application


Washington, D.C. 20002(202) 546-6666

to

in



——._-r

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

175

Crohn’s disease, at the time of application having somewhere

in the neighborhood of 1,500 patients, or I think the Fredd

article said 1,500, the guidance document says 1,500, but

mentions issues regarding disease size.

But is that practical? Is

that the guidance that this guidance

developers?

that appropriate? Is

should be providing to

DR. HANAUER: Answer the question. Dr. Sachar.

DR. SACHAR: Could you restate the question?

DR. SIEGEL: This disease, given its seriousness,

given its uncommonness or commonness, is it reasonable to

tell companies developing, as we would in many other

indications for chronic disease, that we expect 1,500

patients

too big.

I think.

to raise

to be treated by the time they are going to market?

DR. SACHAR: I think the number is a little bit

DR. HANAUER: So, what number?

DR. SACHAR: 681,

DR. HANAUER: Dr. Rutgeerts, how many?

DR. RUTGEERTS: I think 500, 600, is a good figure

DR. HANAUER: Dr. Kirschner, how many kids?

DR. KIRSCHNER: That is a question I had asked him

because I think it”is too many, but that is, as we

talk about this, should there be a number of children if we


Washington, D.C. 20002(202) 546-6666



.-%=-

.-..

aj h

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

177

think the 1,500 in Crohn’s disease where there are so many

subgroups in different types, is unrealistic.

DR. HANAUER: Bill, how many?

DR. STEINBERG: I would just be pulling it out of

the air. Six hundred sounds reasonable.

DR. ELASHOFF: I think in view of its being a

relatively unusual disease, it would be reasonable to make

these numbers smaller. If I were to make a specific

recommendation, I would like it to be based on a goal like

excluding a certain rate or detecting differences of a

certain sizer and whatever goal people agreed on, then, the

number that goes” with that.

DR. HANAUER: Giving industry the last word.

DR. GRAFFNER: I think that yesterday in this

discussion here, actually, it was fairly historical, because

from industry viewpoint, I believe it is a very small area.

It takes just the same amount of money to produce a drug for

IBD as it does for hypertension, and I do know that there

are people out here working with very small firms, having

very good ideas in this field, they are not able to evaluate

and do research in this. I looked at the guidelines, I

looked at the 1,s00. I think the experience yesterday and

perhaps decreasing of the number here today, it will be do

very good for the IBD community.

DR. HANAUER”: Thank you.


Washington, D.C. 20002(202) 546-6666



p-.

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

178

DR. SACHAR: Does the agency have a position on

concomitant therapy versus monotherapy? So often our

industry protocols require that there be washouts, and they

stop everything else, may not be on concomitant drugs, and

that this be almost monotherapy.

DR. HANAUER: As of yesterday, the answer was no.

I am just answering for the agency because you saw a drug

where 80 percent of patients were on other therapies.

DR. SACHAR: So we can take almost anything and

either add a new drug or a placebo?

DR. SIEGEL: A lot of drugs are developed as add-

on, drug plus placebo. There are cautions you want to have.

You want to fairly clearly specify what is of isn’t allowed

both at the time of randomization and also Harlan Weisman

was mentioning the issues in post-randomization, because if

people start altering what you have added on to, it will

interact with what you observed as drug effective. But if

you designed it right, there is absolutely no problem, and

quite common to develop drugs as add-on therapy.

DR. SACHAR: It is not as common in the industry

protocols as we would like it to be

DR. SIEGEL: Well, it depends on the disease. In

HIV and cancer, typically, the three drug regimens versus

the three drug versus this new drug is a very common way to

develop.

MILLER. REPORTING COMPANy, INC.507 C Street, N.E.

Washington, D.C. 20002(202) 546-6666



E==.

.—-—__

ajh

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

179

DR. HANAUER: Based on what it takes to get it,

sample size, et cetera.

I promised to end at 2:00. It is approximately

2:00. I want to take this opportunity to -- I think we have

come a considerable way. This is the beginning of a

process, so actually we are midway through the process. We

had a document to work from, and I think that that document

did suffice to gain the first drug that has been recommended

for approval for Crohn’s disease. So, I think that that had

a considerable success, but it was never meant to be the

definitive document, and the comments and instructions and

questions that were brought up today I think were very

useful for the evolution of this document into a formal

hopefully accredited guidance document that we will be

pursuing over the next time interval.

Specifically, I want to thank the consultants to

this committee: Dr. Sachar, Dr. Rutgeerts, Dr. Ki~s~hner,

Dr. Feagan, Dr. Simon, who have been extraordinarily helpful

in these discussions. It broadened the scope of this

committee which was necessary for this unique situation.

I need to thank the Agency, Dr. Talarico and her

group from CDER, Dr. Weiss, Dr. Siegel from CBER from their

invaluable drafting and guidance for the guidance, and Joan

Standaert for her continued tremendous assistance for this

committee.

MILLER REPORTING COMPANY, INC.507 C Streetr N.E.


(202) 546-6666



[---

ajh

1

2

3

4

5

6

7

8

9

10

11

12

DR. ELASHOFF:

think what I said in the

180

I just would like to say that I

beginning is that I would like to

have the opportunity to put these questions out there on our

web, so that other people can respond to these questions and

naybe add some additional things, and then, as I said in the

beginning, I think the next step is for us to assimilate all

~f this into a very first draft that then we will put out,

perhaps take again to another meeting of the Advisory

2ommittee at a future. date.

DR. HANAUER:Thank you. Good afternoon.

[Whereupon, the meeting was adjourned at 2:00

2.m.]

MILLER REPORTING COMPjlwlf,INC.507 C Street, N.E.

Washington, D,C. 20002

(202) 546-6666



181

(—

@-

CERTIFICATE

1, ALICETOIGO, theOfficialourt ReporterforMillerReportingCompany,

Inc.,herebycertifyhat1 recordedthe foregoingproceedings;thatthe

proceedingshave been reduced to typewritingy me, or under my directionnd

thatthe foregoingtranscript a correctand accuraterecordof theproceedings

to the bestofmy knowledge,abilitynd belief.

uALICE TOIGO



F ood & Dr ug Ad m in is t r a t ion Hea r in g Vo lu m e Nu m be rGa st r oin t e st in a l Dr u gs Ad vis or y Comm i t t ee

May 29,199

+~..

+1 48:21+248:21+348:21

0

0.667:70.867:7

1

1 48:21; 50:4; 95:8;115:18; 128:7; 165:1, 12;171:201,500161:9, 15; 175:2,3,3,13;176:10; 77:1,221/2102:21,23; 03:6,10,21;105:8, 4;110:9,17,

20,24,5;111:9;12:19;123:71089:10;3:8;9:21;101:25; 02:3;10:9,7,20,25;111:6;12:19, 3;121:12, 7,17,22;22:9;125:12; 28:2;37:23;138:2;39:10; 49:18

. 10,OOO-patient 8:2010-year-old 138:6100 27:14; 49:19, 25;91:10; 94:7, 14; 161:7,1410th 137:25; 138:711 126:5,7; 137:24; 138:21251:15 ;68:21; 70:13,25;73:2; 78:15; 80:20;100:19; 02:12; 05:14,16;124:7;26:5, ;128:5,7;131:6136:19; 37:10;138:2; 43:6,0;144:25;145:2,;151:4,6; 62:17;172:1312-year-oid 128:2; 138:712A4:2513128:1514-year-old 128:1614056:415 102:3; 111:9;121:12;133:11

15018:15, 8,19,21;27:1432:11; 0:24;45:14; 9:19;9:7;9:7;94:3,71670:23;03:1916-week1:25184:18;37:9;44:2s;1452,;151:6———.18896:1719137:241990s7:319956:2519985:121:3010:20

2

2 10:20; 23:21 ;27:21;47:1; 48:21; 50:5; 79:7;80:6; 100:20; 125:12;128:5,52-week 88:8

2.291:22.4153:17203%4;41:11;47:2; 4:492:9;3:2,;99:21;106:22; 76:1420094:12;62:16; 64:1(200,000127:162084:1823rd34:92468:21;8:16;0:2025125:13; 31:20;150:14,2125091:42668:19,5;0:1;3:528-day7:9295:12;2:242:00179:3,4

3

) 47:2; 48:21; 75:17; 78:4;10:14;102:13; 105:1,9,3;124:15l-month 77:24L491:2L6 153:171047:2; 91:3; 96:16, 23;10:12;131:20; 150:14,1; 176:15lo-minute 10:18

O-point 98:141 0 0 4 7 : 1 3 ,5;48:13;3:24;94:15;161:5,13;64:9,12,18,24os 148:151047:153149:18590:135091:46 67:8; 84:7

4

69:2,13,16,22,24, 5;0:4,8,9,10,13,17, 8;1:13,14 72:2; 3:24;4:2,3;76:1,3;77:16;1:7,2,17;85:4, 1,16,7,19,5;8:2;4:24;5:1,398:9;02:13;11:15, 7,25;24:16;72:3

4-week5:1,34.8153:1740106:21:110:12:

115:15, 19; 122:12,13,14,15; 126:16,17,17

4 0 0 93:24; 94:1I, 14;164:1o

400,000127:194591:34884:6;03:19

5

511:4 ;110:18; 111:3,6;112:19, 22,22; 124:10;127:25; 153:255-ASA 60:22; 70:23;153:165-minute 11:15-year-old 133:1850 48:9; 49:24; 67:10;54:17, 19; 90:7; 101:24;140:18; 176:19500175:20

6

) 73:6, 15, 16;74:6,7, 11,?0,22; 75:1,3, 22; 76:4,12;77:3, 4;78:13,19, 25;‘9[4,4, 5,6, 10,11 ,14 , 16;10:6,6, 15,21 ;81:9;13:24;84:3; 94:24; 105:9,3, 15; 111:14; 127:22, 25;43:7i-month 74:13, 17;‘7:24;78:23

i-MP 24:17; 55:18; 69:13;‘9:12; 146:7; 168:5;70:8; 171:8i-week 88:8

0 90:7;15:17; 50:130094:11;64:19; 6%2;75:20;76:11,17,23,24467:865146:7,17, 3;147:5,6,23;148:2466-pound 138:1681175:186990:6

7

799:23;02:21, 3;103:5,10, 1;105:8,4;I1O:9, 7,20,24, 5;111:9; 12:19; 23:7;127:25; 30:20; 39:8,97.5103:217089:21;90:4, 1;1256;L26:17; 47:11; 71:6;L76:197190:675146:7

868:19,5;70:1; 3:2;81:7;5:1193:9; 4:24;95:1,;98:9; 38:1,68-week77:168090:11;26:8;67:12;

171:6;78:8

94:3;05:14; 38:2,690138:790th137:259242:239545:11164:13,25

Aa 4:9, 15, 23,24; 5:3, 21;6:1,5,10,11,14,19, 23;7:1, 15,16 ;8:1, 11,14,19,21;9:3,5,1,13,18,21,24, 25; 10:2,5,7,10,15,18,18,25 ; 11:1,4,11,11,15,19, 24; 12:4,5,9,11,17,21;3:5,6,7,15,18,19,20,21,23,4;14:2,6,12,14,7,18,21, 3 ;15:13, 15; 16:4,22, 25;17:25; 18:15, 19; 19:11,12, 12;20:2,5,6,9,10, 24;21:4; 22:5, 14,21, 24;23:10, 12, 16, 25; 24:7,8,10,11,22,4;25:1,8,

24;26:1,2,3,5,6,7,8,21 ,25;27:2,9,9,3,18;28:6,7,18;29:2,7,8,9; 0:5,10,14,17,20;31:7,0,16,18;32:6,8,9,10, 8,~l,21;3:2,8,19,22;\4:3,,10,13 , 0;35:1,5,14,15,9;6:14,3;37:4,13,15,17, 3;38:1,3,4,9,15,22,3;39:2,3,10, 3,~1,5;40:5,6,7,8, 4;~1:11, 3;42:14; 3:7,5,13;44:2,8, 0,12,14,16,17,9;45:7, 1,14,9;i6:14,21,24,24; 7:l,ll,[2,2,13,16,17;8:6,8,[z,8,18,2;9:3,4,5,:4,14,22, 3;50:15,18,!5;1:4,4,7,8, 3,14;;2:4,4, ,9,2,13,13,14,.7,9;3:3,4,5,7,7,8,!2,24; 4:1,5,7,11,14,!3,4;55:3,6,10,16, 9;;6:1,4, ,8,9,9,11,12,2,14,15, 5,24,24, 5;;7:3,7, 0;58:1,6,8, 0,2,25;59:7,9, 3;0:10,5,17,0,2461:1, ,5,6,1,22;62:7,8, 7;3:2,8,~,2,12,15;4:1,5,7,9,0,12,6,16,0;65:9,9,

19,19,20,20,21,22,23,

24, 25; 66:4,6,9,9, 10,115, 16, 18,22, 25; 67:18,19,21,23 ;68:1.2, 14, 1969:17,23, 24; 70:4, 14, 271:1,5,8,9, 10;72:1,1,5,6,14,18, 18, 19,20, 2173:4,7,8, 13, 16,22, 24;74:1,5,8, 10, 13,17, 17,19,20 ;75:12, 15,16,16,23;76:2, 4,12,14,17, 1877:13, 13,16, 18;78:1,7,16,20,21, 24; 79:3,3,9,16, 23;80:6, 11, 16;81:7,9,14,24,25, 25;82:2, 1217,18, 22; 83:7,8,10, 1213, 18,25 ;84:1, 1,2,2, 1013,15,24 ;85:1,1,4,9,11,24;86:4,5,6,7,8, 13, 22;37:4,5,11,13,13, 14, 14;38:3,16,17,21, 24;89:2,;,8, 10, 10, 12, 13, 14, 1517,20,21 ;90:5, 12, 19;)1:1,,3,3,4 ,4,5,19 ,20,13;92:5,7, ,10,13 ,15 ,!o,21;93:2,6,8,9,9,9,16,17,18,19,2;94:5,,1,10,13,16,17,20,2;)5:8 ,9,24,5;96:3,6,9,0,12,17,17,24,5;17:1,2,5, 3,23 ,24,4;)8:1,,12,14,18,20,0;}9:14,4,15; 100:3, 5>90,10,17, 22; 101:2,8,2,18,24, 25; 102:2,3,3,2,14,17,22,23, 24;03:3,3,6,8, 10, 16, 16,‘4,25 ;104:1,4,5,9,12,5,16, 18; 105:9,20,24,

25; 106:3,5,6, 13,13,15,

20,20, 24; 107:8,9, 12,17, 17,22; 108:1,3, 11,14,16,19,25,5;109:5,15,18,19;110:1,2,5,10,12,16,5;111:3,16,9,21;112:2,3,5,8, 3,15,16,24;113:5,5,6,8, 818,24;114:1,22,3;115:3,7,9,13,20, 5;116:8,6,21;17:5,1,12,15,7,21;18:1,6,11,11,12,15,16,21,25;119:1,)8,10,19,22;120:1,4,10,15,18, 0;121:1,3,4,4,8,12,17,22;122:2,3,4,9,10, 415,16,21,2;123 :2,5;124:1,1,10,11, 5;125:7),11,25;126:7,0,14,15,16,7,24;127:1,0,21,25;28:1,4,15,16,

19;129 :2,2;130:21;[31:7;32:1,4 ,6,8,14,[5;133:5,4,15,5,18,[9,22,3;134:12 ,16,24 ,25 ;135:4,8,9,1,12 ,13,[4 ,16 ,24 ;136:2,22 ,5;37:17;138:1,3,7,24 ,24,!5 ;139:3,8,4,19 ,22 ,!4;140:8,8,6,17;141:9,0,12;142:2,2,3,9. 1.

6, 25; 143:3,6:7:19, 2~,Mille r Re po rt in g Co m pa n y, In c . Min-U-Scripti



He ar in g Vo lu m e Nu m be r 2Ma y 29, $)$)8

‘,25;144:1,3, 14, 16, 23;145:1,2,14, 17; 146:4,13,

n2_23, 25; 147:1,9, 15,18,23; 148:5,10, 11;

149:4, 23; 150:4,8, 12,21;151:1,9, 13, 18,20; 152:6,18,22; 153:5,5,6,10,17,21; 154:2,13,22, 23;155:2,2,3,5,16,19, 23;156:5,6,6, 12,16, 22;

157:1,2,9, 15,20; 158:10,10,14,14, 16, 17; 159:11,13,22, 23; 160:8,9,10,10,15,16, 19; 161:5,8,14,21; 162:1,4,7, 12,15;163:4,6,9, 22,22; 164:2,8,14,24, 25; 165:2,3,3,7,9,11,12,19, 20,24;166:3,4,5,6,8,9,10,10,15,18, 23; 167:3,21, 25;168:2,3,5, 17; 169:8,9,12; 170:2,5, 22; 171:1,3,13, 15,21, 22,23; 172:10,15, 16, 18,20,20, 25;173:2,3,9,18, 24; 174:1,

2,4,5,6,7,9,12,13,21,24; 175:15,20,23, 25;176:14,14,15,16, 18,21;177:6,8,9,10, 10,16, 17;178:1,7,10, 10, 11,24;179:5,5,7,10, 13abdominal 13:19; 28:23-~lity 12:24; 83:25;

:14~u[e 11:11; 29:3; 37:18;41:18 ;42:20,20;44:17;52:2; 73:2; 82:25; 99:17;105:8; 110:16; 120:24;121:13, 21; 122:9; 152:15;163:12; 171:7; 177:20

abnormalities 28:15;29:14, 17;73:6abnormality 28:9about 10:5; 11:1,7;22:22; 23:10; 24:4; 25:22;27:10,12,16, 17,18, 21;29:1; 30:23, 24; 32:3,5,13; 33:3,7; 34:16; 35:7;38:4; 39:2, 16; 40:13; 42:3,4;48:25;49:10, 15, 15;51:24; 54:12, 13; 55:11;56:6, 6; 58:19; 59:13;60:13 ;61:10, 11,13;63:3;66:2,2;67:3,14,7;68:10,11,4;69:12,4,

20,22;72:13;75:15;77:25;8:10;9:4,4,5,;81:3;2:9, 4;83:1,1;84:9,6;85:20,1;86:23;87:20,2;89:17;0:7;92:7;3:10,1;97:10,22,22;99:6,1,12;101:17,

102:11,2;103:1,6;“:24;05:16,9;.1:23;08:3,7,8;

109:13,8;110:1 ,8,23,23;112:17;15:3,9,0;116:8;17:1,4;19:3,3;120:10;23:8;25:7,14,16;126:9,6;127:3;

129:10;30:2;31:19;132:16;34:2;35:3;136:1;38:24;39:10;142:22;44:11;45:8,9;146:5,5,2,14,7;147:18 ,24;49:17,1;150:13151:1;52:1,3,7,7,13,21,24;153:2,3;154:5,,6;156:7,19,1;157:2,3,5;158:2,3,4,6;

159:23;62:25;63:2,5,11,14,18,0 ,25;164:6,7,25;166:18;69:16;170:11 ,14,7;174:15;175:25;76:1,17

above 18:20;15:20

abscess 23:23;6:1;30:1147:16;48:13

abscesses 165:10

absence 59:22; 64: 18;67:24absentia 9:2absolute 87:6absolutely 15:14; 34:14;41:11 ;63:25; 86:10;14823; 176:21; 178:18absorption 14:19absorptive 14:20abstract 163:21academia 139:11academic 34:18Academy 130:23accelerated 141:23accept 65:5, 24; 72:19;51:7;85:9, 11,12,16,24,24;92:10;03:5;69:19;172:15acceptable 20:1I; 31:19;51:16; 71:16; 74:2; 101:9;113:8; 115:2; 161:15, 19;162:1; 169:13acceptance 36:19; 72:1accepted 35:22; 73:23;74:13accepting 81:12; 85:8accordance 4:18according 15:19; 16:2;17:10, 15;4S24accordingly 10:23accredited 179:14accumulative 38:3achieve 32:15; 39:1;52:19; 62:6; 101:13;111:7,20achieved 42:23; 53:16;70:23achievement 103:5achieving 38:4; 96:21acknowledged 165:4acknowledgment 162:5ACR40:11;43:22ACR-20 39:15, 23; 40:17;53:25 ;54:2,4across 132:17; 154:24;155:1

a bd om in a l - a ll-c au se (2 )

F ood & Dru g Adm in is t ra t ionGa s t ro in t e s t in a l Dr u gs Ad vis or y Comm i t t ee

act 125:2;30:13;31:3

acting 79:15action 154:21aCtiVe 18:19; 23:3,5,9,15,21 ;24:2, 10,19, 23;25:22; 26:1,6,16, 19;27:3, 11; 30:3,8, 13; 32:3,5; 34:25; 39:5; 42:4; 49:16;50:5,19; 51:19,20; 52:1;

58:20; 61:21, 23; 62:12,21, 22;63:12;64:20, 23;68:2o, 24; 69:13; 71:2;75:10, 20; 79:15; 80:25;62:5; 84:18, 20; 85:5; 88:5,6, 22; 101:18, 20; 109:2,15; 110:3,21; 116:10,17,19; 120:23; 123:21;150:19; 164:7; 168:11,12,15; 169:20; 171:11; 173:3,5,6,8, 10,12, 19; 174:8~CtiVeiy 7:7; 37:23; 77:12activities 20:24; 44:4;?2:17activity 13:14; 14:18;

15:1; 16:4,10, 11;17:2,[1;18:15,18,0;21:8;}1:17;2:10;5:11,14,[6;42:9,4;44:3;6:11;[8:23;2:22;3:4;4:20;;5:20,2;78:5;07:8,0,[0,13;108:20;11:13,22,12;120:19 ,25Ictual 21:20; 93:24ictual[y 1S.18; 21:21;!6:17, 20; 29:5, 24; 36:17,!0, 25;40:19; 43:23;i3:16;55:l,8; 57:13,15;.’9:7;93:21; 94:2, 2; 101:7;103:8; 104:15; 105:10;

114:14; 116:3,19, 25;119:4; 120:11, 20; 122:8;124:15, 24; 136:2; 138:22;140:16; 154:20, 22; 157:8;163:21; 166:21; 168:9;170:15; 177:15; 179:6actuarial.1 2:4acute 22:25; 23:5, 9;25:23; 30:23; 31:7,13, 16;}2:4; 34:25; 37:16; 38:18;39:5, 12;45:19; 64:13;72:1;75:8; 81:12, 14, 17;33:20, 22;84:10; 117:8~CUtely 43:25; 77:15;78:4;122:16

~dd 114:24; 178:10, 11zdd-on 178:19added 37:14; 103:8;171:8; 178:16zdding 61:15; 107:17, 21;[09:14 ;110:24ddisonian 117:5,6,7;[20:7; 123:8,12, 13iddition 45:21; 51:7;19:15;90:9; 123:2, 3;[33:2additional 7:22; 20: 18;!1:16; 61:7,7,9,15;;3:22;88:7; 89:25; 131:4;

132:8; 140:11; 141:21address 5:8;90: 18;97:6;106:11; 135:21; 144:10,16; 151:7; 161:2; 164:9;167:12addressed 51:2; 105:2,4; 167:21addresses 4:8;97:8addressing 124:15;

166:24adequate 79: 13; 107:24;143:17; 156:13; 159:2adequately 135:6adjust 100:4, 9; 137:14admirably 55:3Admittedly 73:25adolescent 128:16152:11adolescents 128:6,8,9,14, 18;131:1; 139:18;140:5; 143:5~duit 125:19; 126:16;128:16; 133:4; 135:16;138:20; 142:3; 143:3, 13;153:18; 155:3, 5; 160:2,7,[1, 17id ult s 9 6:1 9; 1 24 :1 2,1 8,!0, 23; 125:1; 126:16, 25;[2 8:1 0 ;1 30 :1 6; 1 31 :1 2;[3 6:3 , 2 5; 1 37 :2 ; 1 39 :2 0,

!3,24;40:23; 41:6,3;.43:8; 44:1;53:20;154:24; 55:9;59:12;!72:14, 6idvance 19:4; 20:11;.59:15advantage 22:9adversarial 5:22~dvice 136:6Bdvisory 7:14; 39:9;98:22,23ndvocate 9:25; 149:2dfect 14:19; 16:6; 36:1Mfected 4:21Bffecting 126:10Bffirmative 111:20after 9:17; 10:2; 18:7;~8:8;86:7; 110:5; 116:13;123:13; 147:14; 150:1;164:22afterwards 151:9Rgain 8:2,6; 37:12; 46:4;48:17;63:8; 65:24; 66:6;57:3;78:10; 80:9; 81:10;35:18;86:14; 92:7,19;)4:8; 97:2; 105:12, 18;107:16; 111:13; 130:2;136:4; 142:21; 143:4lgainst 21:8; 66:5; 95:12;)9:10; 129:3; 130:7;165:9,13~ge 125:12; 126:4; 127:9,?1,23,25; 128:10, 21;[30:20, 25; 136:18; 137:8;[38:4,8. 21; 143:10,17:

23; 147:5,10, 10, 11,13,17; 148:8, 20; 149:8, 10;1 50 :1 3; 1 51 :3 ,2 1; 1 52 :11;163:18

a ge-r ela ted 152:17

a gen cy 7:6; 19:6; 20:11;3 4:1 8; 3 7:2 1 ;3 8:1 3;

5 7:1 5, 2 0;8 6:1 6; 113 :1 0;130:12; 134:17, 22;1 35 :1 9; 1 41 :9 ; 1 43 :2 3;166:25; 170:4; 178:1, 7;179:21

Agency’s 4:24; 132:22;160:21agenda 4:11; 5:2

agent 72:6; 77:11; 81:22;82:7; 118:4; 122:1; 124:1,8; 142:7; 155:18; 162:18;167:16, 19; 168:1,3;171:11agent’s 135:8agents 24:21; 125:4;155:1; 172:8,9ages 132:17aggressive 125:25aging 149:13ago 75: 12; 79;7; 106:6;135:14; 137:17; 139:9agree 30:25; 45:6 46:1;50:5;78:18, 23; 85:7;39:12;97:7; 111:24;[12:3,9; 122:11; 123:15;136:17; 153:13,19, 22;161:11; 176:23agreed 37:9, 24; 102:25;[77:11agreeing 122:8; 129:19agreements 141:17

agrees 152:3aim 111:8; 120:2airned 102:23air 177:5ala 168:7albumin 15:1ali 4:12, 13, 19; 5:7, 24;7:25; 13:16; 16:14; 18:21;23:25; 25:9; 27:17; 29:3, 5;30:12; 32:3; 36:13; 37:10,14; 38:19; 39:6, 8; 42:8;43:3; 46:9, 12;49:3; 50:21;55:20; 56:20; 57:18;58:16 ;62:11;63:4;68:1o;

70:3, 5;72:17; 73:17, 18;74:23; 79:9, 24;82:10;63:1, 4; 84:19; 87:9; 88:4;89:lf$90:5;94:ll, 12;99:5,16, 23; 103:2, 4;106:9; 107:25; 110:14;112:23; 114:2,4; 116:7;117:9; 118:1, 22; 119:7,11; 123:1; 125:8;127:14;129:3; 130:4, 11;131:24;132:13,7;133:1;35:2;144:1;152:23;60:4;164:5,1;168:22,3;173:4,17

!44:25; 145:2,5; 146:14, I all-cause 77:9 —

Min-u-seript@3 Mille r Re po rt in g Co m ~a n v. In c .



.->—-

—

—.=—

a[!OW 7:21;0:7;18:9;138:5allowed 120:21;78:13

allowing 77:18;23:6diows 131:23aiMOSt 67:20; 76:3;114:4; 147:9, 14; 161:1;166:2, 12; 168:8, 12;178:5,9alOne 62:5; 138:4along 41:23 ;73:17, 18;132:12; 153:1; 167:11alongside 173:23alpha-1 15:3already 5:2; 18:24; 24:8,21; 25:7; 26:5,7; 54:11;74:1,9; 84:25 ;102:11;150:21; 152:1,17, 19;165:9; 166:5; 172:17A[s05:21; 6:18; 7:21;8:10, 12; 10:11; 11:4, 10;12:13,21 ;15:11,25;27:20; 29:18; 38:20;

41:16 ;42:11;43:7; 46:24;51:6, 12; 52:3, 21; 56:2;58:3; 60:12; 66:24; 74:12;75:4; 76:6; 92:11, 14;101:2, 5; 102:17, 25;106:2; 108:19; 120:9;125:7; 130:23; 133:23;135:21; 139:21; 140:11;145:21; 159:16; 164:23;165:14; 166:2; 168:14;174:13; 178:14alter 158:10altered 15:19altering 178:16although 16:4; 20:8;62:8; 74:13; 82:24; 88:20;90:4; 99:24; 105:1;109:17; 152:14; 166:20always 26:8; 28:7; 47:21,24; 55:25; 56:3; 89:5;90:17; 112:10; 114:24;147:9, 14; 151:8; 153:11;155:14; 168:12am6:12; 10:2; 1I:1o;33:19; 34:7; 44:14 ;46:19;50:20, 22; 51:23; 52:7,7,23, 25; 56:3; 57:17; 58:17;61:1o; 67:14; 68:9; 75:5,6;80:23, 24; 81:9; 82:17;86:3; 90:24 ;91:19; 94:15;95:21 ;99:12; 100:12;109:23; 113:21; 118:23;123:5; 127:3; 128:25;129:2, 5,25; 133:8, 10;139:13; 140:12, 19;142:23; 143:9; 144:2, 5;146:3; 148:3; 150:9;154:12;157:12; 158:1,4;159:3; 164:9; 166:13;171:21; 172:6; 178:7ameliorate 23:6ameliorated 27:3American 37:11;41:5,8;60:12; 96:15; 130:23among 30:8; 96:15

2 3;2 1:1 ,1 , 1 0,2 0,2 1;2 2:5,6 ,7,12 ,21, 25;2 3:L12, 13; 24:6,11,22, 24;25:4, 10, 19;26:2,6,6, 1:20;27:1,5, 11;28:2, 11,14, 21; 29:2,3,4,9,9,10,12,13,19,23, 24; 30:8,13, 17; 31:5,6,17, 23;32:22,25; 33:1,8,14, 14;

34:9,10,17,18,18,20,20,21; 35:3,19,23, 25;36:4,7,12,15,16,19,19,2 1, 2 4;3 7:5 ,9 , 11,1 4,1 7,20 , 24 ; 38:4,11 ,13 ,22 ,23; 39:2,4,5,10,12, 13,15, 20; 40:2,8,8,13,14,1 5, 1 8,23 ;41 :3, 10 ,12,1 3,18 ,18,2 0, 2 3; 42 :5,5,

6,13,18, 23,24 ;43:2, 5,10,15 ,18, 24;44:3 ,4 ,9 ;45:2, 11,13,20; 46:1, 11,

12, 19;47:5,6,9, 13, 15,15; 4 8:5,1 3,15 , 17,2 0,23; 49:5, 10,16,19, 25;

50:1,6, 17, 18, 19, 20;5 1:1 ,3 , 1 0, 12,13,20;;2:2,,24;53:1,4,0,11,!3,24,25,5;54:3,3 ,[6,0,20, 5;55:2,8,17,17,19,20,22, 5;56:3,4,~,16,19,24;7:1,4 ,6,8,19,16 ,19;58:6,13,4,.5,15,16,20, 4;59:4,9,25;60:6,4;61:6,7,0,11,12,19.22.24:6’2:2,3,4,’7, 0,11,3;63:2,4,5,7,18,23, 5;64:1,7,10,11,12, 4,20;65:10,5;6:6,10, 3,22,

24,24;7:4,5,12,13,14,24;8:21;9:24;0:4,4;71:8,9, 3,14,5,17;72:6,9, 5;73:5,7, 1,11,13,13,17,18,19, 0;

174:9,12,12,14,21,22,24;75:6,8, 1,11;76:3,4,5,5,7,7,9,15, 8;77:1,10,12,14,15, 6,18,8;78:6,;79:19;0:5,8,13,17,2581:6,11,11,13,18,21;82:13,4,13,18,18,19,9;3:3,9,10, 4;84:2,18,18, 9;85:7,8,

~ 14,18,22,24, 5;6:3,6,9,13,13, 6,19,20,21,25;87:3, 2,15,21,21;88:2,4,8, 4,1;89:10,20;90:6,0,13,20,21,23,24;92:1, ,4,6,8,14,16,19,20, 1;93:2, ,7,13,17,19,23, 4;94:4,

‘ 11,15,22,25 95:2;96:1,2)7,9;7:11,3,15,6,17,18,20,21 98:1,4,9,13,14,16,7,0;99:5,7,14,15;100:10, 4,19;101:2,7,10,18, 3;102:9,13,13;103:2,5, 1;104:6,6,13,16,21, 4;105:9,11,15,22,2,25;06:21,

F ood & Dru g Ad m in is t ra t ion Hea r in g Vo lu m e Nu m be rGa st r oi.n t e st in d Dr ugs Ad vfio ry Comm it t e e

Ma y 29,1998

amount 6 :13; 36:22;

9 6:6 ; 1 02 :3 ; 1 56 :8 ;173 :10; 177 :17

amounts 135:24ample 102:9amplify 54: 10; 77:8

an 4:15; 5:3,22, 23; 7:22;8:3; 9:5; 10:9, 11; 12:13;

13:11,22, 5;15:7;7:9;24:5;5:23;7:22;9:6;30:11,18; 1:19;3:19,20;34:24,25, 5;35:1, ;41:2343:17,17;44:15;46:19;8:15,3;51:16;52:8;3:1,6, 0;54:2;57:20, 5;58:1;60:23;61:4;2:3,16, 3;63:13;65:3,3;6:16,0;8:20,24;69:15; 1:2572:1,6;73:1775:14, 5;76:3;77:11, 6;79:13; 1:12,17;2:8,5,18;3:16,2;$4:10; 5:13,4;8:24;S9:7,5;0:25;2:2s;>4:4,22, 4;95:2;9:7,8,Z2;00:7,4;101:9;[03:2, ;107:24; 11:20;112:25; 13:3;16:22;[17:6,8; 18:23; 20:24;L22:18; 23:2, 1;124:8;.26:16; 28:16, 6;129:5,.0;34:21; 35:5,13;36:1;38:6, 0;141:7;43:17,23; 46:14,15, 9;47:10,12, 4;149:2;53:13;54:18; 55:3;57:13,17, 3;160:10, 5;61:23;62:12; 66:3,3;67:4,4;169:15, 0;70:1;71:11173:3,5;74:8,9,25lnalogous 41:14analyses 97:14; 98:2, 25;99:1; 147:14; 151:9;154:4,5analysis 74:13; 87:18;B8:11, 24;97:12; 106:8;145:3;148:11; 151:2;166:23analytical 99:9anastomotic 19:9anatomically 28:21ANCA 13:4

md 4:3,9, 11, 14; 5:5, 15,19,23 ,25 ;6:1,3,5,8,10 ,1 2,1 3,1 3,1 4, 1 9, 19 ,2 0,Z3;:8,0,12,0; :1,6,12,16,0;9:5,6, 4,15,16,8,19;10:2,1,12,14,18,18,19,20,22,22,~s;1:44,8,9, 7,22,23,?5;2:3,4,4,9, 0,13,16,20,23;3:1,8, 3,16,21;14:1,4,8,13 15:4,7,11,12,13,14, 8,20,25;16:5,7, 0,20,22, 4;17:1,4,9, 5,18,21;8:1,7,9,1,13,8,19;19:10,

108:2,6,6, 11,14, 25;109:15; 110:5,8,13,17,18,20,22,23,24, 24;111:2,8; 112:5,10, 12, 17

1 9,19 ,22, 2 3; 114 :7,9,17,18 , 23; 115 :8 ,13,14 ,16, 17, 18,20, 25; 116:7,10,14, 15, 15,21; 117:5,

8,10,12, 16,21; 118:1,

1 4,18 ,20, 21 ; 119 :4,5,11, 16; 120:2,2,6,20,20,

23 ,24,2 5, 2 5; 12 1:3,1 0,14, 16; 122:1,7, 18;123:13,16, 17,18,19, 19;124:1,5,18,22,22, 23;125:10,13,16,17,22,23,

23 , 25 ; 126:3 ,3 ,5 ,7 ,13 ,14,17,19,20,21, 25;127 :8 ,10, 11,13 ,22,23 ,23; 128:1,6,7,18, 23;1 29 :5 , 1 6, 2 4; 1 30 :1 5,2 0,25; 131:1,5,8,10,12,14,15,20; 132:1,3,7,16,17,20,20 , 25; 133 :2 ,4 ,7 ,13,

1 5,1 8, 2 3,2 4; 1 34 :4 ,1 8,19, 19; 135:16,18,19, 25;136:3,3,5,7,7,9,19, 25;137:11, 12,19,19,20,20,?1,2 4; 1 38:3,4, 19,21,!1, 23; 139:7, 12, 16, 24;[40 :10 , 12,2 1,25 ; 141 :1,J , 1 3, 1 7,2 1; 1 42 :7 ,1 4,!5 ; 14 3:6, 10, 13, 14,2 4,!5 ; 1 44 :4 , 1 4, 1 7,2 5;45:3,4,8,10, 24; 146:7,13, 16; 1 47:1 ,12, 2 3;1 48 :8 , 1 4,1 5, 1 7,1 7,1 8,

25; 149:3,7,8,9,14,14,20, 25; 150:13, 20; 151:4,4,14, 16; 152:2,5, 12,24;154:7,19, 22; 155:3, 12,13,23; 156:1,4, 14, 14,22, 23; 157:2,2,5,10, 18;158:10, 19; 159:3,14, 16,18,24, 24; 160:5,7,9, 10,12, 12,13, 15, 16,17, 18,20, 22; 161:6,8,14,17,21; 162:11,22; 163:1,12,17,20, 22; 164:6, 18;165:1,5,7,15, 15; 166:10,22, 22; 167:9, 11; 168:1,11, 19; 169:6,17, 18;1 70 :7 ,11, 1 4; 1 71 :8 ,9 ;172:1,3,13,14, 19; 173:5,6 , 17,24 ; 174 :1 ,1 ,4 ,5 ,6 ,

1 7, 2 0; 1 76 :1 5, 1 7,2 0,2 1,24; 177:11,18,21, 22;1 78:3 ,4,9 ,14, 1 8,2 3;179:7, 11,11,11,21,23,23

Anderson 98:3anecdotal 146:8Anemia 14:17; 29:23;40:14

ngiogram 66:17ankylosing 14:7announcement 4:7anomalies 158:5Another 19:5; 30:19, 19;

I

63:21; 65:6, 10; 76:23;77:9; 81:13; 82:7; 89:6;95:13; 106:2; 113:19;116:9; 117:3; 142:7;

22,22 ;20:10, 11, 11, 16, ” I 22,24; 107:15, 18)24;43:21;47:5; 48:22; 51:10;

Mille r Re po rt in g Co m pa n y, In c . Min-U-Script@ (3) a llow - a fmlicd

159:5; 167:15; 169:6answer 62: 17; 86:9;102:10; 111:20; 112:18;118:1,2,3; 122:18; 123:5;130:4; 133:16; 155:14, 19157:23; 158:14; 170:12;175:8; 178:6answered 133:4; 158:17answering 140:13; 178:7answers 120:9;43:14Anti-metabolites 69anti-TNF 173:22antibiotic 167:15Antibodies 77:7anticipate 174:25anticipating 63:24anticonvulsant 135:13antimetabolite 168:22antimetabolites 24:17;168:23antitrypsin 15:4any 5:1,8,9 ;7:4; 22:10;25:16; 29:12, 13, 13;34:14; 37:17; 45:8; 46:5;52:17; 57:23; 58:7; 64:5, 6;68:7; 79:8; 87:25; 91:7;93:1; 97:9; 103:22;113:25; 121:23; 23:5;129:4;30:4;43:1;145:13; 55:23; 68:11169:3Anybody28:l;131:ll;

139:15anyone28:8;2:4,2;70:17;44:15; 70:12anything 22:9; 63:3;71:17,18; 77:3; 91:5; 95:9;106:25; 113:13; 127:3;156:23; 158:22; 178:9anyway 104:14anywhere 139:1 I;162:17aphthous 16:13apparent 34:14lppeal 33:19ippealing 67:14

Ippear 12:9; 13:6; 88:13,13Appearance 4:10, 15;.6:3Ippeared 125:3Ippears 28:20Ipplaud 131:15; 136:24applicable 41:24 ;42:lo;31:1; 151:3Implication 95:21;31:25; 141:17; 163:10,:2;174:25; 175:1applications 135:2pplied 106:20; 133:7;

66:13



Hea r in g Vo lu m e Nu m be r 2 Food & Dru g Ad m in is t r a t ionMa y 29, $)$)8 Ga st r oin t e st in a l Dr ugs Ad vis or y Comm it t e e

_SpplieS 130 :17; 137 :18;1 57 :8 ; 1 61 :1 9; 1 66 :2 3

-~iy 110:2,6; 140:11;,24

a ppr ecia te 39:4

approach 33:9; 44:19;64:2; 86:24; 118:25;137:1; 139:22; 141:2appropriate 10:3; 80:20;

87:2, 10; 107:11; 114:15,22; 129:1; 134:13; 135:5;143:11; 146:19; 160:25;175:5appropriately 12:21;36:13; 155:1approval 19:7, 23; 20:3,17; 58:2,4; 102:18; 113:6;124:6; 128:20; 132:21,22,22,23, 23; 141:9,13, 23;142:5; 165:22; 167:24;179:9approve 11:11;85:22;165:19approved 70:8; 113:5,20; 114:8,18, 19; 130:16;131:15; 132:8; 133:23approving 115:3approximately 4:3;10:17; 12:15; 171:6; 179:3ARAMIS 34:8; 41:4arbitrary 75:22; 77:17;Z12, 15;90:7; 97:16

.5:4, 19;6:4, 20; 7:6,11,11,13, 18, 19,23 ;9:8;1 0:25 ; 11:16 ; 12 :21; 13:3,16; 14:5 ,8, 14 , 25; 1 5:10 ,21 ,25; 16:5 ,12 , 1 2,17 ;17:3 ,8 , 18; 18:1 ,3 ,5 ,6 ,

12,21 ;19:15; 21:19,21 ;23 :5,1 5, 22; 24 :15, 18 ,20,22, 24; 25:2,4,7,9,10,13,17,20, 22; 26:9; 27:2, 15,15, 16, 17, 25;28:13;2 9:11,11, 1 2,2 1 ;3 0:1 2,16,17 ,20, 23;31:5 ,6 ,23;32:25 ;33:2,3,3,4,7,7,7,8, 17;34:2, 11,15, 17,22;35:7,11,12,20, 24; 36:3,25; 37:4; 38:10,15,16, 17;39:1 ,6 ,7 ,15 ;40:1 ,4 ,13,16, 18;41:22, 22;42:3, 10;4 4:8 ; 4 6:3 , 1 2; 4 8:2 3;49:10 ; 51 :21 ;53 :13,14 ;54 :2, 1 3;55 :12; 57:7 ; 58:2,4,9, 23; 59:8,18,19, 24;61:15, 20;62:13, 14, 25;6 3:5 ,9 ,1 7,1 7, 2 4;6 4:2 ,6 ,13,14, 14;65:11;66:8, 14;68:23 ;69:5, 5,12,14, 17;71:14,19, 24;72:3, 4, 13,17, 18, 25;73:3,3, 10, 11,

20,21, 25;74:7, 10;‘7, 9, 23;769, 11, 25;.22, 25; 78:6; 79:16, 16;

8 0:1 3, 1 6;8 1 :5 , 1 2;8 2:4 ,14,23 ,25 ;83 :1 ,7 ,11 ;8 4:9 ,1 5,1 9,1 9, 2 5;8 5:4 ,4,5,8,17,20,21, 23; 87:2,9; 88:7, 10; 89:5,9, 19;

a pp lie s - ba ck (4)

90:15 ;91:13,21;93:16;95:4,6,8,9,10, 15; 96:4,8 ,9 , 20 ; 97 :2 ,14 ,16 ,17,19,20,21,21,22,24, 25;98:1 , 1 8;99 :5,8, 10 ,16,18 , 20; 10 0:9 , 13 ; 10 1:6,18 ; 10 2:9,10, 16 ; 10 3:3,16; 104:2,3,19, 23; 105:8;106:22; 107:11, 17, 23;108:1,2,3,4,6,7,8,16,17,19,21,23, 24; 109:4,6,12,14,18,21, 25;110:1,5,21,22, 23;111 :1 3; 112 :1 2, 1 4;114 :4 ,

5 ,7 ; 115 :7 ,9 ; 116 :5 ,8 ,11,1 2,1 3,2 2,2 5 ;117 :1 ,5 ,14,16, 19,24, 25; 118:3,7,12 ,15,16, 17; 11 9:3,8,10 , 16 ;120 :1,10 , 11,11,20,23 ,24; 121 :1 ,11,12 ,12,13, 14; 122:4,19, 22;1 23:4 , 11,11, 18 ,24;1 24 :1 2; 1 25 :1 0, 1 6,1 8,2 0,20 , 23 ; 126:2 ,6 ,12,13 ,15,16,17,17,19, 23;127:16,21,21,22,23,24;128 :12 ;129 :3 , 11,15 ,21,24 ; 13 0:2; 1 31:11; 1 32:2 ,5, 11,2 5; 13 3:3,6 ; 1 34:1 8;135 :1,18 ,23, 2 4; 136 :8,17; 137:23; 138:8,15, 23;1 39 :1 , 1 ; 1 40 :1 3; 1 42 :2 0,21 ; 1 43:1 , 15 ; 14 4:2;145:4,7,12,22,22,23,24; 146:1, 12,13, 13;147:4,5,5,15, 16,22, 25;148:6, 14 ; 149:2,12 ,13 ,17,19,20,21, 25; 150:7,3,13,16, 16,18, 19;151:10,13,14,14,18, 19,

20 ,22; 152:1 ,5 ,11,13 ,1 3, 1 6,1 7, 1 7,2 1,2 4;153:4,10 , 14 ,20,21 ,22 ,23; 154:4,5,8,11, 13;1 55 :1 0, 1 2, 1 2; 1 56 :2 ,4 ,10,19, 21; 157:21,23, 24;1583,5,16,23, 23;159:10,11,14,15, 22;160 :1 ; 161 :6 ; 162 :7 ,8 ,21,24 , 25 ; 163 :2,5,9, 12,1 3,17 ,18,2 0, 2 3; 164 :6,7 ,21 ; 165:8; 166:9,10 ,11 ,12 ,18, 23 ; 167 :1; 1 68:2 4;16 9:18 , 20 ; 170 :17, 23 ;171 :5 ,5 ,8 , 9 ; 173 :4 ,6 ,15,Z5; 174:7,15,17, 25;175:14; 176:1,1,6, 17;177:1, 19, 20; 178:11, 12;179:6

a rea 36:7; 46:24; 51:9,1 0;5 7:1 7; 7 2:1 0; 7 3:1 7,1 9; 1 03 :1 5, 2 0; 1 04 :2 3;1 05 :1 ; 1 37 :1 8; 1 77 :1 6

a rea s 7:8; 35:10; 36:7,1 8;3 8:2 ; 6 1:1 3 ;110 :1 2

aren’t 3 4:1 4; 3 8:5 ; 8 7:2 5;9 7:1 6; 1 38 :1 4; 1 50 :2 0a rgu ably 54:22

argue 54:16;5:2,1;68:25;15:17;44:18

argument 169:15, 16arm 104:8; 108:8; 119:5;120:8,9arms 119:5around 33:2, 12; 86:13;87:22; 88:19; 94:12; 96:5;110:24; 127:25; 136:7;138:15; 154:14; 156:9;173:14

arrangement 5:22arthritides 14:5arthritis 14:4, 6; 29:19;34:8,12, 24; 35:16; 37:8;38:10, 21; 39:9; 40:2; 61:5;81:8; 82:16; 92:4; 163:3;168:7; 171:12; 172:1, 19arthropathies 14:9article 45:10; 50:15;175:3artificial 129:5as 6:14,25; 7:6, 15, 20;9:1,8,18, 19; 10:15; 11:4,11,17, 23; 12:9,13, 24;13:3, 16,24; 14:2,4,7,8,10,20,22, 25; 15:16, 20;16:4, 13; 17:2,2,4,4,9,13, 15; 18:16; 19:2,8,12,15, 16, 17; 20:8,8,15,15,16, 19;21:12, 24, 25;22:24; 23:10,21, 23;24:1,4,9, 12;25:6, 17, 18; 26:1,2, 15; 27:3,11,14,18,22,23; 28:6; 29:8,9, 24;31:16,18, 22; 32:9,14, 14;34:13,21,24, 25;35:8;36:16; 37:13; 38:16;39:21;40:3,3,23; 41:14;42:19; 43:17,21 ;44:3;

45:4,11, 18,21 ;46:9,19;48:21;49:6,6,18,22, 24;50:6; 51:15; 53:4; 54:5;55:3; 56:16,23,24, 25;57:6,9,20, 25; 62:12, 20;53:2, 20;64:6, 10; 65:13;56:5,9, 10, 22; 69:19;70:3; 72:19; 73:23 ;75:14,19;76:8, 8;78:7, 13,15,15, 16,24,25;79:16;81:7,22, 22;83:1, 12;84:13, 14,14;85:4; 86:18; 88:15, 20;90:18, 19;91:2, 13;92:3,10, 11;93:6, 17,19,22,25;94:5,24;95:1, 1 , 11;3 617 , 25; 9 7:16 ; 10 1:22 ;10 2:2; 1 03:6 ,9, 15; 104 :4;106:13, 23; 107:20, 25;1 08 :1 ; 1 09 :1 6; 111 :3 ,9 ,1 4, 1 5; 112 :5 ,6 ;114 :1 9;115 :1 4; 116 :4 ; 118 :1 ,6 ,11 ; 11 9:2; 122 :3, 4; 123 :2,10 , 25; 12 4:18 , 19 ; 1 26:2 2;1 27 :1 0 ;1 28 :4 ,9 ; 1 29 :11,25; 130 :13; 131 :1 ,2 ,2 ,12,2 3; 1 33 :3 ; 1 34 :4 ,4 ;136:14; 138:7,7,10, 13;139:16; 140:4,15, 15;141 :13; 142 :4,4; 14 3:8,16; 145:1, 20; 148:2,5, 23;149:2:150:23:151:22:

152:3,4; 153:10, 20;1 57 :5 ; 1 58 :1 4; 1 60 :2 5;1 61 :2 3; 1 62 :1 1 ; 1 66 :3 ,9 ;1 68 :5 ,6 ,6 , 11; 1 69 :2 1,2 1;1 70 :2 3; 1 73 :1 7; 1 74 :1 2;175 :12,24 ;176 :21;177:18; 178:6,11, 17, 19,20,21

Asher 46:7

ashore 82:3aside 108:3; 134:21;165:17ask 5:7; 10:2; 28:7; 33:12;72:2; 106:17; 111:18;130:1; 136:16; 145:9;155:18; 168:17; 170:6asked 9:12; 38:17; 86:12,16, 17; 109:24; 112:17;120:10 ; 132:11,21;150:25; 155:12; 159:23;165:15; 167:12, 17;175:23asking 23:22; 38: 16;71:24; 72:17; 73:10, 25;145:8; 157:23; 162:21;163:12, 24; 176:6aspect 35:8; 86:16aspects 9:4, 23; 20:8, 8;21:12 ;35:13;67:2; 68:18;86:23; 160:2; 167:8assess 42:14; 46:24assessed 47:23assessing 21:10assessment 46:1; 49:12;136:1assessments 10:11assistance 38:8, 12;

179:24associated 57:21; 108:2Association 41:5, 8;58:12, 14;92:19assume 23:14; 125:22;139:19; 142:25assuming 85:17; 100:8assumption 28:8; 100:7assumptions 89:4at 4:10, 16; 5:25; 7:13;B:23;9:I, 13,22; 11:11;13 :5, 1 0; 1 5:24 ; 16:1 4;17 :17; 18:1 5; 19 :9, 1 2;2 1:5 ,1 9, 2 0; 2 2:11 ;2 3:2 2;25 :8; 31 :7,8; 34:1 ; 36:1 5;37:23; 38:2; 39:8,11, 21;40:2 5 ;41 :19;4 2:8; 43 :3,24;4 4:21 ; 45:2 ,7 ;46:2 ,11 ,12 , 16 ;47 :25;48 :13 ,16 , 1 9;49 :3; 50:2 1; 55 :4,20; 59:2 5; 60:1 , 2 2; 64:5 ;65 :1 ;6 6:1 3;67 :21; 68 :3;6 9:2 5 ;7 0:4 , 1 3, 1 8;7 2:9 ,10;73:16, 16;74:4, 14, 20;7 5:6, 22 ; 7 8:25 ; 79 :9; 80 :2;8 1:25 ;8 3:22 ; 8 4:3, 5,1 6,19; 85:3 ; 87:23; 88:7 ,8 ,9 ,1 0;8 9:4 , 7 ; 9 2:1 8 ;9 3:2 ,2 1;9 4:3 ,7 ; 9 5:2 2 ;9 6:1 ,2 ,

9 ,1 3, 23 , 2 5; 1 00 :1 6,1 9,23; 104:23, 25; 105:12, 13,14 , 16 ; 1 08:1 5, 2 3; 10 9:7;112 :2 ; 113 :2 5; 114 :6 ;118:20; 119:6, 10,12, 18;121 :17, 18; 122 :2 ,12,13 ,23 ; 1 23:7 , 14 ; 12 4:10 ;125:3,8,12,15, 24;126 :20, 21 ; 128:13; 13 0:4 ,2 0,25 ; 13 1:14 ,21; 132 :18;

1 36 :2 3; 1 37 :2 4; 1 38 :3 ,1 7,19 ; 14 0:16 , 18; 141 :3;142:8; 143:1; 144:1, 11;145:5; 146:14; 147:10, 20;1 49:1 2, 16 ,23; 15 0:1;151:4, 8; 152:16, 20;1 56 :5 , 8 ; 1 57 :1 6; 1 58 :2 3;160:7; 161:6,7,8, 13;1 63 :1 , 9 ; 1 64 :4 ; 1 66 :1 2;168:6,15,20,22, 23;169 :17; 170 21; 171:19,20; 172:8, 10; 173:13, 14;17 5:1; 1 76:11, 13 ; 17 7:21 ,2 2; 17 8:14 ; 17 9:3

a tt ach ed 122:2o

at ta chm en t 122:22a tt ain able 67:21; 68:1

a tt ain ed 107:20

attempt 33:20; 64:8,10attempted 64:1attempts 84:4; 122:12,13attention 33:6; 130:6attitude 111:14attractive 93: 19; 138:11AUC 103:21

audience 22:18; 46:5;87:25; 151:1

author 6:25availability 135:4available 6:4; 13:11;53:22; 74:9; 97:14; 99:9;141:16; 142:3; 166:5;173:23average 95:3; 103:18, 20averaged 103:21avoid 159:16avoiding 97:15aware 5:4;7:6; 16:18away 35:22 ;41:8; 58:21;61:22, 24;90:2, 15; 114:6azathioprine 24:17;

123:21, 25; 146:7; 168:5;170:7; 171:8

B

b 22:25;9:9, 3,20;63:10;3:14,2292:21;110:17B(268:13B12 14:21back 9:21; 10:19; 36:8;47:6; 4&17; 61:24; 63:7;75:12; 80:3; 81:4; 82:21;86:7:87:14:100:24:0; 97:2,9, 18; 98:4,5,9, ,

Min-u-scr ip t i Mille r Re por t in g Co m pa n y, In c .



Food & Dru g Adm in is t ra t ionGa s t ro in t e st in a l Dr ugs Ad vis or y Comm i t t ee

126 :1 8, 2 1; 1 44 :1 4;1 50 :2 5; 1 51 :2 ; 1 53 :1 7;

- 157:1;159:19;171:21;1 72 :2 3; 1 74 :11

background 9:10;127:10; 165:9,13bad 44:24, 24; 156:10badly 58:14,15,16balance 58:23

baldness 165:25Barbara 9:21; 32:1;131:1,23; 138:13; 139:6

base 102:21; 133:5Based 4:ll; 11:11; 19:4;20:7, 9; 28:9, 13; 35:20;44:18; 45:14; 58:3; 70:8;71:22; 104:22; 106:6;124:6; 156:13; 157:13, 20;158:5,22; 164:19; 165:20;173:11; 177:9; 179:1baseline 18:7; 47:25;68:3; 88:2; 170:2; 173:21baselines 94:11

bases 13:9basic 33:14; 64:2; 152:25basically 6:5; 44:7;48:16 ;74:4;80:1; 114:19;135:2; 138:5; 139:12;143:22; 150:4; 158:23basis 9:4; 48:24; 51:14;_—_84:1, 2;92:25; 108:18;142:2, 10; 153:17; 156:6;165:4; 173:8bathroom 55:21be 4:20, 23; 5:5, 14,23;8:3; 10:20; 11:24; 12:25;13:5,6,7; 14:1, 1,18,20;15:1,11, 13,25; 16:5,5,11,13, 18; 18:5; 20:9, 23;21:19; 23:25; 24:23; 25:4,25; 26:12, 18; 27:6, 9;28:9, 20; 29:2,3,10,15,18,19,22, 24; 30:2, 9;31:14 ;32:6,19,20; 33:14;34:5; 35:4, 14, 24; 37:10,10,13, 13,15, 18,25;38:1; 39:10,16, 17;40:13,17;41:13, 18, 23;42:12;43:24 ;44:10, 12,16, 16;45:7; 46:16, 24; 47:2, 17,23;49:5, 15, 15; 50:1,4,5,6;51:15; 52:2,5,14,20;56:10,11,12,14, 17;

57:20, 25; 58:11, 14;59:11,12,22, 25;60:10,15;61:1, 13;62:1,6,23;63:10, 23; 64:2o; 66:17,19, 23; 68:24; 69:14, 15,23, 25;71:16;72:12, 14;73:2,4,5, 10;74:20, 25;75:9; 76:17; 77:10,13,16,16, 19; 78:4,12, 13,17,20,22, 22; 79:12, 14;80:6,7, 15;81:18, 22;82:19, 22,23,24 ;83:1,16;84:1,2,4,17;85:18; 86:7,8, 17;88:16, 23; 89:9, 12, 23;90:10, 23;91:11, 23;

92:13,13,14,17, 8,25;93:1,13, 7;94:22; 5:1,3,13;6:4,0;7:23;98:7,9;9:17,4;100:8,20;101:25; 02:1,12, 4;103:1,1,15,15, 8;104:25; 05:15, 6,3;107:12; 08:12, 3;109:2;110:20,25; 11:8;12:7,24,25;113:3,8,18, 9;114:11,22,22; 15:6,17,18;116:16,20; 18:18;119:17; 20:21; 21:6,12,21;123:13; 24:16;125:17, 9;126:9,6,5;127:5,8,9,9,12,17,21,22,23,4;129:24; 30:6,7,18;132:3,9,14, 4;133:4;34:2,3,4,5, 3;135:2,6;136:9,10, 4;137:3,4,6, 2;1381;139:13,17,23, 4;140:4,B;141:5,2,18,9,20,22,23,24,5;142:2,5,7,3,13,22,5;144:3,6;145:14,5;146:9,15,22,25;147:1,2,3, 0;148:11,25;149:8,9,21,24, 5;151:19152:15;53:3 ,6;154:8,18,19,20,22, 3;155:3,4,9;156 :17;157:5,7;158 :13,4;159:9,16,18, 3;160:2,12,17,8;162 :1,6,4,14,17;163:8,12,5;165:11;66:8;67:4,5,18;169:13,19,3;170:4,f;172:9,6;173:11,1;174:22,23, 4;175:6,14,z5;176:1o ,1,20,5;[77:4,,9,23;178:3,4,5,

11;179:10,4>ecame 130:14>ecause7:4;:21;7:5;?0:6;1:1;2:18 ;3:15;;5:14,7;26:13,25 ;18:18;2:18,5;34:13;}5:11;8:5 ,2;39:9 ;1:4,~;42:6,9;4:8,1;51:24;j3:21;4:5;5:9;6:5,1,[9;58:24;9:8;0:10;;2:3;3:16;8:1,;73:7;76:24;8:4 ;0:15,4;11:16;2:4 ,0,17,22,5;$3:4;7:14,5;89:4;0:4,!1;1:12,9;93:3;4:17 ,

~8;5:11;6:17;7:6;18:23;00:7 ;01:3;[02:10;03:2;04:7;.06:20 ,5;108 :24;I1O:21,25; 12:4;14:5;[15:9;16:8;17:7;.18:8;19:7;23:11;.25:8,3;129:7,0;.3620;137 :2;38:5;140:2;42:3;43:4,;146:14,3;147:1,5;148:1,11 ,5;150 :8;153:20;55:4,2;156 :2,4.16;158:6.10 .11.15.

167:6; 169:10; 170:13;174:14; 175:24; 177:15;178:7,15become 123:19; 129:10;139:10becomes 51:11,2;121:16;68:20been 4:13, 19; 9:3,9,14,18,23,24, 24; 10:7, 16;

11;2, 12, 18; 16:22; 17:4,14, 23; 18:24; 19:6, 15;20:21; 21:7; 22:8; 23:7, 7;26:8; 32:6; 33:5; 34:13, 20;37:6, 22; 38: 12; 39:20;40:25 ;41:11;46:17,18,25; 47:6; 49:18, 24; 54:11;64:1; 74:13,19; 77:24;86:12; 93:25; 96:14;98:11; 100:25; 104:12;106:7; 112:10; 115:4, 24;117:13; 121:13; 122:8;129:15, 18; 130:20; 131:2,14, 22; 132:7; 144:8;147:9; 150:10; 151:18;

153:11, 12; 157:16; 158:7;159:7; 163: 16; 166:6;168:2, 4; 170:14; 174:1;179:8,18Before 6:7, 9;7:9; 20:22;49:13;66:7; 72:18; 75:15;36:12;89:3;90:1; 101:17;109:24; 119:3; 140:10, 23;141:9; 144:9Degan 146:23Oegin 4 :4 ; 1 7:1 7; 3 7:5 ;1 04 :1 3 ;1 24 :11; 1 53 :8

a ;gin nin g 8:25; 40:25;96:2 ; 179 :5

Oegun 12:9; 19:11

~ehalf 13:2~ehave 124:19; 143:2;144:19; 145:9]ehaving 87:20>ehavior 143:5>ehind 160:20leing 10:24; 22:9; 25:24;Z9:12,14, 14;35:21; 39:7;;6:3, 17; 67:22; 82:7; 98:7,13;104:22; 106:23; 108:9,[2;111:21,25; 112:1,7;L19:8;120:1, 11; 124:7;129:3,4, 11; 132:4; 137:1;[55:12; 173:20; 177:6

3elgium 9:14>elievable 153:5>elieve 54:15; 79:18;106:3;115:23; 132:11;L50:7;151:1,14, 19;[52:10; 177:16]elieved 102:21>elow 18:18; 27:14;31:19; 32:11 ;49:19; 87:5;95:8, 8; 96: 18; 105:8;110:17,17, 18, 20; 119:8;122:9,12,13bend 88:16

beneficial 22:22

Hea rin g Vo lu m e Nu m be rMa y 29, 9

benefit 45:2; 77:15, 17;91:21; 101:20; 102:1;107:24; 108:2,16, 17;109:7; 111:18; 117:2;118:8, 10; 119:14, 20;129:18; 132:1; 133:24;173:10,13,14, 15,17,18benefits 108:4; 132:10;165:21benefiting 97:25Berardi 10:14best 54:16; 68:13; 70:23;?9:8; 111:7; 114:3;138:23; 151:17; 173:16Oet98:10better 12:5; 13:9; 17:19;25:16;29:11, 12; 36:20,Z5;43:I 1;44:10; 45:6;54:17;55:1; 56:19; 59:20;$4:13,24;65:1; 66:11;71:8,8,11 ;72:12;73 :1;

L0 4:1 3, 1 4; 1 05 :1 4; 1 08 :4 ,~ ;110 :2 5; 112 :2 2, 2 2;[1 6:2 0; 118 :9 ; 1 59 :1 3;

!6 0:1 4, 2 1, 2 2; 1 70 :2 2

)et ween 8:11; 9:6; 10:20;.6 :1 o; 1 8:2 , 11; 2 4:7 ; 2 6:4 ;!7 :1 0; 3 2:2 1; 3 9:5 ; 4 0.2 ;[2 :1 8 ;4 3:1 4; 4 6:1 0;iO:1 7, 1 8; 5 2:2 4; 5 3:2 4;;4 :1 9; 5 8:1 3, 1 4;6 0:6 ;;6 :2 2; 7 3:1 3; 8 0:2 4;]2 :2 3; 8 3:1 8; 8 6:1 9; 8 8:2 ,i , 1 4 ;9 0:5 , 1 2;9 2:2 1;1 2:1 9; 1 26 :5 ; 1 33 :2 2;4 3:1 3; 1 54 :1 8; 1 60 :9

leware 121:5~eyond 63:24; 70:8,9,O;75:4; 79:15; 129:21~ias 92:1; 117:19lig 90:5, 12;92:2; 114:23;36:25; 175:16lill 47:10; 177:3liologic 8:20; 54:20;15:4,5,6; 60:19; 78:2;11:22;154:19, 25; 167:22tioiogical 99:18; 152:22;55:15, 16; 157:19; 167:5,

tiologicals 65:21lioiogics 6:10; 8:11;31:16; 163:15liopsy 51:9

lit7:4;8:21;15:13;38:3,4;157:2;60:19;74:13;75:15tlack114 :23;54:1,2danket 136:12Ileed59:19Ileeding 13:20; 14 :20 ;65:10

>Iinded 64:8

]Iip 70:4

)I ood 31:5

)I ood y 93:8,9; 94:24

d ue 39 :256 , 2 4; 159:1, 3; 15; 166:3;

body 42:23; 65:22body’s 12:3

bone 29:23; 110 :23;111:1; 146:8; 157:6)9 ,167:2

border 65:18

borderline 82:24

Boston 54:9 ; 154 :13

both 12:8 ; 1 6:6 ; 2 0:1 6;

29:8; 34:17; 37:21; 38: 14 3:1 4 ;9 0:2 0, 2 1; 1 09 :1 ;112 :2 1 ;114 :1 8; 118 :1 8;119 :5 ; 1 61 :1 7; 1 78 :1 4

bother 45:3 ; 119 :1

bottom 141:8;47:3bowel :19; 6:3,11, 24;3:5,7, 23; 10:1,9, 12;11:1 5,2 2; 1 3:7 ; 1 4:6 ; 1 517:lq 18:9; 21:5,7 ;28:19

55:1 3 ;3 8:2 0; 4 0:1 5;il:1 2;4 6:2 1; 5 5:2 0;

59:2 1 ;84:15; 93:8,9, 12)4 :2 0,2 4 ;9 5:5 ,6 ; 9 9:2 1,1 2; 1 41 :2 ; 1 63 :3 ; 1 70 :8

>OX 114:23

3radshaw 55:2 5; 1 29 :2

xain-wash 77:5

)r ea k 10:18; 86:12;[00 :18; 132 :19

weakdown 150:13rian lo~ 54:1 0; 1 43 :1

wief 1 0:2 ; 2 1:! 5 ; 2 2 :1

>riefly 47:10

)r in g 4:4; 33:20, 22; 47:.0 6:1 0; 1 29 :1 ; 1 30 :5 ;.5 3:1 0; 1 55 :2 1; 1 67 :2 1

winging 78:10; 152:2;

.60:21woad 7:15; 10:10;22:15;!3:3; 25:24; 40:8; 135:12;50:5; 165:25~roadened 179:19~roader 33:20; 166:16]roadly 149:24; 156:1~roke 41:20wought 19:6 ; 54:14;.33 :2 ; 179 :12

lr uce 54:9

mdesonide 105:13

~uffer 156:8

wild 37:5luilding 4 :2 5; 1 36 :1

luilt 78:7, 13

wmping 107:19lut 6:25; 7:19; 12:16, 21;3:5; 15:13;1612; 18:16;9:16; 20:18 ;21:5,11,22,!4;22:11; 23:9; 25:8; 26:9!7:3, 15; 28:10, 25; 29:21;31:8,10,19, 20; 33:5;}4:15; 35:6, 15;36:10;$7:23;38:6, 20; 40:6; 42:7[1; 44:19, 22; 45:7; 47:14,?2;48:12; 50:19 ;51:1,8,[4; 52:8,11,13,18. 25;

Mille r Re po rt in g Co m p an y , In c . Min-U-Script@ (5 ) ba ck grou n d - Bn



Food & Dru g Adm in is t ra t ionHe ar in g Vo lu m e Nu m be r 2

Ma y 29,1998

53:15, 17; 54:12, 15; 55:(56:2, 12, 15,18, 25; 57:1!

__#%~, 11, 18; 60:7; 61;12,;2:16, 19, 21;63:6,9,

LL;64:5,13; 65:5,22;67:20; 68:9, 15; 69:12,1520; 70:10, 13;71:6, 18;72:4,7, 13;73:20, 25;74:7; 75:10, 19; 78:4; 79:!

11;80:3, 11,20; 81:18,2(82:12,20,24, 25;83:5, 1425;85:3,9, 10, 12,23;86:5, 15; 89:12; 90:7,13,18,24 ;92:8;93:21; 95:1,9;96:13; 97:1,7; 98:8,12,22; 99:9,11, 20; 102:2;103:17, 19; 104:3, 10,23;105:5, 14; 108:2, 14;110:4; 112:2; 114:16;115:18;117:1,3; 119:4,5,17; 121:5,20; 122:1,2,1921; 123:12,20; 124:9;126:2; 127:7,20, 25;129:1, 19,22; 130:1, 12,

16; 131:19; 132:22; 134:8,135:11, 17; 136:17; 137:8,14, 18, 24; 138:4, 5; 139:715, 23; 140:22; 141:24;142:20,21; 143:16; 144:5,5,14,20; 145:20,21;146:24; 147:10,12, 16;148:8, 20; 149:2,11, 13,

19; 150:4, 19; 151:2,9;.11, 13,23 ;154:4;

~>>:18; 156:12; 157:23;159:10, 12; 160:1,5,6;162:8; 163:5, 13,24;164:10, 21; 166:5; 168:14;169:16; 170:16; 171:6, 11,

23,25; 172:5,23; 173:4;174:2,7,13, 16,20; 175:3,5, 24; 176:10; 178:17;179:10buttoning 35:23buyer 121:5by4:12,14,21,24 ;6:12;9:2; 10:20; 12:12,12,13,15; 13:21; 15:7; 17:14;18:12,21 ;20:22;21:11;22:4,9, 11;24:16,21;25:6; 27:13; 36:25, 25;44:21 ;49:19; 50:2; 54:14;56:3; 57:20; 63:3, 15; 67:8,10, 13;68:7;73:1, 10;

76:11;78:2; 80:6; 82:6, 13;6:17,20 ;91:10;93:25;4:19; 96:23; 99:23;100:20; 106:5,13,14, 16;108:4, 25; 114:16; 115:20;24:12, 15; 129:4; 131:10;33:4; 136:15; 138:18;47:17; 148:7,20, 20;:14; 157:19; 161:22,

164:17; 175:14

c

23 :1; 27:2 4; 31 :8;10:18

C-reaCtiVe 14:24calculatable 96:7calculate 91:14calculations 94:1call 4:2; 25:9; 26:4; 51:558:8,10, 21; 59:6; 67:23;94:13; 105:21, 22; 135:7,19; 172:20

called 6:22; 7:9; 26:10;28:19; 34:8; 37:7; 55:18calling 79:13calls 123:18; 161:5Came 37:1 1;75:16;98:14; 122:14; 124:5;166:5can 7:23, 24; 10:21;11:19; 13:22; 14:2, 5;15:11, 25; 19:10; 23:25;26:19; 27:5; 28:1, 21,22;31:5; 32:6; 34:15,21; 35:636:13, 17; 37:5; 38:5;}9:21; 40:13, 17;42:2, 12;

f3:l,4,24; 44:17; 45:5;i6:16; 49:5, 19; 50:1, 25;$1:9, 13 ; 52:1,4,16 ;;3:1 6; 5 5:5; 56:1 4; 5 7:8 ;j9:2 2; 61:6 ; 62 :I 9; 63 :23 ;;4 :1 4; 6 8:1 ; 6 9:1 3; 7 2:2 4;

‘6 :17 ;79:18; 81:17;12:19,19,22, 24; 83:7, 9;

!5:2, 15 , 1 7;8 6:17 ; 9 1:1 ,i , 5 ; 9 7:1 7; 9 8:1 7; 9 9:1 4;0 1:19 ; 10 2:1 8; I 1O :1O;12:21,23; 113:12,13, 19;1 5:2 2; 117 :1 8; 119 :1 5;2 3:1 3,2 1; 1 24 :1 7;2 6:1 9; 127 :3, 15; 128 :12 ;

30:21; 131:1,7, 15;33:4; 134:16; 135:16, 19,2 3; 1 36:2 ,6, 10; 13 7:12 ,14; 1 38:1 ; 1 39:1 3; 1 42 :9,13 , 1 8; 144 :7, 1 4; 14 7:24 ;150:25; 154:4; 157:22, 24;1 59:2 1; 1 60 :11, 17 ;1 70 :1 2; 1 71 :1 8; 1 74 :5 ;1 76 :1 , 1 3; 1 78 :9

ca n ’t 11 :3; 19 :1; 39 :14 ;4 0:1 3; 4 4:11; 4 5:3 ; 5 8:2 4;7 3:7; 78 :9; 91:1 4, 22 ;1 21:2 3; 1 22:1 8; 123 :5, 1 7,2 0; 1 29 :7 ; 1 37 :2 ; 1 44 :2 0;1 53:1 8; 159 :6,7 , 18 ; 174 :5

~anada 162:8, 10

:ancer 31:4; 52:12;j7:21; 58:6, 12, 13; 59:1;[65:19; 178:23:andidates 150:18:annOt 29:10; 57:20;.34:6:apable 32:19;apetOWn 129:24:aptured 160:13:are 51:24;79:3;93:1o,1;95:25; 96:4; 113:16;14:19,21 ;119:13; 143:6ares 56:6,6

Carl %6:8

ut t o n in g - c oe ffic ie n t (6)

136:17; 142:14, 23;152:11; 160:5, 11; 163 :1

certainty 52:17;95:4;153:23cetera 26:23; 27:1; 28:293:12; 135:16; 141:22;179:2

chair 130:23

Chairman 8:25challenge 169:19change 31:8; 32:10; 41:-44:20; 46:21; 68:14; 78:35;87:4, 12, 18;88:11, 24;89:8,15,15, 20,21 ;92:1120; 93:10;94:7; 96:6,7,25;97:5; 98:21 ;111:17;138:21changed 90:6, 6; 104:20

changes 9:20; 19:10;35:24; 39:18; 93:4; 95:10;99:18; 165:12changing 16:5; 100:6

sharacter 87:16characteristics 36:21;55:2;73:12; 87:20; 89:3;173:21characterized 54:25;12:13:harge 100:22:heck 153:10

:hecking 151:15

:hest 58:8Chicago 9:22

child 126 :15; 135 :16;1 38 :1 ; 1 39 :7 ; 1 42 :2 2;144 :3 ; 155 :3

child’s 125:16children 13:24; 124:19,23; 125:1,5, 11,13; 126:1,25; 127:1,8,13,16, 24;128:1,5,7, 11,13, 15, 18;130:16,25; 131:2, 11;132:2, 25; 133:7, 7;136:17,21, 25; 137:13, 19;138:14; 139:18, 19; 140:1,8, 11,21; 146:5;151:3,24;154:24; 155:6, 10; 156:6;157:4; 158:16; 159:13, 17,25; 171:5,20; 172:12;175:25; 176:2choice 114:24; 174:3

choose 50:2; 120:23chose 76:1, 23; 77;4;102:4; 110:19chosen 112:20

Christine 31:1; 123:10‘ chronic 20:25; 23:7;32:6; 35:1, 15; 65:6; 76:15;80:21 ;82:12;83:23; 84:1,2,5,20; 101:17; 119:19;161:2; 162:25; 163:6,18,20; 175:13chronically 35:2; 43:25;85:5; 101:20; 164:20chronicity 21:1; 81:6

Ga st r oin t e st in a l Dr u gs Ad vis or y Comm it t e e

carried 78: 12; 150:21carry 13:4carrying 56:13case 76:21; 86:14; 93:2(108:3,7; 131:11; 139:16;140:5; 151:22; 152:21;155:1; 158:21; 162:13;167:5

case-by-case 142:2Cases 97:21; 162:1cast 120:14catch 47:1categories 22:16; 23:3;25:25; 49:17; 51:15;62:11; 63:20; 75:9; 150:3categorizing 52:5Category 25:24; 26:2;30:13, 15; 50:9; 62:9;63:21; 105:19; 112:4Catholic 9:13caucus 113:18saught 158:11:ause 92:16, 16:auses 57:18:ausing 21:21; 100:5:autions 172:25; 178:122BAI 64:9; 66:112BER 179:22

2CFA 127:15 ;38:18;40:18;42:12X)AI 18:17;7:13;9:24;io:ll,3,22;42:7;5:14;i7:6,,15;48:13,9;9:11,18;53:25,5;54:5,4,18;55:1,3,4;56:4,

8;59:7;5:19,0;66:3,,22;67:19;6:13;7:17;8:2,3,3;89:8 ,1;91:3;‘3:17;4:5;5:21,22;96:13,7;98:13;9:20,23;111:17;17:7;29:17cDAls 129:8CDER 10:15 ; 179 :22

Celgen e 75:5

cel ls 31 :4

Center 4:14; 8:11, 12,14centers 60:12; 137:10;138:24; 139:4,12:entimeter 46:23

centimeters 47:2,3~entocor 13:2; 49:24;;2:8; 70:17; 88:1; 98:4;L40:16:antral 14:6:ertain 12:15; 58:2;;5:11; 67:23; 70:24; 73:1;13:11;86:7; 96:6; 118:16;.19:8; 127:21; 131:6;50:3; 155:19; 163:5;65:23; 167:1, 8; 177:10,1

circumstance 115:6circumstances 76:20;114:24; 131:6; 133:20Claim 38:25; 45:17, 25;51:4; 61:6,6; 62:3,7claims 22:21; 61:7, 12;62:2; 134:16Clamp 129:23clamped 99:25clarification 20:19;80:24; 134:16clarify 50:22; 145:7clarity 45:12; 57:4; 67:12classic 163:4classical 15:12classification 9:7; 11:23;12:5; 13:11classified 74:9classify 11:19; 13:10;62:11,20classifying 11:14

Clear 22:5; 45:8; 55:19;57:5clearance 15:3Clearly 32:5; 57:24;59:19; 99:10; 114:17;154:25; 178:13clinical 6:2;9:4,9, 19;10:8, 10; 13:8; 15:13; 16:6,11; 17:1, 17;18:21; 19:5,11, 11,21,25 ;20:7,9, 16;27:2; 32:12, 21; 35:6; 37:8,11, 14; 42:18, 23;43:6, 15;5:2,20, 24; 46:11; 47;7;7 :16,22 , 24;64 :5 :6 ;1 :2 4, 2 5; 7 6:2 ; 9 0:1 8;5 :15; 98:21 ;101:2 ;0 5:9; 106 :4, 8,9 ; 10 9:7;1 5:13 ; 116:4 ,8; 118 :7,~ ; 11 9:14 ,19 , 21 ; 12 3:3;2 4:8 ; 1 28 :2 3; 1 29 :1 3;3 0:24 ; 1 33:1 6, 25 ; 14 3:4;4 7:6 ; 1 49 :1 6, 2 3; 1 55 :2 3;5 4:5 ; 1 68 :8 ; 1 69 :1 4

Iinically 55:10; 89:10;1:25;92:5; 94:15; 98:19;):7, 18, 24; 171:1Iinician 93:6Iinicians 95:15; 120:4;i3:23

ock 157:1OSe 37:2; 47:13; 55:23;L:21osed 47:22; 48:2, 5;k25,25;62:18oser 70:14osing 62:3osure 30:10 ;48:20, 25;!:24;63:1

CiUeS 126:12clustered 94:12clustering 97:22co-complication 14:21so-morbid 148:6,20,24

coefficient 67:6,7

:ertainly 6:3; 23:9; 27:5;2:12;81:13,21 ;112:22,2; 114:3; 128:1; 130:17;

32:15; 134:21; 135:6; I circulatory 145:16

Mifi-U-Scrip@ Miller Re ~o rt in ~ Co m oa n v. In c .



F ood & Dru g Ad m in is t ra t ionGa st r oin t e st in a l Dr ugs Ad vis or y Comm i t t ee

disease 4:22; 5:19, 20;6:3,11,23, 25;8:5, 18;

____ 9:5 ,8,16 ,17 , 24 ; 10 :1,9,12; 11:7,9,15, 17, 22,22;12:2,6,9, 12,12, 18; 13:7,

8 ,1 3, 1 4, 1 4; 1 4:3 ,6 ,1 3,16,18, 18; 15:10, 14, 25;16:3,17; 17:1,2,4,9, 11,1 2,2 1,2 4, 2 5; 1 8:2 ,3 ,5 ,8 ,

10,15,16,18, 19,20;1 9:3 ,7 ,8 ; 2 0:2 5; 2 1:5 ,7 ,8,18,19, 22; 22:7, 25;23:4,9,15, 21; 24:2; 25:6,22, 23; 26:1,16, 19; 27:11;28 :2,8,11,11, 23 ; 30 :3,8 ,13,21 ;31:7, 13,16, 17;32:4,6,10, 16; 35:1, 17;3 6:6; 38 :18,1 8, 20 ; 40:3 ;4 1:1 2, 1 9;4 2:4 , 1 3;4 3:2 ;4 4:1 ,3, 1 7;4 5:19 ; 4 7:2 ;49:3, 16; 5 0:5, 1 9; 51 :1,3 ,8,13, 19,20; 52:1,10, 11,1 5, 2 2; 5 3:9 ; 56 :2; 5 8:16 ,20;59:11 , 18;61:21 ,23,

2 5;6 2:1 2, 2 1, 2 2;6 3:1 2;6 4:11,1 3,2 0, 2 3;6 5:2 ,6 ,

10; 67:20, 24; 68:2 ,5 ,5 ,20,2 5 ;69 :13 ;71:3; 73 :4,6 ,7 ; 7 5:8 , 1 0; 7 6:2 ,9 ,1 5,17,17,23, 23; 77:14; 78:3,21;79:3, 15,21 ;80:13, 14,17,22, 25;81:12;82:5, 12;

-. 83:6 ,7, 12 ;84 :3, 15 ,17,18 , 20;8 5:5 ;86:1 5; 92:1 6;94:11 ;96 :14 , 18 ; 10 1:2 ,18 ,20,2 1 ;1 03:1 ; 10 4:19 ;109:1,2,2,15, 17; 110:3,21; 113:1,4,7; 114:5, 12;115:3,8,9 ,10 , 11 ; 118 :24;

1 21 :9 ; 1 22 :2 1; 1 23 :4 ;124 :6,2 0,23 , 25; 1 25 :5,11, 1 5, 22 ,2 2; 1 26 :6 ,11;127:13, 16; 134:18, 19, 20;135:3, 22; 136:2, 3;139 :18 ; 1 41:2 ; 1 44:1 7, 19;145:8, 20; 146:13, 14, 15,17 ,23, 25 ; 14 7:4; 14 8:8,18; 149:7; 150:14, 21;1 53 :1 ;1 54 :2 ; 1 61 :1 2;163 :3 ,6 , 20; 167 :3 ,9 ,13,18; 170:8; 175:1,4, 10, 13;1 77:1 , 7 ; 1 78:2 2; 179 :9

d is ea ses 6:14; 11:16,21,24 ; 12 :8; 1 3:1 0; 1 6:8; 18 :1,1 4;3 9:2 4; 6 4:1 ; 7 9:2 4;14 5:9, 2 2; 1 48:6 , 25;15 0:20 ; 1 60:12; 16 2:5, 25 ;16 3:16 ; 165 :15,16, 24;167:10

dismayed 93:25dismiss 99:17disorders 136:14dissimilar 58:25—dissuade 121:4distinct 14:1; 84:9distinction 26:4; 90:1zdistinguish 18:11;73:11;90:5; 154:18

distinguishes 88:4,5

distinguishing 117:6distributed 96:5distribution 86: 19;149:10disturbed 56:3disturbs 59:16diversity 40:5, 10;86:4divide 49:16

dividing 26:15; 51:14divorce 85:22DMARDS 172:3do7:15; 13:1,10, 13;15:17; 16:1,14, 19,21;17:5, 24; 18:19;21:5, 10;22:2; 25:13,15, 16; 27:2;33:21; 34:11;36:6; 37:4;40:18,19; 43:21,24;44:11 ;45:3,6;46:3; 51:6,24; 53:21; 55:6,17, 20;56:20; 59:2; 60:24; 63:4,17;66:15, 24; 68:15; 69:2;72:24;73:17, 18, 18;

74:16;77:11;79:5; 82:3;B7:8,18, 19;88:23; 89:14;35:2;96:24; 97:14, 17;)8:20; 99:2,3,4, 11;105:17;06:3,1,18;110:15;12:11;13:9,2,13;114:2;15:12;17:8,[8;118:14,9,21,21;[19:11,6,17;120:6;[23:23;26:3;27:1,2;~28:3,6,0,10,13,4;[29:8131:8;32:1;[34:7;36:9,0;140:5,7,.0 ,11;144:16,9;145:2,!,3;147:6,4,17;148:10,.8;149:14;52:10;55:2,.7,24156:1 ,,15,23;59:12,0;162:23;66:13;68 :6;71:13,5;72:3;73:4,4;174:2,;77:18,21,23Ioability 148:410CtOrS53:11; 76:13;‘7:1Iocument 6:22,23; 7:1,,2,16 ;8:1,2,4; 38:9,21,:2;39:7, 20; 45:1; 83:23;01:1; 105:4; 140:25;65:5; 166:20, 20; 175:3;79:7,7,11,13,14

Documentation 45:22,3documents 71:19does 16:18; 54:21; 57:15;59:4; 60:7, 21;62:17; 71:4;72:17; 76:6; 85:16; 88:20;B9:23; 115:6, 10; 116:7;129:10; 134:23; 136:z1;139:12; 144:15, 19;161:11; 165:1,2,7;177:18; 178:1doesn’t 25:19; 41:20;i2:8; 44:11; 55:4; 63:3;$6:24;76:13, 13;88:16;~5~7;96:13; 112:11, 18;

138:20; 143:11; 158:12;159:3; 164:12doing 7:13; 31:z4; 55:1658:14, 15, 16;68:14;71:19; 90:3, 19; 108:7;117:11, 16; 118:12;131:15; 139:2; 149:12;153:10; 172:2; 173:1dominant 35:22dominating 35:16,17don’t 19:17; 23:8; 25:15,16; 28:10,12, 17; 30:13;31:9, 10; 32:4, 12;40:1;44:13; 45:8; 46:2; 48:19;49:2; 50:23; 51:24; 52:9,10; 53:21, 22; 54:15; 55:6;57:16, 23; 59:6, 14;65:5,21, 25; 67:1; 70:2; 71:7,17;78:18,21,23; 79:3;82:2, 9; 83:3; 84:22,23,23; 86:14; 90:2,14, 19;94:8, 15; 95:19; 97:7, 9;100:17; 103:8; 105:2,4,23; 106:25; 111:25;112:11, 14;113:21;116:11; 117:12; 119:13,17; 122:21; 124:24; 125:2,3,9; 126:1; 127:5,6, 17;128:15; 130:4, 11; 137:5,13; 142:9, 23; 143:6, 11;14 5:8 ; 14 8:10 ; 1 49:1 , 18 ;1 54 :1 0; 1 55 :2 3; 1 56 :2 3;1 58 :2 2,2 5, 2 5; 1 59 :8 ,1 5,[6 ; 1 61 :1 9, 2 3; 1 64 :2 3;[6 6:2 0; 1 67 :6 ; 1 68 :1 o;1 69 :1 6; 1 70 :1 2; 1 72 :1 9,?4; 174:17

ione 10:5; 30:24; 34:10;}8:10; 41:15; 43:7; 90:3;

J5:9;100:6; 105:23;.06:25; 125:20; 135:13,.6; 136:14; 137:1, 12;.38:25; 139:13; 142:2;47:15; 153:12Iose 42:22; 72:6; 102:23;03:20; 104:17; 106:3;07:20; 111:4, 5; 112:2o;21:16; 122:24, 25;24:11 ;126:14; 137:3;40:7, 8; 159:17; 161:6,3; 168:24, 24; 171:13, 15;76:15Iosed 84:7; 124:10loses 88:6, 21; 126:13,

4, 14; 137:2, 14; 153:14losing 124:10doubt 66:19; 139:16doubtless 80:8down 7:4; 34:2; 49:2, 23;59:3, 8; 71:15; 75:20;B2:19;83:21; 88:16; 91:4;101:24; 103:4, 10; 106:22;110:13,24 ;111:21;121:14; 138:12,21,23;143:10; 150:15; 151:3;152:11, 12; 156:7; 160:19down-regulation 78:5~ownward 138:8jozen 30:1619:1;22:15;29:2;

IMille r Re por t in g Co m pa n y, In c . Min-U-Scripm

Hea r in g Vo lu m e Nu m be rMa y 29, 1

DR4:3;5:14; 6:17; 8:8,10, 12,13,15, 16,23, 25;9:3,3,8, 12; 10:6,6,14,14; 11:17; 13:1; 19:8; 22:417; 23:2; 26:8,8, 10, 12;27:8; 28:4,4,6,17, 25;29:15,18,21,25 ;30:1,1,4, 16,22 ;31:1,2, 14,20,23; 32:2,5,23,23, 24;33:24, 24; 34:1; 38:7,9,15,17, 19; 39:7,23, 25;40:10,20,20, 21;41:2, 2,3,7,9,25, 25;42:1, 16,1617;43:20, 20,21 ;44:6, 13,15,16, 25; 45:10; 46:4,6,7,9; 47:18, 19, 20,21;48:2,3,4,6,7,8,10,12,14, 15;49:7,8; 50:11,12,14;51:8,12, 18; 52:7;54:8,8,9; 55:13, 14, 15;56:13, 16,21,21, 22;$7:11, 12; 58:2, 11, 18;59:2,6, 10, 16; 60:4,4, 5,[5 , 17 ,19, 20 ;61:1 , 3 ,4,5 ,

), 1 7, 18, 19 , 20; 62 :1,8 ,16, 2 5; 63:9,15,22, 25;;4:16, 18, 19, 22, 23, 24;

;5:2,4, 5,6, 12, 14, 15, 16,7,19; 66:9, 12, 18,21;i7:l, 3 , 12, 12, 2 5; 68 :4,7 ,~,11,13, 17;69:l ,3,4,5,‘,8,9, 10, 10,11,17, 19;‘0:2, 5,6,7,9,10,12,16,9 ,2 0,2 1,2 2 ;7 1:1 ,4 ,6 ,0 ,12,1 3, 24 ; 72:3 ,16 ,:0 ,21,22,2 3, 2 4; 73:1 5,5 ,18, 23; 74:4 ,12,16 ,8, 25; 75:3,5,25, 25;6:1;77:5,7,21,21,22;

8 :9 ,15, 18; 79:1 ,2 ,5 ,7 ,18,22,23,25, 25; 80:1,

0 ,1 0,11, 1 9,2 1,2 3;1 :1,3 , 10 , 16 ,24 ;82 :1,2, 16 ;83 :5, 14, 18;84:7 ,,11,11, 13;85:7, 16,20;6:2, 11; 87:9; 89:6, 16,3 , 25; 90:23; 91:9 ,12,15 ,8,24,24, 25; 92:22, 24;3:6,6, 13,15,15, 16;4 :1 0,1 4,1 9, 2 1;9 5:1 5,7,17, 19,23 ;96:11, 11,2 ,2 0,2 2, 2 4; 9 7:3 ,4 ,6 ,6 ;8:12, 16 ; 9 9:8, 12 ; 10 0:2,6,22; 10 1:15 , 16 ; 1 02:5 ,,16 , 20 ; 103:7 ,8 ,10,12 ,~ , 2 0,22,24, 25; 104:9,1; 10 5:4,7, 1 0; 106 :2,5 ,; 1 07:6,6,7,14,15, 22;08:19, 22; 109:8, 10, 11,2,21,23; 110:15, 19;11:2,2,5,9,11,12,23,

23,24; 112:16, 24; 113:2,3 ,12,13 , 14,21 ,23,24 ;114:2, 1 3, 1 3, 14; 11 5:1;116:3,3,6, 25; 117:3, 24;118:5 , 12 ; 119:2,3,13 ,24,25; 120:13, 17, 17, 18;121:7,7,8,19,20, 23;122:6,7,11,13, 17; 123:6,7,9,10,15,16, 24; 124:3,

[1, 14, 21; 1 26:22; 127 :2,

6,15,18, 0;128:3,9,119,22,23,24, 5;129:18,22;130:9,9, 0;132:19,20,21,24 13,6,8,9,10,12,14,120,22;34:1,4, 5;1321;136:5,2,16,23;137:7,0,16;138:9,9,1017;139:3,6,14, 4,15140:6,9,9,14,22, 5141:7,1;142:1,11,12,20,23,5;143:16,16,1921,22;144:9,9,11,16,22,23, 3;145:6,146:2,2,4, 0,11,16,19,1;147:3,8; 48:21;149:6,0,12,16,20,23;150:7,12,23, s;151:12, 5;152:2,6;153:1,9, 1,18154:10,15,7;155:11,21,25;156:2, 2,21;57:1,2;158:1,3,4, 9;159:5,1021;60:23; 61:16,17zz,5;162:7,7, 0,15,19,21,4;164:2,4,8,166:2, 5,17,9;167:11;168:9,17,18, 9;169:3[,8,,10,15,23,4;L70:1,6,9,9, 0,16,19,?1,25;71:3,3,4, 3115,6,17,19,21,23,24!5;72:5,6, 2,18,2;.75:8,8,9,10, 5,17,189,19,20,22,22, 3;76:3,4,5,5,6,8,9,2,13,22,22, 3;177:3~,6,3,14,5;178:1,6,9,1,20,22; 79:1,17,17

7,18,18,21,22,22kdl6:4,2;7:8;:1,1;1:12;5:21;8:24;9:20;2:23;3:1;8:19,:1;45:18;68:19; 5:6Irafting 179:23Irag 82:3kaining 47:12kamatic 78:4dramatically 15:19; 78:6draw 26:3drawback 66:25driven 94:19; 114:16driving 97:24; 117:6drowning 82:2,4Drug 4:14; 5:18; 11:8,14:21;6:4;0:6;1:12;26:7,7,21;30:16;6:11;42;20;4:7;7:7;9:3 ,5;54:23;6:8,1,12,15;58:6;0:16,8,20;62:19;$4:7;9:16;71:5,0,14,16,21,2;72 :1;4:2,,17;75:13,21; 8:1,24;79:13,7,24;80:6,6 ;14:1,285:1,11;6:6,8,[7;89:8,1;90:12;1:7,[4,17,21;92:15;4:13;~5i4 ;04:6,1;106:24;

07:17,9,21;108:25;

(9 ) d ise a s e - DIW



Hea r in g Voh u n e Num be r 2 Food & Dru g Adm in is t r a t io nMa y 29, 9 9 8 Gastrointestinal Drwz s Ad vis or y Comm i t t ee

110:2;13:5 ,6,8,19 ,20,24;114 :1,11 ;15:3,10,_=l.18:9;23:21;27:7;

!3;133:6 ;36:24;1-,,:19,22, 4;141 :9;142:4;43:11;45:14;148:5;49:25;54:3 ;155:23;60:8 ,;164:20;166:3,5,10,11, 3;167 :3;

168:5,;169:6;73:2 ,6;174:12,8;176:14,18,0;177:17;78:7,0,12,17,23,24,4;179:8

drug’s 134:12,18drugs 4:22; 8:12,14,18,20; 16:6; 26:18; 32:17, 19;39:17; 44:24; 46:3; 60:24;66:24; 70:22 ;74:6; 75:9,19;77:18; 80:7; 81:19;82:10 ;83:16; 84:22;85:22; 103:2; 114:4;127:14; 130:15, 17;131:15;132:8,12; 133:15;142:15; 145:11, 17;150:17, 18; 153:14,16, 19;165:19; 166:15; 167:18;168:16; 169:5, 11; 174:22;178:4, 11,19due 7:3duly 80:19

duodenal 18:4d,,~abil~6:9;8:3,8;-- .

25;72:7;1:14;e-.i5;10l:ll;O8:l5duration 56:3, 14;68:19,24;69:21;70:20; 2:14;74:14,9;81:4;4:24 ;87:1;9:2;02:16;

105:12;07:23;09:25;115:16

durations 169:18

during 47:14; 123:18dying 149:20

E

each 30:17;8:16,7;96:22,4;97:1;17:11;122:8;74:18earl ier6:6;06:7;120:10;38:13;44:7 ;152:7;59:23

early 7:2,13;25:4 ;8:11;142:17;74:23ease142:13easier 22:15; 57:10;140:22

ea sily 57:5; 63:23; 138:7

ea sy 37:21; 51:21;=7:18; 156:5

“> 170:10

etinoed 67:13economic 36:12ecstatic8:22effect6:11;54:23;55:10;2:6;8:2o;4:7;

75:15,16, 17;83:25;86:17,8;87:4 ;0:25;96:21;9:2,,4 ;107:13;111:22;18:8;20:24,5;121:6;66:3;68:2;176:14,15,18,19effective2:14 ;4:18;25:17,0;69:16;35:15;139:25;41:13;48:17;

171:11;78:17effectively 7:25effects2:22;9:23;66:24;4:23;6:25 ;97:18,22111:1,1;120:19,5;126:3;27:4,4;134:18;66:12efficacious 153:15;15917efficacy 70:10, 23; 75:4;78:22;85: 19;87:3;124:18; 127:1, 14; 131:19;133:13; 134:7, 8; 135:8;136:3,4, 10; 139:17;140:3,12,14, 21,23;141:4,6; 142:17, 21;148:25; 152:9, 12; 156:1,13; 159:12; 160:14; 168:6;171:17; 172:14; 173:8;174:8,20?fficiency 55:9; 93:24;)7:12; 100:14dficient 93:20; 94:2, 17;)7:15Mciently 97:19dfor t6:13;8 :ll,ll;9 :5,~ ; 87:13; 122 :2

dfor ts 7:3; 115:24; 132:4

eight 37:19; 56:12

sighties 25:4sither 14:15; 19:4; 21:11;24:1,11,23 ;31:5; 49:24;5 0:1 ; 6 1:2 1 ;6 2:1 2; 6 3:7 ;6 5:1 8; 6 7:9 ; 8 6:1 7; 9 2:1 5;1 04 :5 ; 119 :5 , 2 3; 1 21 :2 5;1 46 :1 8, 1 9; 1 50 :1 5;167 :14; 178 :10

Elashoff 40:20, 21;68:13; 87:9; 89:16, 25;95:23; 96:24; 145:6;146:2;151:12; 159:5;161:16; 164:8; 177:6elderly 145:1o, 12, 13;146:7; 148:7; 149:3, 8;

150:9element 107:2elements 29:1; 54:19, 20;55:4; 135:1elevated 30.14; 121:16elevation 14:23eliminates 123:7elimination 101:10else 10:1667:11,11;70:4, 17; 82:7; 92:14;110:9; 178:4elsewhere 79:1embarrassed 92:7emerging 163:17

d r u g’s - e xp e rie n c in g (10)

emphasized 13:3,16,24; 19:15,17, 20; 2022;118:1emphatically 90:24;133:1; 136:13employed 169:13

encapsulation’ 22:6encourage 5:23; 46:4;53:17encouraging 74:14encumbered 22:9end 54:23; 56:4; 74:23,24; 80:2 ,;94:8 ;5:22;96:2;47:5;76:17;79:3endoscopic 9:15, 20;15:10,14, 17; 16:2,7,10,20, 20; 17:19, 20; 18:13;19:5; 20:8, 12; 23:17;2622; 27:1, 4;309, lx42:2,13,18, 24;43:4, 13,15;45:1, 5;46:10, 15;49:11; 51:23,25; 57:13,23;60:6,8,9,11,13, 16,

24en doscopica liy 43:9,11;47:1

endoscopies 60:12endoscopy 47:5; 58:23,24mdpoint 43:17, 17;45:7,11;46:19;48:21,24;57:22;60:9, 21, 24; 66:15;S9:20;70:12; 76:3; 77:17;97:9;98:5,6,8,13, 24;116:22, 23; 118:7; 119:10;122:4; 123:2; 124:2endpoints 9:15; 16:25;19:3;20:1; 37:10, 12;45:4;48:18; 57:25; 58:3; 135:4England 106:6enhance 55:8ENL75:14enormous 99:22enough 59:12; 62:4;73:24; 78:10; 90:12;99:17; 105:18,21, 22;112:13; 118:22, 23;135:22; 147:22; 151:21,23; 156:13enrolling 140:1ensued 29:4enter 143:10, 12entered 47:13enteric 29:15entering 168:25enteropathy 15:2enthusiasm 100:17entire 35:3entirely 90:2; 146:15entirety 86:3; 90:15entity 61:2; 146:24entry 116:5epidemiologic 160:10equal 47:24equivalence 173:8

Min-U-Script@

equivalent 174:8era 169:20erosions 37:18;43:23;44:20,20,21esophageal 18:4essential 140:21essentially 65:9, 20;84:20;6:25;09:3;

126:20;28:16;72:16establish 68:20; 72:16estimate 173:9, 10,16estimated 127:16,18estimates 163:25;164:11estimation 38:6et 26:23; 27:1; 28:24;93:12; 135:16; 141:22;179:2ethnic 150:1Europe 17:15European 169:11Europeans 115:17evaluate 167:19; 177:20Evaluation 4:14; 22:7;112:4evaluations 161:1even 4:10; 14:9; 33:13,17;43:23, 25; 45:3; 58:22;~O:l;63:24; 64:23; 69:2;33:19;88:15 ;90:13,15;)4:16; 104:18 114:6;1 22 :2 0; 1 24 :2 4; 1 29 :1 9,2 5; 1 47 :1 5; 1 48 :1 5; 1 53 :7 ,1 8; 1 55 :9 ; 1 56 :6 ; 1 57 :8 ,20 ; 159:22

even t 5:1; 154:19, 22;

155 :5 ; 160 :10; 164 :11,13m r en t s 11 6:12; 156 :20;1 60 :11; 1 63 :2 3; 1 64 :2 0,22 ; 165:2

eventually 13:9; 16:7ever 35:13every 60:16; 71:15; 85:2;101:25; 102:4; 105:19;111:9; 126:7; 127:7;129:6; 130:12; 160:9;168:8ever ybody 6:6; 98:2, 9;11921; 121:25everyone 10:16; 152:3everything 27:7; 36:5;45:8; 61:10 ;81:21;100:18 ;115:1; 126:13;130:20; 178:4evidence 23:17;44:22;45:8; 52:15; 53:8; 57:23;65:14; 151:15; 154:3;1561evidence-based 144:21evident 77:19evolution 34:13;36:19;179:13eVOIVe 38:5evohring 125:10

exacer bat ing 167:8

exacerbation 82:15, 18exacerbations 82: 13;84:18exact 143:5; 144:18exactly 7:13; 39:14;40:5;76:22; 88:10; 89:3;100:19; 140:13; 143:8;171:8examination 159:4examine 89:2examined 77:16examining 89:1; 167:24example 12:14; 17:9;26:24; 29:22; 31:19;33:1O;34:23, 24; 35:21;36:22; 47:8; 65:7; 72:6;75:14; 81:24; 89:1, 7;116:19; 117:15; 137:23;162:2, 15; 163:4examples 24: 14; 26:14exceed 165:1,3excellent 75:16except 108:8; 157:sexception 121:9exceptions 4:17excessively 94:19exclude 5:4; 129:6;148:6; 152:15excluded 129:4, 12;150:6excluding 129:24;146:22, 25; 150:8, 10;165:6; 177:1oexclusion 5:5exclusive 36:4exclusively 147:7

exclusivity 131:5,6,7excretion 15:7Excuse 8:10; 78: 18;153:12Executive 56:25eXt?I@fkd 17:2; 107:16exemptions 166:11exhaustive 36:4exist 46:3; 159:3existing 8:1; 22:23exists 28:10eXpeCt 77:23; 85:9;139:21; 175:13expectation 44:23, 24;84:21;92:1expectations 44:7; 93:7expecting 73:3; 84:25;85:4,8expedite 142:13expedition 156:22;157:15; 158:18expeditions 156:22experience 25:9; 106:9;122:23; 143:4, 5; 144:13,19; 145:13; 160:7; 166:16;177:22experienced 36:25experiencing 87:6

Mille r Re po rt in g Co m p an y , In c .



Food & Dru g Adm in is t ra t io nGa s t ro in t e s t in a l Dr u gs Ad vis or y Comm i t t ee

experiment 157:9experimental 150:16

.-= expert 10:9experts 76:11, 24; 136:5;137:20, 21; 168:24explained 67:8, 10explicitly 118:13; 119:23explored 114:8exposed 36:22; 168:1

extend 6:18; 68:21extended 63:23; 70:9extending 138:8extension 61:4extent 76:6; 108:8; 160:6external 66:5, 13externality 66:15extra 29:15extraintestinal 14:3;170:23extraordinarily 78:20;179:18extrapolate 124:17;

126:18; 134:6; 135:23;137:3; 139:17; 140:3;145:1; 159:18; 173:18extrapolation 131:18;132:17; 151:5extreme 97:21

—- extremely 39:20;32:2;174:9extremes 138:1exudation 15:5

F

faced 133:14facilitate 7:20fact 7 :1 ; 2 3:1 8; 2 5:1 2;2 7:23; 37:15; 42 :11, 20;46:3; 47:22; 49:8 ; 59: 17;73:3; 80 :5 ,7 ;83:14; 84:4;8 7:1 9; 9 2:7 ; 9 5:2 ; 9 6:4 ;9 8:2 5; 1 04 :3 ; 118 :1 4;1 23 :2 4; 1 27 :2 0; 1 33 :3 ;134 :2 ; 139 :15; 154 :19;1 55 :2 2; 1 56 :4 ; 1 57 :1 2;1 58 :2 2,2 4; 1 60 :4 ; 1 65 :2 0;169:5

factor 13:25;00:14;119:15factorial 117:11factors 12:22, 24; 13:3;21:21;95:11; 99:23;123:1; 174:19facts 22:10failed 84:25; 94:13;104:7; 113:19; 114:18;

—..- 121:10;132:5; 133:15;172:3,5failure 64:8,10, 16;102:2; 148:2,2fair 74:25; 82:1; 127:25;142:11fairly 58:13; 152:13; I

164:25; 177:15; 178:13fairness 5:8;124:14fairy 142:17fail 112:3; 134:23fallen 36:9false 100:10familiar 130:1far 11:22; 20:15; 40:3;78:15; 102:22; 160:8;

168:6, 9; 169:21farther 35:5fashion 117:7; 153:5,5fast 77:11father 56:24favor 62:4; 65:15, 17;143:9favorably 70:3FDA 5:3;7:1, 23; 8:3;113:16; 130:12; 131:14,17, 25; 132:7; 141:4;143:24; 169:19FDA’s 38:7FDAMA 13013

Feagan 10:7; 32:23, 24;39:25; 54:10; 59:2, 10;65:15, 16; 66:12; 67:3;69:4, 7; 93:15, 16;94:14;95:17, 19; 107:6, 7;111:12; 120:17,18; 138:9,10; 143:1, 16; 149:16;162:7, 10; 168:18, 19;169:15, 24; 170:9,10,19,25; 176:12, 13; 179:18Feagan’s 111:3; 129:18fear 97:7,8Feasibility 138:11feasible 137 :14; 148 :10;153:5; 176:24

feature 14:13,23Features 11:21; 14:12,14;15:4,8, 10,15, 17, 24;16:7, 15,20, 21; 17:4, 16;19:5;21:24; 57:24; 147:18Iecal 15:3!eel 46:5; 53:1,9; 69:13;71:8;81:17; 89:21 ;95:16;112:19; 120:22; 122:21;136:13; 168:10; 170:22beling 71:7, 14;73:1;141:11‘eels 17:6; 42:14; 44:5;54:22; 56:19; 80:20;

159:19‘en 32:11‘elt 55:17; 56:1; 58:11;~40:20; 163:8‘ever 13:23; 28:12; 29:22‘evers 23:6ew 10:5; 65:21; 108:11;L2O:1O;147:4ibrosing 125:23ield 6:6; 54:14; 177:20igure 89:19; 175:20igures 164:15inal 167:11

finalizes 89:3Finally 37:2; 67:24; 135:9financial 4:12; 5:3,9find 22:14;3:12;2:24;78:1;11:16;28:13;139:25;43:14;53:18;156:23,4;159:1,9,17finding 176:15findings 13:1, 23; 46:16;

49:11,11fine 83:15; 93:13; 11024;156:16; 157:12, 18; 165:6finished 10:20; 100:18,20fire 83:8,10,12firm 5:9; 135:13firms 4:14; 5:2; 177:19fkSt 7:15; 8:1; 17:24;22:4,12,17, 19; 23:20;32:3; 37:7; 38:19; 43:4;46:9;49:16; 81:4; 88:4;39:18;90:5; 101:8;104:11; 106:21; 107:1;

114:8,8,8; 116:6; 125:17;139:23; 164:21, 23;168:22; 172:15; 173:4;[79:8‘irst-line 113:25ishing 156:22, 22;[57:15; 158:18,23istula 14:2; 23:23; 25:25;}0:10, 18;40:24; 46:15;[7:9, 11,12, 4,23;48:8,!9, 0;49:1;5:19,23;;1:14,2,23;62:3,4;;3:1,8; 4:9istulae 23:6; 40:14;i5:16; 49:23; 59:8; 62:15,

8; 105:20; 170:24iStUh 47:14; 59:23;25:13,14istulizing 19:1istulous 59:10; 61:25it 96:13; 138:6its 110:14; 165:18;76:18ive 37:6; 75:12; 125:6,3,17,21ixed 124:11Iare 28:3; 64:21, 22;~3 :7,2 ,2 5 ; 84:10,0;04:8;06:21;17:8;

22:9,1;170:22Iare-ups 82:14Iares 65:8Ieshing 135:17,18Iexibility 162:11Iexible 90:239Ca[ 15:12,5;51:8LJCUS :20; 86:14, 15

~cused 38:23; 83:25;55:17)cuses54:21>cusing 157:21)Iks 160:7

He ar in g Vo lu m e Nu m be r

May 29,1998

follow 7:ll;38:19; 46:21,69:22; 70:1; 71:22; 78:8;139:21follow-up 46:24; 75:1;144:23followed 46: 16; 70:13following 4:7,16 50:7,8;87:2; 158:19follows 42:19

for4:ll, 14,15, 22; 5:2,5,12,16,18, 19;6:6, 19,22,22;7:7; 8:2,4, 11,12,14,18, 22;9:15; 10:17,21, 25;11:23; 14:12, 13; 16:21,25; 17:24, 25; 19:6, 12;20:12, 17; 22:5,13, 24;2 3:7 ; 2 5:5 , 1 4; 2 9:2 2;30 :18; 31:24; 32:6, 14;33:10, 19; 34:9,9, 23;35:3, 21; 36:6,9, 22;37:21; 38:10, 17,20, 21;39:11, 15;42:19; 43:2, 3,16 ;45:12 , 17 ;46 :14,20 ;47:1,7,7,8, 10;48:17, 21;

i 9:5 ,1 4; 5 0:4 ; 5 1:1 6,2 1;53:1,6,9, 10; 54:1,4, 14,2 3; 5 5:3 ,8 , 11; 5 6:4 ,7 ,8 ,$11,12,15,15 ;57:4,15;58 :1; 60:11 , 16, 20;61 :6,~ ,14;64:6 , 16, 21;65:7 ,8 ,[0 , 14; 66 :9 ,10, 15; 6 7:7;58 :24; 69:24; 70:22, 22;7 1:2 ,8 ,9 , 1 2, 1 3, 1 4;7 2:1 ,

~4;73 :4 ,6 ; 74:2,4,5,6,6,[1, 17,23 ;75:1,10, 11;?6:2, 12, 14, 23; 77:13, 24;78 :12, 19 ,2 0,21, 24;

~9:11, 13,24, 24; 80:7, 14,!6 ,18,21 ; 81:10 ,11,11 ,.2, 17;82:10;83:12, 16,.9,2 0, 24; 84:22; 85:22,!5; 86 :1,6,6, 20; 87:3;)8 :1 ,3 ,7 , 1 3,2 5 ;8 9:1 ,7 ,‘,2 0, 2 2; 9 1:7 ; 9 2:2 0;J3 :13 ;94:7; 96:18 ,19 ;.00:17; 101:12,16, 17;.02:12, 13,14,16, 18;03:7; 104:20,21; 105:1,}; 1 06:15,21 ;107:3,9, 11;08:11, 13; 109:22 ; 110:3,i,22; 111:25; 112:4, 12,5, 25; 113:3,6,6,9, 10,8,25; 114:12,22 ;115:3,!, 11,15 ,20, 2 2; 116:3 ,9; 117:15,1 7; 11 8:18;

1 9:1 7, 1 9; 1 20 :1 4;21:14,22 ;123:11; 1 24:6,i, 2 5; 125:10; 126:3, 10,5 ; 127 :7 , 10; 128 :13,14 ,4, 19 ; 129:4, 18; 131:3,3,4,15,15 , 24; 13 2:6,8,9,23,23; 133:1, 11;34:6; 135:19; 136:18, 19;37:13, 23; 139:4, 14;4 0:2 ,1 9, 2 0; 1 42 :3 ,5 ,8 ,8; 145:11,13 , 17 ; 14 6:6,1 ,1 3,2 2,2 5 ; 1 47 :1 ,2 1;4 8:1 7; 1 49 :11; 1 50 :6 ,9 ,4,16, 18; 151:6,16, 21;

155:4, 9; 156 :2 5; 15 7:8;

1 58:19; 1 59:12, 12;160:14; 161:3,3,5,7,8,12, 12,13,14,15,16,18,20; 162:2,15,16,18,21,22,23, 25; 163:4,6, 11,1 3,1 6,2 0, 2 4; 1 64 :3 ,1 3,19, 19; 165:6 ,8 ,14,19 ,21; 166:3,6,8, 10, 11;1 67:13,19, 24; 170:2;

171:9, 11 ,17, 25 ; 172:8,10,16, 25 ; 17 4:15; 1 75:1177:17, 1 8, 24; 178:7;179:9,9,13,20,23,24,24

foresee 142:6forget 80:3form 131:5formal 7:1; 20:22;167:19; 179:13format 8:9formed 48:12forming 48:8; 165:10formulate 136:7formulation 114:16;132:4, 5; 135:5; 144:4formulations 132:16forth 47:6; 129:24;150:20; 173:24fortunate 11:18forward 8:6; 54:14;~l:ll; 133:2

found 139:24; 143:8Foundation 57:1Iounded 169:16‘our 43:5; 108:13; 115:16128:4; 132:6; 139:9‘our-week 84:24; 119:1‘rank 10:14; 32:2; 59:16;$5:19;70:2,6,9, 19;75:3;78:9‘rankly 18:20; 117:25;[44:18%edd 6:25; 175:2‘ree 20:23; 44:18; 46:5‘reedom 4:24‘rench 42:21 ;43:7requency 137:3‘requent 51:14requently 151:10;[56:17%ieS 33:24; 34:1,7;

}8:17; 41:4,7, 10; 56:13rightens 151:25rom 5:5,21,24 ;7:14, 14;10:7,15; 11:24, 25; 12:2,L,3,4,6; 13:18,20, 22;!0:5; 21:16,22, 23; 22:22;!3:15; 25:1; 28:4; 29:6,8;J1:15;34:7, 24; 35:14, 15,!2; 36:24; 38:15, 23; 45:7;[6:5;47:15; 50:14; 52:7,8,1;57:4; 60:10; 61:24;;4:12;67:7; 68:2, 21; 69:6,!5;70:16; 71:25; 73:22;‘5:5;76:7:81:5:82:8:

.52:16; 153:10,13, 16; 3:3; 84:9; 16; 85:14 ;86:2,

Mille r Re po rt in g Co m p an y , In c . Min-U-Seripm (llJ ex~e rim en t - f r om



He ar in g Vo lu m e Nu m be r 2 Food & Dru g Adm in is t ra t ionMa y 2 9, 1998 Ga st ro in t e st in a l Dr ugs Ad vis or y Co mm it t e e

9 ;8 7:11; 8 9:1 7; 9 0:3 ,1 5;9 1:2 ,3 ,4 ,2 1 ;9 3:7 ,8 ;

&M:14, 16,17, 24; 95:3, 17;7 ,7 ,9 ,12 ;99:21;

Au I:2,2,2 1,24 ; 102 :2;1 03 :1 8, 1 9; 1 06 :2 ; 1 07 :8 ;110 :6 , 1 2; 113 :9 ; 115 :2 5;121 :4 ; 123 :4 ; 126 :18;127:2 , 4; 12 9:4, 1 2;

134 :21; 136 :23; 137 :9 ,22,2 3,2 3,2 4, 2 5; 1 38 :3 ,11,12 ; 13 9:11, 11 , 11; 14 1:24;1 43 :2 5; 1 44 :4 , 2 5; 1 45 :1 ;14 8:4; 151 :1,6,2 2; 162 :8,16, 17,23; 165:17, 25;1 67 :9 ; 1 68 :1 4; 1 70 :1 ;173:18; 174:9,12,14, 17;176 :10; 177 :16; 179 :7 ,22,22,22

front 80:2front-line 114:10full 30:15; 45:24; 64:4;100:18fulminant 46:20functional 44:1; 135:3fundamental 53:24;124:17fundamentally 76:9;152:10; 174:16further 8:2;83:17; l15:5,7; 147:20fl~ure 5:18; 8:21; 12:18;_.——

1 6 ,18;70:16;71:18;.):14

G

Gain 144:13; 179:8gained 160:17,18gaining 20:17gamble 120:21,22gaStritiS 57:20; 58:15gastroenteroiogist28:6; 46:8gastroenterolog ists33:12; 140:19; 143:13, 14;153:19Gastroenterology 9:Iga ve42:22;85:ll; 113:5

geared 139:1general 4:18, 21; 10:10;16:3; 22:3; 34:15; 36:1o;38:15 ;61:10, 12; 148:7;149:21; 163:8,24; 164:2generally 14:15; 37:15;41:24 ;87:11; 150:20;161:11; 163:1; 169:13;173:12generate I41:1o; 160:13—flerated 134:3;

:14, 16genetic 9:8, 10; 12:1, 22;13:9; 14:8, 10; 21:20gentlemen 131:12George 56:22; 67:13;108:25

fr o n t - HANAUER (12)

geriatric 144:15; 145:18,21,23,24, 25; 146:3geriatrician 148:22;149:4geriatrics 144:10,17get 7:15; 10:21; 12:20;30:18; 31:15; 33:13,15,17; 35:8; 36:13; 37:3, 16;

39:21; 49:10, 20; 55:4;60:2; 61:6,7, 10; 62:19;63:17; 68:1, 16;70:1; 75:7;77:9; 79:22; 80:22; 81:17,19, 21;82:18;85:2, 17;90:1,2, 15; 91:3; 93:4, 23;95:7; 99:15; 100:18;101:24; 102:23; 103:10;105:24, 25; 106:24;110:16; 111:2; 117:12;118:8; 119:7; 120:5,9, 12;123:18,20, 22; 126:21;127:13; 128:19; 129:2;132:1,4, 20; 134:4; 136:8,20; 138:3, 15; 140:22;142:17; 143:25; 146:1;147:15,18, 24; 149:2;151:9; 153:4,7; 154:24,z5; 167:9; 169:15; 172:23;174:18; 176:13, 20; 179:1Jets 56:4; 93:23; 121:2,~5

letting 27:7; 49:19, 23;i9:25; 63:7; 64:13; 78:25;10:24;82:17; 101:12;[02:12; 108:4; 125:20;[26:10;132:6; 141:14;50:7; 156:8; 163:22;65:23; 169:20~1136:5; 137:11

Jive 6:9; 10:2; 24:14;L4:5;38:17;42:21 ;43:1;;1:4; 53:18,20; 57:15;i4:7;74:5; 85:14 ;91:12;102:19; 112:18; 136:6;164:15; 167:3qiven 6:l; 24:ll; 45:15;;7 :1 4;6 4:5 ; 6 5:7 ; 6 6:1 8;1 4:2 ; 1 08 :1 6; 1 30 :6 ;I34:1O; 172 :13; 173 :23;[7 5:1 0, 11; 1 76 :9

J ives 164:24; 165:2

3 iVi ng 7 2:5 ,6 ; 8 4:1 5;[0 0:1 0; 1 26 :1 7; 1 77 :1 3

J la ss 67:9

Jlimpse 47:1~lobal 52:5jlobals 66:6,13,14]Iucocorticoid 104:13,6,18Jucocorticoids 104:20~naWing 76:15108:2;11:2; 23:21 ;35:5;,9:11;41:20;48:17; 49:2;,6:7; 58:21; 61:22; 72:9;‘4:6, 10; 75:12; 78:21;~1:4,18; 99:6; 102:6;05:15; 112:11; 116:20;26:13, 14; 135:24; 144:4;

50:25; 153:16; 155:23;

1 56 :7 ; 1 57 :2 4; 1 63 :4 ;171 :21; 174 :21

goa l 8:3; 26: 1; 30:8;44 :12, 14; 51:1 6; 52:1 2,1 2, 1 3; 5 3:18 , 21 ; 55:2 2,2 3;5 6:1 ,4 ; 8 3:1 3 ;9 6:2 1;102:1 5; 1 03:2 ,6, 24;1 04 :9 ; 112 :5 ; 116 :4 ;118 :11; 119 :1 4; 1 73 :5 ,7 ;177:9,11

goa ls 19:20; 21:16; 30:9;

35 :5; 55:1 8,22, 22 ; 56:1 7,18

goes 18:18; 45:22; 53:23;76:4, 15; 8 2:21 ; 93:8;9 4:2 4; 9 8:1 6; 1 07 :1 0;116 :1 6; 1 24 :1 9; 1 51 :2 ;164 :14; 177 :12

going 5:14, 19; 10:2;11:24;15:21; 18:3,5,6;21:19 ;29:10;33:17; 36:8;39:1, 8; 42:15; 48:23;51:15; 56:6; 57:12; 59:19;

53:10;72:25; 73:3, 11;7 8:2 4; 8 0:1 3; 8 1:2 2; 8 3:1 ,};88:10; 89:2,9, 19;91 :1,13,21 ,22 ;99 :21 ,24;1 00 :2 ; 1 02 :2 ; 1 03 :4 ;1 06 :1 0; 1 08 :2 3, 2 4; 1 09 :2 ,[,6 ; 11 0:11, 13; 115:7;117 :2 0; 118 :1 7, 1 8; 1 21 :6 ,12; 122:16 ; 127:9 ,12,17 ,Z3 , 24; 129 :24; 134:2 , 5 ,!2 ; 136 :8 ,9 ; 137 :3 ,4 ,6 ;~38 :15; 143 :19; 144 :2 ;[4 7:5 ,6 ; 1 48 :11; 1 49 :2 ,6 ,1 ,8 ,2 5; 1 51 :1 9; 1 52 :1 2,!3 ; 1 53 :3 ; 1 54 :8 ; 1 55 :2 4;.5 6:7 ,1 0, 1 0; 1 57 :1 7;.59:16: 162:17:164:9:71:4; 174:7; 175:14; ‘76:1, 17,20gold 41 :ll; 66:5,16;1 34 :5 ; 1 68 :1 2,1 8; 1 71 :1 0

Goldstein 56:21,2,22;57:13;9:25;0:1;30:9 ,10;133:1,8 ,0,14,0;134:1135:1;36:12;137:16;39:6 ,5;143:19,Z2;159 :21gone61:23;3:4;0:5;[47:12;68:9Sood 7:10,0;37:15;}9:2;6:11,2;58:13;50:6;6:18,1;72:5;T3:24;5:18 ;1:22,4;12:1091:7;04:23;[12:13;20:4 ;24:1,;[37 :11,1;141:12;!44:20;66:24;67:9;.71:23;73:7 ;75:20;.77:20,24jot6:20 ;2:20;7:19;[4:25;09:4 ;14:23;15:18;27:11;74:11Iotten5:10;8:4Government 71:7%abowsky 125:10

Irabs162:23

grade 19:16; 48:20; 125:8graded 46:16gradual 36:18gradually 70:14; 114:9;149:13GRAFFNER 51:18, 18;82:1; 119:24; 177:14granted 4:19; 33:4grappled 92:3gratified 34:17great 6:1, 10; 22:9; 38:12;44:16; 48:22; 71:14; 86:4;114:6; 120:6greater 47:24; 48:9;133:5group 15:15; 37:7, 25;86:18,20, 20; 87:4; 88:21;90:25; 91:22; 92:23;96:16, 20; 116:17, 18;129:2; 136:14; 139:4, 6;140:20; 142:15; 143:18;145:1, 5; 148:9; 151:21;156:15;165:11; 179:22groups 100:1;17:12;127:9;28:10,21;30:25;139:1;74:3growing 58:8;9:1

yown 35:19growth 13:24;10:24;111:1;34:21;37:21,25;[57:4,6

~uard 9 9 : 1 oJuess 33:1, 19; 34:9;[2:1, 3; 53:17; 72:3; 82:20;15:2;91:15 ;101:21;

113:15, 17; 120:18;.38:12; 141:5,7,8;.55:15; 157:14; 162:24;.65:17 Iguest 8:24

guests6:19

guidance 4:21; 7:l,4,7,1 0, 1 0, 12,16;8 :2,4;22:23;8:9;5:18;8:19;71:2472:8;74:5; 01:1;102:19;13:10;16:4;117:22;19:18;36:7;145:11161:20,25;162:23;63:7 ,9;166:10;173:25;74:1,;175:3,6,$;179:14,3,23guide 123:16~uided 142:9~uideline 18:24; 31:21,?1;71:19; 74:5; 161:5;[62:12, 13; 164:18;165:14; 166 :10; 176 :21

~uidelines 5:18; 6:5, 22;}:25; 11:12; 15:21; 17:24;.9:21 ;21:25; 26:15;!7:15; 33:1, 1;74:5; 75:6;.02:19; 126:21; 161:1;74:21; 177:21luinea 144:3

lUyS 93:7; 104:10; 118:3 -

H

H 57:17,18,19,19,19,20; 58:15had 7:2, 9; 32:8; 40:5;41:7; 42:24 ;43:12; 44:8;46:15; 47:8,11,21,22,23,24; 48:2,4,7,10,10, 18;52:19; 53:7; 55:19,22, 25;58 :7; 6 0:12; 6 6:16 ; 68 :11;6 9:22; 70:1 0; 79:1; 8 0:4;9 8:8; 99:2, 3,3; 105:2 0;11 3:24 ; 114:6 , 18; 115:23 ,24, 25; 122:12; 125:13, 13;

140:9, 16, 17; 141:2, 17;1 46 :1 2, 2 5; 1 49 :4 ; 1 50 :1 4,1 7;1 55 :1 5, 1 6; 1 59 :1 3;1 71 :3 ; 1 75 :2 3; 1 79 :7 ,9

hadn’t 109 :24; 115 :20

Ialf 10:18;7:24 ;5:7;[17:11,2;165:3,12

lalf-empty 67:9Ialf-ful[ 67:9lalt 26 : 21+ANAUER 4:3; 5:14; 7:3;k8, 12, 23; 22:17; 26:8,.2; 28:4, 17; 30:1, 16;~l:l,14,23; 32:23 ;33:24;k8:7,15; 39:23; 40:20;il:2,25; 42:16 ;43:20;i4:6, 15; 46:4; 49:7; 50:11;;1:12; 54:8; 55:13; 56:21;~7:ll; 60:4, 15, 19;61:1,,9, 18;63:9, 22;64:18;;5:2, 5, 12, 17;67:1, 25;i8:7, 11, 17;69:3, 5,8, 10,

7; 70:5,7,10,16, 20;‘1 :1 ,,12,24 ;72 :20,2;4:4 ,16,5;75:25 ;7:5,,1;78:15; 9:1,22,25;10:10,9;81:1,10,24;14:1185:7,20;6:11;19:6,3;91:24;3:6, 5;J5:15;96:11; 8:12;[00:16,2;102:5 ,6;103:7,10,20, 4;104:9;105:7;06:2 ;07:6,5;108:19;09:8,11,1;[10:15;11:2,3;112:24;113:3,3,21 ,24;14:13.16:3;17:3,24 ;20:17;.21:7;23:6;24:3;.26:22;27:6,8;128 :3,9,23;129:14;30:9;32:19;33 :6,9,12 ,8;34:15;37:7;38:9;40:9;41:7;42:1,0;43:16,1;144:9,3;46:2, 0,16, 9;147:3;48:3 ,1;149:12,0;50:7,3;153:9;60:23;61:17,2;162:7,15,1;64:2; 66:2,7;167:11;68:17;69:3,8,10, 3;70:1 ,9;71:3,13,5,17 ,4;175:8,17,19, 2;76:3,5,8,12, 2;177:3,

3,25;178:6 ;79:1

Min-u-scr ip t@ Mille r R eu or t in Q Co m o an v . In c .



Fo od & Dru g Ad m in is t ra t ionGa st r oin t e st in a l Dr ugs Ad vis or y Comm it t e e

hand 11:10;5:1332:17;43:7;9:21;63:9

_.———.handle 43: 16;86:11handled 97:19; 100:25hands 37:18Hans 51:18happen 91:22; 130:23;139:24; 156:10

happened 34:6, 16; 37:5;81:11 ;99:13; 147:1happening 34:22; 63:7;116:13,14happens 18:17; 103:12;149:19; 170:20happy 77:10; 85:19;110:20hard 36:23; 40:12, 18;71:5, 19,20; 113:18; 155:6hard-to-deal-with 90:19harder 36:21; 165:12;167:9Harlan 52:7; 57:6; 141:1;

178:14harmful 173:7Harmonized 145:11Harry 130:18Harvey 55:24; 129:23has 4:5, 13; 5:3;9:3,9, 14,18,22,24, 24; 10:7, 10,

.+=% 16; 15:20; 16:22; 19:6,8,15;20:21; 21:7; 26:7,8;28:8, 8; 29:7; 30:1; 32:6,20; 33:5; 34:6,13, 16;37:5,6, 21; 38:7; 39:20;41:10,10,11,15 ;46:17;47:5; 48:22; 49:18, 24;54:11,11,14 ;55:1; 56:8,10;59:18, 23;61:23;72:16; 74:19; 78:13; 79:9;80:12,14,15, 17;81:25;83:21 ;84:13;86:12, 16;87:19; 93:25; 99:22;100:25; 105:17; 106:7, 11,20;107:12;12:9;13:17;115:3,17,8;116:15;118:14125:11,22;127 :15;29:19;30:6,0;131 :14,2;132:7,4;134:5;43:7;47:9,2;151:18;53:11;57:16,16;158:11;60:4,;161:21;62:4;66:6;

167 :4;73:10 ,6,17;174:1,9;176:10,1,14,18;179:8hasn’t 46:25hat 148:22hate 170:10haunted 116:15hav 115:7—.=have 4:19, 20; 5:25; 6:10,13;7:18; 8:18, 19, 24;9:12; 10:5, 14,21; 11:2,18, 19,21,23; 12:9; 13:1,10; 14:7, 10; 15:19; 16:3,24; 17:4.9.9.11.14.20.

19:11, 13,16,17, 19; 20:5,19; 21:5, 10; 22:8,13, 18;23:7,7; 24:21; 25:9; 27:1,2,3, 10,23; 28:2,6,7,11,12, 18, 22; 29:2; 30:6;31:2 ,4 , 10; 34:9,19 ,20,23 , 24 ; 35 :6 ,10 ,18 ,19 ,21, 22; 36:2,9,15, 20;

37:17; 38:12 ;39:16;

4 0:1 2,25 ; 42 :2,7 ; 4 3:1 ,4,7 ; 4 4:6,19, 25 ; 4 5:8 ,8;4 6:1 ,2,5 ,18 , 1 8;4 7:1 6,22, 24; 48:7,9,10,12, 13;4 9:8 ; 5 0:9 ,25 , 25; 51 :1,3 ,6 ,9 ,1 3; 5 2:1 ,4 ;5 3:1 ,3 ,5 ,6,10,11,12, 15,22; 54:3;55:25; 56:16; 57:6 ,16,18 ,23 ; 5 8:4 , 2 5; 5 9:2 0; 60 :1,13,16 ,17, 20;63:4 ;64:1 ,2 0; 6 5:7 ; 6 6:2 2; 7 0:3 ,8 ,24;71:17;72:18, 18;73:15 ;7 4:1 ,12 ,13 ; 7 5:1 ;76:2, 3; 77:10,15,17, 23;8 2:1 0 ;8 3:2 ,7 ; 8 4:1 7,1 8,20, 25; 85:3,3, 22; 86:13,15 ; 8 7:1 3,2 2, 2 4; 8 9:14 ;90:11,11,19,20,20, 22;9 2:5 ,2 4, 2 5; 9 3:2 ,7 ,11,14;95:1, 1,7,16, 19;9 6:1 3, 1 4;9 7:1 , 1 4;9 8:11,12,21 ,22 ;99:13,21 ;100 :4 ,6 ,9 ; 101 :4 ,19,20 ,22; 102:1,11,20,23, 25;104:12, 25; 105:5,10, 17;1 06 :9,1 7,2 0, 25 ; 107 :17 ,20, 25; 108:10, 16, 25;109:23; 112:13,17, 20;113 :17 ,19 ; 114 :24 ; 115:1,12; 116 :13; 117 :4 ,13,15 ,2 1,2 2; 118 :1 ; 119 :1 4,2 1,

22; 120:6, 22; 121:10, 13;122:8,21 ;123:1 ,16 ,20 ;124:15, 17; 125:20, 25;126:7, 18; 128:4,13, 14;129:14,17, 17; 130:4, 4;131:2; 132:5; 134:3,7, 19;135 :3 , 12; 136 :3 ,8 ,9 ;137 :2, 11,11,2 0; 13 8:1 5,22 ; 13 9:8 ,14, 1 6; 14 0:1 5,23 ; 14 1:2 0,21 , 2 5; 1 42 :20;143:17,17, 22; 144:8, 19;1 46 :4, 12; 1 48:1 4; 14 9:1,24; 150:2,4,10, 14,15,17,20; 151:23; 153:12, 14;154 :11 ;155 :2 ; 156 :1 ,2 ,3 ,

12,15, 23; 157:7,18, 20;158:6,7,8,10,14, 17;1 59 :2,7 , 1 3; 16 0:4 ;161:22; 162:15; 163:9, 16;1 64 :14 ; 1 65:9, 21 ; 16 6:15 ;168 :2,4,9 ; 169 :11 ; 1 70:2 ,14; 17 1:1 ,13, 1 5,2 5;172:2 ,8 ; 173:9 ,13,13 ,15 ,18,22, 22; 178:1, 12, 16;179:4,18

haven’t 11:12; 30:22, 24;68:4; 73:20; 86:2; 95:8;103:22; 104:10; 106:22;112:15havent; 107:18

24:22; 28:11,15, 23;29:13, 14; 51:23;63:8;84:22; 95:5; 108:10;109:17; 117:25; 120:1,3,8; 121:21; 133:15; 150:19;152:6; 163:22; 175:1;177:19He 10:9, 10;65:17, 17, 18;79:2, 9; 97:4; 98:4; 116:4;121:21;129:19; 137:8;143:19; 171:9,10head 98:3head-to-head 169:8,9heading 10:25; 102:6heal 43:2; 170:24healed 44:8healing 23:12,17,18, 23;25:24, 25; 26:1, 22; 27:18;30:10,14,18, 19; 31:22;32;14, 20, 22;33:10, 11;42:21; 43:4,17, 22;44:10,20;45:1, 5,22, 23; 55:19;57:19; 59:20, 21; 60:3,6,

!3,14,21, 23;61:14;77:19health 112:8; 132:10;139:7hear 48:25; 58:19; 61:12;30:8;85:23; 146:8; 153:9heard 8:18;:1;11:7;12:14;8:14;9:2;0:13;i5:8;0:25;6:13;7:3;$9:21;3:20;4:23;6:7;30:8;1:22;3:2;5:7,9,12;86:2;5:16108:10;111 :16113:15 ;15:1;119 :21;34:19;38:19;154:6Iearing 36:16; 59:17;113:21; 118:23; 174:17Ieavily 38:21; 39:8Ield 77:16Ielp 10:12; 11:19;44:22;36:6; 102:10; 104:14;159:6; 165:7Ielpftd 39:20; 41:13;179:18Ielps 88:9Hemoglobin 99:15Iepatic 148:2Ier 6:9; 179:21,24Iere 6:20, 20; 7:23; 8:8;10:22;22:8; 23:21; 27:23;28:7;32:25; 34:22; 36:16,22;50:2; 62:25 ;66:17;57:4;69:11, 19;72:4;31:24;85:21;89:5; 93:16;107:24; 117:9; 121:25;125:20; 128:4; 130:4;137:18; 141:8; 145:21;150:13; 153:10; 159:6;177:15,19,23heretofore 130:15leSitate 172:24Hesitations 160:24leterogeneic 40:5;}9:12; 170:14

heterogeneity 12:10, 12; —

Hea r in g Vo lu m e Nu m be rMa y 29, 1

33:18

heterogeneous 12:10;18:1; 104:19high 42:22; 95:22; 125:5;156:4; 164:25high-dose 69:15higher 59:25; 93:23;126:15; 140:8

highlight 50:16highlighted 11:9highly 94:20; lo4:7;127:21; 139:25him 82:3; 97:7; 143:21;175:23his41:16; 116:4; 141:1histologic 15:24; 16:7;45:1; 49:12; 57:14, 24;58:15histology 16:2historical 173:17, 23;174:19; 177:15historically 76:1; 144:8;

173:11history 135:25HIV 178:23HLAB-27 14:8HLQOL 50:3holding 159:10home 26:21; 27:6homogeneous 18:25;19:13; 20:1honored 141:20hope 8:16, 20; 21:18;37:25; 39:21; 151:16;176:6hopefully 10:20; 11:1;13:9; 68:17; 129:21;179:14hoping 116:25Hospital 9:1; 46:8host 160:15hour 100:18hours 10:18how6:20; 8:19; 13:13;17:6, 19; 18:14; 31:12;40:13, 15;42:14; 43:16;44:4; 52:25,25; 53:15, 21;54:12, 22; 55:17, 20;56:19;59:2;63:11; 71:3;72:6,8, 17;73:11, 25;80:18 ;82:2,6; 85:20,21;86:22; 87:19; 88:10; 89:3,19;90:10,22; 99:11;100:13; 105:18; 106:18;109:5,8,8; 116:7; 117:8,23; 119:18; 123:17;126:18; 127:17; 130:6;132:1; 135:22; 138:25;145:21; 148:10; 154:10,12; 156:23; 157:22;161:19, 23; 162:22;166:22; 175:19, 22; 176:3,8; 177:3however 24:17; 58:3;63:18; 67:18; 77:22;

80:13:97:20:102:25:3: 25; 18:2,3,4:8, i9, 24; I having 15:16;22:8; -. –,

Mille r Re po rt in g Co m pa n y, In c . Min-U-Scr ip t t3

162:4huge 66:16; 126:7; 155:176:18Human 139:8humanistic 35:18hundred 154:11; 176:4;177:5hundreds 84:14; 95:2;

143:24hung 39:3hurting 123:19hypertension 166:1;177:18hypocritical 166:12hypothesis 98:7; 157:1317,20; 158:21; 159:13

I

i 4 : 3 ;5 :15,22 ; 6 :7 ,7 ,9 ,12, 18;7:2;8:6, 10,12,

15, 23; 10:2,2,4,5,12,24; 11:8,10, 17; 19:16,20:2, 19; 22:1,8,9,14,23:2,4,8,11, 12; 24:4,15; 25:21, 23; 26:4,12,27:8, 20; 28:6,7, 17; 305 ,1 3,2 3, 2 5; 3 1:2 ,2 ,7 ,8 ,8,9 ,10 ,10 , 11 ; 32:4,12 ,20,24, 25; 33:11, 19, 134:2,3,5,7,7,9,17, 2336:21; 37:24, 25; 38:7,39:2,3,4,7,13,21, 25;40:1,3,9,12, 17,21 ;4112 ,16, 22 ;42:1, 2 ,3,3,81 7;4 4:6 ,9 , 1 3, 1 4;4 5:3 ,6

11 ,12, 14 ;46 :1 ,4 ,19 ;47:4; 49:13; 50:12, 12,2 0,2 1, 21 ,2 5 ;5 1:1 9,2 2,23; 52:4,7,7,9, 10, 18,20,21,22,23,24,25,25,25;53:1, 1,3,4,5, 10,117,17,19,20, 25; 54:3,10, 10,15,16, 18; 55:6,11,1 5, 1 5, 1 7,1 7,2 5;56:3,7,10, 14, 15, 16;57:1,3,7,12,17, 22;5 8:1 2, 17 , 1 9; 5 9:3 ,6 ,7 ,10,11, 13, 14, 17;60:2,5 ,9 ; 6 1:3 , 1 0; 6 2:4 ,4 ,7 ,1 0;6 3:1 ,4; 64 :2,2 5 ;6 516,21, 23;66:6, 10,12,14,23 , 25; 67:3 ,5 ,6 ,14,17, 25; 68:9, 15, 20; 6911,12,19, 21;70:2, 2224, 24;71:17, 18,22, 272 :3; 73 :20 ;7 4:1 ,18 ; 76,12,13,19, 22;76:5,22; 77:1,8, 10; 78:9, 181 8,2 1,2 3,2 4,2 5 ;7 9:1 ,13,4 ,5,1 8, 23 ; 80:1 9,2 3,23 , 2 4;8 1:9 ;82 :1, 1 7,120; 83:2, 23; 84:9,15, 2B5:2,7;86:3, 11,13, 13B7:11, 24 ; 88 :8, 2 5; 89 :90:17,23, 24;91:15, 1922, 25; 93:6,7, 18; 94:8

15 ,15,21 ;95 :19 ,20 ,21 ,

{13J h an d



He ar in g Vo lu m e Nu m be r 2Ma y 2 9 , 1998

23;97:6,7,7,;98:2,0;99:7,11,12, 6;100:2,12 ,=U]6, 17,24;o1:3,21,

03:8,4 ;104:4,4;.~>:l,4,,15,23;106:3;107:2,7,9, 5;108 :19;109:12,23,5;110:9,9,19,20,21;11:6,12,13,17,24,24;12:1,2,3,3,5,6,9,10,6;113:2,14,17,21;114:3;15:1,14,23;116:25;17:4,13,21,21,24;118:5,4,23;119:2,17,21;120:4,13,3,18,21;121 :3,8,0,20,23;122:6,7,1,11,7,17,18,19,5;123 :2,5,5 ,0,13,15,7 ;124:4,11,15 ,16,17,21;125:7,8,9, 5;126:1,7,7,13, 8;127 :2,6,15,17,20;28:12,15,25;129:2,5,9,11 ,14,15,21,25;30:4,4,5, 0,11,21,23,24131:14,20;132:11,11;33:8,0,10,

14,17;134 :15;35:3,7 ,12,23,3;136:4,12,15 ,16,16,23;137:7,0,14,17,20;38:11,19,24;139 :13 ,14,6;140 :6,7,12,14,19,3;141:5,7,8;142:9,1,12,5,22,23,

=2+43:6,9,12;144:1,2,11,18,20;145:25;

.:3,4,7,16, 9;147 :8,11,12,22;48:3,0,21,22,22;49:1,1,2,3,3,6,14,18;150 :7,9,12, 5;151 :1,2,12;152:2,5 ,6,10,20;153:3,9,9,12,16,18,22,3;154:1,2,6,10 ,11,11,12,12,17,24,25;155:15,17,5;156:8;157:12,14,4,18 ,9,24;158:1,4159:3,5,10,11,19,20,21,2;160:16 ,0;161 :19 ,23;62:11,2,24;163:1,3,3, 9;164 :8,9,10;165 :5,6;166 :13,19 ,20,21,22167:4,21;168:19,19,20,21, 5;169:6,5,16,8,24;170 :6,10,1;171 :4,21,21,25;172:1,6,8,9,19,20,22,23,24174:11,12,14,16,7;175:2,15,20,

21,23,4;176 :6,9,0,13,17,23,23,24, 5;177:4,6,8,9, 4,16,18,21,21,2;178:7;79:3,4,4,7,9,12,16,21IBD 1 32 :1 2; 1 39 :4 ; 1 43 :3 ;177:18,24

_A~Q 50:2; 54:16, 21;

,8 ; 5 6:1 7, 1 8;6 6:1 0,~ L, 2 3; 6 7:2 ,7 ; 8 9:1 ;1 28 :1 3; 1 29 :2 5

iceberg 121:11ICH 161:1; 174:1idea 37:16; 38:25; 51:19;

59 : 9 ,10; 67:17; 84:3;?2:15, 15;93:3; 126:18;141:12, 15; 147:24; 150:4;157:7; 158:6; 163:2ideal 35:2; 102:1ideas 177:20identified 105:10, 11identify 15:5; 21:17, 18,21

idiosyncratic 154:18;156:20; 167:2if 11:1 ; 2 0:1 0 ;2 2:11; 2 3:5 ;24:12, 15; 25:8; 29:6, 18;3 1:7 ; 3 2:6 ; 3 3:1 2; 3 4:2 3;36:13 ;41:23; 42 :3 ,21 ;$ 3:1 7; 4 4:8 ; 4 5:5 ; 4 6:5 ;i 7:1 2, 2 1, 2 3; 4 8:4 ,1 0,1 8,2 2; 5 0:2 4; 5 1:3 , 2 5; 5 2:3 ,1 9; 5 3:3 , 5 ,7 ; 5 4:2 0;57:22; 58:5,9,20, 22;

59:8,20, 23; 60:1, 12, 17,~ o, 22;61:21, 23;62:5, 17;

5 5:9 , 1 9; 6 6:1 6, 2 3; 6 9:1 2,!2; 70 :3 , 17; 72:24, 25;

73:2; 77:17, 22; 78:7, 19,?4 ; 7 9:1 5; 8 0:1 6; 8 1:1 3,1 6; 8 3:8 ,1 0, 1 4; 8 4:2 ;1 5:11, 1 4,1 6, 1 9;8 6:5 ;17:10; 89:1,6,10, 21;)0 :11, 1 3;9 1:1 5; 9 3:3 ;)4:1 0, 1 4, 23; 95 :2, 8,9;>6 :4 , 2 4; 9 8:8 , 2 0; 1 00 :3 ,i ,9 ; 1 01 :2 4; 1 02 :1 0,2 5;1 06 :1 3,2 0, 2 5; 1 07 :1 0;[1 0:1 5; 111 :1 7; 113 :2 4;~14:6 , 21; 115:7,20,23,?5 ; 116 :11, 1 9, 2 2; 117 :1 5,1 8; 118 :1 2, 1 5; 119 :2 ;[20:6, 22, 22; 121:2, 5;[2 2:8 , 1 2, 2 0; 1 23 :2 0;[2 5:1 4; 1 26 :2 2, 2 3; 1 27 :9 ;[3 2:5 ; 1 33 :1 4; 1 35 :11;~ 37 :2 0, 2 4; 1 38 :1 5;139 :15,21 ,22 ;141 :12,15 ;[42:1 7,21; 143:11, 14;[4 4:2 5; 1 45 :4 ; 1 48 :1 3,1 6,z2; 149:1,3, 12, 16;

150:13; 151:3, 13, 18;153:17, 24; 155:15,16, 18;1 56 :1 2,1 6,1 7, 1 9; 1 57 :2 0,21, 23; 158:21; 159:6160:6; 163:19; 164:11, 12;1 65 :9 ; 1 66 :5 , 9 ; 1 67 :3 ;1 68 :1 6, 2 0; 1 69 :1 7;1 71 :1 9; 1 72 :2 0; 1 73 :4 ,4 ,

7 ; 1 74 :7 , 2 5; 1 75 :2 5;1 76 :1 4, 1 8; 1 77 :8 ; 1 78 :1 5,17

ignore 118:21; 119:16;158:12II 141:3111176:16ileal 43:2ileitis 46:20ileostomies 129:7ileum 46:23ill 165:21illness 35:4, 15

Food & Dru g Adm in is t ra t ionGa s t ro in t e s t in a l Dr u gs Ad vis or v Comm it t e e

illnesses 12:10; 166:1imagine 130:21; 155:9imbalances 116:14,21immediately 31:4immortal 130:18immune 12:23; 126:10immunoiiflammatory12:23immunomodulatory125:4; 167:15; 168:1,3immunosalicylate167:14immunosuppressive171:18

impact 12:18;8:10;26:19;36 :12;99 :22;113:17;32:13145:16impairment152:23,23impetus 176:19Implication 83:6, 8;168:14implications 14:25;io:16,mplicitiy 118:13; 119:23‘replies 64:19; 67:15,20mportance 5:17; 11:14;$0:25;90:18; 92:11; 99:1mportant 5:16; 11:24;12:25; 13:25; 24:5; 40:6;fl:22; 50:15; 54:23;55:16;56:2; 60:8, 22;77:14;80:18; 83:6; 89:5,~2;90:4; 92:12; 93:2; 98:6;)9:5; 101:1; 105:11, 1 2;1 08 :11; 116 :2 3; 118 :2 4;1 34 :2 1; 1 35 :9 ; 1 39 :2 5;144:1, 5; 147:17,19, 2 5;

1 48 :1 3, 1 8; 1 55 :4 ; 1 57 :5 ;159:25; 165:7,8,21

mpossible 46:13;127:12; 132:2lmpraCtiCai 132:2Impressed 6:12; 41:3, 16reprove 6:4; 26:20;55:23 ;91:14, 17

improved 43:8, 10; 44:9itIIprOVt?nK?M 1 9:2 1, 2 5;2 7:1 3; 3 0:9 ; 4 2:2 5; 4 3:6 ;56:8; 60:7, 14; 64:1 1;6 5:1 2; 6 7:2 2, 2 3; 8 5:1 2;1 05 :2 1,2 2, 2 4,2 5; 110 :11;130:14

improves 58:6improving 27:14; 91:10in 4:13, 18, 20; 5:1,7 ;6:2,24, 25; 7:1,2,7, 9;8:13,21;9:2,4,9, 13,14,19, 23;10:8,8,9, 11,12 ;11:18,22; 12:11, 15; 13:15, 16,23; 14:6,16, 18; 15:5, 15;16:3, 24; 17:15,18,19, 23;18:1,2,21,23 ;19:1,3,9,12,20, 23; 20:7, 11,24,25;21:1,5,6,18,20;22:6,9,8,21;3:2,8,25;24:7,8 ,0,15,20,4;

25:1,3,5,6,7,7,12,15,17,18, 2Q 26:5,5,5; 27:9,13,21,23, 25; 28:20; 30:6;31:5,16, 20; 32:10,12,13,15,22 ;33:1,3, 11,16,20,20; 34:6, 10,10, 11,12,12,14,17,19,20, 23;

35:1,2,6,15,16, 24; 36:2,3 ,5 ,7 ,7 , 1 0; 3 7:5 ,8 ,1 0,14,15,22 ;38:1 ,10,11,

11,13,14, 16;39:7, 12,17, 24; 40:4,7,8, 11, 17,22,24, 25;41:4, 12,14,20; 42:4, 19; 43:8,11, 22;45:10,10,17, 19,21 ;46:3,B,21, 24;47:4,9,9, 11,17,20, 22 ; 48:4 ; 49 :3 ,8 ,8 ,22 ,2 4;5 0:1 4, 1 5,2 1,2 4 ;5 1:1 ,7; 5 2:1 0, 14; 53:8,8; 54:2,23, 2 5; 55:7,15, 16; 56:1,2,3,7,10,17, 1 7; 57:4,17,18; 58:4,5,6,8,16, 25;5 9:1 3, 1 7,2 1, 2 4; 6 0:9 ,11,24;61:5, 11, 20;62:19, 20;53:15,22 ;64:1 ,4 ,5 ,9 ,11,

1 8;6 5:5 ,6 ,7 , 1 3,1 5,1 7,2 1; 6 6:4 ; 6 8:3 , 5 ; 6 9 :2 ;7 1:11,1 3, 1 8;7 2:6 ; 7 3:3 ,5,7,8; 74:1, 2, 10, 19;7 5:1 4,1 4, 1 6,2 1 ;7 6:2 ,2 0,2 4; 7 7:3 ,1 4, 1 9; 7 8:5 ,7 ,13, 22; 79:20, 20; 80:5, 7;31:3,5, 12,13, 20; 82:3,ZO, 22, 25; 83 :2,11 , 23;34:3,4,4,4,6,9, 24;35:15, 23; 86:3,14,21, 25;37:19, 25; 88:9 ,14,15,20,2 0, 2 1;8 9:2 , 11, 1 5;9 0:3 ,5 ,5 ,9 , 2 0; 9 2:9 ; 9 3:2 2;)4 :6 , 1 0,2 2, 2 2; 9 5:2 ,7 ,2 0; 9 6:4 ,1 0,1 6, 1 8;9 7:9 ,1 7; 9 8:1 4, 2 5; 9 9:1 5;100:12,22,22, 25; 101:1,48, 12,18,20, 22; 102:5;103 :23, 25; 104:3 ,4 ,6 ,7 ,1 8; 1 05 :1 9; 1 06 :2 , 5 ,8 ;107:1,8, 14; 108:3,6, 15,22; 109:19; 11 0:1,3 , 16;111 :3 , 1 7; 112 :2 4; 113 :1 6,19; 114:2,3,4,8, 15;116 :1 4,1 7,1 7, 25; 117:5,6 ,7 ,1 0,11,11 ;118 :8 ,1 5,2 0,2 2,2 4, 2 5; 119 :4 ,1 9,23,24, 24; 120:1,3, 15;1 21 :1 , 1 2,1 4; 1 22 :3 ,2 3;1 23 :1 ,3 , 2 0,2 4; 1 24 :8 ,9 ,

14,18,23,23, 24; 125:1,5 ,6 ,11,1 2, 1 6; 1 26 :1 ,4 ,6 ,7,9,12,16,19,23,24, 25;1 27 :1 ,6 ,7 ,8 , 1 3; 1 28 :2 ,6 ,7,10, 17, 18,20; 129:3,1 3, 1 4;1 30 :11, 1 3,1 4,1 6,16,18 , 25; 131 :4 ,5 ,7 ,11,23; 132:9,10,14,14, 15,15,16 , 25; 133 :2 ,4 ,7 ,7 ,10,15,21,23, 25; 134:8,11,12, 14,24; 135:9, 15;136:3,4,5,7,14,14,17,2 0,2 1,2 5,2 5 ;1 37 :1 ,9 ,1 0,1 2, 1 7; 1 38 :6 ,1 4,1 7,22,23;139:12 ,5,18,18,

18,20,23,24, 25; 140:1,4,21,23; 141:1,2,6,13,14, 19,21; 143:3,4,5,8,9,22; 144:4,15,17, 17,24;145:10,12,13,18,22,23,25; 146:2,5,7, 17; 147:6,11, 13; 148:4,5,7,9,14,15,17,19, 24; 14 9:1 3;150:7; 151:13,18,20, 21;152:7,14, 16,18, 18;

153:4,5,5,5,7,19,21, 24;154:1,7,19,19,23,23,24; 155:1,3,3,4,6,19,22,23, 23; 156:3, 4,6; 157:4,4,10,10,12, 17; 158:13,1 5,2 2, 2 4; 1 59 :8 ,9 ,1 2,14,15, 17,19, 25; 160:4,11, 21; 161:25; 162:5, 13;163:9,15,15,21, 22;164:5,10,12,14,21,23,2 4;1 65 :2 ,4 , 11,11,1 8,23; 166:5,6,7,9,17,21,23,24,24, 25; 167:3, 18;168:21; 169:4,10,13, 17;170:8, 12; 171:5, 20;172:2,3,10,12,14,18,

1 9,2 2, 2 4; 1 73 :2 ,1 9,2 0,21, 23; 174:8,17,22, 25;1 75 :2 , 1 2; 1 76 :2 ; 1 77 :1 ,2 ,6 , 1 4,2 0,2 1; 1 78 :1 5,2 0,22; 179 :19

inactive 109:2inactivity 108:21inappropriately 100:7incentive 81:18; 83:16incentives 131:3,8incidence 152:14; 158:2;165:1,8; 167:4inclination 118:18include 15:3; 17:1; 29:3,

B;36:4; 43:22; 60:23;129:19; 134:17; 147:9, 23;151:3,16included 25:25; 37:14;56:17;60:10includes 29:5; 139:4including 13:19, 2 3 ;16:12; 19:21;45:3; 57:13,25; 143:9; 160:12inChISiOn 136:18; 137:8;149:18inclusive 15:7; 61:19incomplete 27:12, 16inconsistencies 111:14

inconsistent 107:7incorporated 9 2 :18;102:20;68:8incorporating 61:16incorrect 47:18, 19increase 64:9; 117:6;143:12increasing 107:19; 149:7incredible 71:16; 126:6incredibly 6:12incurring 109:18IND 174:23indeed 57:9; 82:12;

IBD - in d e ed (14) Min-U-Script@ MWer Reu or t im Com oa nv. In c .



Food & Dru g Adm in is t ra t ionGa st r oin t e st in a l Dr u gs Ad vis or y Comm i t t ee

———_

_—_

_—___

160:17independent 29:16;122:23indeterminate 11:20;15:16Index 17:2, 11 ; 1 8:1 5, 1 8;20:1 0 ;2 1:8 ; 3 2:11; 39 :14 ;41 :23 ;4 3:2 2;4 4:1 ; 48 :15 ,1 6;5 4:2 ,6 ; 7 1:1 5 ;8 7:5 ,13,14, 18; 100:3,4; 156:7

indexed 108:6indexes 36:15,16indicate 96:17indicated 62:22indication 22:2o; 23:11,20; 27:22, 24; 30:5,14, 15,18;38:25;44:10,15;48:17; 49:4, 6; 50:4,5;53:6, 10; 57:21; 58:1; 61:2;62:22, 23; 63:2, 14; 64:12;65:3, 13; 66:2o; 80:16;82:20; 83:23; 85:14;101:9, 10, 13; 102:18;

103:9; 107:11; 110:7;112:25; 113:3; 115:8;120:16; 122:4; 153:8indications 22:12, 15,24; 23:2, 22; 30:2, 21;38:16,17, 23; 47:7; 49:15;53:14, 15; 56:11, 14;57:15; 63:23; 64:18; 65:8;83:19; 102:6; 126:2;137:23; 166:22; 175:13indicators 14:25; 17:8;29:7indices 17:1, 1,12, 14;18:20; 21:6, 11;86:14individual 5:25; 13:15;35:3; 61:13 ;62:2,3; 63:13;65:13 ;67:2;86:21; 94:22,25; 96:22individualized 92:25individuals 28:21; 95:2induce 42:21 ;60:21, 23induced 26:7inducing 26:20, 22;50:19 ;75:10; 117:4induction 19:21; 22:25;23:10, 13; 26:16; 27:11;30:3,4,6 ;31:11,17,22;39:5; 42:5; 45:17; 83:21,22; 169:21; 170:1

industry 5:24; 34:18;37:21; 51:14, 22; 52:8;53:5, 20; 57:5;82:8; 101:4;135:19; 139:11; 153:7;160:4, 5; 177:13, 16;178:3,20industry’s 176:25ineffective 25:5, 14;132:3infant 128:5infants 127:23infection 57:19inflamed 15:6; 51:3, 10,10; 58:23

inflammation 14:15;

17:7, 16; 50:24; 51:1, 7;57:18; 58:16;75:20inflammatory 5:19; 6:3,11 , 24 ; 9:4 ,7, 2 3; 1 0:1 ,9,12 ; 11:1 5,2 2; 12 :8; 13:7,2 5; 1 4:6 ; 1 5:1 ; 16 :18 ; 17 :8;1 8:11; 1 9:1 0; 2 1:5 ,7 ;3 8:2 0; 4 1:1 2; 4 5:1 9;48:23 ; 84:15; 125 :14,15 ,17 ; 141 :2; 163 :3; 17 0:8

i nfl ixim a b 1 2:1 4; 1 5:1 8;1 6:4 ; 4 3:3 ; 6 0:11; 8 3:4 ;117 :1 5; 1 24 :5 ; 1 52 :2 2;1 53 :2 1; 1 54 :1 ; 1 56 :5 ;167:23

influence 12:22inform 22:21Information 4:25; 9:16;22:10; 41:6; 88:9; 91:6,13,16, 18; 132:9; 141:6;142:16, 18; 146:11; 154:6,7; 160:16informative 97:16

inherent 80:12, 15;154:20inhibit 155:2; 156:18inhibiting 78:6; 158:5inhibition 43:23; 154:21inhibitors 157:3initial IO:22; 64:23;71:22; 72:8; 84:4; 137:9initiated 141:5initiation 119:6initiatives 160:15,21input 7:14, 15,25 ;40:8;134:4; 146:1insight 6:13insights 9:8insist 71:7; 149:4insisted 90:11instance 46:14, 20;47:10; 60:11; 70:23; 89:7;124:25; 125:11; 136:19;146:6; 150:6; 151:6;153:16; 163:12; 166:6instances 46:13; 90:21instead 89:1; 103:4Institutes 139:7institutions 139:5instructions 179:11

instrument 54:17; 66:19;143:17instruments 34: 10;138:14insufficient 69:14intellectual 37:3intended 7:19; 8:8;40:18 ;84:1,2; 161:7;162:2intending 113:25; 173:4intents 74:24interact 178:17interaction 160:9;167:20

interactions 145:15;

158:6, 9; 168:6; 174:12interactive 97:18Interest 4:6,8, 16; 5:3,8,11; 1 0:11; 1 54 :8; 1 72 :22

interested 41:4; 57:17;144:4; 174:17interesting 43:8; 47:22;155:21

interests 4:12, 13, 20;10:1

intermittent 161:3internal 73:12international 9:6; 37:7,20internationally 37:24;145:11interpret 176:21interpretation 94:5;121:3interval 164:13; 173:14;179:15intervals 85:3

intervening 19:12intervention 9:18; 44:3;78:2into 6:13; 12:20; 21:24;29:11 ;33:15; 35:10,21,25; 36:10, 14;38:8; 45:2;49:10, 16; 50:20, 23;51:15; 77:9; 78:19; 79:22;87:13, 14; 93:24; 99:6;100:1;05:6;11:14;112:3;16:16;17:19,20,21;121:3;25:21 ;33:18;135:24;45:3;50:23;164:18;68:8;69:20;173:19;74:11;79:13intraocular21:15intravenous 69:15introduce 6:7, 8;8:23;25:15; 46:6; 67:6introduced 9:2; 10:6,16introducing 5:16introduction 11:2; 22:1;24:7; 25:6introductory 4:5; 5:13intuition 157:21intuitive 53:1, 9; 124:21invalidated 21:6invaluable 179:23

invariable 94:20invariably 20:25; 29:8, 9;155:20invest 131:4investigators 17:14;36:9; 95:16; 153:21invited 8:24involve 5:1; 167:8involved 7:7; 9:3, 23;37:22, 23; 39:8; 50:21;Yl&53:7; 158:13;

involvement 5:5,9;14:10

involving 160:5

Hea r in g Vo lu m e Nu m be rMa y 29,

iron 14:19irrelevant 46:13; 59:22irritable 17:10; 28:19is 4:3,9; 5:14, 17, 18, 22;7:6,10,12,15,16, 20; 8:8,16,17,19,21,25, 25;9:5,11, 13,21 ; 10:3 ,9 ,15,17 ,22; 11:1,4,15, 16,24;

12:2; 1 3:4 ,21 , 24 ; 14 :17 ,23; 15:7, 13; 17:24; 18:8,14;19:7 ; 20:21 ;21:4 ,22;22:14,20, 21;23:8,9, 14,18 ;24 :5,6,6,8, 10,10,11,12,13 ;25:1,11,21;26:25;27:23, 24; 28:2,12, 16,18,25; 29:6,10,11, 19; 30:5,6,8 , 14 ;31 :3,6 , 11,12,12,12,19,20,20,24, 24;32:5,8, 15; 33:5,10, 22;3 4:8 ,9 ,1 3, 2 0; 3 5:1 ,4 ,8 ,1 7; 36 :7,18, 22 ; 3 7:2 ,8,2 0,2 3,2 4, 24 ; 3 8:9 ,25 ,25; 39:2,3,7,13,14,14,15,18,19,19,21,23, 25;

40:1,3,4,9,10,11,17, 18;41:5,6; 42:5, 20;43:3, 17,18,18, 23;44:10, 13,15,17, 18,21,23,23, 24;45 :11 ,13 ,25 ,25; 4 6:1 3;47:4,6,18, 19; 48:14, 15;49 :5 , 21 ; 50 :2 ,7 ,16 ,17,18,18 ,23,24 ;51:1 ,2 ,3 ,4 ,8 ,9 ,1 0, 1 5, 21 ;5 2:1 0,11,1 2, 13, 1 5, 17, 18 ,21 ,22 ,23; 53:4,14,19,24,24,25;54:1,1,2,5,6,7,7,11,15,17,18,22, 23,24;55:4; 56:4,5,6,9,10,18,19,19, 23; 57:3,15, 21;

58:3,11,11,12,16,18,19, 24; 59:1,9, 12, 17,19,23; 60:6,8,20,21, 24;6 1:5 ,22,23,24, 2 5;6 2:1 ,

3,4,8,10,13,14,14,14,1 7,2 2, 2 5;6 3:1 , 4,5 ,6,7 ,10,12,15,16, 19,21;64:2,12,12,16,24,25,25 ;65:1, 2 ,4 ,5 ,9 ,9 ,12 ,14, 15,17,18,19,20,21,22,23, 24;66:3,4,4, 15,1 5, 1 9,2 1, 2 5; 6 7:8 ,9 ,1 0,11 , 14 , 15 ,19 ,21 ,21 ,25 ;68:3,5,7,18,18, 25; 69:3,1 6,1 9,2 0,23 , 2 4; 70 :5,7 ,7 ,20,21 ,21 ;71:2 ,3 ,5 ,6 ,15, 18,20,25 ;72:1, 1, 1,2,5 ,8,13,17, 24 ; 73 :7,11,12, 15, 19;74:2,7,8, 12,1 8,1 9,2 1,22 , 22 ;75 :1,13,18,19, 22;76:3, 12,12,14,14,15,17,19,21,22; 77:4; 78:1, 1,7; 79:3,15, 19, 19, 23; 80:6, 14,18 ,20 ,21 ;81 :5 ,6 ,16 ,21 ,24, 25;82:1,3,4,8,9, 12,13,14, 16,17, 17, 21;83:10,11,14,15,15,17,1 8,2 1,2 2,22 , 2 4; 84 :2,8,17;85:13; 86:4,23, 24;87:3,5,19,21, 25;88:14,

19, 20;89:2,9, 10,13,21,

22;90:2,7,5;91:6,7,16,18,19,21,5;92:7,;93:9,10,11,19,20,20,22;94:2,4,6, 5,16,1719,20,21,23,5;95:6,9,10,12,18,20,4;96:3,6,18,25;97:4,8,1,13,20,21;98:1,3,7,18,22;99:8,3 ;100:2,3,4,5,5,7,10,12,14;101:1,5,6,8,8,9,11,11,12,13;102:21,21 ,2;103:2,3,4,21,24;104:9,12,18,23,24;105:5,18,22,24,106:3,7,10,13,15,16,17,18 ,0;107:2 ,2,4,7 ,9,11,15,23,24,24 10813,14,20,4;109:2,4,5,6,13,15,15,16,18,19,20;110:3,4,10,10,11,11,13,20,21,22,22,24,25;111:5,7,9,11 ,18,21 ,21;112:5,13,18,18,19,22,22, 3;113:8,8,14,15,16;114:3,6,1,20;115:11 ,23;16:3,7,14,17,24, 4;117:2,4,9,2,13,13,16,18,20,25;118:5,13,18,19, 3,2119:11,4,21;120:2,4,5,15,18,20; 21:1,2 ,2,6,6 ,9,10,15,16,18,19,24,24,25;122:1 ,2,2,5 ,6,9,17,22;123:6,7,1;124:3,4,16,16,17,22,22,23,25;125:9;26:1,2,8,8,12,22;127:2,7,8,17,128:3,6,6;129:1,2,9;131:1,1,12 ;132:3,13,

13,15, 7,18;133:16 ,21,22,23;134:1,2,5,0,11,16,19,20,21,22,23,135:11,12,6,19,22;136:4,9,15, 8,21;37:13,4,6,7,8,9,14,21,22;138:11,12,24, 5;139 :6,8,10,15,18,22, 2140:5,7,7,0,22;141:4,7,9,12,5;142:1,11,12,14,21;143:3,,8,25;144:1,2,3,5,14, 6;145:14,15,19,20,20,22,25;146:2,9,19, 1;14710,12;148:10,11,3,16,16,18;149:8,10,13,17,18;150:2,2,4,4, 2,2151:2,6,13,5,16,21,23;152:1,18,21,22,23,25;153:3,3,13,17;154:8,13,3,16;155:6,11,13,14,18,20,20,21,22,24,5;156:2,5,7,8,9,10 ,13 ,14 ,14 ,16 ,16 ,19 ,21;157:3,4,7,7,15,17,17, 9,21;158:1,5,17,19,20,20,21,21,24;159:3,4,5,17, 9,21,225;160:8,0,20;161:1o,12,15,17,18,20;162:2,3,4,10,12,12,17, 2

163:1,2,4,7,7,11,13,21

Mille r Re po rt in g Co m pa n y, In c . Min-U-Scripti (15) inde~endent-is



Hea r in g Vo lum e Num be r 2 Food & Dru g Adm in is t r a t io nMa y 2 9 , 1 99 8 Ga st ro in t e st in a l Dr ugs Ad vis or y Co mm it t e e

23;164:2,,4;165:4 ,6,10,11,14,18,22, 4;4zzK,2,7,23;167:9,7;

2,7,7,2,14,14,17,Au,169:4,6,7, 2,16,4;170:5,7,16,17,19, 1;171:6,8,10, 1,24;72:1,6,7,8,10,16,18,19, 0;173:2,5,7,7,15,20, 4;174:2,4,6,9, 7;175:5,5 ,5,11,15,20,23,24, 4;176:20,5;177 :2,6;178:13,18,20, 4;179:3,5isn’t 4 2:1 5 ;7 7:4 ; 8 0:11;83 :9, 13 ; 9 4:1; 1 00:8 ;113 :2 0; 1 22 :1 6; 1 52 :2 2;1 54 :1 5; 1 69 :1 ; 1 70 :1 6;173 :6 ; 178 :13

is ola tion 97:9; 135:8

issue 4:8; 25:23; 27:20;33:1O;40:1,3; 50:8, 22;65:23; 68:14; 73:19;

78:10,11 ;84:11;85:13,23; 86:1 1;87:15, 18; 90:3,15, 18;92:1, 3;93:17, 25;94:4,4 ;95:13;99:8; 101:1,4,6; 105:2, 18; 109:25;111:13; 112:17; 113:17;117:4; 118:6; 120:18;121:24; 123:7; 129:10;134:22; 137:17; 138:11,--—-4; 141:2,8; 143:24,

44:10; 150:12, 22;1>3:13; 156:16, 17;157:18; 166:22; 172:24issues 11:8;8:13;9:3,5;42 :10;6:9;5:4,4;78:1292:19;3:16;100:23;14:17;16:6,4;117 :9,0,19,22;149:17;152:5;60:5;67:7;174:16;75:4 ;78:15h 4:3, 3;5:22,2;8:13;9:19;0:3;1:1;2:20;13:5;0:2521:20,24;22:13,5;23:9,2;24:4;26:20;7:5,4;28:9,10 ,18;29:5,8;31:3;2 :2,;34:5,13,5;35:1,4,4;36:18;7:15,0;39:14,19;40:11,8;41:7,2,23;42:6;3:3 ,5,16,7,24;44:2,4,10,11,11,13,15,16,17,23,24,5;45:6,11,20;46:2 ,3;47:22 ;50:2 ,2,12,2,23;51:5,8,10,15 ,2152:12,13,16,18,23;3:21,3;54:1,5,7,18,20,24, 5;55:1,2,4,6,19;56:10,12,3;57:2158 :3,0,11,11;i5~13,16;60:15 ,17,20,

‘1:22,4;62:4,,10,...14.14,14;63:4 ,6, ,12,15;64:24,5,25;65 :4,5,5,9,14,20,21,23, 4;66:4,15 ,8,23,4;67:11,18,21,5;68:7,3;69:2,4,19,23 ,5;70:7,8 ;

~n~t - l eaves (16)

71:1,4,5,9,13,18, 19;72:1,1,2; 73:8,9,12,16,22; 74:2,6, 19; 75:3,13,18, 22; 76:3,3,4,6,13, 22;77:1,2 ;78:1,6,7,19;79:7,12,15,16, 23; 80:4,6,9,13,17,17,17, 18;81:14,20, 21;82:1, 13,17,18,21,22 ;83:15,21,21,22, 22; 84:5; 85:2,3,11,1 3,17, 19 ;88:10 , 1 3,15,20, 20; 89 :4,13, 20; 90:11,13,20 ,20,2 2, 25; 91 :12,14, 19;92:3 , 5 ,7 ,11,24 ,25 ;93:17 , 19, 19,23 ;94 :1,2,4,16, 17,19,23, 25;95:7, 20; 96:1,14, 25;9 7:13 ; 98:7 ,16, 21; 99:2 3;10 0:10; 101 :1,5, 22;102:1,2, 11,21,21; 103:1,

3 ,4 , 24; 104 :18,21 ,23,25; 105:5,13,14,21, 22;106:16; 107:7; 108:1, 12,1 3,1 4, 1 5; 1 09 :5 ,6 ;

110:11,24; 111:7, 11,18 ,21; 112:5,11,11, 18;113 :12, 18; 114 :6 ,6 ,23,25; 115:4,6,12,17,18,19; 116:17; 117:16, 18;118 :13,14 , 14,21 ,22,25 ;119 :1 ,11,11, 1 4,1 6,1 7,17,25 ;120 :18; 121 :1 ,2 ,5 ,

~ , 1 6; 1 22:17 , 18 ; 12 3:22 ,23; 124:8,10,10,15,16,2 2; 1 25 :3 ,1 5, 1 9; 1 26 :1 ,2 ,3,12, 25; 127:2,7,12, 17;1 28:3 ,6 ;1 29:1 ,11; 13 0:1,5 , 1 4; 1 31 :2 5; 1 32 :3 ;13 3:16 ,17,23 , 2 5; 134 :2,4, 13; 135:12,13,14,16,16, 17, 24; 136:9, 18, 21;1 37:18 , 19,2 2, 2 2; 138 :3,20, 25; 139:10,13,15, 17,21; 1 40:4 ,6, 22; 14 1:12,23;142:1,16,21,21;1 43:11 ; 14 5:19, 20 ; 1 46:2 ,21,2 3; 1 47:11 , 16 ; 14 8:10,11,13, 16,18,25; 149:1,2,17, 18; 150:2,21; 151:2,16,18 , 22; 152 :12,22 ;1 53 :3 ; 1 54 :3 , 2 5; 1 55 :3 ,4 ,6,8,13,18,20,21, 24;156:5,9,16,17, 19; 157:5,9 ,2 1; 1 58 :1 5, 1 9,2 1,2 5;159:1,2,2,3,4,9,14, 18;

1 60 :2 0; 1 61 :2 1; 1 62 :3 ,1 2,12, 14; 163 :21,2 3; 16 4:4;165:2,4,11,11,18,22,25; 166:2,2,21, 24; 167:3,4 ,4 , 5 ,9 ; 168 :14,15 ,16,19; 16 9:4,7, 14; 170 :11,13, 17 ,25; 171 :11; 1 72:5 ,19 ,20, 20; 173 :2, 17 ,22,22, 24; 174:6; 175:11, 24;1 76 :2 , 1 0, 11; 1 77 :4 ,7 ,9 ,1 5, 16 ,17,1 8, 23; 17 8:16 ,1 8,2 0,2 1,2 2; 1 79 :1 ,1 ,3 ,10,19It’s 6:10; 62:15; 72:4, 5;1 03 :11 ;111 :2 2; 1 29 :2 3;169:8,9

items 37:9, 19; 38:5itS 7:2; 13:13; 21:20;66:2o; 81:6; 85:19; 162:4;173:21; 174:19,19, 20;175:10, 11; 177:6

itself 63:3; 95:24; 131:3

JJanet 68:1 1;86:23; 87:8Jerry 75:5Jim34:7;41:4,6, 10,15Joan 4:5; 179:23job 57:8; 149:13John 10:15join 9:12joining 10:15joint 8:11; 9:6; 14:9;92:1310intS 123:18Journal 6:24; 106:6

Joyce 125:10JRA84:14iudge 98:17Iudged 98:7iudgment 99:6; 100:3;134:25iudgments 99:9; 16o:6iumped 158:8iUSt 6:19;:13,5;10:24;22:17;3:21 ;4:14 ;25:21;7:8;9:1 ,;30:6;}3:14;34:5; 7:2;0:21;f3:21;44:l ,14;45:23;47:21;9:13;0:16,2;

53:21;4:3;7:12;8:11;63:5,0;68:9;9:23;2:4;73:9;5:6;6:1;8:7;80:23;1:9;3:5;3:3;94:1;5:20 ;6:25;97:11,13;98:3,5,3;99:12;100:15,2;101:12;102:19;07:19;11:2,2;112:16;17:17;18:21,21,22 ;119:13,6;121:8 ,20,25;122:4;23:22;124:14;26:6;27:10;129:1,9;30:5;31:11;134:7;37:25;38:14,20,25;142:25;44:9;45:4;146:3,11,16, 1;147:1,8,23;148 :4,7,5;150 :25;151:14;53:3;54:1;157:13;58:21;63:7,19,24;169:10;71:4,1;177:4,7;178:7@stHy68:21

K

Karen 6:8,14, 16; 165:15keep 35:6; 83:2;26:21;143:22keeping 85:23Kerwin 106:5

Min-U-Script@

Kevan 98:3key 40:9kg 126:17,18kick-in 80:2kid 144:3kidding 146:3kidney 145:16

kids 84:14; 101:17;124:12; 125:25; 126:5,13,19; 144:17; 175:22; 176:3kind 42:11; 52:4; 82:4, 7;83:9; 84:15; 88:9; 95:25;96:3; 151:5, 15; 153:4;162:23; 164:11kinds 34:15; 38:3; 52:6;87:21 ;99:5; 117:9; 130:1;163:25Kirschner 9:21; 41:25;42:1; 64:23; 69:9, 10, 11;84:12,13 ;85:16;96:11,12, 22; 97:3; 101:15, 16;110:19; 111:11;121:7,8,20; 122:6, 11;124:11,21;127:2,15,0;128:12,22,24;132:25;34:5;36:5,23;139:3,4;140:6,14 ,25;142:12,3;144:16;146 :4;49:6;53:11;154:10;56:2;59:10;171 :3,4,9;175:22,3;176:4;79:17Kirschner’s 132:20knew 86:6knock 75:20know 10:5;1:3,,4;23:8 ,1;27:3;3:13;9:7;40:12;4:18;9:2;2:9,13,16,25,5;53:15,15,21;55:5;7:1860:23;74:19,1;75:23;9:4,5,6,6;84:22,23,3;86:5;91:20;7:7;8:2;9:11;100:3;01:3;06:25,5;108:16;14:3,;121:20;124:24 ,25125:3,7 ;126:1;27:5,7;130:11;131:23;36:8;37:5;142:9;44:11;46:8;148:5,10,13, 1;149:1,14,17,8;152:3,5;153:20,24 ,5;154:10;155:23;56:10 ,24,5;157:22 ;58:22;59:1,8,15;161 :19,3;167:2 ;172:20;74:22;77:18knowing 71:20; 95:6;151:10; 158:15knowledge 22:10;46:18;65:22; 102:20known 60:13, 21; 130:13;146:9knows 43:16; 100:13;116:15; 117:4; 156:2Kornbluth 46:6,7,7;47:20; 48:2,4,8,12, 15;

L

142:22

label 17:25; 22:21;113:18

la be le d 6 2:21 ;l13:1 6;161 :22; 162 :8

labeling 130:15; 160:14,22laboratory 14:12, 14;15:4, 8; 16:6, 15; 17:16;19:5lack 14:12; 17:12;21:1lacked 11:21ladies 131:12Laine 10:14; 30:22;44:25; 57:12; 58:11;61:17, 19;62:1; 64:24;~6:18; 71:4, 10, 13;72:16,21;73:23landmark 73:16; 74:13large 14:9; 92:2; 93:3;118:21; 135:24; 156:13largely 7:3larger 94:7; 166:8‘ast 37:6; 46:23; 49:7;~9:22;74:7; 84:ll;88:l;>6:11; 111:24; 119:22;130:14;136:12; 177:13astly 132:4a st s71:13; 72:7; 81:7

a te 25:3; 130:14

a ter 30:23; 39:19; 43:24;78:4; 125:13,18, 23;

147:20la t te r 86:2 4

laudable 52:12; 103:6Laughter 26:11; 144:12laundry 30:17, 20; 102:5hW 130:14; 131:22;132:10lead 22:4; 83:9leader 9:19leaders 6:14leading 9:5; 120:8leads 20:25leap 65:22learn 17:18; 60:10; 82:6learned 112:13; 130:21learning 14:9least 11:11; 1 7:1 7; 2 1:5 ;37:23 ;39:11; 46:2, 11;74:20; 78:25; 84:3,16, 19;93 :2; 10 5:1; 11 2:2; 11 4:6;119 :1 8; 1 22 :2 3; 1 25 :4 ;1 30 :2 5; 1 44 :1 ; 1 52 :2 1;15 6:5; 1 61:7 ,8; 163 :1;171:20, 20; 172:8, 10;176:11

lea ve 10:21; 13:5; 68:2;7 1:9 ; 1 00 :2 5; 1 38 :1 ;146 :16; 172 :24

144:22,23 I leaves 144:9

Mille r Re po rt in Q Co m o an v . In c .



F ood & Dru g Ad m in is t r a t ion Hea r in g Vo lu m e Nu m be rGa st r oin t e st in a l Dr u gs Ad vis or y Comm it t e e Ma y 29,19

lecture 11:5Ied 9:16; 15:20; 104:3

_—- ieft8:25; 14:14; 16:2;118:3

leftover 90:19Iength71:21; 72:14 ;74:2;166:24leprosy 75:14

lesions 16:12,12, 13;27:1,4 ;43:5, 10;44:9less 66:4; 73:8; 77:3;86:24; 87:15; 96:13;101:25; 102:3, 21,22,23;103:5, 21; 105:25; 108:5,5,9,10, 12; 109:5lesser 112:10let 22:4,7, 17;71:1; 80:3;89:25 ;112:11; 121:5;132:19; 136:7; 137:16;141:12; 143:10, 11;145:7;169:10let’s5:2;1:10,5;

79:22;16:9;19:13;158:20,20,4;168:17letter41:1

leukemia 31:4leukocyte 15:6,6leukocytes 15:5Leuven 9:14level 12:25; 14:15; 16:18;.—— 18:15, 19; 19:10;26:19;27:14; 31:19; 33:23;41:20 ;64:24;65:1; 67:21,22, 23; 83:22; 86:22; 95:4;108:20; 119:8; 136:24;174:20levels 87:23liability 160:5life 10:11; 20:21; 21:4 ,10,1 2;2 3:2 4; 2 8:1 4 ;3 9:1 9;5 0:1 ; 5 4:1 7, 2 0; 5 7:1 0;65:1 3, 20 ; 6 6:1 9; 67 :19;7 9:8 ; 8 2:2 5; 1 01 :1 3;125 :16; 13 0:2; 160 :8, 8;165:14

life-t hr ea ten in g 83:8;163 :16; 165 :16

lifetime 79:2, 3; 163:6light 107:8like 4:4;6:8; 8:12; 23:2;29:22; 33:16; 35:3, 23;37:16; 39:14; 40:14;42:17 ;47:4; 49:3,14;50:12, 16; 51:19, 23; 52:4,14; 53:6,10,11,12, 17,20,25;54:1066:16;67:17 70:22;1:8,17;72:5;4:18;7:8;2:22;85:10,2586:1;8:12 ;

—.= 89:16;0:23;5:23;97:1O;9:20;03:3;111:12112:6;16:1;120:13,14;21:8;22:23,24;123:21;24:4 ,1;125:6,;126:8;28:20 ;129:9;30:10;34:15;135:7;36:5;37:1; .

141:5, 23; 143:23; 148:15;149:10; 150:1, 6; 152:3,20; 160:6; 163:2, 19;164:8, 10; 172:23; 174:11,13; 177:9,9; 178:21likelihood 17:17; 93:11likely 95:1; 116:20; 125:1;127:21; 132:3, 14; 145:14,15; 172:9Likewise 53:7limit 7:19; 11:1; 147:13limited 44:21; 114:17;124:25line 33:20; 54:19; 82:9;132:12 ;41:8;47:3linear 15:12; 88:13; 100:9lines 41:24; 141:20;153:1;167:11linked 162:3list 13:21; 15:7; 30:17, 20;37:14; 102:5; 132:8lists 132:12,13literature 24:15; 96:19;101:19; 131:16little 5:21; 23:13; 33:6;35:22; 37:4; 54:12; 64:12;56:4, 11; 7 1:5 ; 7 6:4 ; 8 1:9 ;3 2:1 7; 8 8:1 7; 9 2:7 ;111 :1 5; 1 21 :8 ; 1 34 :1 6;1 35 :11; 1 38 :3 ; 1 57 :1 ;1 74 :1 2, 1 3; 1 75 :1 5

liVe41:18

lived 28:7kr 145:15; 152:23living 58:7local 142:9

location 12:12; 13:8logarithmic 100:11logic 50:20, 22; 164:18;165:6logical 40:8; 111:13;165:4long 25:18; 32:6; 34:13;35:5, 5,9; 36:2; 42:12, 22;43:11;72:7,8, 17;74:1;76:16;77:13; 79:9; 80:18;109:5,8,8; 110:12; 112:8,15;118:25; 119:19;135:13;146:13; 147:1long-term 41:14 ;42:15;

56:14;84:23; 112:5;161:2, 16, 17, 20; 162:19,22; 167:23, 25; 168:3,4longer 29:12, 13; 38:2, 3;i3:12; 58:7; 73:25; 78:13;31:14;86:25; 105:15;161:3; 168:11longitudinal 78:8ook 8:6; 19:12; 21:20;Z3:22;25:8; 31:7,8; 48:19;50:22;72:10; 73:16; 74:4,14;84:5; 88:10; 89:4;?2:18;93:21; 97:9; 98:5,?3;108:15, 23; 122:2;137:24; 138:3; 147:20;149:16, 23; 150:1; 151:4,

MWe r Re por t in g Co m pa n y, In c .

8;153:25;60:7;64:4;168:6,5, 0; 173:13 ,14

looked 43:24; 48:16;70:3; 81:25; 98:25;105:12; 126:20; 168:22,23;177:21,22

looking 22:11; 38:2;66:13; 75:6; 80:16; 88:9;96:20; 97:2, 17; 100:23;105:15; 109:7; 116:3;118:20; 119:10, 19;126:21; 128:13; 132:18;145:5; 150:9; 152:16, 16;156:25; 157:16; 158:23;165:8; 166:12; 174:15lookout 147:21looks 15:24; 169 :17

[OOSe 113 :8

Loren 75:12loses 85:19

[OSing 15:2 ,3

[0 SS 1 3:2 3; 5 1:6 ,7

lot 6:14; 33:2; 34:3, 10;3 5:1 9; 3 8:2 2; 3 9:3 ; 5 0:2 5;5 1:1 3 ;5 2:1 3; 5 4:11;5 7:1 0; 6 0:1 0; 8 6:1 3;6 7:1 3; 8 8:1 6; 9 3:1 6;1 04 :1 , 1 2; 112 :1 3; 117 :2 1;1 26 :1 0; 1 28 :1 ; 1 29 :2 2;1 30 :2 1; 1 35 :2 4; 1 42 :1 6;1 45 :1 4; 1 54 :1 3; 1 55 :2 ;160:16; 165:8,12,19, 20;174 :21; 178 :11

lot s 44:1 8; 9 7:17 ; 1 21:1 2;135:18

10Ve 117:22

IOW44:8 ; 9 3:7 ; 1 06 :3 ;152 :13; 158 :2

low-incidence 157:25

lower 88:15, 21; 94:8;122:9; 136:18; 144:25;147:9lowered 176:10lowering 137:8lucky 114:5lunch 10:18; 100 :18

klf3US 38:12;04:1,4,18

M

made 4:9; 45:23; 66:2, 8;75:12 ;87:13; 90:14;1 04 :2 1; 116 :7 ; 1 32 :4 ;159:23

magnitude 99:4mainly 73:7maintain 41:13 ;43:12;54:14;75:8, 18,21 ;77:12;79:18maintained 24:12, 12,22;41:10; 119:8maintaining 28:1; 75:1 1;108:20, 22; 117:2; 121:17?IiZtitItWItirrCt? 19:22;

20:15, 17, 18; 23:1,4;

Min-U-Script@

24:2,3,5, 16; 25:5, 14, 17,2 0; 2 6:3 ; 2 7:2 4; 3 1:8 ,9 ,11; 39:6; 78:24; 79:13, 23;

11 5:11 ; 118 :12; 168 :5

major 9:25;0:8;6:22;56:1;6:25;3:9;39:12mSjOrity5:12;7:24;123:12;48:14

make 8:14; 10:3; 26:21;30:4; 41:23; 42:7; 45:6, 24;48:23; 50: 16; 56:18; 57:8;61:22; 65:25; 71:15,21;87:13; 88:17; 89:16, 25;93:14; 96:1; 99:9; 100:3;112:16; 123:2; 131:7;136:1; 143:19,21; 151:5,15, 20; 152:23; 159:7;160:14; 164:8; 177:7,8makes 30:24; 50:13;71:10; 159:14making 33:19; 35:7;40:22; 53:20; 90:9, 10;96:6; 103:5; 116:22;

155:25; 159:3; 165:5;166:11malabsorption 15:2maldistribution 100:5man 82:2manage 33:21manageable 160:19managed 47:13Management 41:5,9mandated 132:7mandates 130:14manifestations 14:4;29:16; 170:23manner 19:9manufacturers 131:4,8,21manufacturing 174:21many 7:7, 8;9:4; 16:12;17:9; 18:6,8; 21:11; 28:20;33:22; 34:12; 42:9; 55:20;74:21; 86:22; 89:19;90:10,22; 94:1; 95:5;99:21; 101:4, 17; 109:10;111:3; 114:7; 123:17;125:19; 128:15; 136:14;138:6, 17; 139:5; 140:18;145:16; 147:11; 148:6;153:14; 156:23; 160:12,

12; 162:22; 163:15; 166:7,7;167:7, 25; 169:11;175:12,19,22, 24; 176:3,6;177:1,3margin 19:9mark 22:14; 32:11marked 124:15marker 21:18market 133:23; 141:14,24; 148:16; 175:14marketing 141:16; 163:9marrow 29:23;46:8;167:2mass 14:1

master26:8

matching 29:4

material 130 : 11matrix 33:3,7matter 4 :18; 64:25;

94:23, 25; 95:7, 24; 16

MATTHEWS 47:21; 46, 14;80:23;81:3, 16;82:16 ;83:14

maximum 69:18; 161:6may4:23; 5:10, 12; 12:18,22,25; 13:5,7,18, 214:1,1, 1, 1,7, 10, 17, 119,19, 20; 15:1,4, 14;16:4; 22:18 ;23:7,7; 24:126:18; 27:9; 28:9; 29:15,21, 24; 30:9; 32:19; 35:146:3; 52:14; 56:11, 12;58:14; 59:25; 60:1; 64:2o20; 71:18; 73:2, 5;75:9;78:4,8 ;80:7;81:18; 82:284:17; 89:11 ;93:13;94:22,23, 25; 95:1, 3;97:23; 98:19, 21; 108:1213; 109:16; 114:24;115:17 ; 116:16,21;118:10; 125:17, 19; 126132:9; 134:4; 139:23;140:8; 142:5, 7,8; 146:915, 23; 147:3; 154:19, 2155:2,3,4; 158:10, 13;159:18; 162:1,5, 14;165:11; 167:3,4; 168:2,4172:16; 173:21,22, 22;174:22, 23; 176:20; 178maybe 43:18; 49:4;53:23 ;54:1;72:4,4; 81:719; 103:18; 105:13;124:14, 14; 125:23;126:12; 138:2; 147:20;148:15,19me 8:10; 11:3; 22:4,8, 131:3; 32:2; 44:25 ;45:5;52:11; 53:3; 59:16; 62:5;66:18; 71:1; 72:4; 75:3;78:18; 79:12; 89:25;91:18, 23; 104:3; 106:10116:15; 132:19; 137:16;143:20; 145:7; 151:25;155:8; 169:10; 170:25;176:6mean 31:11 ;40:1;44:11,13;58:12; 59:11, 13, 1760:7; 63:3, 4; 64:25; 67:56, 16;68:14; 69:12 ;71:174:1; 76:13,13 ;80:12;83:2; 85:17; 86:18; 87:4,18;88:10, 24; 89:8,15,2023;90:19; 91:2, 3,3,4,4,5,9,10, 22; 92:2; 94:9;95:21; 96:7; 97:2, 24;98:13; 105:5; 107:9;110:21; 121:10; 126:4, 1127:20; 135:23; 136:23;138:24; 140:7; 142:15;146:8; 153:12, 16; 154:112; 158:12; 159:11; 163:168:20; 170:13meaning 15:18; 80:16;

67:4; 164:15

(17) lecture - meaning



Hea r in g Voh un e Nu m be r 2Ma y 2 9 , 19$)8

Food & Dru g Adm in is t ra t ionGa st r oin t e st in a l Dr ugs Ad vis or y Comm it t e e

meaningful 5s:10;76:19,2 5; 7 7:4 ; 7 8:2 0; 9 4:1 5;

&’”8, 9, 18; 99:7; 108:11,11:1 6; 112 :7 ; 1 32 :1

l,~eaningless 80:14;91:1;9:24means 13:21;5:7;20:17;1:10;9:13;31:24;2:11;3:2;7:10;81:1;5:20,0,21;106:15;07:4meant 7 6:2 5; 7 7:1 ; 9 2:5 ;157 :19; 179 :10

m ea su ra bilit y 68:12

m ea sur able 28:13, 14;29 :19; 6 8:7, 9; 73:1 ; 92:8

measure 17:25; 23:16;30:7; 31:5; 33:14; 36:23;42:12 ;43:24; 44:17;46:13; 49:4; 52:16, 25;53:16; 55:5; 64:11 ;65:20,23; 67:9; 69:25; 72:9; 73:8,21;74:14; 80:13 ;87:19;92:17,22; 107:24; 108:14;118:7; 143:17; 170:15measured 35:2, 3;49:6;54:5; 66:5; 69:20; 73:10;93:1; 103:15; 104:22;108:4measurement 54:24;55:7;73:13; 80:5; 88:25;

_~16, 17;97:11;00:6;‘“12-surernents 35:20;

46:19; 79:9; 92:18; 93:5measures 23:20; 24:1;35:23;36:10,11,11,11,20, 21; 38:3; 40:4; 58:4;

67:5; 86:15; 99:20; 108:6measuring 16:17; 36:21;54:19; 59:5; 73:20;108:17; 118:6, 10; 159:7,9mechanics 138:25mechanism 154:20;158:23mechanisms 153:1Medera 56:22median 86:19mediators 16:18medical 24:4; 50:8; 81:6medication 24:9medications 148:1Medicine 9:13; 106:6;131:13meeting 4:4,9, 10, 11,16;5:14,15,17,21,23;6:8;7:17; 8:17; 20:23;9SS2; 138:20; 140:16, 18;

member 9:24; 10:15;=-4; 56:25

nbers 5:25; 6:7, 18;22:18; 129:16mention 6:21; 8:10mentioned 11:17; 46:17;57:7; 65:12; 80:3; 107:25;118:15:139:7

mentioning 53:25;178:15mentions 175:4met 9:11; 10:14, 15; 20:2;90:8; 162:14metabolic 29:24metabolized 159:18metaphors 26:9; 29:4method 40:8methodologic 117:9methodological 116:6methodology 144:24methods 42:13methotrexate 168:7, 13;171:9; 172:3metric 59:13mg 101:24, 25; 102:3,3,21,24; 103:6,10, 21;105:8, 25; 106:21; 111:3,6; 115:16; 121:12,17, 17,22; 123:7; 126:16,17

mgkg 42:23; 115:18;124:10; 126:14, 21;153:17; 171:20microscopic 16:1middle 148:7midget 131:13midway 179:6might 34:5; 35:24 ;46:24;47:1,2,16; 78:1; 90:11;92:13,13, 14; 100:8;107:22; 108:14; 114:22;116:20; 118:2; 133:24;143:14; 146:21; 147:2;148:25; 151:22; 154:18,22, 23; 155:5; 157:5;160:19; 162:13; 166:7;171:10mimic 15:14; 117:7mind 35:6; 83:2; 85:23;109:22; 143:23mindedness 22:14mine 41:llmineralization 110:23minima146:15; 71:2,25;72:13 ;89:15,24;92:10;163:8minimize 148:9minimum 69:17; 70:20;71:6; 74:19,20; 78:16;85:25; 102:12, 18; 161:5;163:13minus 149:18minute 6:19; 11:5minutes 34:6; 75:12miserable 122:22misperception 84:16missed 69:12; 113:2missing 107:2mixing 26:9; 27:9; 29:4;109:12mixmaster 26:10model 19:5,7, 12; 20:16;

144:24

m e an in gfu l - n ew (18)

models 34:21moderately 148:18modern 97:8; 100:12Modernization 130:13modest 176:14modification 44:2;99:25; 154:20modifications 129:17,20,22modified 19:23; 27:6;30:2; 63:23modifier 78:2; 96:17;157:2modifiers 154:25; 167:6modify 21:25; 68:22;129:16Modigliani 115:18molecular 152:25; 153:1Molndal 51:18moment 13:6, 10;42:19;43:16; 57:2; 60:1; 143:1;149:12moments 56:23money 177:17monitoring 9:15; 43:9monotherapy 178:2,5month 56:7, 9;75:15, 23;83:8,10, 13;85:2; 86:6;109:9; 111:19; 115:20;122:16; 123:22months 39:ll; 43:2;56:10 ;68:21;73:6, 15, 16;74:6,8,11,21, 22;75:1, 3,23; 76:4, 12;77:3, 4;78:13,16,19, 25; 79:4,6,10,11,14, 16;80:7, 14,15,20, 21;81:9;83:24;84:3; 102:12,13, 13;105:1,9,13,14,15, 16;1 09 :9 ,1 0, 11; 111 :1 4,1 9,20; 116:1,2; 123:13, 17;13 1:6,7 ; 1 37:1 7; 14 4:6;1 61 :3 ,7 , 1 4; 1 62 :1 7;163:1, 5 ; 164:19 ,21,22 ,23

m or e 5:23; 18:8; 19:12;21:22; 33:17; 35:18, 19;

3 7:1 7; 3 8:6 ; 3 9:2 3; 4 0:1 0,17; 4 1:24 ; 47 :3; 4 8:2; 52:9;5 5:11; 5 7:1 7; 5 9:2 4;6 0:13 ; 64:15; 6 7:16 ; 76 :4;

84:25; 85:4,9,10,13,13,1 4, 25 ; 8 6:1; 88:2 5; 9 3:20 ;94 :2; 9 7:15 , 1 9; 1 02:2 2;111 :11 ;112 :2 ; 114 :1 0;115 :1 6; 116 :2 0; 118 :9 ;1 25 :1 , 2 2; ’1 30 :1 9; 1 34 :4 ;13 6:13 ; 14 2:22 , 23; 1 43:9 ;14 5:14 , 15 ,21, 25; 1 47:8 ;14 8:16 ; 1 49:8 ,8, 20 ;1 52 :5 , 8 ; 1 59 :2 5; 1 60 :1 9;1 63 :11, 1 3; 1 64 :1 5;1 65 :2 3; 1 66 :1 ; 1 69 :2 4;170:6

morning 49:9; 100:17;123:20; 170:11

mortality 36:10; 77:10

Min-U-Script@

Most 11:3; 22:6; 24:18;26:25; 35:21; 46:20;54:23; 55:16; 56:2; 62:7;76:20; 89:12; 104:25;112:19 ;120:4; 121:11;123:20; 125:20; 131:21;136:13, 15; 160:1; 164:20,20; 167:18; 172:9

mostly 114:16mouth 127:7move 10:22; 35:15; 37:3;49:13; 68:17; 94:14; 95:2;114:9; 174:11moved 34:23, 24; 35:21,22; 49:8; 174:13movement 35:18; 61:11;92:1movements 18:9; 40: 15;93:9,9, 12;94:20, 24;95:5,7; 99:21,22moving 9:8; 36:20; 38:1;61:9, 11;160:25

MP 143:8Mr7:3; 154 :2

MRI 44:22MS 4:7Mt 9:1;46:8much 5:23; 7:20; 9:3;11:9; 12:20 ;35:5; 41:3, 24;55:24; 60:13; 72:2; 76:13,14;78:13; 83:25 ;88:14,15; 94:6; 96:13; 105:18;112:6; 119:16; 125:1;126:15; 127:24; 131:20;134:5; 143:9; 145:19;149:20; 152:3, 24; 166:1mucosa 36:22; 50:24;51:1,3mucosal 23:12, 17, 18;25:23; 27:18; 28:11;30:9,10, 14; 31:22 ;32:14;33:1O, 11;42:21; 43:17;44:10; 45:22,23 ;49:21;59:17,18, 21; 60:3, 23;105:20multi-dose 137:1multifactorial 29:2multiple 65:7; 176:11multiplicity 118:2

multiply 99:23must 23:14; 74:6,7, 10;131:17mutually 36:3my 6:18; 8:8, 13, 25;10:17, 22; 22:14; 25:21;28:25; 46:17; 49:14; 50:4;55:15, 17; 57:6,12, 14;59:9; 61:20; 63:15; 81:16;83:14, 17;84:16; 105:16;112:10; 120:14 ;121:19;122:23; 123:18; 127:2;130:19; 142:1, 22; 143:4;144:3; 148:22; 152:7;158:1

myself 95: 17; 140:20

N

n 63:13naivete 55:15namely 23:17; 53:9;107:4narrow 88:21National 34:8; 139:7natural 77:19; 135:25nature 71:20; 76:14nausea 13:20; 28:23nay-sayer 142:25nearer 72:11necessarily 5:25; 16:1;17:5; 21:23; 23:8; 25:23;45:3, 15; 52:8; 54:15 ;64:4;72:22; 121:4; 127:4;148:19; 150:2necessary 101:14;126:25; 127:7; 128:3, 6;

136:17; 165:22; 179:20necessitating 19:25necessity 42:2; 74:17need 5:4 ; 8:1 9, 22; 11:2;12 :5; 16 :5, 17 , 21; 1 7:18 ;18 :11 , 1 3;20 :12; 2 1:11 ,1 5, 1 7; 2 6:3 , 1 2;3 2:1 8;42:11; 48 :19, 20; 5 5:9;5 7:4; 62:1 6; 6 6:9, 10; 67:1 ;70:24, 25; 75:3; 78:12, 21;80:23; 8 2:6, 9 ; 83 :9; 89 :14,19 ;90 :9; 11 0:15 ; 11 2:14 ;11 3:9 , 21 ; 115 :6; 12 7:9;12 8:10 ; 13 6:4, 1 4; 1 37:1 3;138:3, 22; 140:10, 11;

14 4:5 , 1 6; 1 45:2 ; 151 :20;1 53 :1 4, 2 2; 1 59 :1 2;1 61 :2 3; 1 68 :6 ; 1 73 :9 ;179:21

needed 48:9; 112:15;132:5n eeds 10:4; 20:18; 76:7;7 9:11 ;9 5:1 3; 1 42 :2 ;145:12

NEEMAN 47:19; 48:7, 10;61:5; 74:12; 84:7; 103:14,22; 171:21, 25; 172:6, 18negotiated 166:21neighborhood 175:2

neither 16:1; 54:21;69:21neonates 128:5net 77:17never 103:12; 153:12;179:10new 8:18; 24:7, 7; 25:6;26:5; 32:17; 46:8; 47:14,16,23, 25; 48:8, 12; 64:7,9;74:6,17; 84:22 ;85:11,22; 106:5; 107:17, 19, 21;114:15; 119:6; 127:7;131:22; 134:1; 135:8;141:11,14; 148:5; 154:13;166:3,8,10, 11; 172:9;

178:10,24

Mille r Re po rt in g Co m oa n v. In c .



Foo d & Dru g Ad m in is t r at ion Hea r in g Vo lu m e Nu m be rGa st r oin t e st in a l Dr u gs Ad vis or y Comm it t e e Ma y 2 9,

newly 25:15next53:2395:1;16:4;

____ 124:4;27:8;34:10;162:18 ;64:15;67:19;179:15

n ice 36:23; 97:13; 103:1

nicer 39:25night 88:1

NIH 34:9; 137:20n o 4:15; 11:4; 13:21; 15:7;

30:3; 43:11, 12;44:16, 16;4 6:1 5, 1 8;5 1:3 , 1 3;5 2:11,15; 5 3:8; 59 :6, 17 ; 60 :6;6 2:6 ; 64 :25; 66 :19; 68 :7;69:9; 70:6,8,10, 19;71:13 ;80:12,14;81:18;9 1:1 2; 1 03 :9 ; 1 05 :1 3;111:11 ;113:10,11,23;115:18; 120:6; 122:13, 13;1 26 :1 8; 1 30 :4 , 1 9; 1 31 :1 2;13 2:1 ; 13 9:1 6; 143 :5, 22 ;1 46 :1 0 ;1 50 :1 8; 1 51 :1 3,15; 156:7; 157:7,8, 18;

15 8:6 ; 15 9:1 4, 2 1; 16 5:1 ;1 68 :1 9; 1 69 :4 ; 1 70 :5 ;171:14; 176:8; 178:6, 18

Nobody 43:16; 159:19nodules 58:8; 59:1noise 59:4 ; 118 :22

non 18:7non-fistulizing 19:2

———. non-inflammatory18:10, 12nonbiologic 157:2nondisease-specific167:1nonetheless 28:10

nonlife-threatening161:4; 165:24nonspecific 14:14nor 129:18

normal 28:21;3:12;121:16normality 100:8

normally 7 1:2 1; 1 37 :9

normative 77:19

Nor t h 9 6:15

n ot 5:2,22, 25; 7:19, 23;1 0:18 ; 11:1 7; 1 2:1 6; 1 3:4,10, 16; 14:1, 1; 15:17, 19;1 6:1 ,3, 14 , 19 , 1 9,2 1;1 7:5 ,8, 2 5; 19 :6; 20 :5;21 :23 ;22:8,9,1 8; 24:12;26 :21,21, 25 ; 27:1 5; 28:2 ,6)9, 18;29:12,12, 12,13,21 ,24 ;3 1:6 ,20; 39:1 6;41:19; 42:10, 20;43:2, 12,18 ,21 ,25 ;44 :13 ,15,23 ,23 ;45 :11, 13 ,13 , 15)24;

_m— 46:1 , 1 2, 19;48:2 ; 50:20,.2 1;5 1:1,1 0,2 4; 52:8 ,16 ,17 , 25 ; 53 :14 , 18 ; 5 4:6;5 6:5 ,12, 2 4; 57:1 5; 58:1 4,24; 59 :9; 60 :1,7 ,8, 21,2 1,23, 25; 62:10, 20; 63:5, 18;64 :4,11, 1 3;65 :17; 6 6:3;67 :21 , 25 ; 6 8:7 , 7,9;

69:16,17, 20;71:16, 18;72:9, 22; 74:7; 75:1, 11;76:21; 77:8, 16; 78:7, 8;79:12,15,16,20,22, 24;80:3; 81:20, 21; 82:23, 25;83:1,4,5,10,20, 24;85 :13, 2 0; 87 :12; 89 :13;9 0:2 0; 9 1:9 , 2 1; 9 3:2 ,5 ,10; 94:16,17,22,23, 25;

95 :8,1 0, 2 1; 96 :8; 9 7:2 5;98 :19,2 1 ;99:1 2; 1 02:1 4;103:16, 18; 104:2, 23;1 05:11, 14; 10 6:7 ; 10 8:7,1 3, 16; 10 9:18 ; 110:11;111 :5 ,8 ,22 ;113 :16;114 :6 , 1 8,2 1; 115 :1 0,2 1;117 :14 , 18 ,20; 118 :2;120:11, 19; 122:8,13, 25;12 3:13 ; 12 4:8 ,10, 19 ,22 ,22; 125:24; 127:3,23, 24;12 8:25 ; 12 9:1 8, 25 ; 13 0:6 ;13 1:11 ; 1 32:2 1,2 2; 13 3:1 ,10 ; 1 34:7 ; 13 5:1 3, 17,2 2;13 6:2 ,3,1 8, 2 1; 1 37:7 ;138:4,4, 25; 139:6,23, 25;140:12, 20; 141:12, 16;142:7; 144:2,6; 145:8, 19;146:24; 147:5,6,10,12,16, 25; 148:3,7, 19;149:11,20; 150:2,8, 16,18; 153 :6; 15 4:4,5 , 1 2,1 7,2 5; 1 55 :4 , 6 ,7 ; 1 56 :1 0,1 5,19; 15 8:1 ,7,11 , 17 ,21 ;160:2; 162:3,5,8,12, 14,19 ; 1 64:6 ,9, 2 1; 16 5:1 ,3,7, 22; 166:17,21; 167:3,24, 24; 168:1,22, 24;1 70 :2 3; 1 71 :5 ; 1 73 :1 6;1 74 :4 ; 1 76 :6 , 2 1; 1 77 :2 0;

178:4,20n ot e45:12;69:21; 156:24

n ot ed 5:5; 45:15; 133:4

n ot es 161:25

nothing 55:19; 70:4;164:24

n ot ion 111:3

n ovel 44:7; 142:4

n ow 7:13; 8:8, 19; 10:24;11:1 4; 1 2:8 ; 1 4:4 ; 2 7:1 5;3 0:2 2; 37:20, 2 3; 43 :3;4 4:2 2; 63 :10; 80:24; 81:9 ,1 3;8 7:1 7; 1 02 :1 ; 1 08 :1 0;1 09 :2 3; 110 :8 ; 1 31 :2 2;

1 33 :7 ; 1 35 :1 7; 1 40 :1 2;1 41 :1 5; 1 42 :2 3; 1 46 :1 3;1 47:1 , 1 2; 1 50 :14; 160 :4;1 62 :1 5; 1 63 :1 7; 1 68 :1 2;171 :10; 174 :22

Nowhere 48:25

n uclea r 13:4

n um ber 12:21; 16:25;1 9:11 ;3 6:1 4; 4 6:1 2;4 7:2 5 ;50:15;6 3:1 4; 64 :1;9 2:2 ,2 ; 1 01 :1 8; 1 04 :1 5;1 26 :4 ; 1 28 :1 ; 1 32 :1 4;1 33 :1 5; 1 36 :8 ; 1 45 :1 3;1 47 :2 4; 1 50 :9 ; 1 61 :1 3;1 62 :1 ; 1 63 :5 ; 1 64 :2 ;

166:4; 169:5:171:6:

Mille r Re po rt in g Co m pa n y, In c .

173:3; 175:15, 17,25;176:14,23, 24; 177:12,23numbers 40:15; 55:10;67:6; 84:6; 93:5; 100:1;149:7;50:3;52:18;155:7,;162:5;63:8,5;164:15,8;174:14;77:8

00116:4o’clock 4:3; 10:20;100:19,20

object ive 13:22; 17:4, 21;29:21

oblit er at e 118:10

observation 93:5;157:13Observations 106:7;158:12Dbserve 158:25; 159:1,2

Dbs er ved 133:12;163:23 ;78:17

Dbs er vin g 15 7:10 ;164 :24; 165 :1

obst ru ct ion 23:24

~bt ain ed 4:23

obviou sly 20:18; 21:25;3 6:2 ; 8 9:2 1; 1 05 :5 ;1 33 :2 1; 1 59 :2 5; 1 63 :2 1;165:25

>ccu r 14:6; 39:18; 125:1;164:20,21,22,23

)ccu rr ed 42:6; 116:1

>ccu rr in g 165:10

>f 4:6,8,8,9, 10, 15,16,22,23,24, 25; 5:4,8, 11,

~7, 18,22.23.24:6:1.2.8.IO;12:13: 14; 15: 24;’7:3, ‘7, 12,17, 25;8:1,4,7, 77

[8, 24;9:1,4,7, 13,15, 17,~ 2, 2 2,23,25, 25; ~o:7, 8,

10 ,21 , 25; 11:2,3,14 ,15 ,~ 9,2 1, 2 4, 2 4; 1 2:1 ,5 ,1 0,[1, 15,16,17,22,25, 25;[3:2, 5,6,6,8,15,19, 23;14:3 ,5 ,14, 15,16 ,21,23 ,~5; 1 5:2,3,5,7, 10, 11, 15,

~5,21 ,24; 16:7,11 ,18,15;17:3,3,6,8, 2,12 ,15 ,[6,16,17,21;18:2,3,6,8,[0 ,14,15,19,25,5;~9:3,4,7, 0,11,13,21,12;20:1,7,5,17,21 ,23,14;21:1,2,4,10, 0,12 ,~2,18,19;22:3,6,7,9, 4,~5,20,22,25,5;23:1,,},4,0,13,15,17,19,19,!0,20,21,4,25;24:1,2,!,3,,5,7,14 ,16 ,16 ,18 ,!0;25:2,3,,6 ,8 ,9 ,2,,4,17,20,23,24, 4;!6:1,1,3,3,9, 4,14 ,15 ,.6,16,19,22,24, 5;!7:6,6,9, 1,11 ,13 ,14 ,8,23,23,24,24, 5;

!8:12,4;29:3,,7,13,

Min-U-Script@

1 3, 1 4,1 6, 2 2; 3 0:2 ,3 ,4 ,67,8,8,9,10,11,13,14,15,20 ,21 ;31 :3 ,7 ,8 ,9 ,9 ,11,11,13,16,17,18,22,24;32:3 , 13,18 ,19,19 ,2 2;3 3:1,2,5,6 , 10 ,11,1 315,16,16,19,22, 23;34:1,3,6,6,6,10,11,15,21, 25; 35:4,8,10, 14,17,

20; 36:3,12,14,14,18,19, 22; 37:2,3,7, 12,13,15, 18,25 ; 38:1,3,12 ,19,22, 24; 39:3,17, 19; 40:5,10,12 , 15 ,16 ,22,24 ,24 ,25;41:12,17 ; 42:1,2,3,4,4,5,9,9,11,13,22,23,2 4; 43:4, 23 ; 4 4:1, 1,3 ,3,4,7,12,14,18,20,20,20,22,23 , 24; 45:9 ,12,13 ,14,17,18,20,22,23,24,25 ; 46 :9 ; 47:1,5,6,9,13 ,2 5; 4 8:20 ,22 , 25 ; 4 9:1 ,2,4,5,8,13,16,18, 22; 50:1,

5 ,6 ,8 ,1 5,2 5 ;5 1:7 ,7 ,1 3,1 6, 1 9, 19 ,20,20; 52 :1,3,4,5,6,12,13,13,15,17,21, 22; 53:4,8,13, 19;54:3, 11, 17, 19, 19, 20;55:4,9, 10, 18, 22; 56:1, 1,5, 15, 18,23, 24, 25; 57:1,f, 5,8 , 19 , 22 ; 58 :2,5 ,12,13, 20; 59:8,9,10,13,22,25;60:2, 25;61:21, 23, 25;

5 2:9 ,9 , 11, 1 2, 1 2,2 1,2 4,24;63:1, 10,12,12, 13,13,16,16,19,19,20,20,2 1;6 4:1 ,1 3,1 8; 6 5:2 ,1 0,1 3,15 ,20 ,22, 2 4; 66 :1,3 ,7 ,9 ,1 0,1 9, 2 4; 6 7:2 ,5 ,8 ,

10,12,15,17,19,20,22,24;68:2, 3,4, 14, 15, 18,

19, 22;69:21;70:1, 12, 16;71:2,9,20,21,22, 25;72 :7 ,11, 14 ;73:1,4,4,6,?, 9,12,12,22, 24; 74:7,17,20,21,23,24, 24;75:7 ,8 ,8 , 9 ; 76:3 ,8 ,14,15,16,18,19, 24; 77:9,1 3,17 , 19;7 8:5 , 5 ,5,1 0,12, 15; 79:3,8,8,10,13,14,15, 16;80:4, 5, 11, 25;31:1,4,6, 14;82:4, 5,7,15 ,21 ,22 ;83 :5 ,6 ,6 ,7 ,9 ,), 1 6, 2 1,2 4; 8 4:3 ,9 ,1 4,1 5, 16,2 4 ;85 :5, 11,13 ,~5; 86:3,4,7,9, 15, 16, 18,

22, 23; 87:2,3,5,6,9,9,11,13,14,14,15,18,19,~l;88:4,6,9, 11, 16, 17,24; 8 9:7,7,8,8, 12, 17, 18,~ o, 21;90:5,8, 13, 25;

)1:3, 3,4,4,13,16, 16,18,?0,23;92:1,5, 11, 15,22,Z4;93:3, 5, 16, 17,21, 24;

)4 :4 , 5 ,8 ,1 8, 2 5;9 5:2 ,4 ,11,12,21,22,24,25,25;)6:1,3, 4,5,6,9, 12, 14,[5, 16, 21;97:4, 10, 12,[7 , 1 7,2 3, 2 4; 9 8:1 ,3 ,1 0,!3,22; 99:1,1,2,2,2,3,3,

[,5, 5,8,13,13,14, 14,

15,23,25, 25; 100:7;101:10,11,13,17,102:1,2,5,6,7,11,14,23;103:1,1,5,5,16,104:1,4,12,6,17;105:8,12;106:6,6,6;107:3,4,15,20,24,24,5;108:15,18,20,0;109:5,5,25;110:2,3,6,7,12,12,14,16,17;111:1,7,13,4,18,18, 9;112:4,5,8,13,21,25;113:4,6,6,16;114:4,7,7,1,16,19,21,25;115:11 ,16,16 ,19,24;116:1,7,5,24;17:2,4,6,9,10,10,2,19,21,21,24;118:2,6,1,16,20,23, 4;119:3,6 ,8,10,15;120:5,7,8;121:3,5,11,12,19,23,24;22:15,21,24,25123:1,2,4,6,11,12,25124:3,21,23,25;125:3,4,1,12,12,19,20,1;126:3,4,6,6,8,10,15;127:2,1,23,25;128:1,4 ,5;129:3,0,17,22;130:1,2 ,8,15,22,131:5,8,21,24 132:13,13,14;133:15,25;134:1,11,1,12,17, 9,20;135:3,4,8,9, 5,18,18,24,24,5;136:14,15,23,4;137:14,9;138:4,4,13,17,24,139:5,7,8;40:16,8;141:3,8,9, 2;142:3,7,14,16;143:6,9,24,144:6,7,0,24;145:2,4,5,13,16,17,8;146:6,6,

11,14;147:5,10,11,17,18,19,5;148:1,4,5,7,8,9,11 ,14 ;149:2,7,1,25;150:3,3,5,5,9,11,151:5,8,9,15,22,25;152:16,21,25 153:1,14,20,5;154:7,13,20,21;155:1,14,16, 0;156:1,6,8,5;157:9,0;158:8,9,15,16, 5;159:14 ,2;160:2,4 ,8,8,15,16,20; 61:2,5,9,13,15,23;162:1,23;63:5,7,15,23,23,5;164:4,5,9,11,11, 8;165:5,6,8,17,17,19,4;166:4,2;167:1,4,7,8,12,25;168:2,3,3,22,4;169:1,5,12,20,21,22 170:11,17,20;171:1,6,17;172:22 ,25;73:1,3 ,4,8,10,10,12,6;174:3,16,20,21;175:1,2,5;176:9,13;177:4,6,10, 7,23178:6,8,11,13, 4;1713 ,19t#f22:4,1;25:19;9:16 ;52:10;3:17;9:7;100:25;01:12,3;102:12,7;103:1;06:1,22,24;108:12;11:25;

112:1,7;20:5,8,1,12;

(19) n ew lv -



Hear in g Vo lu m e Nu m be r 2 Food & Dru g Adm in is t ra t ionMa y 29, 99 8 Gastrointestinal Dr ugs Ad vis or y Comm it t e e

1 23 :2 2; 1 24 :1 5; 1 29 :1 7

offer 130:10

‘Te4:25. ..c ia l ly 56:25

oft en 18:15 ;23:5; 24:6;4 9:4 ; 1 22 :1 9; 1 39 :2 4;167 :8 ; 178 :2

Oh 70:7

Oka y 68:17; 69:8,23, 25;8 0:2 1; 1 01 :1 2; 1 03 :11,2 4

old 124:7;31:2;37:24;138:2,2,2; 47:1;66:13

older 146:12,13 ,4;147:23 ;66:15

OMERACT 37:8on4:ll,21; 5:2,20 ;6:5;7:4, 22; 8:4, 25; 9:3,7,8,20,24; 11:10;2:18,2;13:2,;16:2;9:4;0:7;22:2,5;23:2124:11 ,8,23;25:10,10,13, 8;26:7;28:9,3;29:23;2:17;

33:25,5;35:9,0;37:12;38:21,3;39:4 ,8,1,13,16;41:17;2:17;43:7,24;44:1845:14;46:21,25;49:2,7,8,3;51:14;2:3,4;53:18,1;54:22;6:7,13;58:3,4;59:2161:9 ,15;62:2;4:6;5:18;_ffi:20; 8:17,0;70:3;

‘,7,2;72:8,;73:9;~,11,17,21;75:13;

76:8,15,5;79:10;0:22 ;81:18;2:7,4;83:3,6,25,25;84:1,,2,11;86:14,5;87:8 ;9:3;

91:14,7;92:25;95:4, 3;96:24;7:1;9:23;00:9;102:19,3;104:2,3,2,22;106:6 ,21,4;107:13,17;108:1,7 ,9,12, 7;109 :1,14,7,19,21,5;110:2,4111:1,1,21 ;112:14,21113:17;14:9,24;115 :2,10,3;116:21;117:15,17,2,23;119:4,5,5,18;120:9,12,19,19,23,24, 5;121:22;22:1,2;124:6,0;126:14,4;127:12,4;129:19;130:20,4;132:12,12,0;133:12,20 ,3;134:16;135:11137:17 ,21;141:14;42:2,9;43:23;145:19,1;146:1;47:20 ,20;148:16,2;149:3,4,4,9;150:10,15,16; 5I:12;152:4,8,9; 53:17;56:5,14;157:13 ,20,21; 58:5,22;159:6;60:14,25,5;–~l:l;163:4,7;164:19;

2,19,20;166:13;:14,25,5;168:3,4,

23;169:3;73:3,8,1,25;174:2,5,3,23;177:9,1;178:1,4,8, 2,16,2;179:1

once 115:9;71:7

offer -partial (20)

mcology 114:3,4on e6:14;7:12; 8:17;11:1 7; 1 5:2 4; 2 2:2 0;23:18, 19;25:13, 24;2 7:2 4; 2 9:6 , 7 ; 3 0:6 ,1 2,1 7, 1 8;3 1:1 4, 1 9;4 0:2 1;4 2:1 , 2 0; 4 5:2 ; 4 6:1 2;4 7:21 ;48:7 , 11; 50 :15;5 1:9; 53:1 3,19 , 2 3; 55 :2;5 6:8 , 2 3; 5 9:11; 6 3:1 9;65:8,9; 67:14, 19, 22;70:12; 71:11,12,13;7 2:10 ; 7 6:22 ; 80 :5; 82 :1,13, 19;86:9, 11,16, 23;87:3,10, 17; 88:11, 17;8 9:1,3 ,4,8 ; 91 :25 ;92 :2;9 3:1 ; 9 4:2 5; 9 5:9 ; 9 7:8 ,1 0,2 4; 98 :22; 100:24; 102 :17;1 03 :1 8; 1 04 :2 4; 1 07 :1 5;108:3,14, 17; 109:4, 9;111:19 ; 113 :14, 15 ;115:24; 116:9,15,24,24,2 5; 117 :1 0, 2 4; 1 20 :2 ,8 ,8 ,12 ; 12 1:2; 122:1; 1 24:3 ,2 1; 12 7:11 ; 12 8:14 ; 13 1:2;1 32 :1 9; 1 34 :6 ; 1 36 :2 ,8 ,12 ; 13 9:19 , 2 1,25 ; 1 40:3 ;142:4; 143:21,23, 23;1 45 :1 2; 1 47 :9 ,11; 1 51 :2 5;1 53 :2 0; 1 54 :1 2; 1 55 :9 ,9 ;157:8; 160:13; 161:8, 14;164:11,12, 24; 165:5, 25;16 6:8, 23 ; 168:23; 1 69:1 7,2 5; 170 :6; 171:23; 1 74:1 6;176:4

on e’s 73:9

one-third 12:16One-time 83:20one-year 102:17, 18;118:15ones 30:23; 47:25; 99:1;121:11OIIgOhg 14:21; 119:24only 30:23; 42:24; 43:3;69:22; 72:24; 76:12; 79:7;85:11,19 ;90:7,13; 91:15,18, 20; 108:17; 113:19;114:17 ;115:6; 121:2;131:15 ;135:17; 136:21;138:12; 139:6; 140:20;144:4; 153:25; 154:12;159:12; 162:21; 164:7,22,22; 171:22; 174:22

onset 125:12, 24; 146:14;149:11, 13Ontario 10:7open 5:23; 22:1; 31:24;63:8open-ended 155:13;157:24open-label 124:9opened 47:14Dperated 46:25Dperating 33:6, 15; 55:1;56:1, 2,7; 67:4; 87:20;)3:21~perations 150:17

~pinion 40:6; 86:4; 99:7;

126:25;42:1opinions 132:20opportunity 129:12;179:4opposed 24:9; 27:14;45:18,21 ;81:8; 83:12;90:24opposite 51:2; 166:3,11

opposition 57:13optimal 139:23or 4:20; 5:2,8; 11:20;12:17,24 ;14:1,1,2,3,7,13,15,18,21,24,24, 25;15:2,3,4, 5,6; 16:2, 14;17:25; 18:4; 19:5; 21:20;22:10; 23:8,16, 19, 24;24:1,2,8,9,12, 17,23;25:16; 26:1; 27:22; 28:12;29:14, 19, 22; 30:3,7,10,10,11 ;31:5,8;33:21;35:4,7,12, 23;37:17, 21;38:18; 39:16, 16;42:13,20,21 ;43:9,22,25;45:1;46:13,14,15,16, 23; 47:1,24; 49:1,4,17,22, 25;50:1,2,2,3,3,7, 20; 51:5,6,15, 16; 52:2,16,16, 17;53:9, 22; 54:4,6, 16;55:24; 56:7,7,9,9, 11;5 7:13 ,16 ,22, 23; 5 8:15 ,22; 59:22; 60:19, 22;61:15,15 ,21 ;62:12,13 ,18,23, 24; 63:8, 13; 64:7,2 2,2 3, 2 4;6 5:1 , 2 4;6 6:1 0;67:9 ,19, 19 ; 6 8:2 o; 70:17;72:4 ,9, 10 ; 73:2 ; 75 :10,23; 77:16,16,24, 24; 80:6,6, 15;81:20;83:19, 20;

84:17; 85:18; 86:6, 20;87:17, 18;88:3, 11,11, 24;8 9:1 ; 9 0:11 ;9 1:1 0; 9 2:1 6,18,23 ;93:18;94:24;

95:12 ;96:21;99:15, 18,22; 100 :1 ; 101 :9 ,12,20 ,25 ; 102 :3,4,7 , 13; 10 3:21 ;104:5 ; 105:13,14,25;108:12,1 3, 20 ; 109 :2;112:2,6; 115:10,16, 19;116 :1 , 1 0; 118 :2 1 ;119 :1 6,2 3; 1 20 :1 9; 1 21 :1 2;1 22 :2 2; 1 23 :2 2; 1 24 :1 9,2 2; 1 26 :1 ,8 ; 1 28 :1 5;12 9:7,2 3,2 3, 2 3; 13 1:6,20,24, 25; 132:2, 3;13 4:25 ; 13 5:7, 22 ; 136 :2,10 ; 13 8:6,6 , 25; 1 39:9 ,9,15, 18 ; 14 0:1 , 11,1 2;144 :6 ; 145 :16; 147 :19,20 ,20 , 2 5; 14 8:1, 1 5; 149 :18;1 50 :1 4, 1 7,, 21 ; 1 51 :5 ;1 52 :2 3; 1 53 :1 7, 1 7,2 4;154:17, 21; 158:22, 25;1 59 :2 ; 1 60 :1 4; 1 61 :2 ;164:9 , 10 ; 165:10 ,10,12 ,22; 166:10; 167:15, 24;168:5; 169:11; 170:3, 5;171 :7; 17 4:5; 175 :2, 11;177 :10; 178 :10

0rder4:2,4; 101:12;

136:20; 159:9

Min-U-Script@

organizations 4:20; 9:7originaI 27:5; 55:18;131:10Originally 131:16orosomucoid 14:25orphan 161:23, 24; 162:3orphans 130:19; 161:19osteoarthritis 38:11other 5:2, 7; 11:10; 14:8 ;1 5:4; 16:1 2, 14 ; 18 :21;21:11; 23:22; 28:12, 14;32:8, 17; 34:12; 36:7, 25;4 3:1,7 ; 4 6:12 ,23; 48:4 ;50:1 1 ; 5 3:23 ; 56 :17; 5 8:5;59 :21,2 3; 64 :18; 6 5:14 ;6 7:4 ; 7 2:8 ; 7 3:4 ; 7 4:2 2;7 5:21 ; 76 :5, 8; 77 :18; 7 8:7;80:7; 84:25; 86:11, 14;87:17; 90:20 ;95:11;9 7:18 ; 1 00:4 , 12; 101 :22,25 ; 102 :4; 1 05:1 9; 10 6:8;108 :6, 8; 10 9:18 ; 111 :9;113 :2 0; 116 :2 4; 117 :1 0;

1 22 :1 ,8 ; 1 26 :2 3; 1 29 :1 6;1 34 :1 5; 1 40 :1 2; 1 45 :1 7;1 47 :1 7; 1 48 :6 ; 1 52 :2 0;160:15; 166:6,7,9, 22;1 67 :9 ; 1 69 :1 1 ; 1 75 :1 2;176 :18; 178 :8

others 7:23, 24; 38:10;110:14; 111:6; 136:5, 15;151:3otherwise 18:9; 42:6ought 37:17; 57:2; 77:15;90:10; 159:9; 160:18;174:240u r7:20; 8:16; 15:17;1 8:1 6; 2 0:2 2; 2 5:1 2;3 2:1 7; 3 6:7 ; 3 9:1 ; 4 4:2 3,24; 55:9 , 12;6 8:22 ; 74 :5;76 :11,2 4 ;77 :5; 84:2 1;8 6:1 ; 9 3:7 ; 9 6:1 5; 9 8:5 ,6 ,2 3, 2 5; 9 9:1 ; 1 00 :2 2;113:14; 126:13,14,20,20,21; 132:21; 136:7, 23;13 9:5; 142:14, 1 8; 1 48:2 4;1 49 :1 2; 1 50 :2 3; 1 53 :1 3;1 60 :6 ; 1 63 :1 5; 1 78 :2

ourselves 77:9out 7:22; 8:2; 10:13, 21;18:17; 22:8; 26:18; 30:17;34:2; 35:5; 36:9; 37:9;39:1; 45:11 ;46:10; 47:4,11;48:15; 56:13; 57:10;59:16; 70:13 ;75:18;78:12,21 ;81:19;83:9,10,12; 84:6; 87:24; 89:19;91:25 ;98:4;1OO:15;101:21; 103:21; 118:22;121:5; 135:18,18; 137:16,20, 22; 138:1; 141:14;142:16; 143:14, 16;146:16;149:19,21;152:20; 156:9; 159:17;162:11; 164:11; 165:16;167:21; 168:20; 172:17;173:1; 176:20; 177:4,19out-of-the-blue 26:4

outcome 23:16, 19; 24:1;

30:7; 34:10, 12;35:1;37:13; 38:3; 40:3; 58:4;66:22; 98:10; 104:15, 17;108:6; 170:13,15, 19;171:2outcomes 35:2, 18; 36:2,3,5, 14; 37:8rmtside 5:24

mtsider’s 29:6m rer 6:ll;8:13; 33:21;

34:16, 19;35:3 , 14; 3 7:6;3 8:5 ; 4 1:11 ;4 2:1 2; 7 2:1 0;7 4:1 5 ;7 6:1 5, 1 8; 1 03 :1 6,17;110:12 ; 111 :17,19 ;112:8; 146:7,7,17, 23;147 :4, 6; 1 48:2 4; 1 50:4 ,1 4; 1 58 :8 ; 1 79 :1 5

ove ra ll 86 :18 ; 87:4 ;> 0:2 5; 9 1:5 ; 9 2:2 3; 9 6:2 0;1 27 :1 9; 1 51 :4 ; 1 54 :1 5;164:5

mrerlap 15:13mrerlooked 24:6; 129:2;160:3overpower 98:17mferview 10:2; 21:15;56:7; 135:12own 22:14; 48:18; 62:2;56:2o; 126:20, 20; 162:4;174:19Dxford 129:23

P

paid 33:6pain 13:20; 20:23; 23:6;

28:23;36:11; 40:15;93:12; 108:5painful 14:2panel 6:7; 9:12, 24;10:15 ;70:2;76:25; 86:12;149:4; 167:22panelists 8:24; 86:9paper 7:4; 106:5; 125:11paradigm 77:14paragraph 22:17paraliei 39:20; 40:5;88:23 ;92:18parallels 38:22; 40:2, 4;65:11

parameter 159:7parameters 43:14;57:14; 159:8paramount 143:25parent 144:2parents 172:14Parklawn 4:25parlance 130:13Dart 4:9; 7:12; 25:6;27:23; 49:9, 20; 81:4;104:6; 114:11; 121:19,24;[34:1, 12; 165:17Oartial 42:4; 49:17, 18,21, 24; 50:1, 18; 101:23;

102:7

Mil le r RC?DOr t i fM2 Omn a n v. Tnr.



F ood & Dru g Ad m in is t r a t ionGa st r oin t e st in a l Dr u gs Ad vis or y Comm it t e e

participant 5:3participants 4:13, 19;

__—_ 5:4,7participate 129:12participating 156:3particular 7:8; 23:16;24:21 ;29:5;44:1; 72:11,15; 89:20; 117:22; 126:9;

133:24; 136:24; 154:7;163:23; 172:3particularly 9:5,19, 25;15:20; 17:19; 22:12;32:13; 52:3; 54:21 ;84:21;95:11; 118:5; 135:9;137:1; 152:4; 172:12,25Partly 35:10; 87:14, 15;92:7; 95:24parts 73:4passed 87:24past 16:24; 163:15pat 34:14pathognomonic 14:12;17:25; 21:17pathologic 15:15pathologically 28:21pathophysiologic 12:17pathophysiology135:15pathway 158:22patient 17:6; 18:2; 19:16;

--—- 24:8, 10;25:18; 26:5,7;35:15,20; 36:5; 41:17, 17,18,19, 20; 42:14; 44:4, 4;45:6; 46:14, 25;47:11, 12,16, 23;48:17, 18, 22;51:21, 25; 53:8; 54:22;55:17; 56:5,6,19, 24;59:18, 23; 62:9; 63:17;66:5,13 ;69:24; 72:18;73:1; 76:8; 77:20; 78:20;86:1,3,4 ;92:11,25; 93:1;94:6; 96:22, 25; 97:1;102:12; 106:12,14, 15,20;107:5; 108:17; 109:13,15,19, 20; 110:1,;114:22;115:25;17:5 ,15,7;118:18;22:5,9,10, 5;123:16;24:7 ,0;133:14,24;154:2;56:12;60:10;161:7;76:9patient’s2:3;6:24;45:16;8:18,1;57:10

patients1:20;2:15,6;13:16,8;15:16;7:9,8;18:4,6,17,19, 0;19:1,2,2,13;20:1,22 ,2321:19;22:22;4:22;5:7,9,12,15;27:1;8:2231:18;32:1136:1;37:1; 0:16,24;41:14;2:15;43:8,9,

---- 10,12;47:9;9:2;1:24;52:6,23;3:11 ;5:10;58:6,762:7,9;64:4;70:13;1:8;6:7,9,4,20;77:1,;78:22;9:6;81:1182:6,23 ;3:4;4:7,21,24;85:6,21,22;86:1,21,22;87:5,;90:8,0 ;

91:7, 3,16,1;92:23,4;94:12;6:21;97:5,3,25;99:21;02:23;04:2,5,12;105:8;07:17;08:4,7,10;110:16,7;111 :16,18,25;12:7;14:18;116:9,0;117:11;18:16;119:3,8 ,5;120:3,0,15,23;122:19;23:12,19,0;

124:3;25:8,1;127:19;129:3,5,7, 5;130:3,;142:19;43:2,3,0;146:12,7,22;147:4,6,22;148:8,9 ,14, 4;149:7,11;150 :9,1;154:1 ,11,14;156:15,3;161:5,9,13,14, 5;162:1,16,2;164:5,7,7,12, 4;165:21;166:4;67:13 ,5;168:23;169:22;70:17;71:1;172:2;75:2,4;176:8,11,11,17;178:8paul9:11;12:9;37:7;138:10;43:9

Paulus 54:4peak 149:13pediatric 9:23; 10:1,;96:12,15,7;101:19;124:18;28:4,9,21;130:15131:17 ;32:9,10,15,16;134:1,3,8,14, 6;135 :2,4;36:5,9,3;137:11;38:19,23;39:2,3,9,12;140:17,9;141:4,16,21;142:2,8,4,17;143:2,3;145:20;50:1;152:8;53:12,1;160:17,21,22;172:13,18pediatrician 6:24;

84:13;36:20;43:7;148:23pediatricians 40:1;142:6Pediatrics 9:22; 42:8;124:5; 130:24; 131:19, 23;132:14; 134:6; 135:9;136:4; 148:15; 150:6;151:2; 153:5,24, 25;159:11,19penicillin 49:3penuhimate 150:24people 7:6; 10:21; 23:14;24:20; 34:17; 50:25;

57:18; 59:8; 64:20; 76:5;89:19; 90:14, 22; 95:4;97:10; 99:11; 104:21, 25;112:14, 19; 113:19;115:16; 117:14; 121:22;126:17; 128:12; 140:17,18; 146:14, 25; 148:17;149:9,19, 25; 150:5,13,19,20; 151:16; 158:16;163:25; 168:25; 176:1;177:11, 19; 178:16per35:25;45:23per-patient 156:5percent 42:23, 24; 48:9;49:25, 25; 67:8, 10; 84:17,19;90:8, 11, 13;92:9;

Mille r Re po rt in g Co m pa n y, In c .

93:2, 10; 96:16, 23; 125:6,12, 13; 126:8; 131:20;153:25; 164:13, 25; 165:1,3,12, 12; 167:12; 171:7;176:15, 19; 178:8percentage 92: 19;95:17percentile 137:24, 25;138:5,7petfect 26:14; 38:6;44:23perfectly 117:16; 124:1,1perforation 59:25perform 20:24performed 60: 12;126:24; 142:13perhaps 12:22, 23;32:17; 42:2; 44:21 ;67:16;72:11; 105:11; 146:24;148:2; 150:18; 163:6;167:6; 174:14; 177:23perianal 46:14; 47:12period 6:12; 35:14;56:15; 70:24; 72:1 1;73:4;76:18;77:13,24, 24;34:24;86:7; 103:7,9, 16;110:12;111:19; 112:8;123:23; 141:19periods 123:11peripheral 14:9Dermit 131:18oerplexed 66:17Serson 44:17, 18;93:8;122:3; 126:18Personally 44:6; 66:2o;111:6Perspective 10:10; 28:5;Z9:6;174:10Oertains 101:5Oertinent 167:4~harmaceutical 51:22;101:3; 131:4~harmacodynamic127:3; 140:20~harmacodynamics159:24~harmacokinetic 127:4;128:23; 140:10, 15; 156:3~harmacokinetics126:23, 24; 159:24~harmacology 130:22,~4;139:9; 152:25~hase 35:16, 17; 37:16;71:22;84:6; 141:3;174:23; 176:16~henotype 57:7~henotypes 9:10>henotypic 52:4~henotypically 146:15,24phenotyping 115:14Philadelphia 138:18

phone 123:18phrase 155:12physician 57:9; 66: 14;

Min-U-Script@

Hea r in g Vo lu m e Nu m be rMa y 29,

118 :19; 160 :10

physician’s 52:9physicians 21:1; 62:7;85:4; 112:11; 125:19physiologic 57:16,22physiological 40:11pick 66:23piCtUre 51:25piece 50:20, 23; 157:9,10pig 144:3PK 134:7; 135:5; 148:24phCt? 107:1; 155:6;172:10placebo 24:24; 64:7;70:15; 88:4, 21; 89:8, 11;90:13 ;98:14; 104:5,8;105:14; 108:25; 116:17;120:8, 12; 122:2; 164:6;168:10; 173:12; 174:5,6,7; 178:10,12placebo-controlled24:16; 116:1o; 123:25;140:2; 172:2, 10,15,20plan 7:20; 10:17,22planned 173:20plans 116:4plausibility 155:15, 16;157:19plausible 157:20play 10:8; 21:24playing 6:5please 46:5; 51:17pleased 11:10plot 88:3, 4,5; 126:4plots 88:7

plus 86:18; 104:17;130:21, 21; 149:18;159:16; 176:16; 178:12plus-minus 135:14pOint 8:23; 18:17; 22:8;28:2, 25; 38:1, 24; 40:22,23;45:7, 22;47:4, 5;53:24; 57:4; 59:4; 64:1o,16;66:2, 14; 67:14; 72:10;73:13,14,22, 22;75:12,19, 22;79:10; 80:2; 81:16;34:11, 16;87:11; 88:8;39:11, 17;90:5,8,9, 14,21;91:25; 92:21,21 ;95:8;)6:9, 12;97:8; 98: 16;

29:15; 100:16; 101:21;106:10; 113:25; 123:14;126:9; 127:2; 129:1;134:10; 136:23; 138:4;142:14; 144:1,6; 146:11;148:22, 22; 150:17;152:20; 154:15; 155:25;158:1; 159:3; 160:4;169:4, 6; 170:21pointed 98:4; 162:11;165:16points 27:14; 46:10;49:19, 22; 53:19; 57:10;64:9; 73:16,18; 80:1;87:12; 89:16; 90:16;

91:10 ;94:14; 97:16; ,

142:8;43:16;59:22;165:5

policy 145:18pent 137:16poor 18:12population 10:4; 59:1177:20; 94:23; 97:23;106:14,15, 19; 107:3;

119:2; 130:7; 144:15;145:23,24, 25; 146:3;148:8, 12; 149:21; 151:4152:18; 153:6, 22; 154:1155:24; 156:6, 12; 158:1160:1; 161:7; 162:2;172:7, 7,8; 173:19, 20;176:10populations 54:25; 92:293:4; 94:6; 109:1; 124:18132:10; 134:9, 14; 148:1154:11; 165:23PORTER 77:7,7posed 22:19; 126:22position 178:1

positive 34:20; 148:3possibility 107:16;136:22; 158:13possible 11:1; 30:7;62:10; 67:22; 78:2; 152:4155:13,18, 20; 156:9;174:6possibly 69:14post 88:14post-op 50:8post-randomization116:12; 117:19; 178:15postmarketing 141:19;160:9

postoperative 19:7;20:16;63:20postoperatively 24:9potential 4:15; 19:12;20:17; 22:24; 23:19;30:12, 20;74:16; 112:4;121:14; 142:6; 158:4potentially 121:18; 158power 89:18,19, 22;141:8; 145:4;151:21;159:2powered 135:6; 147:16powerful 86:24; 87:15PPRUS 139:9practical 164:4; 175:5practice 133:10Practices 7:10, 10;166:25practicing 57:9pragmatic 165:17pre88:14; 174:22pre/pOSt 87:21; 88:22,22precedence 102:9precedent 110:14;162:16preceding 15:18precise 26:13

rxeciselv 164:17

(2 1) Da r t ic iu an t - m-eciselv



Hea r in g Vo lu m e Nu m be r 2 Food & Dru g Adm in is t ra t ionMa y 29,1998 Ga st r oin t e st in a l Dr u gs Ad vis or y Comm it t e e

preclinical 21:20preclude 4:9-— defined 20:1,11

.tict2:17;7:17;19:1071:19,20pred ictable9:9predictor 13:5; 66:9,10predictors 17:15

prednisone I02:21;108:12, 13; 115:16;121:16,22 ;126:15predominantly 145:22prefer 23:4; 81:9; 87:12preferable 33:4; 87:3premarketing 160:8prepared 135:19prescribers 22:21presence 58:12, 13;59:22present 4:15; 9:3; 13:18,22, 25; 14:2; 37:13; 42:20;45:2; 48:16; 55:14, 15;

78:18; 79:5,8,18, 23;80:21; 110:11 ;11:23,24;123:9,10,6;128:9 ;142:25;44:9,1;148:6Present’s 79:2presentation 14:17;15:5;70:3presentations 12:11

--sented 20:22s-sure 121:15

pr esu ma bly 108:23;140:3

presume 108:19; 145:10presumes 145:11

presuming 108:17pretend 52:11pretty 34:17; 78:17;81:21 ;90:7; 126:2; 134:5;152:18, 19; 173:6,7,9,16prevalence 149:15prevent 61:24; 62:13;82:8; 83:3; 106:16; 110:5preventing 61:21; 65:8,10;82:10prevention 31:9; 50:6, 7;51:20; 52:2; 61:25; 62:9,12;63:10, 13, 16,19,20,21;65:2; 68:22 ;78:15;

81:1; 102:6, 11; 107:14;110:7previous 5:9; 15:21;79:2; 100:23previously 11:20primarily 17:15primary 14:2; 16:13;17:8; 45:4; 70:12; 98:5,6,

_& + 13, 24; 100:6; 1o4:15,!1; 116:22; 118:11;

I,+1O; 120:2, 5, 12, 16;122:3,4; 160:1; 170:13principally 131:5principle 110:10; 115:19prior 7:5; 125:4

priori 91:20prioritize 132:7probably 7:6; 11:15, 16;22:14; 35:21; 36:24;40:10; 56:18; 59:24;68:13; 84:14; 103:14;111:11;118:17,25;121:10; 126:15; 127:22,24; 129:15; 138:14, 23;140:6, 22; 152:14, 14;157:22, 25; 159:25;160:12, 20; 165:22;171:10; 172:7problem 16:22; 31:2, 10;54:18; 66:16; 79:19; 94:8;95:19; 106:7; 112:18;121:3; 127:22; 141:3;153:13; 155:11; 168:20;178:18problems 14:20; 17:23;22:6; 33:2, 4;42:1,7; 44:6;89:9; 117:24; 140:1;145:3,16

procedure 7:12procedures 7:11proceed 6:9; 21:25PROCEEDINGS 4:1process 19:23; 20:3;21:13;33:9,20,20, 25;54:25, 25; 35:1,23; 37:22;38:1,14 ;40:4,4,6; 41:21;51:16;77:19; 148:4;174:1; 179:6,6Orocesses 40:11; 125:10Orocessor 138:21~roduce 12:24; 132:9;177:17

m’educes 13:15; 28:20woduct 22:21, 23; 81:13;12:18;83:5; 118:11;141:14,24 ;152:21;[56:14; 158:10]roduction 29:23]roducts 5:2,9; 38:24;13:1;161:12%ofessor 9:13, 22]rofoundly 165:21prognostic 12:4,6]rogress 41:19progression 44:20;;5:10; 124:25prolong 85:18prominent 9:9,14,18promised 179:3promising 8:20promote 61:8promoting 50:20properties 33:6, 15;56:1, 2,7; 67:4; 93:21prophesy 91:19wophylaxis 50:8woportion 31:18; 86:21;37:5, 6; 91:13,16, 20;>2 :22 , 24 ; 9 6:6, 24 ; 97:4 ;105:8; 110:16.17:118:16,

p re clin ic al - r e ason able (2 2)

proportions 54:3; 96:21;150:11

proposal 18:24; 49:14,15; 50:4; 58:22; 59:11;67:13; 130:5; 134:1proposals 57:3; 141:11,15propose 50:6

proposed 19:19; 45:25;115:14; 121:25; 140:10proposing 74:10; 102:16prospective 46:18;106:8; 135:6; 146:5, 6;171:5Prospectively 48:19protein 14:24; 15:2,3protocol 138:21; 144:25

protocols 171:25;78:3,21

prove 45:5; 46:2; 85:15;91:5; 136:3; 173:2

proved 24:21; 169:1;172:16proven 141:13provide 119:18; 160:15provided 130:12provides 81:14; 131:3providing 32:19; 54:14;175:6proximal 47:3

proxy 107:9~sychological 122:22;123:1~uberty 126:3

~ublic 7:14

wblication 7:8mblish 132:8

wblished 6:21, 24;11:12;18:24; 31:21,21;}8:20; 45:10; 96:18;123:24; 131:10lulling 177:4wrpose 6:8;7:16; 22:2o;?6:15;33:5mrposes 74:24]ursuing 179:15

.]ush 70:21put 6:5;7:4,22 ;41:lo;43:17; 53:7; 56:2, 10;78:19; 81:20; 82:7; 83:9,10;86:5; 88:1; 105:6;106:21, 24; 126:7; 127:6;133:18putative 122:1puts 166:2putting 83:12; 121:18;166:11puzzle 43:16pylOri 57:17,18,19,19,19, 20; 58:15~yoderma 112:6

Qqualify 105:18C@itdk 33:23quality 10:11; 20:21;21:4,10, 12;23:24; 28:13;39:19; 49:25; 54:17, 19;

65:13, 20; 66:19; 67:18;79:8; 130:2quantitate 36:24quantitative 33:8, 23;36: 17; 38:6; 173:9quantum 65:22question 22:19; 28:7;37:3; 49:14; 51:2; 52:17;54:7; 59:17; 62:1, 16; 68:3;69:19; 70:21; 81:3; 82:20;86:5; 98:1; 101:6, 11;105:12, 17; 106:17, 18;109:5,9, 24; 113:2;118:19, 24; 122:15;124:15,16, 17; 126:22;

127:8; 131:19; 134:10, 12,15; 135:17,21; 139:14;140:7,8,9, 13; 144:14, 23;145:7; 146:4, 20; 147:8,22; 151:1; 155:16, 18;156:7; 157:24; 158:15, 17;159:23; 164:9; 165:15, 17;167:12, 21; 169:22; 170:5,7, 12; 175:8,9, 23; 176:7Questionnaire 21:7questions 7:18,19,22,24;22:3,6; 101:7; 102:10;105:11;113:14; 118:1,2;130:1; 155:12,13, 16;172:23, 25; 179:12

quick 24:14 ;43:4;143:21; 144:23quicker 136:20quickly 142:16

quiescent 17:18; 82:24~Uiet 82:18quieted 83:21~Uite 11:18;5:11,25;18:1;15:2;20:10;129:25;44:2;55:9,0;178:19quoted79:1

R

RA 38:16;9:7;5:5;74:4,0,19;76 :3,9,4,14,20;7:3;1:5;3:12,23;103:23;06:2;72:11radiologic 42:13; 46:19;49:11 ;58:5radiology 46:17; 47:5raging 47:2raise 106:18; 131:20;167:8; 175:24raised 105:17raising 66:14ramifications 78:9

randomization 117:10;178:14randomize 24:23; 116:11randomized 24:15; 25:3;116:8,9, 13; 136:10;140:12; 153:6; 155:22;172:21randomizing 140:2

range 121:12; 128:2ranges 67:7; 127:21;165:25ranked 99:1rapidity 142:7rapidly 6:10; 77:11, 15;158:8rare 56:23; 57:2; 154:19;165:7rarely 145:24rate 14:24; 37:16; 70:15;127:5; 170:7; 177:10rates 24:25; 35:24;152:14; 156:4; 164 :11 ,3 ;1 6 9 : 1 7rather 22:16; 23:3, 4;25:1,22, 24; 26:2; 32:4;}3 :23 ;56 :18 ;4 :1 ;1 0 5 : 7 ;1 3 5 : 1 4‘at ion ale14 6:2 2,2 5‘each43:18 ;0 :22 ;7 .5 ;1 0 3 : 3‘cached 40:9; 86:22;141:17‘eact ive 37:16‘cad 22:17; 69:19; 130:11‘eading 100:10‘cads 140:25

‘eady 133:6,8‘eagent 19:16; 125:8eagents 19:17eal 5:17; 77:17; 151:13,9‘eality 98:17; 153:10‘eally 7:2, 16; 8:21;!3:25; 24:18; 25:22; 27:6;i2:24; 33:11; 35:17, 19;;6:19;37:6; 42:8,8 ;46:15;il:2; 54:21; 55:7; 56:5;i9:12;62:16; 64:25 ;66:3,3;71:4; 72:17; 73:10,19;‘5:13 ;79:9, 16;82:14;

14:8;87:25; 89:2; 90:24;95:7; 96:13; 97:21; 99:8,24; 100:17; 105:2; 107:23;112:14; 114:l;125:8, g,25; 131:20; 134:23; 137:5;139:1; 142:1; 143:15;151:22; 152:5,16, 24;153:3; 155:17; 163:5;169:18realm 30:21reason 32:15; 54:5;107:22; 110:19, 25; 126:4;129:5; 139:16; 151:13,23;158:19‘easonable 6:5; 45:7;

;3:14; 59:14; 117:13, 16;Min-U-Script@ Mille r Re por t in g Co m pa n v, In c .



F ood & Dru g Ad m in is t ra t ion Hea r in g Vo lu m e Nu m be r 2

Ga st r oin t e st in a l Dr ugs Ad vis or y Comm it t e e May 2 9, 1 99

132:4, 5; 151:16; 162:6;163:8; 164:3; 165:2;

-. 175:11; 177:5,7reasonably 87:10; 88:19,23; 96:5; 135:23reasonably-sized152:15reasons 54:1; 94:25;

98:22; 101:16; 107:15;133:2; 145:13, 17rebounds 78:6recall 115:14receive 7:21

received 104:5receiving 149:25recently 143:7Recess 100:21recognize 5:24; 13:14;14:4; 26:18; 32:9; 118:14recognized 78:17recommend 122:25;137:5; 142:18; 162:19;170:3recommendation 113:6;177:9recommendations161:12recommended 74:20;124:6; 129:17; 132:23;

___ 142:5; 161:6, 13; 179:8recommending 167:24;168:25record 4:9; 5:6;80:22;114:7; 149:3records 99:14reCtal 13:20; 18:2rectovaginal 46:15recurrence 9:17; 20:16;123:4recurring 65:9recurs 19:9redefine 86:15reduce 25:11;39:10;107:10; 122:20; 171:7reduced 47:25; 87:5;108:18reducing 91:2; 96:22;120:7; 148:17reduction 31:3, 16;

39:12;41:17;45:19,21;48:9; 49:1,18 ;89:11;95:18; 96:16; 98:13;101:8; 102:7,8; 103:15,17; 120:20reductions 87:7refer 23:13referenced 47:10

-_ referral 125:21referred 154:2referring 122:6; 129:5;134:2refers 23:11reflect 45:15

reflected 36:24; 37:12

reflective 168:24

refiects 9:20; 115:2;168:21refractory 112:25; 113:4,9,22; 114:5,9; 115:4,8,15; 122:14; 169:22; 172:7regard 4:8; 24:3, 18;27:20; 34:19; 40:17

regarding 9:16; 10:3;61:12; 86:12; 100:23;114:15; 118:3; 123:8;139:15; 148:3; 173:25;175:4regardless 110:12regards 123:10regimen 135:10; 150:16;169:13; 170:2,4regimens 169:11, 12;178:23regular 20:24regulated 4:14regulation 12:25regulatory 19:6; 21:23;38:8, 24; 60:15; 141:8reinstitute 119:6reiterate 57:12reject 65:24relapse 17:15, 18; 24:25;25:11, 19;31:9; 50:6,7;51:20; 52:2; 61:21, 25;62:9,10, 13; 63:10,13,16,18,19, 21,21 ;64:17, 19,22; 68:22; 78:15; 81:2;82:8, 11; 10 2:7, 11 ;1 06 :1 6; 1 07 :1 4; 1 09 :1 9;110:5 ,7; 11 5:25 ; 1 20:1 5

relapsing 65:10;01:21;102:13,14relate4:19,9related 10:1;1:8;4:18,20;15:1;6:11;0:6;35:12 45:13;2:3,8,11;93:4,;96:9,0;101:5,7;135:4;67:22relates 44:4; 157:5relating 100:22relationship 12:17;42:18; 43:14 ;60:13;87:23; 88:2,14,22,23relative 46:9; 137:18

relatively 36:14;37:21;123:12; 145:24; 147:4;148:11; 156:5; 163:17;177:7relevant 43: 19;89:10,13; 97:20; 156:7; 160:16;161:1o; 171:2reliable 33:8; 54:24;92:20; 94:21reliably 36:16relief 32:22; 76:18rely 38:21; 58:24remains 43:15; 68:6remarkable 83:1

Remarks 5:13

Mille r Re por t in g Co m pa n y, In c .

remember 39:14; 152:6;160:7remission 18:14, 21;19:22, 22; 20:5,7,9, 13,15;22:25; 23:1,4, 10, 13;24:2,3,4,4,6,8,11,11,16, 22; 25:5,7,10,14,17,18, 20; 26:3,6,7,14,16,20,24, 25; 27:2,6,11,13,19, 24; 28:1; 29:11 ;30:3,5,6, 24; 31:3,6,8,9,11,12,18, 22;32:12, 13, 18,21 , 2 2; 33:16, 17 ; 38 :18;

39 :13 , 17; 40:2 3, 2 5; 42:6,6,18, 19,24 ;43:12, 13,1 5, 1 5;4 5:1 2, 1 4,1 5,1 7,17, 25; 50:7,9, 19; 51:5;

5 2:1O, 11; 5 3:9, 1 7; 59 :7,9;64:5, 19;67:18, 19, 24;68~20; 72:16,18,19,22,25;73:24;75:9, 11,19, 21;

77:1 2; 7 8:19 , 23 ; 79:1 4,19;80:12, 12, 25;81 :1 ,20;82:21 ,25 ;83 :21 ;85:18 ;89:7; 103:1; 110:4, 22;115 :11; 119 :4 ; 1 20 :3 ;169 :21; 170 :1

remission-maintaining79:17

remissions 82 :13 ;84 :18remit 77:12remits 80:17,8remitted 80:6remove 111 :19; 115 :25

renal 148:2;52:23render 99:7repeated 161:3

replacement 55:3replicate 15:4; 28:22report 35:21; 69:24reported 4:12reporting 108:5reports 146:8represent 14:15; 35:13;146:23representation 150:5representative 149:24;162:8representing 56:25reproduced 129:18reproducible 94:22request 4:24requesting 132:25require 58:5; 92:19;121:22;131:23; 133:16;134:22; 140:8; 153:24;155:7; 166:7; 178:3required 45:18, 19, 20;165:11; 166:4requirement 134:3requirements 166:12requires 86:25; 102:17requiring 42:13requisite 60:15

requisites 142:8

resealing 95 : 2 5Research 4:15;6:16;137:17;39:4,0;142:15;160:15;73:1;77:21researchers 131:8

resection 16:22;8:7;19:14

Reset 77:13,24

resetting 77:18,22resistant 109:16; 110:1resolution 26:23; 30: 11;45:20,21, 24; 58:5, 21;68:2; 81:20resolved 40:7; 58:9Resource 34:8resources 6:4respect 5:7;80:21;107:8; 115:12respective 39:24respects 138:6respond 7:23, 24; 12:16;27:8; 42:8; 114:21;115:10; 122:15,16responded 83:4; 115:20responder 43:22; 48:6responders 168:4responding 104:2;118:16; 170:18response 12:13, 22;15:20; 17:19; 23:16, 19;24:1; 29:1,7,8, 9; 30:7;32:9;42:14, 15; 43:25;44:1, 2;46:11; 49:9; 51:5;55:5, 5,6; 58:9,10, 25;59:3; 67:5,15,20, 22;68:10; 69:6; 70:14; 72:7,7,

9,20,21, 22;73:10, 24;74:8; 81:7, 12,14,17, 25;85:1,10, 25;92:6,9; 93:2;95:12; 100:23; 101:11;105:9;06:4;07:20;117:3;26:10 ;27:5;147:19 ;56:4;57:2;167:5;68:3 ,0;169:17;170:7,1;176:25

responses 42:5; 54:12;55:12; 167:7responsive 33:8; 109:20;110:4; 115:’21responsiveness 66:4,12;80:4rest 71:9restate 175:9restoration 80:4result 158:14; 173:5resulted 35:14; 157:16results 8:17; 38:14;69:24; 78:4; 108:23;126:20resume 100:19retaining 67:17ret reatment 84:6retrospective 171:6return 49:14

review 15:22; 66:1;

142:3; 166:24reviewed 171:25reviewing 163:9

revisit 111:12

r heost at 77:13, 18,23,23

Rheumatism 41:8rheumatoid 34:12, 24;35:16; 37:8; 38:10,21;40:2; 61:5; 81:8; 82:16;92:4; 123:19; 163:3;168:7; 171:11; 172:1,19rheumatologic 11:21;28:4; 100:25Rheumatological 41:5rheumatologists 11:18;33:21; 34:2, 2;76:12;170:2rheumatology 34:7, 19;37:6, 12; 39:17; 73:5;102:19rid 60:2; 68:4; 75:8right 7:13; 19:17; 28:25;30:22; 31:23; 41:6; 44:22;48:3; 73:16; 97:3; 102:9;108:22; 122:7; 123:11;144:2; 157:22; 162:21;168:12; 172:6; 178:18rile 143:20rip-roaring 48:18risk 21:19; 34:1; 59:25;120:6; 121:18; 125:3,4;148:9risks 108:2; 123:8; 142:6;152:13risky 139:17

robust 33:14role 143:1Room 4:25; 33:12;170:12roots 7:2round 10:12rule 131:10;56:9rules 164:11

run 26:21;7:6;17:19;145:3Rutgeerts9:11,2;19:8;42:16,17;6:10 ;9:22,23;60:4,5,17,0;61:3;70:22;11:2,;136:16;137:10;43:9;44:24;169:3,4,9;75:19,0;179:17

sSachar 8:25;:3,9;2:4;23:2;6:8, 0;27:8;9:15,21;30:1,4;1:2032:5;49:8;1:20;2:8,5;63:15;4:16,2;66:9;69:1;9:7;2:12;3:5;90:23;1:12,8;92:22;94:19;5:17;6:20;7:6;

99:8, 12; 102:9; 105:10 ;

Min-U-Scrip@ (2 s) r e a son able - Sach a



Hea rin g Vo lu m e Nu m be r 2Ma y 2 9 , 1998

106:9;07:14;09:12,3;111:9;13:23;15:1;_#%l; 119:3,25;20:13;

.9, 3;122:7,3;.-_/.24; 28:25;29:22;146:11,1;150:12;64:4;170:16,21;71:16;75:8,9,15,18;178:1,9,0;179:17

Sachar’s 67:13; 93:6sacroiliitis 14:7safe 139:25; 141:13;144:6; 148:16safety 75:4; 78:10, 25;84:22; 133:3,5, 13;140:10; 142:22; 143:25,25; 144:5; 146:6; 147:19;150:23; 152:4,5,8,12, 13;153:13; 156:1; 159:24, 25;160:14, 25; 161:1,8, 14;165:19, 23; 166:18, 23;167:7, 9; 172:14, 23;174:19said 32:5; 41:4; 54:11;56:13; 60:5; 62:2, 3;72:17;73:5, 23; 74:1, 6;90:4;102:11; 110:9,9, 20;115:23;122:12; 127:11;128:9; 134:5; 139:16;143:19; 175:3salient 22:6salvage 114:1---e 13:16; 19:1;34:21;

); 62:6; 64:24; 65:1;8u:2; 84:14; 87:22; 88:14;94:9; 96:25; 101:16, 22;105:23; 107:20; 109:3;111:9, 18; 119:12; 124:19,23; 125:2, 24; 126:1;128:9; 143:5,8; 144:18;148:21, 23; 149:5,6;169:4; 177:17sample 93:25; 127:13;145:4; 157:23; 166:8;179:2sanctions 141:22Sands 54:8, 9,9; 56:16;65:14satisfied 69:5,6satisfy 42:15saw 43:10; 69:6; 70:4, 5;72:5; 75:15, 16;99:6;167:22; 178:7

say 6:20; 8:15; 22:9;23:18; 24:10; 25:2, 13, 16;34:15, 16; 35:16; 48:20;50:23, 25; 51:22; 53:1;57:22; 58:20; 62:20, 22;63:1; 65:7, 16, 17;71:10;72:25; 73:2, 3;74:7; 75:22;76:6, 22; 79:3; 80:14; 85:2;_&$ 90:10, 17;94:23;

100:2; 103:19;.10; 110:11;112:12,

23; 115:17, 18; 116:1o;119:13, 16; 128:17;139:18; 144:2,25; 145:2;149:6, 14; 150:13; 151:12;153:24; 158:20,20, 24;

159:6; 166:14; 168:19;171:4, 10,20; 172:1;174:4; 176:1saying 58:25; 69:23, 25;76:5, 5;81:5; 95:6,9; 97:4,20; 100:12; 105:24;107:12; 142:21,21; 144:5;153:4, 23; 157:15; 159:11;171:9; 172:6says 51:4; 56:16; 62:23;55:14;80:17,21;81:13;33:15113:11;171:9;175:3scale 88:16; 92:14, 15;?7:1;100:9,10scanning 15:6scatterplot 88:3scenarios 77:10scene 10:24; 11:7science 112:18; 157:8;158:8,11Scientific 21:17, 23;

S6:23;40:7; 44:19;134:24; 174:9scientists 36:19sclerosis 65:7Scope 179:19storable 46:21Score 16:2; 29:2; 30:9;)1:17, 18;47:13, 15;i8:24; 49:22, 23; 59:13;>1:1,5,0,22;93:17;)5:24,5;96 :23;11:17Scores28:14;7:9;f9:l;92:23;3:23,4;>4:7;5:21,2;96:4SCOrhg 40:14;2:2se35:25;45:23second 22:7; 88:5; 90:2;1 01 :11; 1 05 :1 7; 110 :1 3;1 20 :1 3; 1 32 :1 9; 1 34 :11;149 :14; 171 :21

secondary 14:3; 98:2,25;99:1; 116:23; 118:7Secondly 46:17; 90:7SeCtiOn 23:21 ;27:21;39:13; 49:9; 130:24sections 22:13, 13sedimentation 14:24;35:24; 37:16see 7:14; 8:20; 30:13;42:2; 43:3; 44:17; 51:13;71:18 ;75:19; 89:2;101:21; 105:7, 23; 109:4;112:21;116:21; 125:17;128:1, 17, 18,20; 129:11;133:6; 141:5; 152:12;155:5,6; 156:6; 164:10,12, 12; 165:16; 172:14seeing 72:6; 93:25;116:14; 118:17; 125:23;127:25; 147:5; 164:1seek 147:23; 150:2seeking 16:5; 19:15seem 16:11; 33:14 ;62:5;66:18; 88:16; 143:11;

Food & Dru g Ad m in is t r a t io n

Ga s t ro in t e s t in a l Dr u gs Ad vis o ry Comm i t t e e

155:8

seem s 29:6; 32:2; 44:25;5 9:1 4; 7 5:3 ; 7 8:1 6; 7 9:1 2;8 2:2 2 ;9 6:1 4; 115 :2 ;1 26 :9 ; 1 39 :2 4; 1 76 :2 4

s een 8:1X 11:23 ;46:1;8 4:1 3 ;9 0:1 2; 1 03 :2 2;1 45 :2 5; 1 56 :1 7; 1 69 :11;172:8

s egu e 112:24; 160:25

Segu ein g 150:23

St2iZt? 57:2SeleChd98:12selection 150:12,22Self 35:20self-fulfilling 91:19Senior 10:15; 41:2, 3,9;57:12; 68:4, 9; 172:12sense 23:25; 27:9; 33:3;34:20; 42:7; 50:13, 17;57:14;74:1; 80:11, 15;31:5; 105:5; 130:12;147:15, 18; 151:9; 159:14;172:19separate 23:11; 26:2;30:5,15 ;43:23; 45:11;51:1,2, 14, 17, 18;62:11;56:22;96:8; 112:24;127:1; 128:10, 20; 134:7,3;137:13; 138:24; 139:1;151:23separated 29:10Separately 108:15;151:24sequential 139:22sequestration 135:7SerieS 10:25; 11:15, 19,23; 12:10; 13:6, 23; 14:14;46:22; 139:8serious 121:11; 163:16;165:7; 166:1seriousness 175:10serologic 11:19;3:1,3serum 14:24serve 34:21; 55:2session 6:19;0:19;100:23set10:24;1:7;2:25;37 :9 ,13,3;39:1;40:7 ;59:13 93:7;10:15;111:3,6;12:10;16:24;

126:14;39:8setting 14:16; 20:24;23:16; 52:5; 114:3,4,9;140:17settled 150:15settling 49:14seven 42:22seventies 25:4several 8:24; 14:5; 19:19;24:15 ;31:23; 46:17;107:25; 112:17; 121:14;154:11severe 17:11;46:20;59:18,23 ;82:23;94:11;96:18:126:3:148:18

.Sa ch a r’s - s ize (2 4 ) Min-U-Script@

severity 16:11; 96:14

SF -35 50:2

share 93:6she 6:9; 156:2shitf 37 : 25Shirkey’s 130:18shopping 150:16short 6:12; 76:18; 83:19;123:11; 135:11; 161:17;162:22; 163:17shortened 35:13shorter 85:10; 160:8shortly 139:10should 10:19; 23:22;25:25; 30:2; 37:10, 13;39:11;45:12; 56:17;58:21; 59:12, 14;60:9, 15;6 1:1 , 1 3;6 2:2 3; 6 5:6 ;5 6: 1 9; 6 8:2 4; 7 1 :7 ; 7 2:9 ,14;74:20;89:14,23;)0 :1 7; 9 3:1 7; 1 02 :11;111:8; 112:24 ,25; 113 :3,

3 ; 114 :11; 1 20 :2 1; 1 21 :2 1;1 30 :1 8; 1 32 :2 1; 1 35 :2 ;141:9; 1 47:23 ; 149 :1, 9;1 55 :1 7; 1 56 :1 7; 1 58 :1 2;1 60 :2 ; 1 61 :1 8; 1 63 :1 2;1 72 :1 ; 1 74 :7 , 2 4; 1 75 :6 ,2 5

shouldn’t 44:11; 53:20;57:25; 100:15; 104:12;119:7show 26:13; 27:25;39:11; 51:6; 55:10; 56:8;70:17;78:22; 83:25;39:10;92:20; 98:20;29:14; 136:3; 143:2, 4;147:16; 170:25; 173:5,7;

174:7showed 70:14; 121:15showing 64:14shown 25:4; 43:1; 86:17shows 58:23; 62:18, 18,18; 88:2; 170:25sick 29:12,2,14,14;60:1sicker 94:6; 98:9side 34:18, 18, 18;36:11;66:24 ;84:23; 111:21, 22;138:12; 147:9; 152:5,8,9sides 112:21SIEGEL 38:9; 40:10;

45:10 ;47:18; 50:14; 58:2,18; 59:6; 62:16; 63:25;64:19; 65:4,6; 69:19;70:21; 83:18; 84:8; 86:2;91:9, 15;94:10, 21;97:4;103:25; 107:22; 108:22;113:14; 118:5; 119:2;139:14; 140:9, 22; 145:7;146:18; 149:10; 161:20,25; 162:19; 164:17;166:15, 19; 172:22;175:10; 178:11, 22;179:22sigmoidoscopy 91:1signal 59:5; 160:13;

signal-generating 160:2signals 147:19; 160:13signed 129:19; 131:22;166:20significance 98:21;99:16significant 78:9; 92:6;98:15,19, 20; 99:18;

105:21,24 ;112:1,2;145:21; 146:2; 150:9, 11;165 :9 ; 171 :24

significantly 13o:16;133:15145:12,23Signs 15:2;0:10;9:9,13;39:10,12; 4:3;5:21;61:6;2:25;73 :5;3:24;148:17Similar’ 5:25;9:6;44:10;8:19;9:2;126:23,4;127:5;35:22 ;152:12;71:9similarity 131:18Simon 10:6; 11:17; 28:4,

6, 25; 29:18, 25; 39:7;43:20, 21;44:13, 16;72:23, 24;73:15, 18;77:21,22 ;80:10,11;91:24,25 ;92:24;93:13;102:20; 103:8, 12; 104.11;106:5; 112:16; 114:13, 14;133:4; 152:2; 153:2;154:17; 155:21; 156:12;157:1; 158:1,4; 168:9;170:6; 171:14, 23; 172:5;176:5, 6,9; 179:18simpIe22:14; 32:14;57:5; 109:8simpler 68:18

simplicity 57:4; 67:12simplify 63:9simplistic 52:9simply 23:15 ;31:14;88:8; 93:8; 151:16Sinai 9:1; 46:8; 154:2since 19:8; 23:5; 45:2;66:21 ;96:13; 103:12;121:15; 132:11; 140:3;151:23single 47:12 ;72:6;103:16; 143:3; 160:9SIP 50:3sit 59:8site 18:2sitting 66:17situation 91:23; 151:13,18, 20; 162:13; 166:18;179:20situations 83:11; 166:7six 37:9; 39:11; 56:9, 11;109:11; 131:6; 135:3;161:3,7, 13; 162:17;163:1; 164:19,21,22, 23;177:5size 89:20; 94:1; 127:13,13; 137:19; 145:4; 157:23;160:20; 164:4, 5; 175:4;

163:22 i 176:9,14,15, 19, 19;

Mille r Re po r t in g Co m pa n v, In c .



——.-

–—-

F ood & Dru g Ad m in is t r at ionGa st r oin t e st in a l Dr u gs Ad vis or y Comm i t t ee

177:11; 179:2SiZt?S 166:8

skew 93:22skewing 100:5Slide 11:6; 12:7,9;13:12;4:11;5:9,23;16:9,16,3;17:22;8:22;19:18,4;20:4,14,0;

21:3,9,4slides 10:25; 11:4slight 97:1slightly 19:23S!Oppy 93:23slow 170:17SIOW[y 120:6small 36:14; 46:21; 84:5;95:25 ;97:23; 98:21;131:11;134:7; 148:12;151:6; 152:14,18, 19;154:7,9,10, 12, 16; 155:9;156:6; 162:3; 166:4;169:18; 177:16,19

smaller 55:9; 95:10;136:11; 162:1, 10; 165:20;177:8smallest 173:15SO7:16, 19,23 ;8:12; 9:2;10:4, 19, 20; 12:21; 13:13;16:17, 24; 17:23;21:15;25:21; 26:24; 27:5; 28:10,22; 29:5; 30:24; 31:7; 32:4,20; 36:4, 18; 37:18, 24;41:10,24 ;43:3, 14, 16,24;44:23; 45:22; 47:23, 25;48:4; 51:8,10, 25; 53:3,13;55:11,22; 56:14;57:22; 59:25; 60:2, 23;

61:1,3,6; 62:10; 63:18,22;64:9;65:11, 18, 21,23;66:6,21 ;67:8,11; 69:11;70:16, 20; 72:16, 25; 73:9;74:1, 10;76:22; 78:3, 13,23;79:9, 23;80:4; 82:9,14,16, 16,23 ;83:24;84:17; 85:3; 88:24; 90:14;92:13 ;93:24; 94:10;98:20; 100:8, 9; 101:21;102:5,16, 22; 103:3,10,16, 24; 104:9,14,19, 23;106:17,23; 107:2, 11,14;108:22; 109:5, 14; 110:22,24; 113:21; 114:7, 17,23;115:17; 116:24; 117:18;118:22; 119:22; 120:8, 12;121:3, 17; 123:1; 124:10;125:14, 22; 126:8,12, 14,18, 19; 127:9, 17; 128:6,19; 129:1,21,24; 130:21,24; 131:15; 135:23; 136:6,21; 137:21; 138:2,7, 14;139:13; 142:16, 17; 143:8;144:6; 145:19, 21; 147:4,24; 148:6, 15, 16; 149:18,21;150:1,20; 154:12;155:9; 156:4; 161:23;162:3,21; 164:14; 165:9;166:17; 168:5,9, 25;169:23; 170:1; 172:9;

173:24; 175:17; 177:1;

1 78 :2 , 9 ; 1 79 :6 ,9

so-called 106:11; 172:7Society 96:15soft 37:15softer 36:20Softky 129:23SOftly 99:25sole 49:4,6solid 173:9solutions 18:23some 4:5;6:21; 7:4, 18;10:3; 13:1,3,5; 15:21;17:14; 18:18,20, 23; 20:2;21:5; 26:9; 28:8; 29:22;32:11,19; 33:1; 34:15,21;36:7,18, 25; 39:15; 40:12,22; 42:11; 49:2; 50:14;56:9; 57:21; 61:9, 12; 67:6;68:11, 17;71:15;75:21;76:6,8, 24; 77:16; 78:12;79:24; 80:15,16, 23;82:22; 83:9,15, 22; 87:17;

88:9; 92:19; 95:3, 17; 99:1,2,3, 13,25; 100:5; 101:13,19, 22; 102:3, 14; 105:5;106:7; 113:17; 114:7;116:6; 117:7, 22; 118:20;126:2; 129:16; 130:6, 10;131:14,16,20, 24; 132:12;134:19; 135:1, 14; 137:16,17,22; 138:13, 22; 141:6,22; 142:5; 144:7, 13;145:22,23, 24; 146:1;147:17; 148:2, 19; 150:10;151:5; 160:6, 20; 162:1, 5;168:3; 170:16; 172:14,14,19; 173:25; 174:14somebody 29:10;62 :17;50:14;0:6,;94:10,3;97:11;04:1;10:9,9;121:17 ;50:25;68:16somehow 36:5someone 56:4;8:19;93:25something 7:9; 20:21;26:5;39:9; 52:18, 22; 54:6;55:18; 56:10; 57:7; 58:22;67:11, 11;77:1,1,11,12;B2:7;84:8; 87:25; 88:12;92:14; 99:15, 22; 100:1;106:11; 107:4; 109:14;112:6; 114:6, 11;115:6;116:1;25:6;26:8;129:9;33:23;36:10,15,16;137 :16;41:12;147:19;48:14,6;153:17 ;54:19;55:13;156:10,4;157:20,4;158:24 ;64:14sometime 141:18sometimes 23:12; 49:21;70:23; 114:8somewhat 5:14; 65:15;57:25;76:4; 84:8; 136:10;163:24somewhere 56:7;112:19; 115:19; 132:12;

175:1

sophisticated 99:17sorry 80:23; 123:5sort 27:23; 30:14; 33:19;37:2, 25; 49:8, 13; 57:22;68:15; 74:24; 79:14;82:22; 87:14; 88:17; 96:5;106:16; 114:7; 115:19;134:11;150:15; 152:25;163:7; 165:6; 176:13sound 173:9sounds 151:22; 177:5space 115:24span 101:13spare 120:14Spating 23:23; 27:20, 22;49:5; 50:10; 55:25; 61:14;62:5,8, 24; 63:3,4,6,10,11; 19, 25; 103:22, 25;104:5,9; 107:3; 116:5;119:11, 12; 124:1speak 9:2; ll:3;65:18;90:4speaking 81:10; 87:1 1;140:19SpeCial 148:19SpeCifiC7:22; 10:3; 32:8,18;39:13; 61:13 ;63:2;36:14,16, 22;95:20; 96:3;[15:7, 10; 136:13; 141:19;145:14; 150:3; 158:10;159:13; 161:21; 163:22;~64:9;166:17; 177:8specifically 9:16; 23:12;}1:22; 40:23; 50:16;52:23;88:13; 95:24;[27:10; 131:25; 132:20;[38:18; 139:2, 4; 145:8,9;

[46:17; 150:6; 161:2, 25;[62:3; 167:17; 179:16specificity 17:12;peCifics 39:15; 79:22;L35:11

;p.ecified 32:1o; 171:13,[5;peCify 178:13;pectrum 165:18, 24;peculation 134:20;[57:4;peed 6:11;poke 13:2; 109:13;poken 137:20

;pondylitis 14:7;ponsor 58:1; 81:25;.10:16, 17;113:24;.20:21; 121:4; 126:23;.27:18; 128:19; 132:24;.41:4, 10, 18;pOnSOr’s 127:11;ponsored 129:6;38:18;ponsors 5:16; 38:13;‘4:14, 16;81 :17; 136:7;48:5;pontaneou$.dy 24:8;pread 87:22; 88:19

;tage 64:5; 82:22

Mille r R ep or t in g Co m pa n y, In c . Min-U-Scripti

Hea r in g Vo lu m e Nu m be rMa y 29,199

stages 7:14;1:20

stance148:23Standaert4:5,;179:24

standard7:11;6:16;86:19;93:22;6:7;107:13;13:16;14:19,21;134:6;59:11 ;61:18;168:13,8;169:1;70:4 ;171:10

standardized170:2standards 32:25; 66:5standpoint 11:25; 12:2,3,4,4,6; 13:18, 21; 20:5;21:17, 23,24; 31:15;38:15; 51:14; 52:8,9; 68:2;70:16; 85:14; 93:8; 94:16,17; 101:2, 3; 106:2;138:13; 148:4standpoints 11:25Stanford 34:7start 22:11; 38:23; 39:21;46:16; 59:4, 4; 64:25;

106:22; 109:1; 116:14, 16;118:17; 119:2; 124:14;127:25; 134:13; 144:7, 7;170:22, 24; 178:16started 47: 11; 86:8;114:4,8; 142:17; 144:8;151:7starting 49:10; 91:20;103:18,19Starts 6:9state 18:8; 42:17; 53:8,16;71:1; 77:14 ;80:19;12:2;133:16stated 26: 15;89:6;151:18;157:13; 158:21;160:23;tatement 5:11; 41:16;13:15; 111:24; 114:20;136:12; 142:11;tatements 4:23; 22:20States 9:6statistical 87:1 1;89:12,[7; 95:4; 96:3, 9; 97:13;)9:16; 101:6; 117:18;tatisticai[y 93:20;)8:15, 18; 99:17statistician 31: 15; 151:7;171:22statisticians 18:16

;tatistics 97:8; 98:4;100:7,13status 42:19; 64:6;tay 117:17; 121:22;tayed 48:13;taying 64:24; 65:1;tays 25:18STEINBERG 177:4;tenosing 125:15, 18, 22;tep 7:15

Nephen 6:25;tepping 117:21stereotypic 149:17

;teroid 23:23; 25:10, 19;

27:20, 22; 49:5; 50:9;55:25 ;61:14; 62:5,8; 63:4,6,10,11,18,19, 25;91:10;01:7,8,9;02:7;103:14,18,2,25;104:4,9;106:19,3;107:1,3,4,8,9,10 ,2;108:18 ;109:16,20,0;110:1,2,4,4;115:8,8,15, 2;116:2

5,11,22;117:2;18:6,9,11,17;119:4,0,12,15,19,24;120:10,20,5;122:2,4;123:25;66:6;169:13steroid-dependent106:12, 14; 120:15;121:13122:3,5,10

steroid-induced 26:24steroid-sparing 106:19steroid-t rested 25:12,18steroids 15:20; 25:2,3,4,7,10,11,13, 1 6,2 0; 2 82; 3 5:7 , 1 2; 4 6:11; 4 9:1 ;56:11; 62:6,10,19, 24;63:5 ,6; 6 4:7 , 11 , 15;6 6:969:1 ; 75:1 4 ;91 :2; 1 01 :510, 13,19, 24; 102:13,1 04 :2, 3,6 ,7; 10 5:2 4;1 06 :3 ,1 6, 2 4; 1 07 :11,1 8,2 0; 1 08 :9 , 2 1; 1 09 :5 ,1 4,1 7, 1 9; 110 :6 ; 111 :7 ,1 9,21; 11 2:3 ,7,9 , 14 ; 115:225; 117:17; 119:5,6, 22120:2,6,9, 12,14,23, 2122 :20 ,24 , 2 5; 17 0:2 1;171:7,19

St eVe 22:4; 27:8; 34:1;5 3:1 9; 5 6:2 3; 7 2:1 7;7 3:2 3; 7 7:7 ; 1 06 :1 8;116 :1 5; 1 28 :2 5; 1 31 :1 9;1 33 :2 1; 1 35 :2 1; 1 36 :1 6;170:6

N i[l 19:15; 20:5, 12, 182 9:1 9; 3 0:3 ; 3 4:3 ; 4 7:1 4,1 6; 5 0:2 4; 5 5:1 7 ;6 1:2 5;f8 :5 ; 7 9:1 4; I 05 :1 6;109:12, 13; 119:14, 17;1 20 :2 ; 1 29 :2 4; 1 53 :1 6;172:2,10

~t imUla te 7:20; 8: 17;26:17

st om a 130:2

st om as 129:6,25st op 28:1, 2; 63:5; 70:1112 :12; 178 :4

stopping 75:10straddles 54:19straightforward 117:20street 112:21stressors 157:10strong 151:15Stronger 176:20structural 28:9, 15;?9:16, 18, 22; 39:18;i3:22; 73:6;tructure 29:8, 14, 24;

;1:6

{25) s ize s - s t r u c t u r e



Hea r in g Vo lu m e Nu m be r 2 Food & Dru g Adm in is t ra t ionMa y 29, 9 9 8 Ga st r oin t e st in a l Dr ugs Ad vis or y Comm it t e e

struggled 162:24struggling 53:13s-+ied 127:17; 133:7;

; 172:9; 173:19,20studies 24:18; 25:2, 3,8;42:21 ;43:1; 55:9; 56:3;60:9, 11;69:21;0:17;71:22;2:8;8:2;9:13;

101:18;25:20;26:20;128:3,6,17, 8,20;129:4,14;130 :25;31:9,3;132:2,4;134:14,7;135:14 ;36:13,17,19,21 ,25;137 :12,3;138:19;139:11;40:12,15,5,21;141:18;42:13;43:10;144:7,7;146 :5,;147:11,13,15, 6;148:19;152:8;54:1;60:2,14,21;163:4;64:5 ,6;167:20;70:14;71:5;172:10

study 4:22; 39:1, 10;

43:8; 46:25; 55:16, 18;56:5; 60:11, 24; 62:17;68:19, 24; 69:20, 23; 70:9;72:14, 15;73:25;74:10,21;78:7, 16;81:4; 83:17;84:5; 86:20, 25; 88:3;89:18,22 ;90:12; 94:10;98:15, 20; 104:5; 121:23;

studying 127:23, 24;133:25; 153:21subcategories 61:20subcategory 63:12, 13,16subdivision 24:5subgroup 124:3, 4;145:2, 3; 147:14, 17;148:10;151:1,6,8; 154:4,5subgroups 13:5,6;18:25;20:1; 25:8; 128:5;151:10, 14; 154:7; 177:2subject 100:24subjecting 157:9subjective 13:18; 17:3,21;51:11subjects 161:8

submission 131:24submit 131:16; 135:20submitted 4:11; 131:21submitting 4:24; 144:3suboptimally 169:5subpopulation 155:19subsequently 128:7s’%et 19:13; 40:16.

tance 135:17substantial 131:7; 140:4substantially 86:24;171:7ubstantiate 144:20

ubstitute 55:8

t ru ggle d - t h at (26)

subsumed 23:25subtext 108:1success 23:20; 24:21;47:17; 49:4; 86:21; 179:10successes 86:22successful 104:7successfully 20:6;41:11 ;62:17;64:15

succinct 22:5such 4 :1 0; 5 :5 ; 7 :5 ; 8 :2 2;11 :4; 12 :24; 13:3, 10 ; 1 4:4,7,8,20, 22; 16:4, 13; 17:1,2 , 1 3; 2 2:5 ; 2 3:2 3 ;4 1:1 3;5 1:1 5; 6 6:5 ; 8 6:1 8; 9 5:11;1 06 :1 3; 1 25 :9 ; 1 31 :1 2;132:6; 137:12; 142:4, 4;1 46 :2 5; 1 48 :2 ; 1 66 :3 ;168:5

suffice 174 :4 ; 179 :8

s ufficien t 65:13; 69:3;1 27 :1 3 ;1 31 :1 7; 1 33 :1 6;1 34 :1 8; 1 47 :2 4; 1 62 :1 8

su ggest 20:9; 44:13;6 8:1 9; 9 4:2 1; 1 26 :2 ;152 :11; 168 :10

suggested 18:25; 19:3;20:15 ;30:1; 120:1;129:15; 138:10,13suggesting 30:17, 20;38:18 ;44:14; 58:17,18,19;64:3; 101:19; 137:7,8suggests 65:23; 154:3Sulfasa[azine 14:22SUmmariZe 25:21superb 75:1o, 17superior 66:3superiority 173:5support 6:2; 57:3, 8;88:24supported 67:13;135:14; 136:15supporting 131:17;135:5supposed 124:16suppressing 112:6suppression 146:9;152:4; 167:2SURAWICZ 31:2; 50:12;51:8; 66:21 ;109:10;122:17; 123:15; 176:22,23sure 46:20; 50:16; 52:23,25; 53:10; 54:14;86:3;94:16; 95:21 ;127:3;128:25; 139:13; 140:12;151:15,20; 159:7; 173:6,16surge 132:14,5surgeons 68:1surgeries 130:21surgery 18:7; 66:10;82:24; 83:7, 10; 125:5;165:10surgical 9:17; 16:22;18:7; 19:14; 24:4; 50:7;

68:2

surrogate 58:3survival 58:6susceptible 59:24suspect 33:12; 44:9;160:20sustain 105:9; 106:3sustainable 106:8Sweden 51:18Swedish 43:1; 57:6swim 82:2,6Swiss 135:13symptom 18:13; 36:11

sympt oma tic 13:20;26 :23; 3 2:14 , 22 ; 3 3:17 ;49:17; 59:3, 19; 60:7, 14;65:9 ; 109 :14

sym pt om at ology 56:15;119:7,9

symptoms 13:15,9;16:14 ,19,9;18:1,3,5,12;20:10;3:6 ,;27:2;28:12,20,2;29:9,3;39:1O,2;41:18;4:3;45:20,20,4;49:17;1:7,13,20;52:21 ;5:23 ;8:7,9,20;60:1 ;1:7;2:14;63:7;3:1,;75:8;6:19;83:20,4;105:20;08:11;117:5,7;23:4,5,4;148:17syndrome 17:10; 28:19synonym’ 64:16,21synovitis 35:25system 29:2, 7; 36:6;41:6,9Systematic 118:21

systematically 118:25;129:4, 12; 130:7; 133:25;134:13SyStemiC 104:18

T

T16 88:3,15, 20;90:4T20 40:24; 47:11; 88:7,15,20TA 99:13table 5:24, 25; 33:2tables 137:25; 138:5

tackle 101:4take 6:19; 7:21, 25; 10:18;34:3; 47:8; 62:11 ;64:4;75:15; 89:6; 95:25; 98:1;100:17; 106:22; 109:6;114:5; 120:21; 121:8;122:25; 136:2; 137:20;138:20; 141:10; 142:16;143:6; 148:21, 22; 168:16;169:10; 176:14; 178:9;179:4take-over 79:11taken 45:ll;84:l; 96:4;139:22takes 108:15; 123:22;

139:11; 177:17; 179:1

Min-U-Script@

taking 24:20; 38:3; 63:5,5;86:9; 96:16, 25; 155:6;157:9Talarico 8:13, 15; 179:21talk 23:10; 24:4; 27:21;30:23; 32:3; 49:15; 58:19;63:2; 68:14; 86:23; 110:8;115:3; 117:1; 125:7, 14;

146:4, 17; 157:2; 175:25talked 27:10; 42:4; 61:10,11;86:13; 101:16,22;119:3taking 25:22; 27:12, 16,16, 17;29:1; 30:23 ;33:3,7;42:3; 59:12 ;66:12;69:12,14, 17;72:13;76:24; 77:25; 82:14;83:11 ;84:9; 85:20,21;87:20; 96:15; 98:3;102:10; 103:16; 105:19;107:23; 108:3, 7,8;109:18; 110:1;15:9;116:8;25:16;26:16;

146:12,3;150:13;152:13,21,24 153:2,22;154:5,,6;156:19,21;157:25;58:1,,4;162:25;63:2,5,14,18,20;164:6,;166:18;76:1talks134:2tangent174:12taper 62:19; 64:10; 105:8;116:16; 117:14; 119:5;170:22tapered 104:6; 117:12tapering 104:7,14, 16;116:7,21, 22; 117:5;

118:17; 119:15;122:12,14Targan 13:2target 154:21; 155:2;156:14, 18; 158:11targeted 155:10tastiest 144:4teach 82:2team 166:21techniques 10:11;97:14;99:9technology 28:10;44:21,24 ;92:8tell 123:13, 17; 127:3, 15;

128:12; 175:12telling 67:ll; 124:12;174:24tempo 124:23temporally 139:22tends 15:12; 167:5tens 99:13tenth 99:15term 23:5; 31:3; 36:3;43:11 ;76:16; 77:17;80:12; 83:19; 107:14;113:8; 119:1, 20; 125:7;162:22terminology 68:22;

113:10

terms 32:13, 22; 33:11,16;34:11; 36:3; 38:1; 39:6;42:4; 47:5, 9;66:6; 84:9;97:17; 108:15; 126:6;131:8; 144:24; 145:18;152:16; 159:14; 163:22terribly 58:24test 117:18; 167:19

testable 157:14tested 98:7; 127:8, 9;157:17; 166:6testing 159:14th 146:25thalidomide 75:14,16,18than 5:15; 18:4, 9; 22:16;23:3; 25:16,22, 24; 26:2;31:12 ;32:4;33:23; 35:5;36:21; 39:23, 25; 40:1 1;43:12; 46:23; 47:24; 48:2,9;56:18; 66:11 ;67:16;73:8; 76:4; 77:3; 78:7, 13;

65:1,4 ;95:13, 16; 101:25;102:3,21,22,22, 23;103:5; 105:14, 15; 107:13;108:7; 110:25; 112:22, 23;116:17; 124:12; 125:1;126:15; 128:14; 130:2;136:11; 144:7; 149:21;152:8; 154:24; 155:3;159:20; 160:8; 161:3;162:10; 163:13; 165:20;166:8thank 5:15; 6:17; 8:6, 8;78:9; 177:25; 179:16,21Thanks 34:1that 4:13; 5:l,8,11,24;

5:4,23,24, 25;7:2, 5, 11,12,16,18,21,23,23, 25;9 :10,1 5, 16,2 1 ;9:1 0;1 0:5 ,1 3,1 9, 2 2; 11:1 0,1 2,1 6, 18, 19; 12:10, 14 ,16,18,21 , 22; 13:3 ,4 ,5 ,6 ,7 ,), 14; 14:4,5,7,9, 15;15:12,16,20,21, 25; 16:4,5,6,14, 18, 19; 17:13, 20;18:9, 24; 19:20; 20:9, 21;2 1:6 ,7 , 1 5,2 1,2 2 ;2 2:1 ,2 ,3,13,14,19, 20; 23:8, 11,14, 14, 14, 18; 24:6,6, 10,11,1 4, 1 8,2 3 ;2 5:1 ,11,13,16 , 23; 26:2 ,7 ,18,19 ,19; 27;8, 9,21,22, 25;28:8,8,10,13,16,19,21,25;29:1,4,6,6,7,9,10,18, 19; 30:1,18,22, 24;31:2,3,5,6,12, 12, 19,20,24,24 , 24; 32:2 ,6 ,8 ,9 ,10,15, 15; 33:3,3,5,7,9,12,13, 25; 34:3,15,16, 17;35:2, 25; 36:4,6,18, 25;37:15,17,24,25, 25; 38:1,20,22, 25; 39:2,6,10, 11,1 5, 1 5,2 0, 2 0; 4 0:6 ,7 ,9 ,1 7,2 1,2 3,2 5 ;4 1:1 ,6 ,9 ,12,22 ;42:5,11, 12, 19;43:1,3,4,5,8,10, 18,23;44:1,7,8,9,13,14,15, 18,

22,22;45:1,3,5,9, 0,12,

Mi lle r R e u or t i rw C omn a n v. Inc.



Food & Dru g Adm in is t ra t ionGa s t ro in t e s t in a l Dr u gs Ad vis or y Comm i t t ee

He a r in g Vo lu m e Nu mbe rMa y 29, 9

16, 16,22,23,25, 25;46:1,2,3,3,16,18, 2W

_—_ 47:3,4,5,14,16,17,18,19, 23; 48:14,16,20,21,23, 24; 49:2,5, 16; 50:1,4,6,9,14,15,16,17,20,20,22, 23; 51:4,6,9,10,15,15,21 ;52:5, 11, 14 ,16,1 8,19,19,19, 23; 5 3:1,3,

4,5,5,6,7,9,10,11,12,16, 18,19,20,21,24, 25;

54:1,5,11,13,15,16, 18;55:2,5,12,13,16, 19;56:2,4,5,6,9,10,16,19,19; 57:7,14,16,23,25,25; 58:4,4,5,8,14,16,19,21,22,23,24, 25; 59:9,11,11,12,13,14,14,18,19,23 ;60:5,7,7,21,21;61:8,12,22,22,24, 25;62:4,4,6,18,18,18,23,25; 63:2,3,16, 20; 64:6,12, 14,20 ;65:15, 16, 23;66:3,18,23,24, 24; 67:8,

10,10,14, 25;68:3,6, 15,15, 16,21,22 ;69:3,5, 12,15,16,21, 23,24 ;70:2, 5,7, 12, 14,21,21,22 ;71:3,6,10,14,16, 17;72:2, 3,10,15,19, 24;73:3, 5,7,11,19 ,21,24 ;74:1 ,2 ,10,12, 18,20, 24;75:1, 12,

.~ 13,18, 19;76:7, 12, 12,14,15,21,25,25,25, 25;7 7:4 ,8 , 11,1 2, 1 5,1 5,1 9,23, 24; 78:1,2,3,7,13, 16;79:8,12,14,19, 23; 80:2,5,13,13,16,17,18,19,22;81:4, 5,6,7, 14,16, 19;82:2,3,4,8,9, 16,19, 23;

8 3:2 ,3 ,7 ,1 0, 1 4,1 5,1 5,1 6,1 7, 2 4;8 4:3 , 3 ,6 ,8 ,1 7,20,22 , 24; 85:3 ,12,12 ,16 ,1 7,17,22, 23; 86:7,8,13,16, 23;87:8, 10, 25;88:8,9,12,13,17, 25;89:2,9,11,12,17,21,22,23, 23;90:1, 2,3,8, 10,14,15,17, 19;91:6, 11,18,23;92:4,6,7,9, 10, 13,13,14,15,17, 17,20 ;93:1, 1,3 ,3,4,10,13,1 4, 20;94:3 ,4 ,8 ,1 3,1 5,2 1 ;9 5:4 ,6 ,8 ,9 ,10,13,17,23 , 24 ;96:3,5 ,2 1; 9 7:9 , 1 0, 1 4,1 8,2 1,23,23 ;981,1,1,4,6,7,8,16, 17,19, 22;99:11, 18,23; 100:3,4,5,8,8,9, 15,24, 25; 101:3,5,11, 19,20, 2 5; 102:3,17, 18,2 1,22, 25; 103:2,2,9,12,12,21; 104 :2 , 12,15 ,16,20 ,24 , 25; 105:1, 2; 10 6:3,5,

_ 7, 10,14, 15, 18,20;107:2, 12,17,19,19,19,23; 108:2,2,3,10, 12,16,16, 20; 109:6 ,6 ,14 ,15,1 9,2 1,2 3, 2 5; 110 :1 0,1 4,1 5;111 :6 ,7 ,7 , 1 6;112 :6 ,12, 13,13,16,18,20, 23;113:7,8,8,9, 4,15,19,

20,24 ; 114:1,2,11,11,14,14,16,17,18,19,22,24;115:1,2,3,12,14,19,19,21,21,23,23 ;116:1,2,2,7,12,13,24, 25;117:3,4,8,13,17,17,19,25; 118:2,5,8,14,14, 18,20,23, 24; 119:22, 23;120:1,2,4,5,6,9,10,11,

13,20,21,22,23 ;121:2,5,6,9,9,10,12,13,13,15,19,22,24, 25; 122:6,7,8,9, 11; 123:2,2,6,7,10,14,16,17,18,21, 22;124:3,4,8,17,19,22, 24;125:3,7,7,9,16, 19;126:2,3,9,9,12, 14;127 :3 ,4 ,5 , 12,15 ,20,21 ,22, 22; 128:9,13, 17;1 29:2,9,11,14 , 15,16 ,21; 130:1,6,7,12, 17,22;131:3, 19; 132:12,23, 24;133:2 ,3 ; 134:1 ,2 ,3 ,4 ,4 ,6,6,10,15,16,17,20,22,

2 3,2 5 ;1 35 :1 , 11,1 2,1 8,24; 136:4,6,6,8,13,15,1 7,1 8,1 9, 2 2; 1 37 :1 4,2 2;138:1,5,7,8, 12,15, 18,19,19,20,22, 24; 139:1,6,12,16, 17,19, 19, 21;140:5,8,9 ,1 3, 20; 141:2,10, 12, 14, 15, 18,20;142:1,4,6,9,11, 14, 18;143:2,3,4,12,17,20, 23;144:5,11, 16,18,19, 19,20; 145:4,7,11,12, 25;146 :9 ,15, 21; 147 :2 ,3 ,5 ,12,23 , 24; 148 :4 ,4 ,6 ,9 ,11; 149 :3 , 25; 150 :2 ,7 ,10,15 , 17; 151:6 ,7 ,10,12 ,1 4,1 9,2 1, 2 5; 1 52 :3 ,7 ,10,11,16, 22,24; 153:1,4,4,6,9,10,11,13,14,1 4,19,22,23, 23; 154:15,1 9,2 2,2 3, 2 4; 1 55 :1 ,1 ,2 ,6,8,9,10,11,12,13,14,17 ,18 , 18,21 ,22,22 ,24,25; 156:6,7,8,9,9,11,13,15,18,21,24, 24; 157:4,5 ,7,7,8,8,10, 10,12,1 3,1 4,1 5,1 5,1 6, 1 6,1 7,1 7,1 8, 1 9,2 1,2 3; 1 58 :1 ,5 ,6 ,1 0,1 5,1 5,1 6, 1 7,1 7,2 0,2 0,20,21, 24; 159:3,5,13, 21; 160:19, 23; 161:15;

162 :5 ,14, 17; 163 :1 ,7 ,8 ,9 ,1 3,1 3, 2 3; 1 64 :2 ,8 ,11,17,18, 19,20,22,22, 25;165:2,4,6,6,13,15, 18,20, 22; 166:5,6, 19 >2 1,22; 167:3,4,7,7, 21;168:1,2,1 0,14, 14,16 ,16,21 ,25; 169 :1 ,1 ,4 ,5 ,10, 16,17, 19, 20; 170:5,12,19,21,25 , 25; 171:10,18, 24; 172:1,6,6,8, 13;173:2,6,7,10,13,14,15,18,19, 19, 23,25; 174:1,4 ,8 , 16,24 ; 175 :5 ,5 ,6 ,6 ,13,23 , 24; 176 :1 ,6 ,13,14, 18, 25; 177:12 , 12,14,

Mille r R ep or t in g Co m p an y , In c .

18;178:3,;179:7,7,8,9,9,12,14That’s 29:25; 68:10;156:16The4:7,8,9,10,11,11,12,14,16,21,22,24, 25;5:1,1,2,3,4,6,8,11,15,16,17 ,18, 18, 24;6 :2 ,4 ,4 ,8,8,10,12,14,18,21,24,25 ;7 :2 , 3 ,6 ,7 ,9 ,10 ,13,14,15, 16,25 ;8:1, 3, 12,17, 19) 21,24, 25;9:1, 7,10,12,13 ,1 4, 17,22;10:4,7,8,1 5,19, 21,2 4;11:7,8,10,12,14,16,18,23,25 ;12:1 , 1 ,2 ,3 ,6 ,13,16,18,23,23, 24; 13:6,10, 16; 14:9,15,16, 24;1 5:5 ,5 ,7 ,1 0, 11,1 4,1 8,21 ;24 ; 16:1,2,6,11 ,11,18,21 , 24 ; 17 :2 ,3 ,6 ,6 ,6 ,10,12,17,19,21,23, 24;181,5,10,12,14, 17;19:1,3,4,7,9,9,10, 10,

1 5,1 7,2 0, 2 3; 2 0:3 ,7 ,8 ,11,16 ,22,24 ;21:1 ,6 ,8 ,12, 16,1 7, 18,2 1, 22,23;22:6,8,12,13,15, 17,18,18, 19 , 19,20 ,20 ,22,22 ,23, 24; 23:3,4,11,15,19,19,20, 20;24:1,6,7, 12,13,15, 17,18,20, 24;25:1,3,5,6,9,11,12,13,1 3,1 7,1 8, 1 9; 2 6:1 0,1 4,1 5, 1 9; 2 7:5 ,6 , 1 0,1 3,1 4,15, 15,20,24,25 ;28:1, 1,2,2,4,7,11,17,19,22,25 ; 29:3,13, 2 3; 30:1,8,13,14 ,21,23 ;31:2 ,3 ,5 ,1 5,1 6,2 0, 2 1; 3 2:8 ,9 ,1 0,

11,14 ,17 ; 33:1,1,2,2,3,3,5,6,7,10,12,15,15,20,21 ,21,25 ;34:1 ,3 ,7 ,9 ,9,16,18,18,18,19, 21;35:2,3,4,4,6,7,8,9,13,1 4,1 5,1 7, 1 7,2 1,2 5;36:1,5,5,6,12,14,21,24;37:1,2,6,6,7,11,14,18,2 1,2 4 ;3 8:2 ,7 , 1 3,1 3,1 6,19,21 ,25,25, 25; 39:4,4 ,7 ,8 ,1 0,11, 1 2,1 4,1 4,2 3,23;40:1,2,3,3,4,4,4,11,11,12,17,22,22,23,24,24, 25; 41:4,5,7,9,17,17,18,19, 19,19,20, 20;

42:1,2,3,7,9,9,11,12,15,17,18,19,19, 20,21;43:4,7,7,8,11,14,16, 22;44:4,4,8,21,2 1, 22;45:2 ,6,10,12,13,13,17,18,22;46:1,2,5, 10,14, 16,2 0,2 3,2 3, 2 5; 4 7:1 ,2 ,4 ,6 ,7,8,9,11,11,13,15,15,22,23, 25;48:16, 17, 19;49:4,5,6,9,22, 24; 50:8,14, 17,17,19,22,22, 24;

I51:1,2,3,6,12,19,21,21,22, 25; 52:3,5, 12,15,18,22, 24; 53:13,14,17,19,23; 54:1,4,4,5,13,13,14,16, 16, 18,18, 19,21,22,

Min-U-Script@

—

23;55:1,3,4,7,8,8,11,16,17,21,22,23,23,23,24,24;56:1,1,2 ,4,4 ,5,5,6,8,10,16,17,17,19,23,25;57:1,4,8,8,9,10,13,14,15, 7,20;58:6,9 ,2,13,20,22,22,3;59:3,4,10,17,18,21,21,22,23,23;60:1,9,1,12,13;

61:23;2:1,6,9,6,19,19,21;63:1,7,18,19,23;64:1,1,12,18,24;65:1,8,18,3;66 :1,2,2,3,3,4,10,11,14, 9,21;67:1,2,3,5,6,7,8,9,10,12,15,17,8;68:1,3,4, ,5,12,14,18,18, 4;69:19,20,20,21, 2;70:2,9,12 ,15,16,20,21,23;71:2,4,6,6,8,9,18,20,20,21,22 ,22 ,5;72:7,7 ,7,9,10,10,11,13,14,24,25;73:1,4,10,11,12, 2,17,19,9,21,2574:6,7,

7,8,17,22,23,24, 5;75:1,3,4,13, 9,20,21;76:6,8,8,8, 3,14,16,16,18,19,21 ,5;77:8,3,18,22;78:1,3,3 ,5,5 ,5,8 ,10,10;79:6 ,8,10,10 ,10,14,15, 9;80:1,,2,3,3,5,5,12,19,2;81:3,4 ,4,5,6,8,10,11, 2;82:3,6,9,14,20,2183:5,6,6,8 ,10,12,14,23,23, 5;84:3,4,6,11,14,20, 3;85:18,1;86:2,3,,9,9 ,12,12,15,16,17, 8,19,21,23,4;87:2,4 ,,6,14,15,17,8,19,21,22,22,25;88:2,,3,4,5,5 ,6,7,7,7,8,13,14,14,15,16,19,19,20,20,21,21,22,25;89:1,3,4,8,9,18,22 ,23;90:2,3,4,8,9, 1,12,13,18,20 ,21,4;91 :7,7,9,10,14,15,16,17,18,22;92:1,,1,4,7,9,10,11,15,15,15,6;93 :3,4 ,5,11 ,16,17,20 ,21,22,24;94:4,,6,7,7,8,9, 1,12,18,25,5;95:12,22 ,24,25;96:1,,4,7 ,7,13,16,19,5;97:4,0,11,13,15,8;98:3,4,5, 0,

16,17,22,3;99:2 ,3,4 ,6,8,13,20,23,4;100:4,9,16,25;101:6,6,8,0,10,11,13,16,7,18,22,4;102:6,0;103:4,5,14,15,17,17,18,20,0,21;104:3,6,8,11,12, 2,16,16,17,20,21 ,4;105 :1,4,7 ,11 ,12 ,12 ,7,18,23 ,25;106:5,7,0,11 ,17,17,19,21 ,24107:1,2,3,3,4,9,10,11,13,15,19,20,21, 2;108:1,4,5 ,6,8,8,17,20,23,5;109:1,3,4,13,15,18,24, 5;110:2,2,3,4,6,6,8,9, 3,

13,14, 14,19; 111:1,1,8

9,12,14,18, 24; 112:4,17, 17,18,20, 21; 113:56 ,1 0,1 5, 2 4; 114 :2 ,2 ,4 ,91 5,1 5, 1 9,2 0; 115 :6 ,1 0,11,13,15,17,19,22,24,25; 116:4,5,7, 14,15,17,17,19,24, 25; 117:12,2,4,6,10,11,12,18,

19,20,23,24, 25; 118:12,6,9,10,16,18,18,19,1 9,2 0,2 2, 2 4; 119 :6 ,1 2,15, 17,25 ; 120 :3 ,9 ,14,1 8, 1 9,2 1,2 2; 1 21 :5 ,6 ,9 ,11, 11,11 , 12,24 ,24,24 ;122:1,1,2,3,5,9, 14;123:3,4,6,7,8,12, 20;124:4,5,7,8,9,9,11,16,19,21,22,23, 25; 125:2

3,4,4,12,12,12,16,19,20 ,21,24 ;126:1 ,3 ,4 ,4 ,5 ,1 0,2 2,2 2, 2 3; 1 27 :4 ,5 ,8 ,11,15,18,20, 25; 128:29 ,13, 25; 129 :9 ,12,17 ,

22,25; 130:1,2,5,11,12,12 , 15, 17 ,23; 131 :3,5,10,10,18,24, 24; 132:9), 12,13,14,15,17,21,22,23 , 24; 133 :1 ,3 ,4 ,12,16,20,21,21,23, 25;134:1,2,5, 10, 11>11, 115,17, 17, 18,18, 19,2020,22,22,23, 24; 135:34,7,9,15,17,19, 22;13 6:2,5,18,19, 24 ; 13 73,5,8,9,17,18,19,24,25; 138:1,3,5,10,11,12,12,13,16,17,19,21,21,22, 25; 139:6,7,16, 17;140:5,7,7,9,17,18,19,25;141:1,3,3,4,4,8,9,11,11,14,15,16,17,19,23,24; 142:3,4,6,7,7,13 , 1 4; 143:5,8 , 11,12,13,13,14,23, 24; 144:13,4,6,7,10,13,15,18,19,24 , 25; 145 :1 ,1 ,2 ,5 ,10,10, 12,13,18, 18,1922,23, 25; 146:3, 6,7;147:3,4,8, 11,15,20, 2148:3,4,5,5,7,7,9,14,1 4,1 6,,1 7,2 1, 2 2,2 3;149:2,3,4,6,7,10,12,13, 14, 16,21,24,25, 2150:1,4,4,5 ,8 , 1 4,17,1

19,20 ,21; 151 :1 ,4 ,10,14,17,22,24, 25; 152:14,5,7,7,8,9,10,11, 115 ,20,21,21,25 ;1 53:1,4,7,7,11, 14, 1 6,20,22,23,25 ; 154:1,3,3,12,15,1 5,2 0,2 1,2 1 ; 1 55 :1 ,4 ,811,11,12,12,14,18,19,25; 156:3,8,14, 14, 161 57 :1 ,2 2, 2 2; 1 58 :8 ,11,12,14, 19,20,21; 159:317;160:1, 1,6,7,7,8,17,20; 161:1,2,5,6,6,11,13, 18,20,22, 25; 162:23,10,11,13, 18; 163:2,47 ,7 ,9 , 1 3, 1 5,1 9,2 1,2 3,

(27) That’~ - T



F ood & Dru g Ad m in is t r a t ionGa st r oin t e st in a l Dr ugs Ad vis or y Comm i t t ee

52:5;5:18;1:1;2:24;79:9;7:10;9:2,;90:3,

>—.. 5,20;96:1O,8;97:13,4;101:22;03:4,4;118 :21;119:25 ;20:1;25:2;130:22;31:10;38:8;140:25;46:18;53:6;154:23155:11,12;159:21 ;61:22;64:17;178:24 ;79:5ways 27:25;4:12;36:9;50:14,5;129:15;35:18;139:25

we 5:7,19 ,4;6:3,9 ,20,20;7:9,11,1,13,15,18,21,25;8:18,9,20,4;9:1,8,1,12;0:14,14,19,22 ,5;11:2,2 ,3,7, 0,16,21 ,3;12:4,14,20,21;13:1,10,13, 4;14:4,8,12,13;15:16,21 ;6:5,5,17,17,4;17:9,16,18,24;18:11,2,13,3,25;19:2,3,5,17,19,5;20:5)8,2,15;21:5,0,12,15,17,8,25;22:11;23:5,0,15,18,21,2;24:3;5:8,8,9,13,16, 2;26:3,3,12,13,18, 0;27:3,2,15,6,17,1;28:18;9:1;0:22,22,4;31:15;2:3,8,7,25;

.~ 33:3,7,2,13;34:2,3,9,11,19,23,4;35:10,18,19,22;36:16;38 :17, 9;39:1,3,6,21;40:12;41:7;2:1,3,3,7,11;43:3,4,21,4;44:2,7,18;45:8,8; 6:1,247:1,

8;48:20,20,5;49:2,8,10 ,13 ,19 ,20 ;50 :2 ,9 ,3;51:13,24,25, 5;52:2,4,16;53:5,7, 0,13,15,15,16,21,2254:12,13;5:5,6,9,12,13,22, 5;56:2,20;57:1,7 ,23, 5;58:4,8,10,19,20,1,24; 9:12;60:10,2;61:10,1,15;62:2,3,16,5;63:2,4;65:5,7;6:16,7;67:1,,16,18,19,3;68:14,5,23;69:12,3,14,15,7,21;70:4;1:17,7;72:4,5,13;73 :5,7,23;74:1 , 2,13,18,23;76:1,2,7, 1,23,24;77:3,4,5,;79:19;80:8,8,9,22;81:5;82:10,4;83:2,,11,16,19;84:15,22,22, 3;85:2,7,9,12,12,13,14,20,20,21,21,22,23,23, 5;86:1,2,12,3,15;87:12;89:9,4;90:1,0,11;

_—- 92:3,4,6,8,10, 4;93:1;94:12;6:12,4;97:14;98:8,22,5;99:16;100:15,19,9,24;101:16,17,22,4 ;102:2,3,10,11,20,23,5;103:3,5,8 ,9,16,22;104:11,23;

105:2. 2,2.19.20:106:9.

17,18 ;107:11,18,3;108:3,7,8,0,16,17,9;109:18 ,5;110:8,15,19,21,22,23,4;111:6,6;112:13 ;13:9,13,15,17,21;114:2,5,4;115:13,14,23;18:1;19:15;121:15,20,21 122:4,7;124:23 ,4;125:3,7,7,14 ,

17;126:4 ,13,17 ,19, 9;127:3,5,23,24, 5;128:1,4,13,13,14,17,17, 8;129:21 ;30:17 ;34:19;136:4,6,4;137:2,2,5;138:2;40:7,14,15,16,17,20;141:2,;142:15,18;143:8,14,2;144:5,7,14,19,5;145:1,2,3,4,7,10;146:1,4,12, 3;147:14,16,3;148:6,23,24,25 ;149:1,3,9,2;150:8>0;151:8;52:1,11,13,14,21;53:10,13,14,14,16,1;154:17 ;155:5,22,3;156:2,;157:1,7;58:6,8,2;159:12,13,14,15,16,16,18;160:4;61:18;62:21,24,25;163:2,13,17, 8,19,19,24;65:16,9;166:19,3;167:6,7,2,22;168:4,6,9,0,22;169:11,0;171:9,9,20;173:25;74:11,13,15 ,17,20,24;175:12 ,13,24, 5;176:1;78:9,1;179:4,6,6,14wean 121:14weaned 120:11wearing 34:1web 7:23week 56:9; 69:22; 72:1;85:5; 88:3; 103:19, 19;172:4weekend 10:21weeks 42:22; 43:5; 56:12;68:19, 25; 69:2,13,16,22,24;70:1,1,4,8,9,11,13,13,17, 18,24, 25;71:14,14;72:2; 73:2, 2,5, 24;74:2, 23; 76:2, 23; 78:4;80:6, 6;81:7,7,13, 17;84:6,7 ;85:11, 16,18,19,

25; 98:9, 9; 108:11, 13;111:15, 17,25 ;115:16weighing 95:12weight 13:23; 40:15;42:23; 137:19; 138:4,4WEISMAN 52:7,7; 57:6;75:25; 76.1; 97:6; 98:16;100:2; 116:3,6; 118:12;119:13 ;123:7; 151:25;153:18; 154:15; 155:11,25; 156:21; 157:12; 158:3,19; 178:14Weiss 6:8, 17;8:10, 16;38:19; 70:12; 72:3; 73:15;74:18; 105:4; 113:2, 12;

114:2:124:14:132:21:

1 33 :2 2; 1 35 :2 1; 1 38 :1 7;1 41 :11; 1 42 :11; 1 47 :8 ;1 48 :1 3; 1 49 :2 3; 1 50 :2 5;1 52 :6 ; 1 62 :2 4; 1 79 :2 2

welcom e 6:18

IVeicoming 9:21uVelI13:14; 14:10; 16:19,~0,21; 17:4, 24; 20:8;29:8, 11; 32:2,3, 14;49:6;50:23; 54:21,22, 24; 55:1;50:17;64:19; 65:4; 66:12;57:9;68:4; 74:8; 75:19;76:8;78:14,17, 25;80:1;31:24;84:14; 90:18; 95:3;108:1; 111:5; 112:12;117:16; 125:3; 132:1, 13;133:10; 134:4; 136:21;140:15; 148:5; 151:10, 22;153:25; 160:23; 161:17;162:10; 166:19; 167:7;169:16; 170:10; 176:19;178:22well-being 18:16

~elldefined 171:1tvell-powered 98:15ivell-tolerate 135:10ivellness 17:6Went 41:8; 47:15; 50:20,22;55:20; 73:25 ;84:6;39:1; 115:2; 148:25;164:18Were 9:2; 11:9, 11; 19:20,23;20:2,10, 11; 21:6 ;26:15 ;27:12; 29:1 ,1 ;

}2 :11; 3 6:1 6; 3 7:1 7;3 8:2 2; 3 9:3 ; 4 5:1 6; 4 8:6 ;50 :11 ; 53 :19 ; 5 5:18 ; 5 8:7 ;7 0:1 3 ;7 6:5 , 11, 2 4;7 7:3 ;!34:7 ; 90 :3 ; 93:4 ; 94:11;10 4:1 ,6,1 3, 20 ; 1 05:19;1 07 :1 ; 1 08 :6 ; 1 21 :2 0;12 2:7 , 1 8; 12 8:9; 13 3:2 ,1 4; 1 38 :1 7; 1 39 :2 4;14 0:1 7, 18,21; 141 :16 ;14 2:2 2; 152 :8,9; 15 4:1 ;15 5:8 ; 15 6:2 5; 16 3:8 , 2 4;16 4:1 9; 167 :12 ,13 , 13,25;168 :23 ; 169 :5, 5; 171 :7,19; 1 74:18; 17 7:8 ; 1 78:8 ;179:12,12

weren’t 113:25; 173:23Western 10:7what 7:13; 16:12; 17:23;18:13, 17; 25:9; 26:4;27:23; 28:20; 30:5,8, 24;31:11,11, 12,20; 32:5;33:1O,21; 34:6,11, 16;35:8; 37:4,5, 12; 38:15,25, 25; 39:21; 40:6,16,18,19;41:4, 14, 17; 45:25;47:20; 50:17; 51:2; 52:10;53:1; 54:10, 22; 55:4; 56:5,6, 13,20; 58:19; 61:13;62:13, 13,25 ;63:4,6, 16,24;64:2,25; 65:19; 66:15;68:18, 24; 69:6; 70:7, 20;71:2,6, 25;72:13, 13, 17;73:10,11,12, 20;74:18;

75:23:76:4.6.11:81:11:.. ,., ,-,

Mille r Re por t in g Co m pa n y, In c . Min-u-scriptto

Hea r in g Vo lu m e Nu m berMay 2 9, 1

32:3,4;83:1 ;4:9,6;37:12,21,4;89:2,9,2;}1:13,20,21; 2:5,8,11;)3:10,1194:21;5:6,9,16,21;96:18;7:7 ,8,20,21;98:17;9:6,8,10,2;100:2,2,13;01:11;103:7,7;104:19,20,2;105:21,2;107:23,24;

108:1,6,15 113:24;114:3,0;115:2;16:5,13;117:1;18:23 ;19:21;120:5;22:5,6 ,24, 5;125:15;26:3,19,9;127:9;32:13,17,1;134:4,2;135:7;37:3,3,5,5,9,9;40 :7,7,3;141:1,;142:20;45:25;146:5;49:10,9;151:12;152:2,4;153:10;54:18;156:8,14,14,21, 5;157:14,9;158:3,22,3;159:6,8,15,17, 4;162:23,4;166:13;67:3;168:4,20,4;169:23;170:3,7,11,13,14,19,20,20;171:9,6;172:6,16;173:15;74:15;175:17 ;76:25;78:13,16,17;179:1tvhatever 35:4,8; 41:9;50:2, 3; 51:4,6; 64:9;57:19;73:21; 75:23;77:25;78:6; 79:2; 90:14;?2:6,9; 108:5; 116:16;126:4; 150:15; 165:11;177:11when 10:3; 15:24; 16:17;18:17; 23:10, 21;25:11,14, 16; 26:3, 13; 27:21;33:15; 35:6; 38:24; 40:13;66:25; 49:20; 53:15;55:15, 17; 59:18; 63:2;66:4;68:14, 15; 71:19;73:15; 75:15; 76:2; 89:18,18;90:15; 91:6; 93:21,23;94:6; 109:25; 112:1O, 13;113:20; 119:11; 121:16;122:20; 125:7, 17; 126:4,5; 128:12, 25; 133:22;134:10,12, 17; 136:9;140:16, 18; 146:4; 149:23;150:4; 154:8; 158:25;165:8, 15; 168:22, 23;170:22,22, 23; 172:15;

174:5whenever 7:11where 10:25; 11:2, 2;23:22; 25:4; 31:4; 34:19;35:17; 42:5; 46:13 ;47:2;50:18; 51:9; 59:4; 64:14,25; 69:20; 75:20; 79:2;80:4; 82:9,21, 23; 83:12;86:8; 88:3; 91:23 ;94:11;99:13,20; lo4:5; 105:13;108:3; 110:10;18:7;121:24;37:2,2;141:3,23;151:13,8,20;152:22;162:2;63:4,11,8;165:18 ;68:7;74:18;

177:1;78:8

whereas 32:11; 54:5;76:20; 97:24; 142:6whereby 78:2; 141:20whether 35:12; 39: 16;50:2; 52:16; 53:14,15,54:6; 56:9; 65:24; 72:9;60:6; 83:20; 87:17,18, 2B8:11;91:7; 93:17; 99:6;105:19; 109:1; 118:13;120:18, 19; 124:19, 22;126:1; 129:23; 130:11;135:22; 136:2; 138:25;140:4; 145:9, 19; 147:25152:17; 154:17; 159:1;174:6,6which 4:20; 5:2, 17, 186:22;7:15; 8:2; 11:15;12:2; 14:1,17, 18; 19:6;20:2;27:25; 33:4, 14;3421;35:1,2, 13,14,20,24;36:3,16, 20; 37:8,9,9,1221, 24; 38:5, 12; 40:7, 841:4;42:7; 45:14, 19;5051:13; 52:14; 53:8; 54:211, 22; 55:24, 25; 56:357:17; 60:20; 62:17, 16 5:8; 6 7:1 5,2 1,2 3 ;697 5:7, 8 ,9; 7 6:17 ; 8 0:5 ;81 :8; 82:7; 86: 16; 87:2B8:1 , 1 7, 2 3; 9 0:6 ; 9 4:22 3; 9 5:1 2, 25 ; 96:3; 9799:22; 100:5; 104:2, 11 06 :1 0, 11; 1 09 :2 4;110 :11; 113 :1 6; 114 :3115 :10, 11; 117 :11,12 ;118 :8 ,9 , 1 6; 1 20 :1 5;12 3:4 ,7; 12 4:1 6; 1 25 :12 9:1 7; 1 31 :18 , 22; 1133 :4 ;1 34:11,2 1; 13

19; 138:1 1; 139:4,10,142 :13; 143 :8 ; 145 :16,23 ,24 ; 1 51 :21 ; 15 2:18157 :3 ; 160 :6 ; 162 :4 ,1625; 16 7:1 8; 1 70 :21 ; 110; 172:24; 173:20, 2174 :12; 179 :20

while 24:3; 59:1; 64:15108:21; 109:21White’s 36:8who 4:19; 8:24; 9:11, 210:21; 13:2; 17:9, 10, 118:2,4; 19:13; 20:22;21:19; 24:8; 25:7,9 ;29:32:11 ;43:8, 10, 12; 44:18;47:11; 57:18;62:19,20;63:1; 76:11 ;80:21;81:25 ;84:13,25; 90:6,614;91:16;93:1,8,25;95:16; 97:5; 98:3; 105:8107:4, 17; 109:13,16,1619; 110:3,4; 112:14;113:19; 116:7; 117:5;119:3; 122:15; 125:19,128:16; 129:3; 133:24;137:10, 11;140:17;146:12,5;150:19,0;159:19;61:6;67:13;172:2;79:18whole 26:2;2:24;3:9;

50 :8; 92 :3; 14 2:1 4; 1

(31) wa vs - wh



Food & Dru g Adm in is t ra t ion Hea r in g Vo lu m e Nu m be

Ga st r oin t e st in a l Dr u gs Ad vis or y Comm it t e e Ma y 29,

5,7, 13; 151:3,13, 14,18,20,20 , 22; 152 :3 ,16,17 ,

- 24 , 25 ; 153:4 ,4 ,20 ,20 ,22,23,24,24,24, 25;1 54 :4 ,4 ,5 ,6 ,8 ;1 55 :11,1 5,1 6,1 7, 1 8,2 1,2 5;156:1,9, 10, 12, 18, 19,21,22,23,24,24, 25;157:12,20,21,21,23,24;

158:3,10,14,21,22,23,23,25 , 25; 159 :1 ,1 ,2 ,2 ,6 ,7,7,8,10, 11; 160:7, 23;161 :22, 23; 162 :7 ,8 ,11,15, 19, 23; 163:5,9, 12;16 4:6 ,7,1 2, 14 ; 1 65:8 ,9;166:5,7,9,10,11,12,13,18; 167:2, 3; 168:16, 20;16 9:15 ; 17 0:3 , 5 ,6; 17 1:3 ,13,15 , 18; 173 :1 ,4 ,6 ,8 ,13,13, 14,15, 18; 174:5,6,7,18, 22; 175:9; 176:6,13 ,14,15,16, 2 0; 1 77:25;1 78 :7 , 1 2,1 3, 1 6,1 7,1 8

young 131:2; 148:8

younger 55:15; 151:21youngest 124:7,9

your 26:24 ;35:25; 36:15,22; 44:7; 48:13; 74:4; 75:6;86:1; 91:3; 100:3,4,6,6,17; 102:5, 10, 19; 113:2;116:22; 118:3; 119:14;126:25; 127:6,7; 131:18;132:20; 135:21; 144:14;.-—..151:6; 158:12; 159:8,8;160:23; 163:4; 173:4,7,20yours 93:13yourself 46:6YZ 155:24

zZELDIS 75:5,5zero 49:23 ;71:15;110:14; 112:22; 137:23;164:12

IMille r Re po rt in g Co m pa n y, In c . Min-U-Script@ (3 3 ) vou n g -



Lawyer’s Notes.- m.

us food and drug administration: 3423t2

Documents