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AT DEPARTMENT OF HEALTH AND HUMAN SERVICES
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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 Bethesda
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Bethesda, Maryland

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_f—>. PARTICIPANTS

Stephen Hanauer, M.D., Chairperson
Joan Standaert, Executive Secretary

MEMBERS

Rosemary R. Berardi, pharm. D., (Consumer
Representative)
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.

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.8-.

PAGE NO.
Call to Order: Stephen Hanauer, M.D. 4
Statement of Conflict of Interest: Joan Standaert 4
Introductory Remarks

Stephen Hanauer, M.D. 5
Karen Weiss, M.D. 6
General Discussion of Questions 22

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1
@ -–
2 Call to Order

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

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

5 Joan Standaert has some introductory comments.

6 Conflict of Interest

7 MS. STANDAERT: The following announcement

8 addresses the issue of conflict of interest with regard to

9 this meeting and is made a part of the record to preclude

10 even the appearance of such at this meeting.

11 Based on the submitted agenda for the meeting and

12 all financial interests reported by the committee

13 participants, it has been determined that all interests in

14 firms regulated by the Center for Drug Evaluation and

15 Research present no potential for an appearance of a

16 conflict of interest at this meeting with the following

17 exceptions .

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

19 tiaivers have been granted to all committee participants who

20 have interests in companies or organizations which could be

21 affected by the committee’s general discussion on guidance

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

23 A copy of these waiver statements may be obtained

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

25 Information Office, Room 12A of the Parklawn Building.

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1 In the event that the discussions involve any
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2 other products or firms not already on the agenda for which

3 an FDA participant has a financial interest, the

4 participants are aware of the need to exclude themselves

5 from such involvement, and their exclusion will be noted for

6 the record.

7 With respect to all other participants, we ask in

8 the interest of fairness that they address any current or

9 previous financial involvement with any firm whose products

10 they may wish to comment upon.

11 That concludes the conflict of interest statement

12 for May 29, 1998.

.—-. 13 Introductory Remarks

14 DR. HANAUER: This meeting is going to be somewhat

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

16 ~Ponsors yesterday for introducing the important topic

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

18 tihich is to discuss the future of the guidelines for drug

19 development for inflammatory bowel disease, and we are going

20 jo focus on Crohn’s disease today.

21 Also, a little different from yesterday’s meeting,

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

23 >e much more of an open meeting and encourage discussion

24 =rom outside of the table. We all recognize that industry
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25 md individual members, not necessarily at this table, have

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1 given a great deal of time and consideration, consultative
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2 support to the development of clinical trials in

3 inflammatory bowel disease, and we certainly want to utilize

4 the resources that are available to improve the draft

5 guidelines and basically put this on a reasonable playing

6 field for everybody.

7 Before I introduce today’s panel members, I would

8 like Karen Weiss to introduce the purpose of the meeting and

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

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

11 come up to speed with inflammatory bowel disease over a

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

13 amount of work and effort and insight they have into these

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

15 of credit.

16 Karen.

17 DR. WEISS: Thank you.

18 I wanted also to extend my welcome to the members

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

20 say why we are here and how we got here.

21 Yesterday, there was some mention to the published

22 iocument which was called Draft Guidelines for Therapies for

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

24 :hat was published in the Journal of Inflammatory Bowel

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

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1 document wasn’t a formal FDA guidance document. In fact,
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2 that document really had its roots I think in the early

3 1990s largely due to the efforts of Mr. Hanauer to try to

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

5 such thing prior to that time.

6 As people are probably aware, the agency is very

7 actively involved in the development of guidance for many,

8 many different areas, and this particular draft publication

9 was developed in the days before we had something called

10 Good Guidance Practices, and Good Guidance Practices is the

11 standard procedures that we are to follow whenever we are

12 developing guidance, and one part of that procedure is

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

14 stages, see input from advisory committees, from the public

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

16 develop a guidance document, so that is really the purpose

17 of today’s meeting.

18 We have some questions that are directed

19 questions, but they are not intended to limit discussion so

20 much as to stimulate and facilitate discussion. Our plan is

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

22 additional time to put these specific questions out on an

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

24 others can respond to those questions.
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25 We will take all of that input together with the

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1 existing draft document and develop a first draft of the

2 guidance document, which will then go out again for further

3 comment. The ultimate goal would be then to develop an FDA

4 guidance document on development of therapies for Crohn’s

5 disease.

6 Again, thank you, and I look forward to these

7 discussions,

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

9 format .

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

11 this effort was a joint effort between Center for Biologics,

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

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

14 :enter for Drugs, to make a comment.

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

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

17 me of the results of this meeting is to stimulate

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

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

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

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

22 ~eed for such things.

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

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

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

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

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

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

4 worldwide basis in many clinical aspects of inflammatory

5 bowel disease, and particularly is leading an effort, a

6 joint effort between United States and international

7 organizations on the classification of inflammatory bowel

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

9 Sachar has been prominent in trying to develop clinical

10 phenotypes that will correlate with the genetic background.

11 Paul Rutgeerts, who we met yesterday, is a

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

13 is a Professor of Medicine at the Catholic University in

14 Leuven, Belgium, and has been very prominent in the

15 development of endoscopic monitoring and endpoints for

16 specifically Crohn’s disease, and led information regarding

17 the recurrence of Crohn’s disease after surgical

18 intervention, and has been very prominent as a worldwide

19 leader in clinical development and particularly as it

20 reflects on endoscopic changes.

21 Welcoming back Barbara Kirschner, who is a

22 Professor of Pediatrics at the University of Chicago, has

23 ~een involved in pediatric aspects of inflammatory bowel

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

25 ~ major advocate of development of guidelines particularly

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1 related to pediatric interests inflammatory bowel disease,

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

3 make some comments when it is appropriate regarding specific

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

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

6 Dr. Simon was introduced yesterday. Dr. Brian

7 Feagan from the University of Western Ontario has been a

8 major play in the development of clinical trials in

9 inflammatory bowel disease. He is an expert trialist in

10 general. He has a broad perspective of clinical trial

11 techniques and also an interest in quality life assessments

12 in inflammatory bowel disease, and I think will help round

13 out that discussion.

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

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

16 1 think everyone else has been introduced.

17 My plan today is to work for approximately two to

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

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

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

21 people who have to leave for the weekend can get out of

22 here. That is my initial plan and we will try and move

23 things accordingly.

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

25 Eor where we are heading with a series of slides and

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1 hopefully limit, if it is possible, to about a 5-minute

2 introduction of where we have been and where we need to go.

3 Most Of yOU know me, know we can’t speak without

4 slides, and they also know there is no such thing as a 5-

5 minute lecture.

6 [Slide.]

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

8 yesterday and I think the issues related to drug development

9 md to this disease were very much highlighted yesterday.

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

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

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

13 iate.

14 Now , the importance of classifying Crohn’s ,

15 iisease, which is probably a series of inflammatory bowel

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

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

18 :he rheumatologists have been quite fortunate in that they

19 lave a series of serologic criteria that can help classify

20 >atients with previously unclassifiable or indeterminate

21 ~eatures of rheumatologic diseases. We have lacked those

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

23 md yet as we have seen, the classification for this series

24 )f diseases is going to be important from a variety of

25 standpoints, from the diagnostic standpoint and

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1 understanding the underlying genetic underpinnings of the.

2 disease, from the therapeutic standpoint which is critical

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

4 standpoint and from a prognostic and actuarial standpoint we

5 need to understand a better classification of Crohn’s

6 disease from the prognostic standpoint.

7 [Slide.]

8 Now , these inflammatory diseases, both ulcerative

9 colitis and Crohn’s disease, have begun to appear as a

10 heterogeneous series of illnesses, and that heterogeneity

11 comes in a variety of different presentations -

12 heterogeneity by disease location, by disease complications,

13 and also by the different response to therapies. As an

14 example, yesterday, we heard that infliximab was effective

15 by certain criteria in approximately two-thirds of patients,

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

17 predict a pathophysiologic relationship or underpinning of

18 the disease that may impact on future trials.

19 [Slide.]

20 We didn’t get much into it yesterday, and

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

22 of genetic factors that may influence response, perhaps on

23 =he immune and immunoinflammatory compounds, perhaps the

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

25 Level of regulation of these may be important.

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1 We do have some serologic findings, and Dr.

2 Targan, who spoke yesterday on behalf of Centocor,

3 emphasized that there are some serologic factors, such as

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

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

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

7 inflammatory bowel disease that may be defined on a variety

8 of different clinical disease location, complication, and

9 hopefully, eventually, genetic bases that will better

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

11 an available classification.

12 [Slide.]

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

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

15 produces a variety of different symptoms in individual

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

17 yesterday’s discussion.

18 From a subjective standpoint, patients may present

19 with a variety of symptoms including diarrhea, ‘abdominal

20 pain, rectal bleeding, nausea, vomiting from a symptomatic

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

22 From an objective criteria, they can present with

23 a series of findings including weight loss, fever. In

24 children, as was emphasized yesterday, growth is a very

25 important factor. They may present with an inflammatory

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1 mass which may or may not be distinct and may or may not be
#-’%
2 painful. They can present with fistula as a primary or

3 secondary component of their disease, or extraintestinal

4 manifestations, such as arthritis, and we recognize now that

5 there are several different types of arthritides that can

6 occur in inflammatory bowel disease, a central arthritis

7 such as ankylosing spondylitis or sacroiliitis that may have

8 other genetic correlates, such as HLAB-27, and we are

9 learning that even the peripheral arthropathies, large joint

10 involvement may have genetic underpinnings, as well.

11 [Slide.]

12 For laboratory features, we lack a pathognomonic

feature for Crohn’s disease or ulcerative colitis, and we

14 are left with a series of nonspecific laboratory features

15 that generally represent the level of either inflammation or

16 complications in the setting of Crohn’s disease.

17 Anemia, which is a very common presentation, may

18 be related to disease activity or in a disease which may

19 affect absorption, may relate to iron deficiency, may relate

20 to bleeding, may be related to absorptive problems, such as

21 Vitamin B12, or a co-complication of ongoing drug therapy,

22 such as sulfasalazine.

23 Thrombocytosis is a common feature, elevation of

24 the sedimentation rate or C-reactive protein or serum

25 orosomucoid are common as implications or indicators of

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1 Iinflammatory activity. Diminished albumin may be related, to
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2 Imalabsorption or protein losing enteropathy. Signs of

3 protein losing include fecal or clearance of alpha-l

4 antitrypsin, and other laboratory features may replicate or

5 identify the exudation or presentation of leukocytes in the

6 inflamed bowel via leukocyte scanning or leukocyte

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

8 laboratory features.

9 [Slide.]

10 The endoscopic features of Crohn’s disease are

11 also quite variable, and they can be the typical of

12 classical linear ulceration and focal ulceration that tends

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

14 Crohn’s disease may absolutely mimic the endoscopic and

15 pathologic features of ulcerative colitis in a group of

16 patients that we consider as having indeterminate colitis.

17 These endoscopic features do not, to our current

18 therapies, and current meaning preceding the infliximab

19 therapy, have not altered dramatically according to therapy

20 particularly as response to steroids, and that has led to

21 some of the previous draft guidelines that we are going to

22 review.

23 [Slide.]

24 When one looks at the histologic features of

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

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1 variable, they do not necessarily, neither the microscopic
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2 score, on the left, according to histology, or endoscopic

3 appearance, in general, have not correlated with disease

4 activity, although with a drug such as infliximab that may

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

6 drugs that will affect both the clinical, laboratory,

7 endoscopic, histologic, and eventually cytokine features of

8 these diseases.

9 [Slide.]

10 Correlates between endoscopic activity and

11 clinical activity seem to be related to the severity of the

12 lesions, but there are many other lesions including what are

13 thought to be primary lesions, such as aphthous ulcerations,

14 that do not correlate at all with symptoms or other

15 laboratory features.

16 [Slide.]

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

18 to be aware that the level of inflammatory mediators does

19 not correlate very well with symptoms, that sfiptoms do not

20 correlate very well with endoscopic features, and endoscopic

21 features do not correlate very well with the need for

22 surgical resection, and this has been a major problem.

23 [Slide.]

24 so, in the past and up until this date, we have
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25 used a number of different therapeutic endpoints for Crohn’s

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1 disease. These include clinical indices, and indices such

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

3 yesterday, are components of subjective components of the

4 disease, as well as objective features, and they have been

5 criticized because they do not necessarily correlate tiith

6 the wellness, how the patient feels, with the degree 3f

7 inflammation.

8 They are not primary indicators of inflammatory

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

10 irritable bowel syndrome, who according to the Crohn’s

11 Disease Activity Index, would have very severe Crohn’s

12 disease demonstrating the lack of specificity of indices

13 such as that.

14 Indices have been used by some investigators,

15 primarily in Europe, as predictors of relapse, and according

16 to composites of laboratory features of inflammation, we

17 could at least begin to predict the likelihood of clinical

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

19 better how to use the endoscopic response in particularly

20 defined therapies that have endoscopic correlates to

21 subjective and objective components of the disease.

22 [Slide.]

23 So, what have been the problems in developing

24 guidelines for Crohn’s disease? Well, the first is we do

25 lot have a pathognomonic measure or label for this disease.

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1 The diseases are quite heterogeneous and vary in sYmptoms.
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2 between site of disease, in patient who have rectal Crohn’s

3 disease are going to have different components of symptoms

4 than patients who have esophageal or duodenal Crohn’s

5 disease, the symptoms are going to be different.

6 Many of these patients are going to undergo

7 surgery, and after surgical resection, their baseline non-

8 disease state is different. Many of them will have more

9 bowel movements than they would otherwise, and that will

10 impact upon non-inflammatory components of the disease.

11 We need to distinguish between inflammatory and

12 non-inflammatory symptoms. We are confronted by the poor

13 endoscopic symptom correlation, and we need to define what

14 is remission of these diseases. You heard yesterday how the

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

16 correlates with disease well-being, but as our statisticians

17 point out, what happens to patients when the CDAI, Crohn’s

18 Disease Activity Index, actually goes below 150, and some

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

20 frankly, some patients with disease activity indices above

21 150 are in clinical remission by all other criteria.

22 [Slide.]

23 We tried to come up with some solutions in this

24 draft guideline proposal that have already been published.

25 We suggested comparison of homogeneous subgroups of

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1 patients. You can’t compare in the same trial fistulizing

2 patients to non-fistulizing patients as we heard yesterday.

3 We suggested defining endpoints of the disease in

4 advance of undertaking the therapeutic trial based on either

5 clinical, endoscopic, or laboratory features. Another model

6 which has not yet been brought to this agency for regulatory

7 approval is the postoperative model of Crohn’s disease,

8 since, as Dr. Rutgeerts has demonstrated, Crohn’s disease

9 recurs in the predictable manner at the anastomotic margin,

10 and the level of inflammatory changes can predict the

11 clinical course. A number of clinical trials have begun to

12 look at this model as a Potential for intervening in a more

13 homogeneous subset of patients, those who have undergone

14 surgical resection.

15 As has been emphasized, we are still seeking the

16 reagent grade patient, but unfortunately, as I have

17 emphasized, we don’t have the right reagents as yet.

18 [Slide.]

19 To date we have come up with several” proposed

20 therapeutic goals that were emphasized in the draft

21 guidelines, including, clinical improvement, induction of

22 remission, and maintenance of remission, and I think these

23 ~ere modified slightly in the approval process yesterday.

24 [Slide.]

25 We defined clinical improvement necessitating

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1 homogeneous subgroups of patients with predefined endpoints,

I 2 which I think were met to some degree, to a considerable

3 degree, with the approval process yesterday.

4 [Slide.]

5 From a remission standpoint we have still not

6 successfully defined a drug therapy related to this because

7 of difficulties in defining remission based on the clinical

8 aspects, as well as the endoscopic aspects, although we did

9 suggest that a clinical remission could be defined based

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

11 predefine in advance and were acceptable to the agency, and

12 we still need to come up with endoscopic criteria for

.—.=
13 remission.

14 [Slide.]

15 As far as maintenance of remission, we suggested

16 both clinical and the postoperative recurrence model as

17 potential maintenance means of gaining approval for

18 maintenance, but still obviously this needs additional

19 clarification as I have discussed.

20 [Slide.]

21 Quality of life is something that has been

22 =mphasized by our patients who presented before the formal

23 neeting yesterday. Patients wish to be free of pain and

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

1, 25 uhronic disease, it leads invariably to disappointment in

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1 physicians and in therapy because of the chronicity and lack

2 of curability.

3 [Slide.]

4 Quality of life is a very complicated determinant,

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

6 invalidated indices that were discussed yesterday, the

7 Inflammatory Bowel Disease Questionnaire, that has been

8 validated against the Crohn’s Disease Activity Index.

9 [Slide.]

10 And we do have means of assessing quality of life

11 either by these indices, but need to consider many other

12 aspects of quality of life as we continue with the drug

13 development process.

14 [Slide.]

15 So, with that very brief overview, we need to

16 consider additional therapeutic goals in the future. From

17 the scientific standpoint we need to identify pathognomonic

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

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

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

21 identify the factors that are actually causing and

22 triggering this disease, but, that is more from the

23 scientific standpoint, not necessarily from the regulatory

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

25 obviously modify these guidelines as we proceed.

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1 With that brief introduction, I open this up.

2 David, do you want to comment on that?

3 General Discussion of Questions

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

5 congratulating you for such a clear and succinct

6 encapsulation of the most salient problems and questions in

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

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

9 great advantage of not being encumbered in anything I say by

10 any facts, knowledge, information, or data.

11 But if we want to start off by looking at

12 indications, and particularly defining the first two

_&=. 13 sections that you have under Sections for the Committee, it

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

15 it easier to think of the indications on two broad

16 ~ategories rather than three.

17 DR. HANAUER: Let me just read the first paragraph

18 oecause the members in the audience may not have this.

19 The first question that was posed to” the committee

20 Ls that one purpose of the indication statements (the

21 ulaims) in a product label is to inform prescribers and

22 ?atients about the beneficial effects from use of the

23 ?roduct. The existing draft guidance discusses three

24 ?otential indications for therapies, as I describe: (a) the
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25 ;reatment of acute disease; (b) induction of remission; and

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1 (c) maintenance of remission.
.n
2 DR. SACHAR:’ I like to think of indications in two

3 rather than three broad categories: the treatment of active

4 disease and maintenance of remission. I rather prefer the

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

6 ameliorate diarrhea, fevers, pain, fistulae, these symptoms

7 may have been very chronic, they may have been there for

8 years or decades. I don’t know that this is necessarily

9 acute disease, but it is certainly active symptoms.

10 When we talk about induction of remission as a

11 separate indication, I know that the definition there refers

12 specifically to mucosal healing, and I sometimes find it a

13 little confusing to refer to induction of remission and then

14 assume that people must understand that that is different

15 from the treatment of active disease, simply because we are

16 setting up a particular outcome measure or response

17 variable, namely, endoscopic evidence of mucosal healing.

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

19 >f the response variables or one of the potential outcome

20 neasures of the success of the first indication, treatment

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

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

23 such as fistula healing, steroid sparing, abscess treatment,

24 obstruction treatment, or quality of life.

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

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1 as response variables or outcome measures of either the

2 treatment of active disease or maintenance of remission.

3 With regard to maintenance of remission, while we

4 talk about it as surgical remission, medical remission, I

5 think there is an important subdivision of maintenance of

6 remission that is often overlooked, and that is the

7 difference between the new introduction of a new therapy in

8 a patient who is already in remission, spontaneously or

9 postoperatively or without medication, as opposed to

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

11 remission on a given therapy, and that remission is either

12 maintained as the therapy is continued or not maintained if

13 the therapy is discontinued.

14 I will just give you two quick examples of that,

15 if I may. There are in the literature several randomized

16 placebo-controlled trials of maintenance of remission by

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

18 of the most effective studies on that regard are really

19 continued active therapy.

20 They are the taking of people in whom those

21 particular agents have already proved their success by

22 having maintained a remission, and then patients are

23 randomize either to continue on that active therapy or to be

24 transferred to a placebo, and there are differences in the

25 relapse rates.

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1 That is rather different from a design in the
.4-%
2 studies, let’s say, of steroids. There are three

3 randomized, controlled trial studies of steroids in the late

4 seventies and early eighties, where steroids are shown to be

5 ineffective for the maintenance of remission in Crohn’s

6 disease as defined in part by the new introduction of

7 steroids in patients who are already in remission.

8 But if we look at subgroups of those studies, we

9 all have the experience of patients who are what we call

10 steroid dependent. They are on remission on steroids, and

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

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

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

14 ineffective for maintenance of remission because when you

15 introduce them newly in untreated patients, they don’t do

16 any better than when you don’t? Or do we say that steroids

17 are effective in the maintenance of remission because as

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

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

20 steroids are effective in maintenance of remission.

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

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

23 necessarily acute disease. I think that an issue of mucosal

24 healing rather than being a broad category of one of three

25 categories, should be included together with fistula healing

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1 or abscess healing as a goal of treatment of active disease
p%
2 rather than as a whole separate category; and third, that

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

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

5 coming in with something new in a patient already in

6 remission, and continued active therapy and continuing a

7 patient on a drug that has already induced remission.

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

9 of metaphors, but you are mixing some.

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

11 [Laughter.]

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

.-. 13 precise when we discuss this because I think you show

14 perfect examples of different definitions of remission. The

15 purpose of the guidelines, as they were stated, and dividing

16 treatment of active disease versus induction of remission

17 was actually to stimulate drug development.

18 We recognize that there may be drugs out there

19 that impact upon the level of active disease, that can

20 actually improve it without inducing remission, and we did

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

22 of inducing complete endoscopic healing, complete

23 symptomatic resolution, et cetera.

24 So, your example of steroid-induced remission,

25 most of us would think is not a remission because those

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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 active
I
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
I
21 think that comes in under Section 2 when we talk about

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

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1 maintaining the remission. Anybody can stop steroids. The

2 point is to stop the steroids and not have the disease

3 flare.

4 DR. HANAUER: Dr. Simon, from the rheumatologic

5 perspective.

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

7 ask a question here. I have always lived with the

8 assumption that anyone that has Crohn’s disease has some

9 structural abnormality. It may not be visualizable based on

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

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

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

—_
— 13 constitutional issues that are measurable based on quality

14 of life scores and other measurable components without

15 having structural abnormalities.

16 Is that true?

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

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

19 condition called irritable bowel syndrome that” the digestive

20 tract produces many symptoms in what appears to be

21 anatomically and pathologically normal individuals that can

22 replicate the symptoms. So, patients can have diarrhea,

23 abdominal pain without having Crohn’s disease - nausea,

24 vomiting, et cetera.
.-———.
25 DR. SIMON: Right, but my point is that the

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1 response elements that we were just talking about were

2 multifactorial and there have to be a composite score system

3 to be able to include all of those issues, and the

4 discussion that just ensued, mixing and matching metaphors,

5 actually includes all of those particular issues, so it

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

7 create a system of response indicators, that one has to

8 include both invariably a response from structure, as well

9 as invariably a response to symptoms and signs, and that

10 they cannot be separated, and that somebody who is going

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

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

n 13 any longer means not having any of the symptoms and signs of

14 being sick or having structure abnormalities of being sick.

15 DR. SACHAR: There may be extra enteric

16 manifestations, though, independent of structural

17 abnormalities .

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

19 is arthritis or uveitis, that would still be measurable and

20 definable.

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

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

23 the cytokine effects on bone marrow production and anemia

24 nay be metabolic, and not actually defined as structure.

25 DR. SIMON: That’s true, constitutional .

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1 DR. HANAUER: Dr. Sachar has suggested that the

2 three current indications should be modified to treatment of

3 active disease, still with induction of remission or no?

4 DR. SACHAR: I think to make induction of

5 remission a separate indication is confusing. I think what

6 you have defined in induction of remission is just one

7 possible response variable or outcome measure of treatment

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

9 those goals may be improvement of endoscopic mucosal score

10 or complete mucosal healing or complete closure of a fistula

11 or complete resolution of an abscess.

12 These are all potential definitions under one

.—=. 13 category, the treatment of active disease, and I don’t see

14 why the mucosal healing indication is sort of elevated to a

15 full separate category of indication.

16 DR. HANAUER: There are two dozen drug companies

17 out there and each one you are suggesting a laundry list

18 that they could get an indication for fistula healing, one

19 company; another company, endoscopic healing; “another

20 company - you are suggesting a laundry list of potential

21 indications within the realm of Crohn’s disease.

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

23 are only talking about acute - I think the later ones talk

24 about what makes up remission. We haven’t done that yet, so
__-..
25 I would agree.

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1 DR. HANAUER: Christine.
.--.=
2 DR. SURAWICZ: I think the problem that I have

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

4 immediately connotes leukemia where you have cancer cells

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

6 they are not, and that is remission.

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

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

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

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

11 tihat maintenance of remission is, I mean what induction of

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

13 treatment of acute disease?

14 DR. HANAUER: Very simply. One would be you could

15 3et from the statistician standpoint, we could define

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

17 lisease Activity score, and you could define induction of

18 remission as a proportion of patients, would they score

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

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

21 ?ublished guideline. The published guideline defines

22 induction of remission as mucosal healing specifically.

23 DR. HANAUER: Right, and there are several

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

25 discussion.

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1 Barbara.

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

3 well, first of all, yesterday, we did talk about active

4 rather than acute disease, so I don’t think anyone disagrees

5 with what Dr. Sachar said about this is clearly active

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

7 time.

8 The other thing is” that we had a specific

9 Definition that the company could recognize as a response

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

11 Index whereas some patients who fell below the 150 mark were

12 ~onsidered in clinical remission. I don’t think anyone was
..
:—- 13 particularly concerned about complete remission in terms of

14 symptomatic, as well as mucosal healing for the simple

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

16 3isease.

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

18 ~eed a specific definition of complete remission because

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

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

21 difference between a clinical remission versus a complete

22 remission in terms of healing and symptomatic relief.

23 DR. HANAUER: Dr. Feagan.

24 DR. FEAGAN: I find this whole discussion really

25 :roubling because here we are trying to set standards and I

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53

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

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

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

4 preferable, yet, there are definition problems which granted

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

6 very little attention paid to the operating properties of

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

8 they responsive, are they reliable, and a quantitative

9 approach to that whole process.

10 For example, the issue of mucosal healing, what is

11 mucosal healing really in terms of validity? I would

12 suspect that if we ask gastroenterologists around the room,

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

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

15 then when you get into the operating properties of the

16 definitions of things like remission, in terms of

17 symptomatic remission, you are going to get even more

18 heterogeneity.

19 I guess I am making an appeal for sort of a

20 broader process in an attempt to bring the process in line

21 with what the rheumatologists manage to do or over the

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

23 quantitative rather than qualitative level of discussion.

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

25 cm that, on the process?

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

2 out rheumatologists, we are down to two rheumatologists, I

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

4 discussion time.

5 I thought it might be just useful to give you a

6 couple of minutes of discussion of what has happened in

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

8 National Arthritis Data Resource, which is called ARAMIS,

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

10 done a lot of work in developing outcome instruments and in

11 defining conceptually what we are trying to do in terms of

12 outcome in rheumatoid arthritis in many other ways.

13 It has been a long evolution because as is

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

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

16 things that you could say about what has happened over the

17 time, and I think that people are pretty gratified, both in

18 the agency side and the industry side and the academic side

19 with regard where we have come in rheumatology” over the

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

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

22 are happening here.

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

24 rheumatoid arthritis as an example, we have moved from

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

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1 an outcome process, a chronic disease in which it is

2 measured chronically, in which the ideal outcomes that you

3 would like for an individual and measured over the entire

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

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

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

7 you are making the treatment decisions about steroids or

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

9 on the long way.

10 Partly there, we have gotten into areas of

11 discussing activity versus damage, because there are

12 cumulative things, whether they are related to steroids or

13 to the ever shortened bowel, which represent damage aspects,

14 which may be resulted from the activity over a period of

15 time, but in a chronic illness patient, move from the

16 activity phase dominating in, say, rheumatoid arthritis, to

17 where the damage phase of the disease is really dominating.

18 We have movement toward more humanistic outcomes,

19 and we have really grown a lot more comfortable with those.

20 Measurements of disability which are based on patient self-

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

22 dominant accepted thing. We have moved away from little

23 process measures like walking times and buttoning things or

24 changes in sedimentation rates are things which might be

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

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1 affect the patients.
.=-.

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

3 term outcomes in terms of dimensions which are mutually

4 exclusive and collectively exhaustive, so that you include

5 somehow in the outcomes everything the patient could want

6 the system to do for them with that disease.

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

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

9 have fallen out different ways for different investigators,

10 but in general, into mortality measures, death, disability

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

12 toxicity of the treatments, and economic impact.

13 If you define thing appropriately, you can get all

14 of the desirable outcomes into a relatively small number of

15 dimensions, and then you work at your indexes to have

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

17 quantitative, you can actually discuss these.

18 So, it is some of these areas that gradual

19 evolution and acceptance and comfort of scientists really

20 moving toward softer measures, which actually have better

21 measuring characteristics than the harder measures, and I

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

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

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

25 better by some other things that are actually experienced by

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1 the patients.

2 Finally, to just sort of close, there is the

3 question of to get this intellectual move toward conceiving

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

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

6 rheumatology over the last really five years, has been the

7 development, first, of the international group called

8 OMERACT, which is outcomes in rheumatoid arthritis clinical

9 trials, which set out and agreed upon six items which they

10 thought should be common endpoints to be used in all

11 clinical trials, and then these came to the American College

12 of Rheumatology, which again reflected on what endpoints

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

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

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

16 idea to get acute phase reactive like sedimentation rate,

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

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

19 got those eight items.

20 There now is international consensus, and it

21 relatively easy for both industry or the agency, which has

22 been very involved in this consensus development process,

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

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

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

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1 that this would be a process point in terms of moving toward

2 looking at longer things, areas under the curve,

3 accumulative outcome kinds of measures, taking a longer

4 view, and working toward achieving a consensus about these

5 items, which can evolve over time, because things aren’t

6 perfect, but more toward quantitative estimation.

7 DR. HANAUER: I want the FDA’s comment. Has this

8 translated into regulatory assistance?

9 DR. SIEGEL: Yes. There is a guidance document

10 done for rheumatoid arthritis, there are others in

11 development in osteoarthritis and early discussions in

12 lupus, which i would concur have been of great assistance

13 both to the agency and to sponsors in conceptualizing the

14 process in designing trials, comparing results.

15 DR. HANAUER: From a general standpoint, what are

16 the indications in RA as you are asking?

17 DR. FRIES: We are asked to give indications for

18 Crohn’s disease suggesting acute disease or remission.

19 DR. WEISS: We follow, first of all, ”the draft

20 that was published for inflammatory bowel disease, but also

21 rely heavily on the draft document for rheumatoid arthritis

22 because there were a lot of parallels, and that document

23 focused, to start with, on indications, and from a

24 regulatory point of view, when companies develop products

25 with the idea what is the indication, what is the claim that

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1 we are going to try to set out to achieve with our study,
E===.
-.
2 and I think that is a good way to think about things.

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

4 confusion, and I appreciate the discussion on the

5 differences between active versus acute, and induction

6 versus maintenance. Those things are all similar terms that

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

8 heavily involved with all these discussions going on at the

9 Arthritis Advisory Committee, because there was something

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

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

12 reduction in the acute signs and symptoms.

13 There is a specific section on remission, and I

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

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

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

17 of rheumatology drugs to be declared in remission.

18 Then, there is structural changes to occur years

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

20 ~arallel and that document has been extremely helpful. That

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

22 ~iscussions.

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

24 2DAI in their respective diseases?

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

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

2 the parallels between rheumatoid arthritis and Crohn’s

3 disease. I think the issue is as far as the outcome

4 measures. The parallels are in the process. The process is

5 exactly parallel. You had a very heterogeneic diversity of

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

7 was set up in which that was resolved through a scientific

8 and logical method in which there was a broad input and

9 consensus was reached. I think that is they key.

10 DR. SIEGEL: There is probably more diversity of

11 physiological processes in the CDAI than the ACR. It is

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

_—- 13 heard about how CDAI can and can’t be used when you are

14 comparing and scoring together things like fistulae, anemia,

15 numbers of bowel movements, pain, how you weight them and

16 what their implications are to different subset of patients

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

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

19 what they actually do’.

20 DR. HANAUER: Dr. Elashoff.

21 DR. ELASHOFF: I just wanted to comment that one

22 of the difficulties with making some cut point in the CDAI

23 and defining that as remission, specifically, the cut point

24 of 150, a third of the patients in the fistula T20 trial

25 would have been “in remission, ” at the beginning of that

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1 trial within that definition.

2 DR. HANAUER: Dr. Senior.

3 DR. SENIOR: I was very much impressed and

4 interested in what Jim Fries said because the ARAMIS, which

5 is the American Rheumatological Association Management

6 Information System -- is that right, Jim?

7 DR. FRIES: We had to change it because the

8 American Rheumatism Association went away --

9 DR. SENIOR: Whatever. The management system that

10 Jim Fries has put together, and has maintained so

11 successfully over 20 years, has been absolutely a gold mine

12 of data, and I think that in inflammatory bowel disease, it

13 would be very, very helpful to construct and maintain such a

14 long-term database in,those patients as analogous to what

15 Jim has done.

16 I was also very impressed with his vocal statement

17 on what the patient wants. The patient wants reduction of

18 symptoms, and the patient wants to be able to work and live.

19 The patient wants the disease not to progress at the tissue

20 level, and the patient doesn’t want to go broke in the

21 process.

22 I think these are things that are very important

23 and would make an index, if it could be constructed along

24 those lines, so much more generally applicable.

25 DR. HANAUER: Dr. Kirschner.

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1 DR. KIRSCHNER: I guess one of the problems we

2 have, I can see the necessity perhaps of endoscopic scoring

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

4 talked about treatment of active disease in terms of partial

5 and complete responses, and that is where induction of

6 remission and remission occurred, because otherwise it

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

8 doesn’t really respond to pediatrics at all. I really

9 underestimates the degree of activity because many of the

10 issues are not applicable.

11 But also the fact that we need some kind of

12 measure that can be used continuously over the long course

13 of disease, and requiring radiologic or endoscopic methods

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

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

16 DR. HA.NAUER: Dr. Rutgeerts.

17 DR. RUTGEERTS: I would like to state on the

18 relationship between the clinical remission and endoscopic

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

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

21 induce mucosal healing. If you give or the French studies

22 gave seven weeks long very high dose of corticosteroids, 1

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

24 remission, and they had only 29 percent of endoscopic

25 improvement .

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1 Other Swedish studies have shown that You can give

2 corticosteroids for months, and ileal disease will not heal

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

4 the first time that we can have quick healing of endoscopic

5 lesions within four weeks and that it correlates with

6 clinical improvement.

7 On the other hand, the French have done also a

8 very interesting study that in the patients who improved

9 endoscopically or they continued monitoring those patients,

10 and they saw that patients who improved their lesions

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

12 not maintain their remission longer than patients who had no

13 endoscopic remission.

14 So, the relationship between both parameters,

15 clinical remission and endoscopic remission, remains a

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

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

18 that is difficult to reach and maybe is not completely

19 relevant.

20 DR. HANAUER: Dr. Simon.

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

22 include in the ACR responder index structural healing or

23 actually even inhibition of erosions. That is a separate

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

25 not even consider response acutely or chronically within

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1 that particular index of functional response of disease

2 modification. We consider it a response to therapeutic

3 intervention, signs and symptoms of activity of disease as

4 it relates to activities of the patient and how the patient

5 feels.

6 DR. HANAUER : Personally, I have problems with

7 that. Basically, your expectations of novel drug therapies

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

9 lesions and improved them, I would suspect that there would

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

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

12 be a goal of therapy.

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

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

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

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

17 able to measure it. We can see a person who is disease-

18 free. We know who that person is based on lots of different

19 criteria, but to have a scientific approach to” understanding

20 healing of erosions, change of erosions, progression of

21 erosions at the time is limited by the technology. Perhaps

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

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

24 bad drugs, it is our expectation of bad technology.

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

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1 document that endoscopic or histologic healing translates.
_——___

2 into clinical benefit, and at the present time, since one

3 can’t do that, I wouldn’t even bother necessarily including

4 those as primary endpoints.

5 If you can prove to me that endoscopic healing

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

7 would be a reasonable endpoint, but at this point from

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

9 of that.

10 DR. SIEGEL: In the article that was published in

11 ’95, it is not taken out as a separate endpoint, and I think

12 for clarity, I should note that the definition of remission

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

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

15 correctly noted not necessarily to reflect remission given

16 that patient’s fistulae were under that.

17 The claim for remission, induction of remission in

18 the draft guidance required, as opposed to treatment of

19 acute disease which required a reduction in inflammatory

20 symptoms, it required resolution of clinical symptoms and

21 signs, resolution as opposed to reduction, in addition,

22 documentation of mucosal healing, so that goes to the point

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

24 without full resolution of clinical symptoms, would not make

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

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1 and I would agree with the assessment that we have not seen

2 it yet, at least we don’t have the data to prove that there

3 are drugs that do that, they may, in fact, exist.

4 DR. HANAUER: Again, I want to encourage comments

5 from the audience. If you have any, please feel free.

6 Dr. Kornbluth. Introduce yourself.

7 DR. KORNBLUTH: Asher Kornbluth,

8 gastroenterologist, Mt. Sinai Hospital in New York.

9 Two issues relative to this. First of all, as Dr.

10 Rutgeerts points out, the correlation between endoscopic

11 activity and clinical response at least with steroids was

12 not correlated at all, number one, and there are other

13 instances where it is impossible or irrelevant to measure.

14 For instance, a patient with the worst perianal or

15 rectovaginal fistula really had minimal or no endoscopic

16 findings at the start that can be graded or followed.

17 Secondly, radiology has been mentioned several times. To my

18 knowledge, there have been no prospective trials that have

19 used radiologic measurements as an endpoint, and I am not

20 sure that, for instance, the most severe fulminant ileitis

21 would change in a storable way on follow up small bowel

22 series.

23 The ileum other than the last centimeter or two

24 might also be a difficult area to assess in a follow-up
.-..
25 study when the patient hasn’t been.operated on

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1 endoscopically. We might catch a glimpse of the TI for 2 or

2 3 centimeters where the disease might be raging 20, 30

3 centimeters more proximal to that.

4 That is the point I would like to bring out in

5 terms of endoscopy and radiology. Another point that has

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

7 for different clinical indications for the drug.

8 Take, for example, the discussion we had yesterday

9 in terms of the CDAI scores in patients with fistula and

10 3ill Tremaine’s referenced this briefly. For instance, you

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

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

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

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

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

16 night have developed a new abscess, that patient would still

17 ~e considered a success in that trial.

18 DR. SIEGEL: That is incorrect.

19 DR. NEEMAN: That is incorrect.

20 DR. KORNBLUTH: In what way?

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

22 had to have them closed, but it was interesting in the fact

23 that new fistula could be assessed, so if the patient had

24 two , they always had to have greater than or equal to half

25 of the number at baseline reduced. So, new ones could

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..
1 count.

2 DR. KORNBLUTH: Not more than they had closed.

3 DR. MATTHEWS: Right.

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

5 three and you closed two --

6 DR. MATTHEWS: You were a responder.

7 DR. NEEW: You had to have one.

8 DR. KORNBLUTH: After forming a new fistula, you

9 needed to have greater than 50 percent reduction?

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

11 one.

12 DR. KORNBLUTH: But you could have formed a new

13 abscess, and your CDAI could have stayed at 300.

14 DR. MATTHEWS: That is true, yes.

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

16 the present correlates index, that basically looked at each

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

18 patient’s own endpoints. If a patient had a rip-roaring

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

20 you say we need closure of this fistula, and we grade that

21 as +1, +2, +3, -1, -2; -3 fbi that patient’s endpoint.

22 If another patient has a great deal of

23 inflammatory activity, and you are going to make that an

24 endpoint, you score according to that basis.

25 Nowhere did we hear yesterday about closure of

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

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

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

4 very often a measure of success or maybe the sole indication

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

6 measured as the sole indication, as well.

7 DR. HANAUER: David, last comment on this.

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

9 part this morning to discussing Section B, the response

10 variables, and we are starting to get into details about

11 CDAI scores, endoscopic findings, radiologic findings,

12 histologic assessment.

13 Before we move on to B, I would just sort of would

14 like to return to a proposal for settling Question A. My

15 proposal would be about indications would be to talk about,

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

17 categories : symptoms, symptomatic, partial or complete.

18 Partial has traditionally been defined as reduction of CDAI

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

20 iiscuss those details when we get to Part B.

21 Mucosal ulceration. Partial is sometimes defined

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

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

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

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

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

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

3 HLQOL or SIP or whatever.

4 That would be my proposal for Indication 1,

5 treatment of active disease. Indication 2 would be

6 prevention of relapse as you propose, and that would be

7 prevention or relapse following surgical remission, which is

8 the whole post-op prophylaxis issue, of following medical

9 remission. Within that category we would have steroid

10 sparing.

11 DR. HANAUER: Were there other comments?

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

13 makes sense.

14 DR. SIEGEL: That differs in some ways from the

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

16 like to highlight specifically, just to make sure that is

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

18 partial and complete is where there is a difference between

19 treating active disease and inducing remission; but then the

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

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

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

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

24 if there is still inflammation in the mucosa.

25 I have heard people say you can have a lot of

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

2 really what was addressed there is the opposite question,

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

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

5 call it - complete response, complete remission, or

6 whatever, or do you want to show also that you have the loss

7 of inflammation in addition to a loss of symptoms.

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

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

10 inflamed and another area that is not inflamed, so it

11 becomes very subjective.

12 DR. HANAUER : And the converse becomes true also.

13 You can have a lot of disease and no symptoms, which we see

14 on a very frequent basis, but industry standpoint, dividing

15 it into 12 categories or such as that, is that going to be

16 an acceptable type of process or goal for you?

17 Please.

18 DR. GRAFFNER: Hans Graffner, Molndal, Sweden.

19 I like the idea of treatment of active disease,

20 symptoms of active disease, and prevention of relapse.

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

22 the pharmaceutical industry, I would say.

23 I am having difficulty with things like endoscopic

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

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

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1 can have those two things, treatment of active disease

2 versus prevention or relapse, and we will be able to decide

3 on the definitions of these things, and particularly also if

4 we can have a phenotypic kind of thing like I think on a

5 global setting, that would be a way of categorizing the

6 different kinds of patients.

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

8 Centocor. Not necessarily from an industry standpoint, but

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

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

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

12 certainly a laudable goal. It is the goal of cancer

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

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

15 there is no evidence of the disease.

16 Whether we can measure that or not, or know it

17 with any degree of certainty or not is a different question,

18 but it is something that I understand. I understand the

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

20 would be desirable I think.

21 Also, control of symptoms is desirable. I think

22 controlling the activity of disease is something I

23 understand, I am sure patients understand it. That is

24 desirable. And I understand the differences between those.
,_.!_
_& .

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

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1 say them, and I think I have an intuitive feel for what that

2 means.

3 So, to me, if I have a therapy that treats

4 activity, that is useful, and I think as a member of

5 industry, if I have a therapy that controls that, we would

6 like to have an indication for that.

7 Likewise, if we had a therapy that truly put a

8 patient in a state in which there was no evidence of

9 disease, namely, remission, or intuitive feel for that,

10 sure, we would like to have an indication for that, and I

11 think patients would like to have that therapy and doctors

12 would like to have that therapy.

13 so, I think one of the things we are struggling

14 with is not whether the indications are reasonable

15 indications, but whether we know how to know when we have

16 achieved that state, whether we can actually measure

17 remission, but I guess I would like to encourage the

18 ~ommittee to not give up on that goal.

19 I think, Steve, that is one of the points you were

20 naking. I would like to think that industry shouldn’t give

21 dp on that goal just because we don’t know how to do it yet

22 >r we don’t have a therapy available to us.

23 One other comment, and maybe it goes to the next

24 ?oint, and that is there is a fundamental difference between

25 CDAI and ACR-20 that is worth mentioning, and I like CDAI

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

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

3 proportions of things, and I have just conceptually

4 difficulty understanding the ACR-20 or the Paulus 20 for

5 that reason, whereas, the CDAI, because it is measured as a

6 continuous index, is something I understand. Whether or not

7 it is valid is a different question.

8 DR. HANAUER: Dr. Sands.

9 DR. SANDS: Bruce Sands, Boston.

10 I think I would like to amplify what Brian Feagan

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

12 discussion about how we describe responses, but very little

13 discussion about the yardsticks that we are using, and the

14 CDAI for sure has brought the field forward by providing a

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

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

17 quality of life instrument is better.

18 I think the problem with the CDAI is that it

19 straddles the line between measuring elements of quality of

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

21 Sees neither particularly well. The IBDQ really focuses

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

23 is most important in the end for a drug effect.

24 It is a very reliable measurement, very well

25 characterized in different populations, and it correlates

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1 actually very well with the CDAI. It has better operating

2 characteristics, and one could argue that it could serve

3 admirably as a replacement for the CDAI.

4 What it doesn’t get at is the elements of biologic

5 response. We know that you can measure biologic response,

6 but we commonly don’t do it. I think a biologic response

7 measurement in combination with the IBDQ could really

8 substitute for the IBDQ and would actually enhance the

9 efficiency of our studies because we would need smaller

10 numbers of patients to show a clinically meaningful effect.

11 so, I would argue for more discussion about the

12 tools that we are using to describe our responses.

..?=% 13 DR. HANAUER: We will continue that discussion.

14 Dr. Present.

15 DR. PRESENT: In my naivete when I was younger, I

16 thought that the most important thing in doing a study was

17 how the patient felt, and I still do, and when I designed my

18 ~riginal 6-MP study, there were something called goals of

19 therapy, and it was clear that healing a fistula had nothing

20 at all to do with bowel activity and how many times you went

21 to the bathroom.

22 So, we had goals of activity, goals, and the goal

23 was close the fistula. The goal was improve the symptoms

24 which would correlate much with the CDAI or the Harvey

25 Bradshaw, and we had steroid sparing, which I have always

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

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

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

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

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

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

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

8 the criteria for improvement for a drug, one has to show

9 some durability, whether that is a month or a week or six

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

11 indications because steroids may be a good drug for six or

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

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

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

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

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

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

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

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

20 what we all want to do.

21 DR. HANAUER’: Dr.” Goldstein.

22 DR. GOLDSTEIN: George Goldstein, Medera.

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

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

25 officially representing but as a member of the Executive

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

2 ought to seize this rare moment.

3 I support David’s proposals. There is a crying

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

5 view of industry, simple, clear, easily understood

6 definitions, as Harlan Weisman and my Swedish colleague have

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

8 can support and would make the job and the understanding of

9 the practicing physician, and, indeed, ultimately, as Dan

10 points out, the patient’s life a lot easier.

11 DR. HANAUER: Yes.

12 DR. LAINE: I was just going to reiterate my

13 opposition actually to including the endoscopic or

14 histologic parameters given the sense that my understanding

15 is the agency does not actually give indications for things

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

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

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

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

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

21 indication unless it is associated with ulcer, cancer, some

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

23 we don’t have any evidence that these endoscopic or

24 histologic features clearly correlate with clinical

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

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1 indication for a sponsor.

2 DR. SIEGEL: There are certain types of approval

3 based on surrogate endpoints, however, it is also correct

4 that we have outcome measures that are involved in approval

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

6 a drug improves survival in cancer patients, and the

7 patients were living longer without any symptoms, but had

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

9 complete response. If the symptoms are completely resolved,

10 we wouldn’t call it a complete response.

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

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

13 fairly good correlation between the presence of cancer and

14 iioing badly, and there may not be that association between

15 H. pylori and gastritis and doing badly or histologic

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

17 I am suggesting.

18 DR. SIEGEL: But this committee is suggesting --

19 what I hear this committee suggesting is that we talk about

20 treatment of active disease, and we say if the symptoms

21 ~ompletely go away, we should call that complete resolution

22 m complete something that was the proposal even if the

23 =ndoscopy shows that the balance are completely inflamed

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

25 5issimilar to saying that you have a complete response in

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1 cancer while there is nodules growing.

2 DR. FEAGAN: How do you define complete

3 symptomatic response? I think this comes down to the cut

4 point versus where does the noise start, and you start

5 measuring signal.

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

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

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

9 that is not my idea of a complete remission.

10 DR. FEAGAN: I think the idea of fistulous

11 disease, I mean one proposal would be that that population

12 is heterogeneic enough that we really should be talking

13 about it in a different set of metric score, I mean that

14 seems reasonable. I don’t think that that should color this

15 discussion.

16 DR. FRANK: It disturbs me to completely throw out

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

18 that when the patient has severe mucosal disease, they are

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

20 setter if they have complete healing.

21 On the other hand, mucosal healing in the bowel

22 can be totally irrelevant to the presence or absence of

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

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

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

I
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60
1 sick even if at the moment they may not have symptoms.

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

3 mucosal healing.

4 DR. HANAUER: Dr. Rutgeerts.

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

6 is no good correlation between endoscopic healing and

7 symptomatic improvement, but that does not mean that

8 endoscopic healing is not important.

9 I think in the studies, endoscopic endpoint should

10 be included because we will learn a lot from these

11 endoscopic studies, For instance, in the infliximab study,

12 if also the American centers had performed endoscopies, we

13 would have known much more about the relationship endoscopic

14 healing and symptomatic improvement.

15 DR. HA.NAUER: Should it be a regulatory requisite

16 to have endoscopic demonstration for every drug?

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

18 drug --

19 DR. HANAUER: Or biologic.

20 DR. RUTGEERTS: If you have a drug for which it is

21 known that it does not induce healing, that endpoint is not

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

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

24 mdoscopic endpoint in a study you do with these drugs is

25 lot of importance.

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1 DR. HANAUER: So, this should be a separate
.P%
2 entity, a separate indication?

3 DR. RUTGEERTS: I think so.

4 DR. HANAUER: An extension.

5 DR. NEEMAN: In rheumatoid arthritis, there is a

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

i’ symptoms and then you get additional claims for additional

8 things that promote --

9 DR. HANAUER: Moving on to some additional things,

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

11 moving in a movement forward direction, and we talked about

12 general claims, and hear some consensus regarding that, but

13 what about these individual specific areas, should there be

14 separate criteria for fistula healing, steroid sparing?

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

16 incorporating?

17 DR. LAINE: Separate.

18 DR. HANAUER: Separate.

19 DR. LAINE: And inclusive.

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

21 of either treating active disease or preventing relapse. If

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

23 is treatment of active disease. If the fistula has gone

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

25 still fistulous disease, but that is prevention of relapse.

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1 DR. LAINE: The question is could those be

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

3 because we said fistula closing is an individual claim, and

4 I think it is different enough that I would favor that, and

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

6 achieve the same effect with no steroids, that would be

7 worth a claim I think to most patients and physicians.

8 DR. SACHAR: Although steroid sparing is then a

9 category of prevention of relapse. The patient could come

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

11 take all of these separate categories and classify them

12 either as treatment of active disease or prevention of

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

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

15 ulcerations, it’s fistulae.

16 DR. SIEGEL: But the question really we need an

17 answer to is if somebody does a study successfully, which

18 shows which shows that fistulae closed or that shows that

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

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

21 treatment of active disease, but would you want the labeled

22 indication to say this is indicated to treat active disease

23 or should there be an indication that specifically says

24 closure of fistula or sparing of steroids?

25 DR. SACHAR: That is what we are here to discuss.

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

2 worthwhile as a specific indication, and that when we talk

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

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

5 is just stop taking steroids, and you are not taking

6 steroids, but it is steroid sparing without what then

7 happening, and it is either without getting symptoms back

8 again or without having a fistula open.

9 DR. HANAUER: A, you are trying to simplify, but

10 now, B, steroid sparing is going to be prevention of relapse

11 but with withdrawal, how would you define steroid sparing,

12 is it a subcategory of treatment of active disease, a

13 subcategory of prevention of relapse, or an individual n

14 number indication?

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

16 subcategory of prevention of relapse, because that is what

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

18 the steroid and not relapse, so however you define

19 ~revention of relapse, steroid sparing is one of the

20 categories of that, just as prevention of postoperative

21 relapse is another category within prevention of relapse.

22 DR. HANAUER: So, additional verbiage, words in

23 the indications, they can be easily modified and extended

24 ~eyond even what we are anticipating.
#=e
25 DR. SIEGEL: Absolutely, and steroid sparing,

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

2 basic approach I think is consistent with what you are

3 suggesting.

4 You take patients not necessarily in full

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

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

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

8 attempt -- blinded usually -- then you define failure

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

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

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

12 and that is why the indication is a little different from

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

14 you are showing that you can maintain where they are and

15 more successfully decrease steroids while --

16 DR. SACHAR: A failure point is a synonym for

17 relapse.

18 DR. HANAUER: In the absence of other indications.

19 DR. SIEGEL: Well, relapse implies remission. You
.,
20 may have people with active disease, and that may be a

21 synonym for flare.

22 DR. SACHAR: Relapse or flare.

23 DR. KIRSCHNER: Or even initial active disease.

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

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

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1 is staying at the same level or better.

2 DR. HANAUER: Is prevention of worsening disease

3 an indication?

4 DR. SIEGEL: Well, it is.

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

6 DR. SIEGEL: In another chronic disease, I should

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

8 different indications, one for preventing the flares, which

9 is essentially a symptomatic one, if it is a recurring

10 relapsing disease, and another for preventing progression of

11 iiisability. Sor there are certain parallels there.

12 DR. HANAUER: This was mentioned. Is improvement

.—.= 13 in quality of life sufficient as an individual indication

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

15 Dr. Feagan is somewhat in favor of that.

16 DR. FEAGAN: I didn’t say that.

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

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

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

20 7DAI ? It is a quality of life measure essentially with a

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

22 quantum leap, but there is a considerable body of knowledge

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

24 of whether you accept or reject it is -- again, a wider
.-=
25 ~onsensus and you don.”t make those decisions without a

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1 considered review of the operating properties.

2 The point was made about the operating properties

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

4 responsiveness is a little less in the CDAI when it is

5 measured against external gold standards, such as patient

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

7 considered overview of operating properties before these

8 decisions are made.

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

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

11 did a little better than the CBAI.

12 DR. FEAGAN: Well, talking about responsiveness, I

13 was really looking at external criteria, patient globals and

14 physician globals. I think the point you are raising,

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

16 huge problem. If we had a wonderful gold standard like an

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

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

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

2.0 an indication on its own personally.

21 DR. SURAWICZ: Since the correlation is so good

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

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

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

25 is a major drawback I think.

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1 DR. HANAUER: We don’t need to discuss the

2 individual aspects of the IBDQ.

3 DR. FEAGAN: I think, again, we heard about the

4 operating properties here and correlation with other

5 measures of response,” and I mean the correlation

6 coefficient, I mean to introduce some numbers, the

7 correlation coefficient for the IBDQ ranges from 0.6 to 0.8,

8 so 36 to 64 percent of the variance is explained by that

9 measure. Well, the glass is either half-empty or half-full.

10 That means that 50 percent of the variance is explained by

11 something else, so it is telling you something else.

12 DR. SENIOR: The simplicity and clarity of Dr.

k—. 13 Sachar’s proposal, echoed and supported by George Goldstein,

14 is very appealing. I am concerned about one point, and thtit

15 is the definition of complete response, which implies

16 perhaps more than we mean.

17 I would like to think about retaining the idea of

18 a defined remission, however we define it, with the ~ality

19 of life, or CDAI, or whatever we use. A remission is one

20 thing, but complete response almost implies cure of disease,

21 tihich is not attainable at this time. It is a third level

22 of possible response, improvement being one level,

23 improvement to a certain defined level, which we call

24 remission, and then finally, absence of disease.

25 DR. HANAUER: I somewhat disagree that it is not

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1 attainable, because the surgeons can get a complete

2 resolution of disease from a surgical standpoint to leave

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

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

5 disease because the disease is still there in the tissue

6 that remains.

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

8 criteria.

9 DR. SENIOR: Not measurable, but I am just

10 concerned about complete response, that’s all.

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

12 ~anted to discuss the measurability?

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

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

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

16 3et to that.

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

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

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

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

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

22 ?revention of relapse to modify our current terminology that

23 we are using.

24 What should the study duration be for an active

25 iisease, is 8 to 26 weeks?

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1 DR. SACHAR: To compete with steroids, you could

2 even do it in 4 weeks.

3 DR. HANAUER: Is that sufficient?

4 DR. FEAGAN: It was yesterday.

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

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

7 DR. FEAGAN: Yes.

8 DR. HANAUER: Okay.

9 DR. KIRSCHNER: No.

10 DR. HANAUER: Dr. Kirschner?

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

12 missed that discussion, but I mean if we are talking about

.—= 13 6-MP, which we feel can treat active disease, then, 4 weeks

14 would be insufficient, unless we are talking about possibly

15 high-dose intravenous; but we consider that to be an

16 effective drug. That is not within 4 weeks.

17 DR. HANAUER: We are talking a minimum, not

18 maximum.

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

20 about not where the endpoint is measured, but the study

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

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

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

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

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

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1 weeks to get 8 to 26 weeks of follow up.

2 DR. FFU4NK: I don’t think that the panel would

3 have looked as favorably on yesterday’s presentation if all

4 we saw was a blip at 4 weeks and nothing else.

5 DR. HANAUER: That is all you saw.

6 DR. FRANK: No.

7 DR. HANAUER: Oh, yes, it is. That is what you

8 approved. You have no data based beyond 4 weeks.

9 DR. FRANK: The study extended beyond 4 weeks.

10 DR. HANAUER: But you had no efficacy beyond 4

11 weeks .

12 DR. WEISS: The primary endpoint of that one was

13 at 4 weeks, but then patients were followed out to 12 weeks,

14 and showed a response that was gradually declining closer

15 towards the placebo rate.

16 DR. HANAUER: So, from the standpoint of future

17 studies, if Centocor or anyone else wanted to show 4 weeks,

18 could they stop it at 4 weeks?

19 DR. FRANK: No.

20 DR. HANAUER: So, what is the minimum duration?

21 rhat is the question that Dr. Siegel is trying to push.

22 DR. RUTGEERTS: I think that for drugs like, for

23 instance, 5-ASA, the best efficacy sometimes achieved was 16

24 weeks. I think you need to have a certain period. I think

25 you need 12 weeks.

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

2 What is the minimal durability for treatment of active

3 disease? How is that?

4 DR. LAINE: It really does totally depend on the

5 drug, though. It is a little hard --

6 DR. HANAUER: But what is the minimum that the

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

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

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

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

11 totally better in one day --

12 DR. HANAUER: For one day.

13 DR. LAINE: No, in one day -- and it lasts for 4

14 Weeks, and for 4 weeks with that drug you are feeling great,

15 and every index is down to zero, let’s make up some

16 incredible drug. Would that not be acceptable?

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

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

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

20 is very hard to predict without knowing the nature of the

21 ~rug. Then, you would normally want to make the length of

22 follow up based on the initial Phase I studies of the drug I

23 tiould think.

24 DR. HANA~R; They. are asking clinical guidance
.-.
25 Erom. us What is the minimal clinical durability of an

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1 acceptance for an acute drug, is it a day, is it a week, is
__&_
-=

2 it 4 weeks? Is that too much to ask?

3 DR. WEISS: I guess there are two things that

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

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

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

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

8 other thing is guidance on how long these initial studies

9 should go on and whether or not you measure the response at

10 one point or look at the area under the curve over that

11 particular period of time. Perhaps nearer to the curve

12 would be better.

13 But what we are talking about what is the minimal

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

15 that particular study?

16 DR. LAINE: This has to establish remission, so

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

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

19 accept that as a remission.

20 DR. HANAUER: A response.

21 DR. LAINE: A response.

22 DR. HANAUER: Not necessarily remission, response.

23 Dr. Simon.

24 DR. SIMON: The only way you can do that is if you
L-.
25 define the remission, so if you are going to say signs and

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1 symptoms of the patient feeling better by certain measurable

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

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

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

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

6 symptoms of disease for 6 months, structural abnormalities

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

8 measure it in less than a year.

9 so, it just depends on one’s considerations of

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

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

12 validity of it, what is the internal characteristics of the

13 measurement, and are there differences between point A and

14 point B.

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

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

17 all along and do an area under the curve?

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

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

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

21 then whatever you are using to measure that with the

22 validity of it from point A to point B.

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

24 that 4 weeks of a remission was good enough response.

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

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

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

3 us .

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

5 guidelines to give us a guideline for our guidance, they

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

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

8 months with a defined response unless the drug is well

9 classified and already available.

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

11 on for 6 months.

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

_—_ 13 accepted a 6-month landmark analysis although we have been

14 encouraging sponsors to look at duration and measure things

15 over time.

16 DR. HANAUER: Do potential sponsors want to

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

18 DR. WEISS: I think that is what we would like to
..
19 know. Is there a minimum duration? In RA, it”has been

20 recommended that there should be a minimum of at least 6

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

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

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

24 intents and purposes sort of the end of that --
&’— .
25 DR. HANAUER: To be fair to the company, they did

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

(- 2 company.

3 DR. FRANK: It seems to me you need the 6 months

4 to detect safety issues beyond the efficacy issues also.

5 DR. ZELDIS: I am Jerry Zeldis from Celgene

6 I am just looking at your draft guidelines, and

7 you are defining two types of treatments, those which get

8 rid of symptoms of acute disease and those which maintain

9 remission. There may be categories of drugs which are

10 superb for inducing or stopping active disease, but they

11 will not work for maintaining remission and vice versa, and

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

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

14 thalidomide in leprosy as an example. In ENL, steroids

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

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

17 superb effect within 3 days.

18 It turns out that thalidomide is good to maintain

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

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

21 in with some other drug to maintain the remission.

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

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

24 dealing with.
,.=-
[.. 25 DR. HANAUER: Dr. Weisman.

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76
1 DR. WEISMAN: Just historically, why we chose 4.
.-..
2 weeks for Crohn’s disease, when we have a clinical trial in

3 RA, it is almost completed, and it will have an endpoint of

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

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

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

7 patients needs and want, and we heard that yesterday from

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

9 patients, RA and Crohn’s disease are fundamentally

10 iifferent.

11 What we were told by our experts who are

12 rheumatologists is that a therapy that is only for 6 months

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

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

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

16 course of the long term.

17 Crohn’ s disease is a disease which can be

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

19 >f those devastating symptoms is very meaningful to the

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

21 :hat is not the case.

22 so, I would say it is exactly translatable, one

23 iisease to another. We chose 4 weeks for Crohn’s disease

24 >ecause we were told in talking to our experts, some of whom
.-..
25 ire on the panel, that that was meaningful, that that meant

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1 something to patients, it meant something to doctors, and, I

2 think it was validated yesterday.

3 We were told in RA, anything less than 6 months

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

5 DR. HANAUER: We brain-wash our patients

6 differently.

7 DR. PORTER: Steve Porter, Therapeutic Antibodies.

8 I would like to amplify the concept that we not

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

10 nortality scenarios and I would be deliciously happy to have

11 an agent that would do something very fast, very rapidly,

12 very actively remit something, and maintain that remission

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

14 Very important paradigm in this disease state, and things

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

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

17 arbitrary endpoint if they have real net term benefit of

18 resetting a rheostat and allowing other drugs and the

19 Iormative process of natural healing be eviden’t in that

20 ?atient population.

21 DR. HANAUER: Dr. Simon.

22 DR. SIMON: However, if you are resetting the

23 rheostat, then, you would expect that rheostat would have

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

25 whatever you are talking about.

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1 The dilemma is that you might find a drug, it is

2 possible, whereby intervention by biologic modifier that

3 would then change the disease so transiently that the

4 results may be dramatic acutely, but 3 weeks later, because

5 of the change in the down-regulation of the activity of

6 tihatever you are inhibiting, it rebounds dramatically, and

7 if it is not built in to study that other than just as a

8 longitudinal follow up, you may not understand the

9 significant ramifications, and I can’t thank Dr. Frank

10 ~nough about bringing up again the issue of the safety

11 issue .

12 Some of these issues need to be carried out for

13 nuch longer than 6 months, so that has to be built in, as

14 ~ell .

15 DR. HANAUER: As far as prevention of relapse, 12

16 JO 24 months as a minimum study. Comments? That seems to

17 ~e pretty well recognized.

18 DR. PRESENT: Excuse me. I don’t agree. I think

19 if you could put someone into remission for 6 months, it

20 would be extraordinarily meaningful for a patient with

21 kohn’s disease. I don’t think you need to go out for a

22 {ear to show efficacy. Patients would be ecstatic to be in

23 5-month remission. So, I don’t agree.

24 If I was going to use a drug for maintenance, as

25 rell as getting safety, I would want at least 6 months.

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1 DR. HANAUER: I wish I had you quoted elsewhere

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

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

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

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

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

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

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

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

10 On the point of the 6 months, then, the

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

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

_.-. 13 calling cyclosporine an adequate drug for maintenance of

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

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

16 6 months, you are really not thinking of it, are you, as a

17 remission-maintaining drug?

18 DR. PRESENT: I believe cyclosporine can maintain

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

20 discontinued cyclosporine in ulcerative colitis, not in

21 Crohn’s disease.

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

23 DR. PRESENT: SO, I think that it is a maintenance

24 drug for some diseases, not for all.

25 DR. HANAUER: Dr. Goldstein.

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1 DR. GOLDSTEIN: TWO points. Well, basically, the
_-—=
2 same point. At the front end was the kick-in time that

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

4 restoration of responsiveness where it had, so to speak,

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

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

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

8 We heard this yesterday and we will doubtless hear

9 it again.

10 DR. HANAUER: Dr. Simon.

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

12 inherent to the term remission? Remission has to mean no

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

14 is meaningless to say somebody has no disease for 3 months

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

16 you are looking for indication meaning that if a drug some

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

18 remits it for how long? That is important.

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

20 committee feels 12 to 24 months is appropriate, but with

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

22 disease. We will get that on the record.

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

24 clarification because now I am getting confused between

25 remission and treatment of active disease.

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1 DR. HANAUER: Remission means prevention of
.-.

2 relapse.

3 DR. MATTHEWS: Then, the question comes in about

4 the study duration. You go back to the first part of that.

5 Are we saying that Crohn’s is different from RA in the sense

6 of its chronicity and that the medical community is willing

7 to accept a response that lasts 4 weeks, maybe 8 weeks as

8 opposed to the rheumatoid arthritis community which would

9 prefer 6 months? I am just a little confused now.

10 DR. HANAUER: Again, speaking for the committee,

11 and for what happened yesterday and for the patients, yes,

12 they are accepting an acute response in their disease for 4

13 weeks. Now , certainly, if another product comes in and says

14 that it provides acute response with a durability of longer

15 --

16 DR. MATTHEWS: That is my point because if

17 sponsors feel they can get an acute response for 4 weeks,

18 but then there may be no incentive then to go on and

19 continue to get drugs out there that will continue, maybe

20 not put them in “remission’! or resolution, but it will

21 certainly get them pretty close to it, and not everything is

22 going to be as good as the biologic agent you heard

23 yesterday --

24 DR. HANAUER: Well, here is a good example. This
4=-%
25 is a sponsor who has looked at a 16-week response --

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

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

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

4 community because they are kind of drowning, and that is

5 treatment of active disease.

6 Then, the patients need to learn how to swim by

7 being put on something else, another kind of agent which

8 would prevent relapse. From an industry viewpoint, that is

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

10 because we all want to have good drugs for preventing

11 relapse.

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

13 it is one characterized by exacerbations and remissions,

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

15 treatment of an exacerbation.

16 DR. MATTHEWS: So is rheumatoid arthritis, so that

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

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

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

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

21 is where it goes back to the definition of remission,

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

23 between where patients may not be so severe that they are

24 borderline on surgery, but they can be quiescent, although

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

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1 not all products are going to be as remarkable about what,
..-=

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

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

4 because not all patients responded to infliximab.

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

6 of the disease, you touched on the important implication of

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

8 life-threatening implication within a month if the fire

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

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

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

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

13 month isn’t a worthwhile goal.

14 DR. MATTHEWS: But my concern is the fact that if

15 there is some statement that says unless it is fine, that

16 there won’t be an incentive for development of drugs that we

17 will study further. That is my concern.

18 DR. SIEGEL: There is a difference between

19 indications we discussed yesterday for short term or even

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

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

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

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

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

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

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

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

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

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

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

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

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

8 DR. SIEGEL: That is really something somewhat

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

10 treating a flare, an acute flare.

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

12 Kirschner.

13 DR. KIRSCHNER: As a pediatrician who has seen

14 probably hundreds of kids with JRA, as well as the same with

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

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

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

18 active disease and they have exacerbations and remissions,

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

20 the time that have essentially chronic active disease.

21 I think our patients’ expectation, particularly

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

23 don’t know their side effects, we don’t know the long-term

24 duration, that a four-week period of time in these patients

25 who have already failed other therapies, are expecting more

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1 than a 4-week response to a drug.
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2 I guess we can say they then get it every month,

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

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

5 week control of disease. These are chronically active

6 patients.

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

8 with you, expecting and accepting are different conditions,

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

10 shorter response. They would like more, but they will

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

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

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

14 and we will give them more from an indication standpoint if

15 they can prove durability in this.

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

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

18 weeks again and prolong the remission, or they would be

19 happy with only 4 weeks if it loses its efficacy?

20 DR. HANAUER: We are not talking about how we

21 treat the patients here. We are talking about how we

22 approve new drugs for patients, and we have to divorce that

23 issue. We are keeping them in mind, but we did hear that

24 they would accept, and this committee would accept, a

25 ninimum response of 4 weeks. We would like more for you and

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1 your patient -- for our patients we would like more.
.=-=
2 DR. SIEGEL: Obviously. , we haven’t heard from the

3 entirety of the patient community, and I am sure, in this

4 patient community, there is a great diversity of opinion.

5 But the question was put yesterday, if you know a

6 drug would help you for a month or two, and you knew for

7 certain that after a period of time you would be back to

8 where you started, would that be a drug you would consider

9 taking, and the answer from one of the panelists was

10 absolutely, yes.

11 DR. HANAUER: I want to handle one other issue

12 before we break. The panel has been asked regarding the

13 CDAI , and I think we have talked a lot around that, and I

14 don’t want to focus again on specific other indices in case

15 we have to redefine the measures of disease, but focus on

16 one specific aspect of that, which the agency has asked, and

17 they asked, the drug effect can be shown either by

18 comparison of overall group effect, such as the mean plus

19 the standard deviation, median, and distribution, between

20 study group and control group or by defining criteria for

21 success in individual patients and comparing the proportion

22 af successes. How many patients reached a specific level?

23 This is one of the aspects that Janet wanted to talk about.

24 The latter approach is substantially less powerful

25 in detecting treatment effects and requires longer study

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1 duration.

2 Which of the following comparisons are appropriate

3 for demonstration of efficacy and is one preferable?

4 The overall group effect meaning a mean change.

5 The proportion of patients whose index is reduced below a

6 threshold. The proportion of patients experiencing absolute

7 reductions.

8 Janet, do you want to comment on that

9 DR. ELASHOFF: Yes. All of them, of course, are

10 reasonably appropriate if one wants to define them that way.

11 Generally speaking, from a statistical point of view, I

12 prefer not to define arbitrary cut points and change what we

13 have made a lot of effort to make into a continuous index

14 back into a sort of a yes/no index, partly because of the

15 less powerful issue and partly because of the arbitrary

16 character.

17 Now, whether one used the CDAI or some other

18 index, the issue of whether you do mean change or analysis

19 of covariance has to do with how the measure is in fact

20 behaving, which was talking about operating characteristics

21 kinds of things, and what the pre/post correlation is and

22 whether you typically have about the same spread around the

23 relationship at different levels.

24 What I have passed out, unfortunately, there

25 aren’t really any in the audience, is something that

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1 Centocor put together last night, which for their two
,#—
2 studies shows the relationship between baseline CDAI and 4-

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

4 first plot distinguishes between placebo and all of the

5 active treatments, the second plot distinguishes the

6 different doses of the active treatment.

7 The additional plots are for the T20 trial at the

8 2-week and at the 6-week point. I would simply say that

9 looking at that kind of information in some detail helps

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

11 change or whether one wants analysis of covariance or

12 something like that.

13 Specifically for CDAI, it appear that the linear

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

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

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

17 which would make one a little unhappy with that sort of

18 thing.

19 The spread around the curve is reasonably similar

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

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

22 pre/post relationship versus the active treatment pre/post

23 relationship do appear to be reasonably parallel, which

24 would support an analysis of covariance or a mean change, so

25 that I would argue for using the more continuous measurement

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

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

3 on with the characteristics before one finalizes exactly how

4 one wants to look at it because the underlying assumptions

5 are always important here.

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

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

8 the CDAI versus a mean change of drug versus placebo, one of

9 the problems that we are going to be confronted with is what

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

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

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

13 it is not a relevant difference.

14 Should we then have two criteria, do you need a

15 ninimal change in addition to a mean change?

16 DR. ELASHOFF: I would like to make two points

17 about that from a statistical point of view.

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

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

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

21 uould obviously, if you feel that a change of 70 is

22 important, that is what you would power the study for.

23 DR. HANAUER: Does that mean that should be the

24 ninimal criteria?
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25 DR. ELASHOFF: Let me make an additional comment

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1 before we get to that.

2 The second is that you don’t entirely get away

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

4 T16, because although you said 70 was the important cut

5 point, first of all, you distinguish in a big way between

6 somebody who changed 69 and somebody who changed 71, which

7 is pretty arbitrary, but secondly, only about 50 to 60

8 percent of the treated patients met that cut point.

9 In addition to making the cut point, you need to

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

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

12 study was big enough, seen a distinction between the drug

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

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

15 entirety get away from that issue even when you are using

16 cut points.

17 Definitely, I would say that you should always

18 address the clinical importance issue, as well, but you

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

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

21 instances because both you define the cut point and you

22 define how many people have to reach it.

23 DR. SACHAR: I like to be collegial and flexible,

24 but I am really unalterably and emphatically opposed to the
.-p=+
25 use of an overall group effect. It is clinically

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1 meaningless. You can deal with a sigmoidoscopy score going

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

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

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

5 You can prove anything with a mean overall score

6 that is worthless, worthless information when to comes to

7 whether the drug is any good for treating the patients,

8 worthless.

9 DR. SIEGEL: Why would not cutting the mean

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

11 would that be worthless?

12 DR. SACHAR: Because it would give you no

13 information as to what proportion of patients are going to

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

15 DR. SIEGEL: I guess if you define the only

16 information of worth is the proportion of patients who

17 improve on the drug --

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

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

20 starting a priori only wanting to know what proportion of

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

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

23 of a situation where that would be useful to me.

24 DR. HANAUER: Dr. Simon.

25 DR. SIMON: I would point out two things. One is

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1 the issue of expectation bias and the movement toward the
-.
_-
2 mean under big, large populations, number one, and number

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

4 rheumatoid arthritis, and the concept was that we decided to

5 create consensus of what it meant to have a clinically

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

7 again a little embarrassed about the fact that it is partly

8 related to technology and what is measurable -- but we

9 decided that a 20 percent response, in whatever the variable

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

11 change of importance as it related to what the patient also

12 thought was important.

13 so, that might be joint counts, that might be a

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

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

16 could cause damage or the disease could cause damage, and

17 there would be activities that you would measure that would

18 be incorporated or parallel measurements to look at those

19 issues, and again would require some percentage association

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

21 between point A and point B.

22 DR. SACHAR: Did you measure proportion of

23 patients or overall group scores?

24 DR. SIMON: Proportion of patients. It would have

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

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1 be measured that we thought that any one patient who didn’t

2 have at least a 20 percent response was not important, and

3 that was because of the idea that if you just did large

4 populations, you would get changes that were related to the

5 numbers of measurements, and not related to the observation.

6 DR. HANAUER: As a clinician, I share Dr. Sachar’s

7 view and I think you guys have set low expectations from our

8 standpoint simply a person who goes from 10 bloody bowel

9 movements a day to 8 bloody bowel movements a day is a 20

10 percent change, that is not what they care about.

11 They care about what the likelihood is to have

12 normal bowel movements without pain, et cetera.

13 DR. SIMON: And that may be fine for yours. You

14 have to make that consensus.

15 DR. HANAUER: Dr. Feagan.

16 DR. FEAGAN: There are a lot of issues here. The

17 issue of the CDAI score and whether it should be used as a

18 continuous or a dichotomous variable, I think conceptually,

19 it is attractive to use it as a continuous variable, and

20 usually the case is that is statistically more efficient,

21 but when you actually look at the operating properties of

22 this variable, as there is a skew in the standard deviation

23 with higher scores, and it gets very sloppy when you get

24 into scores of 300 to 400, and so the actual efficiency

25 issue, as someone who has been dismayed by seeing sample

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

2 actually. It is actually more efficient to continue to

3 dichotomize at that 150.

4 That is an issue and then the issue of treating it

5 as a continuous variable, the interpretation of a delta CDAI

6 in sicker patient populations, when the variance is much

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

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

9 think they mean the same thing.

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

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

12 all the patients wound up clustered around 200, we would

13 call that a failed drug --

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

15 300, I don’t think that is clinically meaningful, and I am

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

17 because it is not efficient from a measurement standpoint

18 because of the variance.

19 DR. SACHAR: It is excessively driven by counting

20 bowel movements, which is a highly invariable count.

21 DR. SIEGEL: I would suggest that what is reliable

22 and reproducible in an individual may not be in a

23 population, which is to say it may not matter if somebody

24 goes from 8 bloody bowel movements to 4 or 6 as an

25 individual, and one of the reasons it may not matter is the

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1 next day they may be as likely to have 8 as to have 4, but,

2 in fact, if you do hundreds of individuals, and you move an

3 average from 8 to 4, you may well be demonstrating some

4 level of statistical certainty that people are on this drug

5 having this many bowel movements.

6 What you are saying is that knowing cutting bowel

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

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

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

10 is that smaller changes, you are not comfortable with

11 because of other factors, such as particularly variability

12 of the response or weighing them against toxicity, which is

13 another issue than cost, that needs to be dealt with

14 differently.

15 DR. HANAUER: Are there clinicians, clinical

16 investigators who feel differently than what you have heard

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

18 reduction is valuable?

19 DR. FEAGAN: I don’t have a problem with using

20 means. I think it is just means in this specific

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

22 at the top end of very high CDAI scores.

23 DR. ELASHOFF: I would like to comment on that

24 specifically. That is partly a matter of the score itself

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

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1 of, and you could make it uniformly variable at the

2 beginning and at the end.

3 That is a specific statistical kind of thing which

4 could be taken care of. In fact, if the scores are

5 reasonably uniformly distributed around that sort of thing,

6 proportion making a certain amount of change is directly

7 calculatable from the mean change and from the standard

8 deviation. They are not completely separate things. They

9 are completely related from a statistical point of view, and

10 they could be defined in a related way.

11 DR. HANAUER : Last comment. Dr. Kirschner.

12 DR. KIRSCHNER: From a pediatric point of view, we

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

14 it seems to underestimate severity of disease, we have been

15 talking among our North American Society of Pediatric

16 Research Group of taking 30 percent reduction in the

17 pediatric CDAI as a modifier because 188 could indicate a

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

19 the literature for adults.

20 DR. SACHAR: Are you looking at overall group

21 affect or proportions of patients achieving that goal?

22 DR. KIRSCHNER: Each individual patient reducing

23 their score by 30 percent.

24 DR. ELASHOFF: If you do a proportion on each

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

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1 on each patient, but you have a slight different scale. You

2 are then looking at a mean again.

3 DR. KIRSCHNER: Right.

4 DR. SIEGEL: He is saying the proportion of

5 patients who reach a threshold change.

6 DR. WEISW: To address Dr. Sachar because I

7 don’t agree with him. I know what you fear, but I think

8 modern statistics addresses what you fear. One point is

9 that you don’t look at any endpoint in isolation. I think

10 me of the things that people like about continuous

11 variables and their measurement, is just somebody used the

12 efficiency of analysis.

13 It is just a very nice way, and the statistical

14 techniques that we have available to us to do analyses are

15 more efficient using the continuous variables and avoiding

16 cut points which are arbitrary and aren’t as informative,

17 and there are lots of things you can do in terms of looking

18 at interactive effects and other things that using the

19 continuous variables are more efficiently handled.

20 However, what you are saying is very relevant, and

21 there are extreme cases, and that is what you are really

22 concerned about. You are worried about clustering effects,

23 that there may be a very small population of patients that

24 are driving a mean value one way, whereas, a majority of
.n.
25 patients are not benefiting.

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

2 everybody wants to know through secondary analyses. I was

3 just talking to Kevan Anderson, who is the head of

4 statistics at Centocor, and he pointed out that the

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

6 primary endpoint was important, that was our primary

7 hypothesis that was being tested, it was judged to be

8 meaningful, but if we had a primary endpoint that was

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

10 I bet the outcome of yesterday’s committee meeting would

11 have been different.

12 DR. HANAUER: But you would have selected a

13 primary endpoint of being at mean reduction and CDAI

14 compared to placebo and came in with a 30-point

15 statistically significant, well-powered study.

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

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

18 a meaningful difference is. There are statistically

19 significant differences that may not be clinically

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

21 Very small change, it may not have clinical significance,

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

23 oecause the advisory committee didn’t just look at our

24 ?rimary endpoint.
_A=
25 They looked at our secondary analyses, in fact, we

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1 ranked our secondary analyses of ones of importance. Some

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

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

4 to do with magnitude of the effect.

5 Those kinds of things are important and all of

6 them go into the judgment about whether what you saw was

7 clinically meaningful to render an opinion, and I would say,

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

9 analytical techniques available to us to make judgments, but

10 you clearly want to guard against what you are concerned

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

12 DR. SACHAR: I am not concerned about just what

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

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

15 tenth of a point in hemoglobin or something and get

16 tremendous statistical significance. I think we are all

17 sophisticated enough to be able to dismiss statistically

18 significant changes that are biological or clinically

19 trivial.

20 But there are measures like the CDAI where you

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

22 Dowel movements or something, which has an enormous impact

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

24 really going to be clinically meaningless although the
.n.
25 softly clamped modification of collapsing some of these

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1 numbers into groups or something --

2 DR. WEISW: What I was going to say, though, is

3 that you make a judgment. You know, if your index is wrong,

4 you adjust your index. The other thing is that if you have

5 a maldistribution which is causing some skewing, that is

6 changing your primary measurement, you have done your

7 statistics inappropriately because there is an assumption of

8 normality that you might be assuming that isn’t there, so

9 you have to adjust the scale, so that if you are on a linear

10 scale, and it is giving you a false reading, use a

11 logarithmic transformation.

12 In other words, what I am saying is modern

13 statistics knows how to deal with what you are concerned

14 with, and I think there is an efficiency factor using

15 continuous variables that we shouldn’t just throw out.

16 DR. HANAUER: At this point, I think the committee

17 for your morning enthusiasm. I really don’t want to take a

18 full hour lunch break to get everything finished.

19 We will resume at exactly 12 o’clock; and we will

20 be finished by 2 o’clock.

21 [Recess.]

22 DR. HANAUER: Just in relating to our charge in a

23 previous session, looking at issues regarding response

24 variables, I want to come back to one subject that we did

25 leave off that has been handled in the rheumatologic

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

2 disease from a clinical standpoint and also from

3 pharmaceutical development standpoint because I know that

4 many in industry have tried to tackle this issue.

5 That is related to steroids. Also, it pertains to

6 the statistical issue. The question is -- there are

7 actually two questions related to steroid therapy and

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

9 steroid use an acceptable indication or is complete

10 elimination of steroids the desirable indication, and the

11 second question is what is the durability of that response,

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

13 achieve the indication, is some life span off of steroids

14 necessary?

15 Dr. Kirschner.

16 DR. KIRSCHNER: For the same reasons we talked

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

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

19 pediatric literature suggesting that steroids can have some

20 benefit in those that have chronically active disease or

21 relapsing disease, so from out point of view, I guess I see

22 it in the same way we have talked about some other things as

23 complete withdrawal and partial withdrawal.

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

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

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

2 of therapy, but we wouldn’t view it as a failure going from

3 15 mg a day to less than 10 mg a day or some amount that we

4 chose or every other day.

5 DR. HANAUER: SO, in your laundry list of

6 indications, this would go under the heading of prevention

7 of relapse, steroid withdrawal, partial reduction or

8 complete reduction?

9 DR. SACHAR: Right, and there are ample precedence

10 to help answer your questions because if we are talking

11 about prevention of relapse, we have already said it should

12 be for about 12 months minimum getting a patient off

13 steroids for 3 months and then relapsing or 4 months and

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

15 goal .

16 DR. HANAUER: SO, for duration you are proposing

17 one year off steroids? That also requires a one-year,

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

19 Rheumatology just give us your guidance on guidelines?

20 DR. SIMON: We have incorporated the knowledge

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

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

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

24 mg a day.

25 Howeverr we have also agreed that if you think

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

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

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

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

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

6 1/2 mg as a laudable goal.

7 DR. HANAUER: For what time period?

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

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

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

11 day and it’s okay.

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

13 come up.

14 DR. NEEMAN: I think probably the way steroid

15 reduction would be measured would be as area under the curve

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

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

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

19 but say starting from week 16 to week 48.

20 DR. HANAUER: The average dose area under the

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

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

23 trials in RA.

24 DR. HANAUER: Okay. So, it is a goal.
-——..
25 DR. SIEGEL: There was a steroid sparing trial in

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1 lupus . Yesterday, somebody commented there were a lot of

2 patients on steroids that are not responding to them, which

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

4 there was a trial, as I understand in lupus, of steroid

5 sparing, where patients received either placebo or a study

6 drug, and steroids were tapered, and the trial in part

7 failed because tapering steroids was highly successful in

8 the placebo arm without flare .

9 DR. HANAUER: So steroid sparing is a worthy goal,

10 but you guys haven’t --

11 DR. SIMON: We discovered three things. The first

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

13 glucocorticoid to begin with and therefore they were better

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

15 Number two, that was actually a primary outcome which was

16 the tapering of the glucocorticoid, and that was a very

17 difficult primary outcome plus the variable dose of

18 glucocorticoid even in systemic lupus, it is a very

19 heterogeneous disease, so therefore, depending-what you are

20 using the glucocorticoids for, that changed what you were

21 using the primary comparative drug for, and it made people

22 uncomfortable based on what was being measured.

23 So, we are not very good at this, but it is area

24 under the curve that one is thinking about, and I would
_n.
25 think that most people would think it would have to be at

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1 least for 3 months that area under the curve although I

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

3

4 DR. WEISS: I don’t think the document addressed

5 it, but I mean there is obviously some common sense you have

6 to put into this.

7 DR. HANAUER: Wouldn’t you rather see the

8 proportion of patients who are able to taper below 7 1/2 mg

9 and sustain a clinical response for 3 to 6 months?

10 DR. SACHAR: You actually have identified two

11 important questions and perhaps not identified the third.

12 The important question of duration. Again, we looked at the

13 budesonide trial where maybe at 3 or 6 months it was no

14 better than placebo, but at 9 or 12 months it was not.

15 I would be looking to go longer than 6 months, and

16 ny thoughts would still be at about 12 months.

17 The second question you have raised has to do with

18 the threshold issue again. How much is enough to qualify?

19 In every other category, whether we were talking about

20 symptoms, mucosal ulceration, fistulae, we had a two-step

21 thing, what was enough to call it significant improvement,

22 and then what is enough to call it complete improvement, and

23 I don’t see why the same thing couldn’t be done with

24 steroids saying a significant improvement is to get to 7 1/2

25 ng a day or less and the complete improvement is to get

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1 completely off.

r 2 DR. HANAUER: Also, from another standpoint in RA,

3 I believe there is data that low dose steroids do sustain a

4 clinical response.

5 DR. SIMON: That was a paper by Kerwin in The New

6 England Journal of Medicine a couple of years ago based on

7 some earlier observations. The problem is that has not been

8 sustainable in other prospective clinical analysis.

9 DR. SACHAR: We all have clinical experience,

10 which is going to bring me to the third point that you

11 didn’t address, which has something to do with the so-called

12 steroid-dependent patient.

,<-—. 13 By definition, if there is such a thing as a

14 steroid-dependent patient population, by definition, that

15 means that there is a patient population for whom continuing

16 steroids prevent relapse. It is sort of by definition.

17 So, the question we would have to ask is the third

18 question that you didn’t raiser Steve, is how do we define

19 the steroid dependent population to whom steroid-sparing

20 therapy is applied, because if you have a patient that has a

21 flare for the first time, you put them on 40 mg and you

22 start to take them off and they are down to 20, they haven’t

23 yet declared themselves as being steroid dependent, so you

24 put them on a drug and you get them off the steroids. You

25 don’t know if you have done anything because you didn’t know

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1 they were steroid dependent in the first place.

2 so, I think the third element that is missing is

3 the definition of the population for whom steroid sparing

4 means something, namely, who is the steroid dependent

5 patient.

6 DR. HANAUER: Dr. Feagan.

7 DR. FEAGAN: I think it is inconsistent to treat

8 steroid use in a different light from activity with respect

9 to the time criteria. I mean steroid use is a proxy for

10 activity. You reduce steroid use, activity goes up if the

11 indication is appropriate for the steroids, so why are we

12 saying then that steroid withdrawal has to be a different

& =. 13 standard than the effect on activity?

14 DR. SACHAR : In term so prevention of relapse.

15 DR. HANAUER : One of the reasons is -- and I think

16 again yesterday’s discussion exemplified this possibility --

17 that you are adding on a new drug to patients who have a

18 5iscussion despite steroids, and we haven;t demonstrated

19 that that new drug, that just bumping up, increasing the

20 dose of steroids wouldn’t have attained the same response as

21 adding the new drug.

22 DR. SIEGEL: The reason you might consider a

23 iiifferent duration is that really what we are talking about

24 here is what is an adequate measure of benefit, and of

25 course, all of this, as several have mentioned through

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1 discussion as a subtext, well, it depends on what are the

2 risks and costs that are associated with that benefit, but

3 that aside, in one case we are talking about a trial where

4 the benefits are measured by patients getting better,

5 reporting to us less pain, less diarrhea, whatever the

6 outcome measures are and what were indexed, and in the other

7 case we are not talking about patients doing better than on

8 the other arm except to the extent we are talking about

9 there being on less steroids.

10 Now , we have heard patients say that having less

11 symptoms for a few weeks is very meaningful and important to

12 them. It may be that being off prednisone or on less

13 prednisone for four weeks is meaningful, or it may not be,

14 but it is a different measure and therefore, one might

15 separately look at durability in terms of what it takes to

16 know that you have a benefit given that we are not directly

17 neasuring patient benefit, we are only presuming one on the

18 ~asis of reduced steroid use.

19 DR. HANAUER: We are also I would presume a

20 component of that is maintaining the level of activity or

21 inactivity while steroids are withdrawn.

22 DR. SIEGEL: Right, maintaining. so, in this

23 trial, presumably the results you are going to look at,

24 because they will come to this committee, is you are going

25 to have a drug versus a placebo, and by George, the Crohn’s

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1 disease on the two populations, whether they both start with

2 inactive disease or active disease is going to be

3 essentially the same.

4 The difference you are going to see is one got

5 less steroids, so it is a different question. How long of

6 that is it going to take to convince you that you are

7 looking at clinical benefit?

8 DR. HANAUER: How long? How long? Simple

9 question. One month? Two months?

10 DR. SURAWICZ: Many months.

11 DR. HANAUER: Six months?

12 DR. SACHAR: I think you are still mixing two

13 things together. You spoke about the patient who is still

14 symptomatic on steroids, so you are adding something. That

15 is the treatment of active disease, and that is a patient

16 who you may want to define as steroid resistant, who is

17 having disease although on steroids.

18 The other we are talking about is not incurring a

19 relapse in a patient who is controlled on steroids. That

20 patient is steroid responsive, steroid dependent.

21 DR. HANAUER: While you are on that, would you

22 mind defining those for us?

23 DR. SACHAR: I am coming to that. Now, YOU have

24 asked the third question, which you hadn’t before.
g--
25 On the issue of duration, I think that when we are

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talking about a steroid resistant patient in whom you are
g-%=.
2 adding a drug on top of the steroid, you apply the criteria

3 for treatment of active disease. For the patient who is in

4 remission on the steroid, who is steroid responsive, but

5 dependent, and you are trying to prevent a relapse after

6 withdrawing from steroids, you apply the criteria of the

7 prevention of relapse indication.

8 Now , we didn’t yet talk about the threshold and

9 somebody said ‘1O, somebody else said 7 1/2. I think the

10 principle is there, that there is a threshold where you can

11 say it is worthwhile improvement which is not present going

12 from 40 to 30 over a long period of time regardless of areas

13 under the curve, and the second threshold is going down to

14 zero. That fits the precedent of all the others.

15 DR. HANAUER: Do we need to set that threshold if

16 sponsor A comes in with proportion of patients able to get

17 below 7 1/2 and sponsor B, proportion of patients below 10,

18 and C, below 5?

19 DR. KIRSCHNER: I think the reason we chose -- I

20 said below 10, and I would be very happy with 7 1/2 -- is

21 because we are concerned -- I mean there is active disease,

22 there is remission, and for us there is toxicity, so we are

23 worried about bone mineralization, and we are worried about

24 growth, and so we want it down around 7 1/2 is fine, and

25 there is a reason why 7 1/2 would be better than 10, because

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1 of the effects on bone, the effects on growth.

2 DR. HANAUER: Just to get Dr. Rutgeerts and

3 Feagan’s notion, in many countries they set 5 mg as a

4 threshold dose.

5 DR. RUTGEERTS: This dose is not very well

6 defined. We set 5 mg, others 10. Personally, I think that

7 it is best to achieve discontinuation of steroids, that that

8 should be the aim, and not decrease.

9 DR. SACHAR: Is 7 1/2 the same as 15 every other

10 day?

11 DR. KIRSCHNER: No, it is probably more.

12 DR. FEAGAN: I would just like to revisit the

13 issue of activity. Again, I think there are logical

14 inconsistencies into the attitude of 6 months versus as

15 little as 4 weeks.

16 We heard yesterday that patients find meaningful a

17 change in their delta CDAI score over 4 weeks. I think if

18 you ask patients the same thing, is it of value, of benefit

19 to remove steroids over a period of one month, “two months,

20 three months, you would achieve an affirmative answer.

21 There is a down side to being on steroids. It is

22 not activity, it’s side effect activity.

23 DR. HANAUER: Dr. Present.

24 DR. PRESENT: I agree with the last statement. I

25 don’t thing patients would consider being off for 4 weeks

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1 significant. I think being off completely they would

2 consider significant. I think at least a year or more, but

3 I agree with you, I think steroids fall into a totally

4 different category for evaluation because of the potential

5 of long-term toxicity, and I think it is a worthy goal, as

6 much as suppressing pyoderma or something like that. I

7 think being off steroids will be meaningful to patients’

8 health over a long period of time.

9 I agree with Paul, discontinuing steroids has

10 always been my criteria, and I think when you set lesser

11 criteria, it doesn’t let physicians do it. They don’t go

12 for that criteria. They are willing to stop and say, well,

13 that is good enough when we have learned that a lot of

14 people are on steroids who really don’t need them. They

15 haven’t needed them for a long time.

16 DR. SIMON: I just want to make a comment that you

17 have asked several times about the threshold issue, and the

18 problem is that science doesn’t give us the answer. It is

19 somewhere between 5 and 10, and most people feel 7 1/2 is

20 the dose that they have chosen.

21 You can see data on both sides of the street.

22 Certainly zero is better than S, and certainly 5 is better

23 than 10, and that is all you can say.

24 DR. HANAUER: Should there be in a separate segue,

25 should there be an indication for treatment of refractory

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1 Crohn’s disease?

2 DR. WEISS: I missed your question.

3 DR. HANAUER: Should there be an indication for

4 treatment of refractory Crohn’s disease? Yesterday, you

5 approved a drug -- yesterday, the committee gave a

6 recommendation for approval of a drug for the treatment of

7 Crohn’s disease that was unresponsive to conventional

8 therapy. Is that a loose term that should be acceptable, is

9 that different from refractory? Do we need to come up for

10 guidance terminology for these definitions? No? The agency

11 says no.

12 DR. WEISS: Can you do it?

[’”- 13 DR. HANAUER: We can do anything.

14 DR. SIEGEL: That is one of our questions, I

15 guess. One of the things we heard yesterday is that

16 standard of care in this is not FDA labeled therapy, which

17 has some impact on this issue, I guess, we will have to

18 :aucus. It would be very hard to write a label for a drug

19 Lhat can only be used in people who have failed another drug

20 #hen that other drug isn’t approved.

21 DR. HANAUER: SO, I am hearing we don’t need to

22 iefine refractory.

23 DR. SACHAR: No.

24 DR. HANAUER: What if the sponsor had a drug that
g-=-
25 ;hey weren’t intending for first-line therapy at any point,

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1 that they really thought was a salvage drug?

2 DR. WEISS: We do that all the time in the

3 oncology setting, which is what I know best. Certainly, in

4 Oncology, almost all drugs are started in the setting of

5 refractory disease, because, you know, we are lucky to take

6 away something, even if it is not great, at least it had

7 some sort of track record, and so many of these things are

8 first started, first explored, sometimes first approved in

9 the refractory setting, and then they gradually move on to

10 nore front-line therapy.

11 Is that something that should be part of drug

12 development for Crohn’s disease?

13 DR. HANAUER: Dr. Simon.

14 DR. SIMON: We actually thought that that was

15 appropriate in the considerations regarding the new

16 Formulation of cyclosporine, but that was driven mostly by

17 uoxicity issues, and so that clearly was limited to only

18 =hose patients that had failed both approved and not

19 approved therapies as the standard of care. Basically, that

20 is what the statement was.

21 If you did not respond to standard of care, then,

22 you might be a patient that would be appropriate for this,

23 md then it got a big black box warning, so under those

24 circumstances you may always have that choice to add on top

25

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1 DR. SACHAR: Everything then that I have heard

2 that reflects what went on yesterday seems quite acceptable

3 to talk about approving a drug for Crohn’s disease that has

4 been refractory to conventional therapy without defining it

5 further.

6 The only circumstance it does need something to be

7 defined further, if you are going to hav a specific

8 indication for steroid refractory disease and steroid

9 dependent disease, because once you are talking about a

10 specific drug to which the disease does not respond or on

11 which the disease is dependent for maintenance of remission,

12 then, you do have to define it with respect to that drug,

13 and we wrestled with this a bit with the clinical

14 phenotyping committees and we proposed, as I recall, that

15 the definition for steroid refractory was unresponsive to 40

16 mg of prednisone or more of four weeks duration, and people

17 ~ould argue and so the Europeans may say it has to be 60,

18 md Modigliani would say no, it has got to be 1 mg/kg, but

19 that was sort of the principle, that it was somewhere 40 or

20 above for about a month, and if they hadn’t responded by

21 Lhat time, that was not responsive to steroids.

22 The definition for steroid dependent -- Dan can

23 ~omment on that, too -- is I believe we had said that if

24 there had been two efforts within the space of one year to

25 remove the patient from steroids, and if a relapse had

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1 occurred within two months of something like that, or three

2 months, that that was steroid dependent.

3 DR. HANAUER: Dr. Weisman is actually looking for

4 guidance as he plans his next clinical trial with the goal o

5 steroid sparing. What are the entry criteria?

6 DR. WEISMAN: Some methodological issues. First

7 of all, who does the tapering and how is that decision made,

a because you are talking about a randomized clinical trial,

9 patients randomized to one treatment versus another, let’s

10 say, placebo-controlled, or active treatment-controlled, and

11 then if you don’t randomize to steroid withdrawal, you are

12 dealing with post-randomization events, things that are

13 happening after you have randomized that are dictating what

14 is happening in the trial, and you start seeing imbalances,

15 and one of the things -- and Steve knows this has haunted me

16 -- whatever goes into the decision to start a taper, may be

17 different in the placebo group than it is in the active

18 treatment group.

19 For example, if the active treatment actually

20 works better, those patients might be more likely to go

21 through a tapering, and therefore, you may see imbalances on

22 your primary endpoint if you are making steroid tapering an

23 important secondary endpoint.

24 so, that is one set of issues. The other one is

25 one the dependents are in. I was actually hoping that Dr.

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1 Sachar would talk about what the definitions are, but there
-__—_.

2 is the steroid dependency maintaining the benefit of

3 response to treatment, but another thing that Dr. Hanauer

4 knows that I have worried about is the issue of inducing

5 Addisonian symptoms in a patient who you are tapering, and

6 distinguishing the Addisonian driving of an increase in

7 CDAI, because Addisonian symptoms will mimic in some fashion

8 an acute flare, and how do you deal with that.

9 There is all kinds of methodologic issues here,

10 and one of the issues of randomization, in other words,

11 doing a factorial design in which half the patients in each

12 of the groups get tapered and half don’t, which is a

__
13 reasonable thing to consider, is I have been told is that

14 people are unwilling not to taper.

15 If you have a patient, for example, on infliximab,

16 and they are doing perfectly well, is it reasonable to

17 demand that that patient stay on steroids for a year, just

18 so you can do the statistical test? If it is not, then, you

19 run into the issues of post-randomization bias” that are

20 going into the decisionmaking. This is not straightforward.

21 I have a lot of trepidation of stepping into this, and I

22 would love to have some guidance on these particular issues

23 on how to design the trial.

24 DR. HANAUER: One of the problems I think you are
_&

25 having is, frankly, you are trying to design the trial that

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1 will answer all the questions, and as we have emphasized, .a

2 trial might not answer the multiplicity of questions that

3 are left to you guys to answer regarding your therapeutic

4 agent.

5 DR. SIEGEL: I think that is particularly true

6 vis-a-vis the issue of measuring steroid withdrawal as a

7 secondary endpoint where you are trying to measure clinical

8 benefit in which you get that confounding effect, because

9 the better drug will allow more steroid withdrawal, which

10 then may obliterate the clinical benefit versus measuring

11 steroid withdrawal as a primary goal of a product.

12 DR. WEISW: If you are doing a maintenance

13 trial, it is implicitly confounding whether you explicitly

14 recognize it, and it has to do with that fact that I

15 mentioned. If you are dealing with a one-year trial in

16 which a certain proportion of the patients are responding,

17 you are going to start seeing steroid tapering probably.

18 That is going to be the inclination for both the patient and

19 the physician. The question is do you try to understand

20 that and looking at the confounding in some type of

21 systematic way or do you just ignore it and just do a large

22 enough trial so it all just works out in the noise.

23 What I am hearing is that this is enough of an

24 important question in the treatment of Crohn’s disease that
.-..
25 you probably want to systematically approach it in a long-

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1 term trial. A four-week trial, it doesn’t bother you.

2 DR. SIEGEL: If you start with a population as I

3 think Dr. Sachar talked about before, of patients who are

4 actually in remission, but steroid dependent and on

5 steroids, and you taper on both arms, but then on either arm

6 you reinstitute steroids at the initiation of new

7 symptomatology, you shouldn’t get confounding because all

8 patients are being maintained below a certain level of

9 symptomatology.

10 You are looking at a primary endpoint of steroid

11 sparing. It is when you try to do it all together and

12 steroid sparing at the same time --

DR. WEISMAN: Let’s just say you don’t care about

14 it, clinical benefit is your goal. You still have to deal

15 with the confounding factor of steroid tapering. We can

16 just ignore it and say you are trying to do too much or

17 don’t do it, but I still think it would be useful for the

18 committee to at least provide guidance on how you deal with

19 chronic steroid use in a clinical trial looking for long-

20 term benefit.

21 What I have heard is everybody wants clinical

22 trials that last a year, so you have to cope with steroids

23 in that context, either implicitly or explicitly.

24 DR. GRAFFNER: In ongoing trials in steroid-
-=

25 dependent patients, defined the way Dr. Sachar defined it,

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1 they are being conducted in a way that you suggested, having

\ 2 one primary aim, and that is to withdraw steroids and still

3 having to the patients in remission.

4 I think most clinicians think that is a very good
.
5 primary variable, that is what you want, to get them off of

6 steroids, and if you do that slowly, you have no great risk

7 of reducing Addisonian crisis.

8 Sor having one arm leading off with placebo, one

9 arm on steroids, you will also get the answers that you

10 asked about earlier, that quite a few patients are steroid-

11 dependent, actually are not that, they are being weaned off

12 on placebo, so one primary variable, get off steroids.

13 DR. SACHAR: I would like to second that. I would

14 like to cast my vote for the ability to spare steroids

15 without relapse in steroid-dependent patients, which is a

16 primary indication.

17 DR. HANAUER: Dr. Feagan?

18 DR. FEAGAN: I guess the issue of whether it is a

19 confounder or not depends on whether the effects on activity

20 and steroid reduction are actually discordant, and that is a

21 gamble. I think the sponsor should be allowed to take that

22 gamble if they feel that the compound -- if you have

23 patients that are active on steroids, and they choose to

24 withdraw steroids, and they are able to discern an effect on
_-..
25 steroid use and effect on activity, and those two effects

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1 are in concordance, it is a win/win.

2 It is only if there is discordance that one gets

3 into a problem of interpretation and confounding. So, I

4 wouldn’t necessarily dissuade a sponsor from conducting a

5 design of that, but let the buyer beware if it turns out

6 that is the effect. It is going to be uninterpretable.

7 DR. HANAUER: Dr. Kirschner.

8 DR. KIRSCHNER: I would just like to take a little

9 exception with the definition that dependent disease is that

10 you have tried twice and failed. I mean that is probably

11 the tip of the iceberg, are the most serious ones. There

12 are lots that are going to be in the range of 10 or 15 mg a

13 day that are steroid-dependent, that you have been able to

14 wean down several times, and yet they are in for potential

15 toxicity. Since we showed that intraocular pressure is

16 elevated and it becomes normal when their prednisone dose is

17 under 10 mg a day, so maintaining somebody at 10 mg a year

18 is potentially putting them at risk.

19 DR. SACHAR: That is part of my definition.

20 DR. KIRSCHNER: I know, but we were just

21 discussing he was having trouble with should we be able to

22 require that people stay on prednisone for 10 mg a day.

23 DR. SACHAR : I can’t conceive of any study design

24 #here that is part of the design. The issue is the design
_@-%
25 that was just proposed here is either -- everybody gets

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1 withdrawn, but one is on the putative agent, and the other
.4-%
2 is on a placebo. But the effort is to look at steroid

3 withdrawal in the steroid-dependent person as a primary

4 indication, as a primary endpoint. We are just trying to

5 define what is the steroid-dependent patient.

6 DR. KIRSCHNER: That is what I was referring to.

7 DR. SACHAR: Right, and I thought that we were

8 actually agreeing with each other that if you have not been

9 able to lower the patient below 10 without a flare, that is

10 a steroid-dependent patient.

11 DR. KIRSCHNER: I agree with that. I thought yOU

12 had said if two attempts at tapering below 40 --

13 DR. SACHAR: Not below 40, no, no, two attempts at

14 tapering. The 40 came up with steroid refractory, a totally

15 different question of a patient who doesn’t respond to 40

16 acutely within a month isn’t going to respond.

17 DR. SU~WICZ: I think it is very difficult. I

18 wish there were an easy answer to it, and I can’t come up

19 with them, but I think Crohn’s patients often are very

20 attached to their steroids even if when they reduce them,

21 they don’t have a flare of their disease, but they feel

22 miserable or there is .a psychological attachment, they are

23 very independent, they like to -- at least in my experience

24 -- they like to decide themselves what dose of steroids they

25 take, not what dose of steroids I recommend.

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1 So, you have all of these psychological factors. in

2 addition that I think would make that as an endpoint of a

3 clinical trial very difficult in addition to the withdrawal

4 symptoms which are different from the recurrence of disease

5 symptoms. I can’t come up with any answer, I am sorry.

6 DR. HANAUER: The copout of that is allowing them

7 at 7 1/2 mg, which eliminates the issue that Dr. Weisman is

8 concerned about regarding the Addisonian risks.

9 Dr. Present.

10 DR. PRESENT: As regards that, Christine, I think

11 you are right, for short periods of time because they are

12 relatively Addisonian, but the vast majority of patients

13 will not be Addisonian after three months, and I can tell

14 you at that point those symptoms usually disappear.

15 DR. SURAWICZ: I agree.

16 DR. PRESENT: And you have to guide that patient

17 through that three months, and I can’t tell you how many

18 phone calls you get during that time, and my joints are

19 hurting, and then they become rheumatoid patients, and they

20 can’t get up in the morning, but most patients, if you have

21 an active drug that is working, like azathiopriner you can

22 get them off. It just takes that two- or three- month time

23 period to do it.

24 DR. SACHAR: In fact, there are published trials,
—-.
_-
25 placebo-controlled trials of azathioprine as a steroid

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1 sparing agent, a perfectly good design and a perfectly good

2 endpoint.

3 DR. HANAUER: That is one subgroup of patients.

4 The next subgroup that I would like to discuss is

5 pediatrics, and this came up yesterday. The infliximab was

6 recommended for approval for Crohn’s disease based on data

7 with the youngest patient treated being 12 years old.

8 It was an agent that was not in the clinical

9 trials, but in the open-label trial, the youngest treated

10 patient. It was dosed on a 5 mg/kg dosing, so it was not at

11 a fixed dose. I would like Dr. Kirschner to begin the

12 discussion by telling. us why kids are different than adults

13 with Crohn’s.

14 DR. WEISS: Maybe in fairness, just to maybe start

15 off by addressing a question. Actually, I have it marked 3,

16 it is supposed to be Question 4, which is I think the

17 fundamental question that I have is can you extrapolate

18 sfficacy as defined in adults to pediatric populations, and

19 that goes to whether or not children behave the same as

20 adults with this disease.

21 DR. KIRSCHNER: I think one of the intuitive

22 thoughts, and it is not data, and that is whether or not the

23 tempo of disease in children is the same in adults, and we

24 actually don’t even know that. In ulcerative colitis, we

25 know, for instance, the progression of limited disease is

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1 much more likely to occur in children than adults. They

2 don’t act the same way.

3 We know that the risk of -- well, it appeared at

4 least prior to the immunomodulatory agents -- the risk of

5 surgery in children with Crohn’s disease was very high,

6 something like 70 percent in five years.

7 We also know that when we talk about a term that I

8 really don’t like at all, reagent grade patients, because I

9 don’t think there is such a thing. I really think that

10 these are evolving processes, ”and Joyce Grabowsky, for

11 instance, has a paper of Crohn’s disease in children under

12 the age of 10, in which at the onset, 2 percent of the

13 children had fistulas, and five years later, 25 percent had

14 fistulas, so if we want to talk about inflammatory versus

15 stenosing versus inflammatory disease, it depends at what

16 time in the child’s life you are talking about, and that

17 they may be inflammatory when we first see them, and five

18 years later they are stenosing.

19 It may be that many of the adult physicians who

20 are here, who have done most of the studies, are getting

21 referral patients five years into the course of their

22 iisease, and so they assume their disease has more stenosing

23 md fibrosing because they are seeing them maybe later and

24 lot at the same onset.

25 I think kids have a really aggressive course, and

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1 whether it is the same or worse in children, I don’t know,

2 but there are some indications to suggest that it is pretty

3 severe, and the effects of puberty and what that may do, for

4 whatever reason, when we plot the number of the mean age in

5 kids when they develop Crohn’s, the years between 11 and 12

6 are just incredible in terms of diagnosis of disease.

7 I have a huge database, and every time I put in 11

8 or 12, it is like 80 percent of them, so there is something

9 about that particular point in time that seems to be

10 affecting the immune response for getting a lot of Crohn’s

11 disease.

12 so, there are clues that maybe it is different in

13 kids, and our doses are different. I mean we go everything

14 on a mg/kg dose, you go on set doses, and so that our doses

15 of prednisone are probably much higher for a child than they

16 would be in an adult. Adults , you are talking about 40 mg a

17 day, and those are 70 kg people, we are giving 40 mg to a 40

18 kg person. So, I have no idea how to extrapolate back from

19 what you are using to what we can use in kids,” and so we

20 essentially looked at our own studies and our own results

21 and keep looking back at mg/kg to get our guidelines.

22 DR. HANAUER: As the question is posed, if the

23 pharmacokinetics are similar, in other words, if the sponsor

24 performed a study demonstrating similar pharmacokinetics in
A
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25 children and adults, would it be necessary, in your opinion,

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1 to do a separate efficacy trial in children?

2 DR. KIRSCHNER: From my point of view, it is. I

3 am not sure that we can tell anything about pharmacodynamic

4 effects necessarily from the pharmacokinetic effects, that

5 we don’t know that the response rate will be similar.

6 DR. HANAUER: In your view -- 1 don’t want to put

7 words in your mouth, but is it necessary for every new drug

8 to be tested in children, and then the next question is

9 going to be, if so, what age groups need to be tested

10 specifically for Crohn’s, and just as a background,

11 yesterday, one of the sponsor’s consultants got up and said

12 that it was going to be impossible to do trials on Crohn’s

13 disease in children, to get sufficient size, sample size and

14 efficacy data on all these drugs.

15 DR. KIRSCHNER: I can tell you that the CCFA has

16 estimated there are 200,000 children with Crohn’s disease,

17 so I don’t know how difficult it is going to be studied.

18 DR. HANAUER: The sponsor yesterday estimated

19 400,000 patients overall.

20 DR. KIRSCHNER: But I mean the fact is that there

21 are certain age ranges that are highly likely to be a

22 problem, and that would be those that are probably 6 years

23 of age and up. We are not going to be studying infants and

24 we are probably not going to be studying children much under

25 the age of 6, but around 5 to 7 we start seeing a fair

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1 number of children with Crohn’s, and we certainly see a lot

2 in the 10 to 12-year-old range.

3 DR. HANAUER: 1s it then necessary to do studies,

4 as defined here -- we have definitions of four pediatric

5 subgroups, neonates, infant up to 2 years, children 2 to 12,

6 and then adolescents -- so, is it necessary to do studies in

7 children 1 to 12 with Crohn’s, and subsequently in

8 adolescents?

9 Dr. Present said that adolescents were the same as

10 adults . Do they need to do two separate age groups in

11 ~hildren?

12 DR. KIRSCHNER: I can tell you when people are

13 looking at the IBDQ for children, that we find we have to do

14 ~ different one for adolescents than we have to do for

15 ~hildren. I don’t think many of us would consider a 13- or

16 ~ 14-year-old an adult who is essentially an adolescent.

17 We would say that we want to see studies in

18 ~hildren, and we would want to see studies in adolescents.

19 DR. HANAUER: SO, for a sponsor to g’et pediatric

20 approval, you would like to see studies in two separate

21 ?ediatric age groups.

22 DR. KIRSCHNER: Yes.

23 DR. HANAUER: Clinical and pharmacokinetic.

24 DR. KIRSCHNER: Yes.

25 DR. SACHAR: Steve, I am not sure when the

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1 appropriate point is to bring this UP, but just so it
___

2 doesn’t get overlooked, I am concerned that there is a group

3 of patients who are being discriminated against in all

4 studies by being systematically excluded from any study for

5 an artificial reason, and I am referring to patients with

6 stomas. Virtually every sponsored study will exclude

7 patients with colostomies or ileostomies, because you can’t

8 do CDAIS.

9 That is something I would just like the committee

10 to think about because this does become an issue of

11 discrimination, as I see it, that they are being

12 systematically excluded from the opportunity to participate

13 in clinical trials.

14 DR. HANAUER: I think in future studies that have

15 been suggested, I think that there probably are ways to

16 modify that. Some committee members and other consultants

17 have recommended modifications off of the CDAI which have

18 not been validated, nor reproduced for Dr. Feagan’s benefit,

19 but he has even signed on, too, agreeing to include

20 modifications.

21 so, I think we are beyond that hopefully.

22 DR. SACHAR: But a lot of the modifications,

23 whether it’s Harvey Bradshaw or [Softky Clamp] or Oxford or

24 Capetown, and so forth, still are going to be excluding

25 patients with stomas. Even the IBDQ, I am not quite as

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1 familiar with it, but the kinds of questions that YOU ask.

2 about quality of life are again different than the stoma

3 patients.

4 I don’t have any answer here at all, I have no

5 proposal. I just want to bring it to the committee’s

6 attention that some thought has to be given how not

7 systematically to be discriminating against that population

8 of patients.

9 DR. HANAUER: Dr. Goldstein.

10 DR. GOLDSTEIN: I would like to offer some

11 Uontext. I don’t know whether you all read the material in

12 svery sense that the agency provided, but the FDA

13 !lodernization Act, known in Washington parlance as FDAMA,

14 became law late last year. It mandates improvement in

15 ?ediatric labeling and “the study” of drugs heretofore

16 approved in adults, but utilized significantly in children.

17 rhat certainly applies to the drugs we use.

18 There should be, in Harry Shirkey’s immortal

19 ~ords, no more therapeutic orphans. My daughter was

20 iiagnosed at age 7 and has been on virtually everything you

21 uan imagine plus two surgeries plus TPN, so I learned a lot

22 ~f pharmacology that way.

23 I also happen to chair the American Academy of

24 Pediatrics section on clinical pharmacology, so I think

25 studies, at least in two age groups, children and

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1 adolescents, is applicable, and as Barbara can confirm,

2 children as young as one years old have been diagnosed with

3 Crohn’s. The Act itself that provides for incentives for

4 pharmaceutical manufacturers to invest in additional

5 development work, principally in the form of exclusivity and

6 six months exclusivity or under certain circumstances 12

7 months exclusivity can make a substantial difference in

8 terms of manufacturers’ and researchers’ incentives to do

9 these studies.

10 The original rule published -- and by the way,

11 children, in case anybody is uncertain, are not just small

12 adults. There is no such thing, ladies and gentlemen, as

.- 13 midget medicine.

14 FDA has been coming at this for some time, and I

15 can only applaud them for doing so, for approved drugs and

16 biologics. Originally, you could submit some literature

17 supporting pediatric use. FDA must conclude sufficient

18 similarity to permit the extrapolation, which was your

19 question, Steve, about efficacy data to pediatrics, but that

20 didn’t really raise much, and I think some 25 or 30 percent

21 of manufacturers at most submitted data.

22 This new law, which has now been signed, will

23 require studies in pediatrics, Barbara, as you know, allows

24 for the deferred submission of some or all data until the

25 application -- unless FDA specifically defers or waives it,

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1 and how do you get a waiver?
132
I
Well, no meaningful benefit. to

2 children, studies are impossible or extremely impractical.

3 Thirdly, it is likely. to be unsafe or ineffective, and

4 lastly, reasonable formulation efforts being made to get a

5 reasonable formulation, if needed, have failed. Those are

6 four criteria for getting such a waiver.

7 FDA has been mandated to develop, prioritize, and

8 publish a list of approved drugs for which additional

9 pediatric information may be produce -- in the words of the

10 law -- health benefits in pediatric populations.

11

12 on lists
There

somewhere
are, I believe,

along the line,
since

some
I was asked

IBD drugs
to comment

on that
I
- 13 lists. What is the impact of all of this? Well, there is

14 likely to be a surge in the number of studies in pediatrics.

15 Certainly, there is a surge in the development in pediatric

16 formulations development, and in thinking about pediatric

17 trial design, and the extrapolation across all ages is what

18 this committee is currently looking at.

19 DR. HANAUER: Let me break for one second there

20 and get your and Dr. Kirschner’s opinions specifically on

21 what Dr. Weiss asked. Should the approval, not our

22 approval, not this committee’s approval, but the agency’s

23 approval for the drug that was recommended for approval

24 tomorrow be withheld until the sponsor has data that Dr.

25 Kirschner and you are requesting in children?

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1 DR. GOLDSTEIN: Emphatically not for all the
-.
2 reasons that were brought forward yesterday, and in addition

3 to the fact that there are safety considerations, as Dr.

4 Simon noted, which can be answered by the use in adult and

5 developing a greater safety base.

6 DR. HANAUER: Are you ready to see this drug used

7 in children now, applied and studied in children?

8 DR. GOLDSTEIN: Am I ready?

9 DR. HANAUER: Yes.

10 DR. GOLDSTEIN: Well, I am not in practice. I was

11 for 15 years.

12 DR. HANAUER: You observed the discussions on

- 13 safety and efficacy.

14 DR. GOLDSTEIN: If I were faced with a patient

15 significantly having failed a number of drugs and in a

16 sufficient clinical state to require it, the answer is yes,

17 I would use it.

18 DR. HANAUER: And you would put a 5-year-old into

19 a trial?

20 DR. GOLDSTEIN: Depending on the circumstances.

21 Obviously, Steve, the devil is in the details.

22 DR. WEISS: There is a difference between when

23 something is approved and on the market, also using it in a

24 particular patient who you think might benefit, and then

25 systematically studying it in the course of clinical trials.

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1 Part of the new pediatric proposal that Dr. Goldstein is

2 referring to talks about the fact that it is going to be

3 requirement that pediatric data will have to be generated,

4 and it may be that as get more input, as well, that what Dr.

5 Kirschner has said is pretty much going to be the gold

6 standard, that for pediatrics, one cannot extrapolate, that

7 you have to do separate efficacy trials, not just small PK

8 trials, but separate efficacy trails in pediatric

9 populations.

10 Given that point, then the next question is when

11 in the course of development, which is sort of the second

12 part to this question, when in the course of a drug’s

13 development would it be appropriate to systematically start

14 studies in pediatric populations.

15 DR. HANAUER: The other question that I would like

16 a little clarification on is that pediatric claims can

17 include studies when the agency concludes that the course of

18 the disease and drug’s effects are sufficient -- the course

19 of the disease is different, and we have heard- some data and

20 speculation that the course of the disease is different.

21 Aside from growth, which is certainly an important

22 issue, what data is the agency going to require that the

23 course really is different? Does that fall upon the

24 scientific community to demonstrate a difference in the
____
25 course or is that a judgment?

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1 DR. GOLDSTEIN: There are some elements that

2 should be common to all pediatric applications. Basically,

3 I have thought about six. The use of functional disease-

4 related endpoints. The availability of a pediatric

5 formulation with supporting PK data. An appropriate trial

6 design, adequately powered. Certainly prospective data

7 collection. What I would like to call the sequestration or

8 isolation of a new agent’s contribution to efficacy.

9 Finally, particularly important in pediatrics, the use of a

10 well-tolerate regimen.

11 That is a little short on specifics, but if you

12 want a broad overview, I think that is it. Companies have

13 done it. A Swiss firm with an anticonvulsant not too long

14 ago with some plus-minus studies, supported it with a rather

15 effective discussion of the comparative pathophysiology in

16 adult versus child, et cetera. It can be done, and it is a

17 question now of not only the substance data, but fleshing it

18 out , and there are lots of ways of fleshing that out, which

19 the agency can call for, and which industry is”prepared to

20 submit.

21 DR. WEISS: Steve, also to address your question

22 how you decide whether or not the disease is similar enough,

23 so you can reasonably extrapolate, I mean I think there are

24 a lot of things that go into it. There are large amounts of

25 natural history databases, workshops, and various types of

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1 consensus building to try to make an assessment about
;-.
2 whether or not the disease -- one can actually take a

3 disease and show efficacy in adults, and not have to prove

4 efficacy again in pediatrics. I think that is why we need

5 experts like Dr. Kirschner and others in the pediatric GI

6 community to give us that advice, so that we can then turn

7 around and formulate this in guidance and let our sponsors

8 know, number one, that they are going to have to get

9 pediatric data, and when they do, is it going to have to be

10 randomized efficacy trials, or can be something somewhat

11 smaller than.

12 DR. GOLDSTEIN: One last blanket statement. I

13 feel most emphatically that more specific pediatric studies

14 need to be done in this group of disorders as in many

15 others. That I think is something supported by most of us.

16 DR. RUTGEERTS: Could I ask something, Steve? I

17 agree that studies in children are certainly necessary, but

18 is it not conceivable that you lower the inclusion age for

19 studies to 12, for instance, and that you cooperate with the

20 pediatrician in order to get quicker data, because to do

21 studies only in children, it does not work too well, so is

22 that a possibility?

23 DR. KIRSCHNER: From our point of view, I mean at

24 the level of this particular drug, we would applaud
-
25 concurrent studies in children and adults in a big,

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1 particularly multi-dose approach like is being done in

2 adults, where we have different doses, because we can’t

3 extrapolate what the dose is going to be, what the frequency

4 is going to be.

5 We really don’t know what to recommend what the

6 use is going to be.

7 DR. HANAUER: I think Paul is not suggesting

8 concurrent, but he is suggesting lowering the inclusion age-

9 in the initial trials from what is normally 18 to what?

10 DR. RUTGEERTS: To 12. I think in centers who

11 have good GI departments and who have good pediatric

12 departments, such studies can be done in cooperation, and

.[—-= 13 then you don’t need to design separate studies for children.

14 You can adjust doses, of course, but that is feasible, I

15 think.

16 DR. GOLDSTEIN: Let me pent something out. Some

17 months ago I did some research on the issue in a different

18 therapeutic area, but it applies here, relative to the

19 developmental, the size and weight of children; and it turns

20 out if you take -- and I have spoken to NIH experts and

21 Cornell growth and development experts on this, so this is

22 where it is coming from -- it turns out that some

23 indications are from, for example, from zero to 10 years

24 old, and from 11 to 1.9, but if you look at the percentile

25 growth tables, from 10th to the 90th percentile, just to

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1 leave out the two extremes, that a 66-pound child can be 8

2 years old, 9 years old, 10 years old, 11, 12, so maybe we

3 need to get a little bit creative and look at it from the

4 point of view of not age, but weight, and not weight alone,

5 but basically the percentile tables that allow you, because

6 in many respects, an 8- or 9- or 10-year-old will fit within

7 that 10th to 90 percentile as easily as a 12-year-old. So,

8 you are extending this age downward that way.

9 DR. HANAUER: Dr. Feagan.

10 DR. FEAGAN: As, Paul, you suggested the composite

11 trial, which is attractive from the feasibility issue, I

12 guess the only down side is that from the measurement tool

13 standpoint, as Barbara suggested earlier, some of the

14 instruments just aren’t probably valid in children, so you

15 have to get around that issue if you are going to combine

16 the data.

17 DR. WEISS: Many of us were at the conference in

18 Philadelphia sponsored by CCFA, that specifically discussed

19 pediatric studies, and the consensus that I he’ard at that

20 neeting was that it doesn’t work just to take an adult

21 protocol and use the word processor and change the age down,

22 that you actually need to have some differences in the

23 study, and those are probably best down in pediatric

24 senters. I mean that is a bit of a separate issue about
_—_
-—
25 just the mechanics of how it is done, whether or not a

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ajh 139

1 separate study. There are groups that are really geared to
&-%
2 doing specifically pediatric trials.

3 DR. KIRSCHNER: There is a pediatric collaborative

4 research group specifically for IBD, which includes centers,

5 many of us could work together within our institutions.

6 DR. GOLDSTEIN: Not only is the group that Barbara

7 mentioned, but the National Institutes of Child Health and

8 Human Development have set up a series of 7 -- this is three

9 or four years ago -- 7 PPRUS, or Pediatric Pharmacology

10 Research Units, it is about to become 10 very shortly, which

11 takes studies from industry, from academia, from anywhere

12 and basically does that in major pediatric centers.

13 so, I am sure it can be done.

14 DR. SIEGEL: I have a question for Dr. Kirschner,

15 Dr. Goldstein or anybody, but regarding if, in fact, it is

16 the case, as you said -- and I have no reason to doubt that

17 -- it would be risky to extrapolate efficacy data, that the

18 disease is different in children, say, in adolescents or in

19 children, one wouldn’t want to assume that a drug that works

20 in adults would work there.

21 One would expect it also to follow then that if

22 this temporally sequential approach is taken, if a drug is

23 first developed in adults, which may not be optimal, but

24 often seems to happen, and a drug were found in adults to be

25 safe, highly effective in important ways, one would not find

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1 problems with children or pediatricians enrolling in

2 randomizing trials for placebo-controlled trials, because

3 presumably, since one couldn’t extrapolate efficacy, there

4 would be substantial data as to whether it would work in

5 adolescents. Do you think that is the case?

6 DR. KIRSCHNER: I think it would probably work.

7 The question is what is the dose, what do we use. I mean

8 there may be a question that children require a higher dose.

9 DR. SIEGEL: The question that Dr. Hanauer had

10 proposed before is do you need pharmacokinetic and safety

11 data to apply to children, or do you also need additional

12 randomized or other efficacy studies, and I am not sure now

13 exactly what you are answering to that question.

14 DR. KIRSC!HNER: I think we would want efficacy

15 studies, as well as pharmacokinetic studies. We have

16 discussed this actually at Centocor when we had a meeting of

17 people who were setting up the pediatric trial. We had a

18 meeting at the CCFA when they were 50 people there, many of

19 them pediatric gastroenterologists. I am speaking for the

20 group, not only for myself. We felt that pharmacodynamic

21 and efficacy studies in children were essential.

22 DR. SIEGEL: But it is probably easier to get

23 those before you have definitive efficacy data in adults I

24 would think.
.——.
25 DR. KIRSCHNER: The way this document reads, and

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1 what Harlan wrote in his letter, and what the consensus was

2 in inflammatory bowel disease issue that we had to approach

3 this problem, was at the conclusion of Phase II, where the

4 FDA is meeting with the sponsor, the pediatric efficacy

5 trials would be initiated. I guess we would like to see

6 some efficacy information in adults.

7 DR. HANAUER: I guess there is an undercurrent

8 here of regulatory power, and I guess the bottom line issue

9 is should the agency withhold approval of a drug before --

10 Sponsor A could take decades to generate that data.

11 DR. WEISS: Under the new proposals, the feeling

12 was it would not be a good idea if you let something that is

13 safe and effective as proven in adults to withhold approval

14 in getting that product out on the market. Under new

15 ?roposals now under consideration is the idea that if

16 ?ediatric data were not available under the marketing

17 application, and you had reached agreements with the

18 ~ponsor, that those studies could be deferred until sometime

19 in the postmarketing period, there would be very specific

20 time lines that would have to be honored whereby those

21 additional pediatric data would have to come in, and there

22 could be some type of court sanctions, et cetera.

23 It wouldn’t be like accelerated approval where the

24 product would be withdrawn from the market, but there would

25 have to be --

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1 DR. HANAUER: It is my opinion that this really

2 needs to be done on a case-by-case basis with a pediatric

3 review of the available adult data, because for a total

4 novel drug, such as this, such as the one that was

5 recommended for approval yesterday, there may be some

6 potential risks that the pediatricians foresee, whereas,

7 another agent there may not be, and the rapidity of the

8 requisites for pediatric trials may vary at those points.

9 I don’t know that this can be guided on a local

10 basis.

11 DR. WEISS: I think that is a fair statement.

12 DR. KIRSCHNER: I think the CCFA is trying to

.——. 13 sxpedite the ease with which these studies can be performed,

14 and certainly that is the whole point of our pediatric

15 collaborative research group. I mean we want these drugs

16 out quickly, too. SO, it wouldn’t take a lot of information

17 if efficacy to get pediatric trials started fairy early, so

18 that we can use this information to recommend them for our

19 ?atients.

20 DR. HANAUER: But you have to watch what you are

21 saying. You are saying it is efficacy, but again, if it

22 were my child, I would be more concerned about safety.

23 DR. KIRSCHNER: I don’t now more. I am certainly

24 concerned.

25 DR. PRESENT’: Just to be a nay-sayer and assume

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1 Brian Feagan role at this moment, are there any control

2 trials to show that pediatric patients behave differently

3 that adult patients? Is there a single control trial in IBD

4 to show that, because again, my clinical experience in

5 adolescents is the exact same behavior, no experience in

6 under 12 because I don’t take care of them, and a

7 pediatrician has recently completed a control trial with 6-

8 MP, which is exactly the same data as we found in adults, ,SO.

9 I am much more in favor of Paul Rutgeerts’ comment including

10 patients down to age 12 and let them enter studies depending

11 upon the drug. If it doesn’t seem appropriate, don’t let

12 them enter. I think that would increase the collaboration

13 between the pediatric gastroenterologists and the adult

14 gastroenterologists, and we might find out the answers if

15 there are really differences.

16 DR. HANAUER: But as Dr. Feagan points out, you

17 have to have an adequate instrument to measure that age

18 group.

19 DR. GOLDSTEIN: Dan said he was going to make a

20 comment that would rile me up.

21 DR. HANAUER: Make a quick one to un-rile him.

22 DR. GOLDSTEIN: No. Basically, we have to keep in

23 mind that clinicians deal one on one. An agency like the

24 FDA deals with hundreds of thousands, and the issue of

25 safety is a paramount issue, and to get safety data from

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1 adults at least to a point is I think important. The

2 parent, you are quite right is going to say I am not

3 submitting my kid to be a guinea pig, the child is

4 interested in only the tastiest formulation, and you go from

5 there, but safety is important, but I am saying that we need

6 not be so safe to the point of waiting months or years to

7 start some of the studies. We can start them earlier than

8 historically they have been started.

9 DR. HANAUER: Before Dr. Present leaves, I just

10 want to address the issue of geriatrics.

11 DR. PRESENT: I wouldn’t know about that at all.

12 [Laughter.]

L’-- 13 DR. HANAUER: Gain some experience. The corollary

14 .- and we can come back to your question -- but is there a

15 5ifference in the geriatric population? Does anyone want to

16 address that? Dr. Kirschner, is there a need to do

17 iifferent studies in Crohn’s disease in geriatrics and kids?

18 I would argue, frankly, the exact same that you

19 io, that we have experience that the disease does behave

20 differently, but I can’t substantiate that with good

21 >vidence–based data.

22 Dr. Kornbluth.

23 DR. KORNBLUTH: A quick follow-up question. Dr.

24 ?utgeerts’ model in terms of methodology designing the

25 ?rotocol, if we lower” the age, say, from 18 to 12, and then

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1 we want to extrapolate the data from the group as a whole, to

2 the subgroup of, say, age 12 to 18, do we need to do a

3 subgroup analysis and then do we run into problems with

4 sample size and power of that conclusion if we are just

5 looking at the age group of 12 to 18?

6 DR. ELASHOFF: Yes.

7 DR. SIEGEL: Let me clarify that question. We are

8 not specifically asking about this disease and don’t

9 specifically ask about diseases, whether they behave

10 differently in the elderly. We presume, and the

11 Internationally Harmonized guidance presumes that for drugs

12 that are used significantly in the elderly, one needs

13 =xP erience in the elderly, for any numbe-r of reasons. There

14 is a lot more likely to be specific concomitant drug

15 interactions. There is more likely to be concomitant liver,

16 Kidney, or circulatory problems which impact use of many

17 ~ifferent drugs for a variety of other reasons.

18 The policy in terms of the geriatric data,

19 :herefore, it is not so much dependent on whether the

20 ~isease is different, but dependent, as it is with pediatric

21 also, but here more so on how significant geriatric usage

22 is. There are some diseases which are predominantly in the

23 Jeriatric population, some which are significantly in the

24 3eriatric population, and some which are relatively rarely

seen in the geriatric population. I think that is more what

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1 we are trying to get some input on.

2 DR. HANAUER: Dr. Elashoff, is it significant in

3 the geriatric population? I am just kidding.

4 DR. KIRSCHNER: I have a question. When we talk

5 about prospective studies in children, what about

6 prospective studies, for instance, of the safety of

7 azathioprine and 6-MP in the elderly, over 65, over 75? I

8 mean you hear anecdotal reports, you know, bone marrow

9 suppression may be worse. Is that known?

10 DR. HANAUER: No.

11 DR. SACHAR: Point of information just for

12 definition, are we talking about older patients who have had

13 disease for a long time and are now older, are we talking

14 about people with onset of disease at an older age, because

15 that may be an entirely phenotypically different disease.

16 DR. HANAUER: I would leave out and just

17 specifically talk about Crohn’s disease in patients over 65.

18 DR. SIEGEL: Either way.

19 DR. HANAUER: I think either is an a~propriate

20 question.

21 DR. SACHAR: It is just that there might

22 conceivably be a rationale for excluding patients whose

23 disease began over age 65, because it may represent a

24 phenotypically different entity, but there would perhaps not

25 be such a rationale for excluding people who had th disease

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1 for a long time and now just happened to be old, because

2 that might be discriminatory.

3 DR. HANAUER: The bottom line may be that there

4 are relatively so few patients with Crohn’s disease over the

5 age of 65 that you are not going to end up seeing -- you are

6 not going to do clinical trials in patients over 65

7 exclusively.

8 DR. WEISS : I think the question was more to just

9 include. One side is there has almost always been a lower

10 age of cutoff, but there usually is not an upper age. At

11 one time I think it was up to the age of 70 in many studies,

12 but I think that has gone now and there usually is not an

..&=% 13 upper age limit in studies.

14 We almost always do subgroup analyses after

15 studies are done to try to get a sense, even though the

16 studies are usually not powered to show it, but we usually

17 do some type of subgroup comparisons by age, other important

18 type of features to try to get a sense about a differential

19 type of response or something, important safety signals to

20 maybe look at or to study further later on, or to be on the

21 lookout for.

22 I think the question was are there enough patients

23 65 years and older that we should just seek to include a

24 sufficient number, so that you can try to get an idea about

25 whether or not there are important differences because of

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1 concomitant medications or because of concomitant conditions
J==
2 such as perhaps some renal failure, hepatic failure.

3 DR. HANAUER: I am not positive regarding the

4 doability of that in that just from the process standpoint,

5 as the sponsors well know, in the development of a new drug,

6 we exclude so many other co-morbid diseases that are present

7 in the elderly just by virtue of the general, not middle

8 age, but young population of patients with this disease and

9 to minimize the risk in that group of patients.

10 I don’t know how feasible it is to do a subgroup

11 analysis of that because it is going to be a relatively

12 small population.

[“=. 13 DR. WEISS: Is it important to know, though, if

14 you have something, and the majority of the patients are in

15 their 30S or so, and just like in pediatrics, maybe even

16 more so, you think if something is on the market, it is safe

17 and effective for reducing the signs and symptoms in people

18 with moderately severe disease, and is it important to do

19 some special studies in populations, maybe not”necessarily

20 defined by age, but by co-morbid conditions?

21 DR. HANAUER: You know, I would take the same

22 point, if I point my geriatrician hat on, I would take the

23 same stance as the pediatrician. Absolutely. We want data.

24 We want PK data in our patients over 65 with co-morbid
i=
25 diseases, and we went efficacy data because it might be

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1 different. I think we should have it. I don’t know if you

2 are going to get it, but I think as an advocate of the

3 elderly -- and I want that on the record -- I think if we

4 had a geriatrician on this panel, they would insist on the

5 same.

6 DR. KIRSCHNER: I was going to say the same thing.

7 With the numbers of Crohn’s disease patients increasing and

8 age going up, there is going to be more and more elderly

9 people, and we should be collecting data on them.

10 DR. SIEGEL: What is the age distribution like,

11 not for onset of Crohn’s, but patients with Crohn’s?

12 DR. HA.NAUER: At the moment, if we are doing our

13 job, they are gradually aging, but the peak onset is in the

14 second and third decade, and I would say -- do you know the

15 prevalence?

16 DR. FEAGAN: If you look at the clinical trials,

17 it is very stereotypic, you know, there are issues about

18 inclusion, but it is 33 plus or minus 10. So, I don’t know

19 what happens to those people. They are out there, but --

20 DR. HANAUER: And they are not dying much more

21 than the general population, so they are about to be out

22 there.

23 DR. WEISS: Usually, when you look at a clinical

24 trial, you want to have the trial be broadly representative

25 of the people that are going to be receiving the drug, and

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1 so you look at things like ethnic breakdown after the trial

2 is completed. It is not that you necessarily seek to have

3 certain specific numbers of different types of categories,

4 but the idea is basically when the trial is over, you have a

5 broad representation of the types of people unless you

6 specifically excluded, for instance, like pediatrics.

7 DR. HANAUER: I believe you are getting that in

8 the trials to date because we are not excluding a

9 significant number of elderly patients. I am looking for

10 ~ome concurrence on that. We have been excluding

11 significant proportions of pediatric patients.

12 DR. SACHAR: I think there is a selection issue

13 Iere. If you are talking about people, say, age 60 and

14 >ver, they have had the disease for 25 or 30 years. NOW, by

15 :hat time, they have either sort of settled down on whatever

16 regimen they are on, they are not shopping for experimental

17 irugs, or they have had operations to the point that they

18 me not no perhaps candidates for the drugs.

19 But the people who are having these active

20 diseases, and so forth, generally aren’t the people who have

21 already carried the disease 25 or 30 years. It is a

22 selection issue.

23 DR. HANAUER: Segueing into safety, as our

24 penultimate topic --
.-,
25 DR. WEISS: “Can I just go back? Somebody asked

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1 from the audience, I believe, a question about subgroup
&--—=
2 analysis -- this goes back to pediatrics, but it is

3 applicable to others -- if you include children down to age

4 12, and then look at the overall population, and then try to

5 make some kind of extrapolation or comparison with very

6 small, for instance, subgroup that is from 12 to 18, your

7 statistician started to address that.

8 We always look at various types of subgroup

9 analyses afterwards to try to get a sense of things, but

10 knowing very well that the subgroups are frequently

11 underpowered.

12 DR. ELASHOFF: I think what I would say on that,

13 if you are in a situation where there is no real reason to

14 believe that the subgroups are different and you are just

15 kind of checking to make sure there is no strong evidence,

16 then, it is reasonable to simply include people and hope for

17 the best.

18 If you are in a situation where it has been stated

19 that they believe there are going to be real differences,

20 then, you are in a situation where you need to make sure

21 there is enough power for that younger age group, in which

22 case you are really, from the sounds of it, might as well

23 have two separate trials since there is enough reason to

24 deal with the children separately.
.-
~——=.
25 DR. WEISMAN: One of the things that frightens me

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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, I
22 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

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1 molecular mechanisms of disease along the lines that Dr.
{A--
2 Simon was talking about.

3 I just really think it is going to be very tough

4 to get the kind of data that you are saying that you want in

5 pediatrics in a feasible fashion, in a believable fashion in

6 a randomized population within way that would not be

7 discouraging to the industry to even get involved in the

8 indication to begin with.

9 DR. HANAUER: I wanted to hear that, I wanted to

10 bring that up as a reality check for what we are doing here.

11 DR. KIRSCHNER: But that has always been the

12 excuse why pediatric trials have never been done. I mean

13 our problem is we agree that safety is an issue, but for

14 many of the drugs that we have, we need doses that are

15 efficacious .

16 For instance, the S-ASA drugs, I mean we still go

17 back on a mg/kg basis if something is 3.6 or 4.8 or 2.4.

18 DR. WEISMAN: I can’t even find adult

19 gastroenterologists to agree that those drugs work in

20 adults. As you know, because you are one of the

21 investigators, we are studying infliximab in a pediatric

22 population. I agree with the need that you are talking

23 about, but I think the certainty that you are saying that

24 you require in pediatrics or, you know, if you say
,,.
f-’--
25 pediatrics, well, look, you know, only s percent of the

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1 patients in the infliximab studies were black, I just
_.-—–
2 referred a black Crohn’s disease patient to Mr. Sinai. I

3 think the drug works there. The evidence suggests it works

4 there. You can use subgroup analyses, but you are not

5 talking about subgroup analyses, you are not talking about

6 trends, I heard you talking about definitive information,

7 and definitive information in small subgroups of particular

8 interest is going to be difficult when you are dealing with

9 small --

10 DR. KIRSCHNER: I don’t know how small these

11 populations are. I mean I have several hundred patients

12 with Crohn’s, so how small -- I mean I am not the only one,

13 there is Boston, there is New York, there are a lot of these

14 patients around.

15 DR. WEISMAN: That isn’t the point. The overall

16 population is small.

17 DR. SIMON: I wonder whether or not we could

distinguish between what might be an idiosyncratic, very

19 care event, and something that may be, in fact; in biologic

20 ~odification, may be actually inherent to the mechanism of

21 ~ction, or the inhibition of the target.

22 That might be actually a very common event, and

23 :hat might be very different in a developmental way in

24 :hildren than in adults. I tried to get that across
/’.-–.

25 ~esterday with biologic modifiers. I clearly did not get it

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1 across appropriately, that in the case of agents that

2 inhibit a target that may have a lot to do with development,

3 and it may be very different in a child than in an adult,

4 because it may not be important for development in the

5 adult, therefore, we might see a very consistent event

6 taking place in children that is not hard to see. It would

7 not require huge numbers.

8 It did seem to me that the numbers yesterday were

9 quite small even for adults, so one could imagine that one

10 could create trials that are quite targeted to children.

11 DR. WEISMAN: The problem is that the way you

12 ~hrase that and the way the questions are being asked are

13 open-ended questions - is it possible that something, and,

14 of course, the answer to that is always yes.

15 I guess if you had biological plausibility

16 questions, if you had a question of biological plausibility

17 :hat was really focused, then, I think, yes, you should do

18 :hat, but if you ask the question is it possible that agent

19 { will be dangerous in a certain subpopulationj the answer

20 is invariably yes, of course, it is possible.

21 DR. SIMON: It is very interesting that you bring

22 :hat up, because that is, in fact, why we design randomized

23 :linical trials. We don’t go in to a drug X and know in any

24 >opulation that it is going to do YZ.
Lee.
‘–

25 DR. WEISMAN: The point I was making is that you

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1 do have evidence of efficacy and safety broadly. you do
&-
2 have, we are -- Dr. Kirschner knows this because she is

3 participating in the trial -- we will have pharmacokinetic,

4 and, in fact, because these response rates are so high with

5 infliximab, it is relatively easy, at least on a per-patient

6 basis, even in a small population of children to see that a

7 relevant index is going to go down, no question about that.

8 What I was getting at is the amount of buffer that

9 you want around that to rule out is it possible that

10 something bad is going to happen. You are not going to know

11 that.

12 DR. SIMON : But if you have a patient population

13 that is large enough to demonstrate adequate efficacy based

14 on what the product is, and what the target is, and within

15 :hat group of patients, they do not have unique toxicities,

16 =hen, that’s fine, because the issue is, if it is a

17 developmental issue, it should be seen very frequently if

18 IOU inhibit that target.

19 If it is not, then, you are talking about

20 idiosyncratic events.

21 DR. WEISMAN: What is that? You are talking about

22 ~ fishing expedition, and fishing expeditions you usually

23 ion’t find anything, and how many patients do you have to

24 lote to know that you didn’t find something that you didn’t

25 mow what you were looking for?

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1 DR. SIMON: Could we turn the clock back a little
[---
2 bit and think about a nonbiologic response modifier and talk

3 about cyclooxygenase-2 inhibitors, which there is

4 speculation that this is up-regulated in growth in children,

5 cyclooxygenase-2, and that it might be important as relates

6 to bone growth.

7 We have no idea that that is true. There is

8 actually even no science that applies to that except for one

9 experiment taking a piece of bone, subjecting it to

10 stressors, and observing that in that piece of bone in

11 vitro, COX-2 was up-regulated.

12 DR. WEISMAN”: I am fine with that. In fact, you

[’- 13 just stated an hypothesis based on observation that was

14 generated, that was then testable. I guess what I was

15 saying is -- that wasn’t a fishing expedition. That is

16 looking at data that has been generated, that has resulted

17 in an hypothesis that is then going to be tested. That is

18 fine, and I have no issue with that.

19 That is what I meant by biological plausibility.

20 If you have a plausible hypothesis based on something, even

21 if it is intuition, that you are then focusing on, then, you

22 can probably know how” to design the trial with the right

23 sample size to try to answer that, but if you are asking an

24 open-ended question, can something go wrong, I think you are

25 probably talking about low-incidence things --

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1 DR. SIMON: My point is that I am not talking
r–
2 potentially about low incidence --

3 DR. WEISMAN: What are you talking about?

4 DR. SIMON: I am talking about potential

!5 developmental anomalies that are based on inhibiting

6 cytokine interactions that we have no idea about, because

7 they have not been studied.

8 We have rapidly jumped over the science of

9 development of understanding interactions with cytokines,

10 and because you have a product that may alter a specific

11 ~ytokine target, because the science has not caught up to

12 your observations doesn’t mean we should ignore the

13 possibility they may be involved in development.

14 As a result, you have a tool to answer the

15 question. Because of that, it is worthwhile knowing that in

16 ~hildren because they. are a unique population of people that

17 ieserve to have that question answered. That is not a

18 Eishing expedition.

19 DR. WEISMAN: It is for the following reason, and

20 :hat is, let’s say that there is, let’s say that the

21 qq?othesis that you just stated is the case. If it is not

22 >ased on anything, in fact, you don’t know what pathway or

23 vhat mechanism you are looking at, you are basically fishing

24 >ecause let’s say there is, in fact, something that would be

25 )f concern or worry, when you don’t observe it, you don’t

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1 know whether you didn’t observe it because YOU didn’t find

2 it, you didn’t have adequate power or you didn’t observe it

3 because it doesn’t exist, and that is the point I am making.

4 It is untargeted examination.

5 DR. ELASHOFF: I think there is another thing that

6 would help here. If you can’t say on what developmental

7 parameter, you can’t make sure you have been measuring those

8 parameters in your trial. You don’t know what your trial

9 ought to be measuring in order to find it.

10 DR. KIRSCHNER: But I think you are holding

11 pediatrics to a different standard. I mean you are saying

12 for efficacy in adults, we only need to do this, but for

J?=. 13 children we had better have a very specific hypothesis that

14 we are testing in terms of toxicity, and it makes no sense

15 because we don’t know in advance what these toxicities are

16 going to be, and we don’t want to avoid them, plus we also

17 want to find out what the efficacious dose in children is.

18 it may be metabolized differently, and we can’t extrapolate

19 back. There is nobody in pediatrics who I think feels

20 differently than I do.

21 DR. GOLDSTEIN: There is no way I can top that

22 dialogue. I won’t even try. There are a couple of points

23 to be made. Earlier, a question was asked about

24 pharmacokinetics, pharmacodynamics, and safety, and what is

25 more important. Obviously, in children, safety is probably

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1 primary, they are the most vulnerable population, but the.

2 signal-generating aspects of adult studies should not be

3 overlooked.

4 Now , industry has, we all have in point of fact,

5 but certainly industry has issues involving liability and

6 the like, which to some extent color our judgments, but if

7 you look at the adult experience -- and remember, folks, the

8 life of a drug premarketing is far shorter than the life of

9 a drug postmarketing -- and every single interaction between

10 a patient and a physician is an epidemiologic event.

11 Those events in the adult community certainly can

12 be, many times and many diseases, and probably including

#-*-_ 13 this one, captured and used to signal, to generate signals

14 for studies on safety or efficacy, to make better labeling,

15 to provide research initiatives, and a whole host of other

16 things, and I think a“ lot of information, directly relevant

17 to the pediatric and indeed adult community can be gained

18 thereby, and ought to be gained thereby.

19 That might cut this down to a bit more manageable

20 sizer and I suspect it is probably behind some of the

21 agency’s initiatives in bringing us better pediatric studies

22 and better pediatric labeling.

23 DR. HANAUER: You stated that well despite your

24 hesitations .
.&----
25 Moving on as an appropriate segue on safety, to

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1 almost conclude, the ICH guidelines on safety evaluations,

2 specifically address the long-term treatment of chronic or

3 repeated intermittent use for longer than six months for

4 nonlife-threatening conditions.

5 The guideline calls for a minimum of 300 patients

6 treated at the maximum recommended dose and who are the

7 intended patient population for at least six months, 100

8 subjects treated for at least one year, and a total safety

9 database of 1,500 patients treated.

10 This is directly relevant to yesterday.

11 Does the committee generally agree with these

12 recommendations for products for Crohn’s disease? Is this

(-= 13 number of 300 patients, at the recommended dose for six

14 months, 100 patients for one year, and a total safety

15 database of 1,500 patients, is that acceptable for Crohn’s?

16 DR. ELASHOFF: For long-term use.

17 DR. HANAUER: Well, both short- and long-term. Is

18 this the standard we should use for Crohn’s, is this

19 acceptable? I don’t know how this applies to orphans.

20 DR. SIEGEL: The guidance is for long-term

21 treatment and it has a specific --

22 DR. HANAUER”: By the way, you have labeled Crohn’s

23 as an orphan by virtue of this, so I don’t know how you need

24 to apply this to orphan --
(=k-
25 DR. SIEGEL: The guidance specifically notes in

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162
1 some cases a smaller number of patients may be acceptable,

2 for example, where the intended treatment population is

3 small. So, it is not specifically linked to the orphan,

4 which has its own definitions, however, there is a definite

!5 acknowledgment that in some diseases, these numbers may not

6 be reasonable.

7 DR. HANAUER: Dr. Feagan, you are a

8 representative, not labeled, but you are from Canada.

9 :omments?

10 DR. FEAGAN: Well, Canada is smaller than the

11 J.S., and I think the flexibility, as you pointed out

12 ~esterday, it is a guideline, I think it is not an

13 mreasonable guideline. In this case, the situation might

14 >e that it may not be met.

15 DR. HANAUER: For example, you now have a

16 )recedent from yesterday, which was 200 patients treated for

17 mywhere from six to 12 months. Is that going to be

18 :ufficient for the next agent?

19 DR. SIEGEL: You did not recommend long-term

20 ,reatment.

21 DR. HANAUER: Right. So, are we only asking for

22 .OW many patients for long-term treatment and short term is

23 p for grabs? What kind of guidance do you want from us?

24 DR. WEISS: I guess what we struggled with are
-
25 hose diseases for which we are talking about chronic

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1 treatment, and that is generally at least six months. I

2 mean the idea is we are talking about things like Crohn’s,

3 inflammatory bowel disease. Rheumatoid arthritis I think I

4 think is the classic example where your studies go on for a

5 certain number of months, but you are really talking about

6 perhaps lifetime therapy for a chronic disease.

7 The guidance that is written is just the sort of

8 general minimal numbers that were felt to be reasonable to

9 have in hand at the time that you are reviewing a marketing

10 application.

11 Where there is concern about more toxicity, for

12 instance, you are certainly able to, and should be asking

13 for more than that, but this is the minimum that we are

14 :alking about.

15 In Biologics in the past, many of our therapies

16 ~ave been for very serious life-threatening diseases,

17 relatively short therapies, and now we are emerging on this

18 ~ge where we are talking about chronic therapies.

19 I think we would just like the guidance. If we

20 Ire talking about chronic treatment for Crohn’s disease, and

21 i.tis obviously difficult in the abstract without actually

22 laving a specific application and getting a signal in terms

23 >f the particular types of events that are observed, it is

24 ~omewhat difficult, but we were just asking for general

25 >stimates about the kinds of numbers people would be

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1 comfortable seeing.

2 DR. HANAUER: Is this a general number that is

3 reasonable for Crohn’s?

4 DR. SACHAR: Is it practical? Look at the size of

5 clinical studies, the overall size of all the patients in

6 the studies. And then you are not talking about the placebo

7 patients. You are only talking about the active patients.

8 DR. ELASHOFF: I would like to make a comment that

9 I am not going to address the specific question of 300 or

10 400 or 200, but I would like to see in these discussions

11 estimates of the kind of event rates that one rules out if

12 one doesn’t see them. If you see zero in 300 patients,

13 then, the 95 percent confidence interval for the event rates

14 goes up to something, so in a discussion, you have those

15 figures next to these numbers to give more meaning to the

16 discussion.

17 DR. SIEGEL: That, by the way, was precisely the

18 logic that went into the guideline, and the numbers of 300

19 to 600 for six months were based on determinations that for

20 most drug used chronically, most events that will occur,

21 will occur in the first six months, not all, but there are

22 only uncommon events that occur only after six months that

23 don’t also occur in the first six months.

24 Observing nothing in 300 patients gives one a

25 fairly high confidence, about a 95 percent confidence, that

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1 the incidence does not exceed 1 percent, and observing no,

2 events in 600 gives on a reasonable confidence that it does

3 not exceed a half a percent.

4 That was the logical basis. It is acknowledged in

5 the document -- and this was one of the points I was making

6 yesterday -- that that sort of logic is fine for excluding

7 rare and important serious complications, does not help a

8 lot when you are looking for incidence of important things

9 against a significant background already, so if you have

10 abscesses forming or bleeding occurring or surgery is

11 required in whatever it is in the control group, it may be a

12 lot harder to detect half a percent or 1 percent changes

&’– 13 against that background.

14 Also, the guideline is written for life-

15 threatening diseases, and when Karen asked that question and

16 pointed out we usually see life-threatening diseases, I

17 guess part of the question, aside from the pragmatic of

18 Crohn’s, is where it fits in that spectrum.

19 We approve a lot of drugs for cancer”on safety

20 databases a lot smaller than this based on the fact that

21 they have important benefits for profoundly ill patients

22 that it probably is ngt necessary or wise to delay approval

23 getting more safety data in certain populations.

24 The spectrum of nonlife-threatening diseases is a

25 broad one obviously. It ranges from baldness to

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1 hypertension through much more serious illnesses.

2 DR. HANAUER: It also puts undue -- it is almost

3 an opposite effect because for a new drug, such as was

4 discussed yesterday, required a small number of patients,

5 but if you came in with a drug that was already available,

6 for instance, a steroid that has been tested in other

7 situations in many, many other conditions, you might require

8 larger sample sizes than would be for a new one.

9 In other words, if you are using this as a

10 guideline or a guidance for a new drug, and yet you are

11 making exemptions for the new drug, are you putting opposite

12 effects, are you looking at almost hypocritical requirements

13 on an old drug applied to this? Do you understand what I am

14 trying to say?

15 DR. SIEGEL: Older drugs will usually have a

16 broader experience.

17 DR. HANAUER: So, this is not in this specific

18 situation, you are talking about a total safety database.

19 DR. SIEGEL: Well, we discussed that”yesterday. I

20 don’t think the document, although I signed the document,

21 actually, I was not involved in the team that negotiated it.

22 I think the issue of use and other indications, and how that

23 applies in the safety analysis is a complex one. We are

24 addressing it in considerable length in Good Review

25 Practices in the agency.

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1 There are certain types of nondisease-specific
____
2 toxicities, you know, idiosyncratic bone marrow suppression,

3 that it may not matter what disease you give a drug in, if

4 it has an incidence of that, it may be very pertinent. I

5 think it tends to be the case with biological response

6 modifiers, perhaps because we don’t understand biological

7 responses very well, that many of the safety issues that we

8 raise often involve exacerbating certain aspects of the

9 disease, and it is harder to get good safety data from other

10 diseases.

11 DR. HANAUER: Along those lines, and the final

12 question we were asked to address, 80 percent of the

13 patients who were treated for Crohn’s disease yesterday were

14 on concurrent therapies with either an immunosalicylate,

15 corticosteroid, antibiotic, or another immunomodulatory

16 agent.

17 The committee is asked to discuss specifically

18 which drugs commonly used in Crohn’s disease would be most

19 useful to evaluate with the next test agent for formal

20 interaction studies.

21 I will bring out a question that wasn’t addressed

22 to the panel yesterday related to the biologic. We saw

23 long-term data with infliximab yesterday, despite the

24 committee’s not examining or not recommending for approval

25 on a long-term use, many of those patients were on

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1 immunomodulatory agent, and data that was not exposed

2 yesterday is that there may have been a concurrent effect of

3 the immunomodulatory agent on a long-term response. Some of

4 those long-term responders may have been on what we consider

5 a current maintenance drug, such as 6-MP or azathioprine, so

6 do we need to look at drug interactions as far as efficacy

7 is concerned ala rheumatoid arthritis, where methotrexate is

8 almost incorporated into every clinical trial.

9 DR. SIMON: We have actually gone so far to

10 suggest that we don’t feel compelled to use placebo response

11 any longer as compared to the active comparator, and the

12 active comparator almost always right now is the gold

‘m.
L’ 13 standard of methotrexate.

14 But the implication from that is that it is also

15 unethical to look at this without comparing it to active

16 drugs, that if you take somebody without that, it --

17 DR. HANAUER: Let’s ask the committee, is there a

18 gold standard comparator yet? Dr. Feagan.

19 DR. FEAGA.N: I would say no, and I think it

20 becomes the problem. I mean if you look at what is out

21 there in the community, I think the trial reflects that.

22 When we looked at the antimetabolite use, first of all, not

23 all patients were on antimetabolites. When one looked at

24 the dose, the dose was not reflective of what experts are
&,.-
25 recommending, so I think that the people entering the trial

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1 proved that, that there isn’t concordance of the standard
/-—.
,r

2 therapy.

3 DR. HANAUER: Dr. Rutgeerts, any comments on this?

4 DR. RUTGEERTS: No, it is the same point, that, in

5 fact, the number of drugs that were used were suboptimally

6 used, and then another point is I think the drug to compare

7 it with is with corticosteroids.

8 DR. HANAUER: It’s a head-to-head trial.

9 DR. RUTGEERTS: It’s a head-to-head trial.

10 DR. HANAUER: Let me just take that, because in

11 many European trials, we have seen other drugs or regimens

12 compared to regimens of corticosteroids. Is there a

g-= 13 generally acceptable steroid regimen to be employed in

14 clinical trials to compare it to?

15 DR. FEAGAN: I think you will get an argument

16 about that, but I don’t think the argument is well founded

17 in data, that if one looks at the response rates and the

18 durations, the differences are small, and I really think the

19 challenge to the FDA would be to accept that conceptually,

20 that we are getting into an era of active comparator

21 therapies as far as induction of remission.

22 The question of refractory patients --

23 DR. HANAUER: So, what would be --

24 DR. FEAGAN: Anti-metabolites, I think is the more
,+–—.
25 difficult one.

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1 DR. HANAUER: So, from an induction of remission,

r 2 the rheumatologists have a standardized regimen for baseline

3 therapy or comparator. What would you recommend to the

4 agency to be the standard corticosteroid regimen to be

5 compared with? Is that a question you want or no?

6 DR. SIMON: Steve, could I ask you one more

7 question? What is the rate of response to azathioprine and

8 6-MP in inflammatory bowel disease?

9 DR. HANAUER: Dr. Feagan?

10 DR. FEAGAN: Well, 1 hate to echo the discussion

11 this morning about what the definition of response it, and I

12 don’t think anyone in this room can answer that question,

13 because it would mean defining what the primary outcome was,

14 and the studies have been very heterogeneic about what the

15 outcome measure actually was.

16 DR. SACHAR: But there is some consensus, isn’t

17 there? It is slow. About two-thirds of patients are

18 responding.

19 DR. FEAGAN: What outcome is that, David, two-

20 thirds of what? What happens to the two-thirds?

21 DR. SACHAR: That is the point at which steroids

22 taper without a flare when they start to feel better, when

23 the extraintestinal manifestations are not as common, when

24 the fistulae start to heal.

25 DR. FEAGAN: Show me the trial that it shows that

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1 two-thirds of the patients have a well-defined, clinically
-.
2 relevant outcome.

3 DR. HANAUER: Dr. Kirschner, you had a comment?

4 DR. KIRSCHNER: I was just going to say the

5 studies in children are not prospective, they are

6 retrospective, but the number is approximately 70 to 80

7 percent were able to substantially or reduce steroids once

8 azathioprine and 6-MP are added, which is exactly very

9 similar to what he says for methotrexate, and we are saying

10 that is the gold standard -- which he probably might now say

11 -— but it is an effective active agent for rheumatoid

12 arthritis.

.--% 13 DR. HANAUER”: Do you have a specified dose?

14 DR. SIMON: Unfortunately, no.

15 DR. HANAUER: Do you have a specified dose?

16 DR. SACHAR: Of what?

17 DR. HANAUER: For the efficacy of

18 immunosuppressive that you can compare with.

19 DR. KIRSCHNER: If we were to use steroids, at

20 least in children, we would say at least 1 mg/kg.

21 DR. NEEMAN: Could I go back just a second? I am

22 only a statistician.

23 DR. SIMON: But a good one.

24 DR. HANAUER: That is significant.

25 DR. NEEMAN: But I have reviewed protocols for

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1 rheumatoid arthritis, and I should say that the community,is

2 still doing placebo-controlled trials in patients who have

3 failed DMARDS in particular, methotrexate, and they do 4-

4 week withdrawals.

5 DR. SIMON: But they failed it.

6 DR. NEEM?iN: Right. What I am saying is that that

7 population, the so-called refractory population, is probably

8 the population, at least for the agents I have seen, that is

9 most likely to be studied for new agents. So, I think there

10 still is a place for placebo-controlled studies, at least in

11 R.A.

12 DR. SENIOR: In children, though, particularly

13 those under 12, given that the pediatric community and

14 parents want to see some efficacy and some safety in adults

15 first, would they accept a placebo-controlled trial when

16 there may be what is essentially a proved therapy for adults

17 already out there?

18 DR. NEEMAN: There is a pediatric trial in

19 rheumatoid arthritis, and it is in some sense ~- I don’t

20 know if I would call it a placebo-controlled trial, it is a

21 randomized withdrawal trial.

22 DR. SIEGEL: In the interest of concluding, I

23 Would like to get back to the safety questions, but I

24 nesitate to leave this issue, which I don’t think was in the
L_——-
_r

25 questions, without a couple of cautions, particularly for

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1 those of you out there doing research.
.*=
2 It is very difficult to prove that a drug works in

3 an active control trial depending on a number of conditions,

4 but if you are intending to do this, first of all, if your

5 goal and result is to show superiority to an active control,

6 and you are pretty sure that the active control isn’t

7 harmful, that is pretty good. If your goal is to show

8 efficacy on the basis of equivalence to active control, you

9 need to have a pretty solid, sound estimate, quantitative

10 estimate of the amount of active control benefit. That has

11 to be based on historically controlled comparisons to trials

12 of the active control generally compared to placebo.

13 You have to look at that benefit. You have to

14 look at the confidence interval around that benefit. You

15 have to determine what is the smallest benefit that you are

16 pretty sure the drug has, not the best estimate of the

17 benefit it has, and then, as with all historical

18 comparisons, you have to extrapolate that benefit from a

19 population that that active control was studied in, into the

20 population which is being studied in your planned trial,

21 which may be very different in its baseline characteristics.

22 It may have different use. It may have anti-TNF therapies

23 given alongside that weren’~. available in the historical

24 data, and so forth. It is a very difficult thing to do.

25 We are working on some guidance regarding that,

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1 and the ICH process, and writing that guidance has been a

2 very difficult thing to do, but there is a guidance on

3 choice of control groups.

4 Suffice to say that -- and this is not a

5 commentary on when you can or can’t use a placebo, and

6 whether it is possible to use a placebo, and whether you

7 should use a placebo -- but if you are going to try to show

8 efficacy through equivalent in an active control trial, that

9 is an extremely difficult thing to do from a scientific

10 perspective.

11 I would like to move back, though. We got into

12 this as a little tangent from drug interactions, which I

e-. 13 would like to discuss, but we also moved on a little bit

14 from the numbers, perhaps because I created some confusion

15 about what we are looking for.

16 But one of the issues that I think fundamentally

17 we are interested in hearing from is -- and I don’t want to

18 get too confused with where you were yesterday -- each drug

19 has its own factors, safety”concerns, its historical

20 development, its level of efficacy, but we deal -- and these

21 guidelines will go to a lot of companies manufacturing

22 drugs, you know, working. They may now only be in the pre-

23 IND phase. They may be early on.

24 Should we be telling a company that they ought to
-=.—. ..
25 anticipate, if they are coming to us with an application in

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1 Crohn’s disease, at the time of application having somewhere

2 in the neighborhood of 1,500 patients, or I think the Fredd

3 article said 1,500, the guidance document says 1,500, but

4 mentions issues regarding disease size.

5 But is that practical? Is that appropriate? Is

6 that the guidance that this guidance should be providing to

7 developers?

8 DR. HANAUER: Answer the question. Dr. Sachar.

9 DR. SACHAR: Could you restate the question?

10 DR. SIEGEL: This disease, given its seriousness,

11 given its uncommonness or commonness, is it reasonable to

12 tell companies developing, as we would in many other

13 indications for chronic disease, that we expect 1,500

14 patients to be treated by the time they are going to market?

15 DR. SACHAR: I think the number is a little bit

16 too big.

17 DR. HANAUER: So, what number?

18 DR. SACHAR: 681,

19 DR. HANAUER: Dr. Rutgeerts, how many?

20 DR. RUTGEERTS: I think 500, 600, is a good figure

21 I think.

22 DR. HANAUER: Dr. Kirschner, how many kids?

23 DR. KIRSCHNER: That is a question I had asked him

24 to raise because I think it”is too many, but that is, as we
_-r
——.
25 talk about this, should there be a number of children if we

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1 are talking about, we are going to say that people can use

2 it in children.

3 DR. HANAUER: How many kids?

4 DR. KIRSCHNER One hundred.

5 DR. HANAUER: Dr. Simon.

6 DR. SIMON: I hope you are not asking me that

7 question.

8 DR. HANAUER: No. How many patients?

9 DR. SIMON: I think given the size of the patient

10 population, it has to be lowered from the 1,500, but I think

11 it has to be multiple patients, at least 600 patients.

12 DR. HANAUER: Dr. Feagan?

z+--%= 13 DR. FEAGAN: I think you can sort of get at that

14 number if you take a drug that has a modest effect size, 20

15 to 30 percent effect size, and you consider a dose finding

16 study plus a Phase III definitive two-way comparison, you

17 are going to end up with about 600 patients, and I think

18 that fits with the other -- if the drug has a huge effect

19 size, 50, 70 percent effect size, well, then, the impetus to

20 get the drug out there is going to be stronger, and you may

21 want to interpret this as a guideline, and not absolutely.

22 DR. HANAUER: Dr. Surawicz.

23 DR. SURAWICZ: I agree with the 600 number. I

24 think the 600 number seems feasible and comfortable. I

25 would be curious what industry’s response to that is. I

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1 think the 1,500 in Crohn’s disease where there are so many
.-.-%=
2 subgroups in different types, is unrealistic.

3 DR. HANAUER: Bill, how many?

4 DR. STEINBERG: I would just be pulling it out of

5 the air. Six hundred sounds reasonable.

6 DR. ELASHOFF: I think in view of its being a

7 relatively unusual disease, it would be reasonable to make

8 these numbers smaller. If I were to make a specific

9 recommendation, I would like it to be based on a goal like

10 excluding a certain rate or detecting differences of a

11 certain sizer and whatever goal people agreed on, then, the

12 number that goes” with that.

.-.. 13 DR. HANAUER: Giving industry the last word.

14 DR. GRAFFNER: I think that yesterday in this

15 discussion here, actually, it was fairly historical, because

16 from industry viewpoint, I believe it is a very small area.

17 It takes just the same amount of money to produce a drug for

18 IBD as it does for hypertension, and I do know that there

19 are people out here working with very small firms, having

20 very good ideas in this field, they are not able to evaluate

21 and do research in this. I looked at the guidelines, I

22 looked at the 1,s00. I think the experience yesterday and

23 perhaps decreasing of the number here today, it will be do

24 very good for the IBD community.

25 DR. HANAUER”: Thank you.

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1 DR. SACHAR: Does the agency have a position on

2 concomitant therapy versus monotherapy? So often our

3 industry protocols require that there be washouts, and they

4 stop everything else, may not be on concomitant drugs, and

5 that this be almost monotherapy.

6 DR. HANAUER: As of yesterday, the answer was no.

7 I am just answering for the agency because you saw a drug

8 where 80 percent of patients were on other therapies.

9 DR. SACHAR: So we can take almost anything and

10 either add a new drug or a placebo?

11 DR. SIEGEL: A lot of drugs are developed as add-

12 on, drug plus placebo. There are cautions you want to have.

p-. 13 You want to fairly clearly specify what is of isn’t allowed

14 both at the time of randomization and also Harlan Weisman

15 was mentioning the issues in post-randomization, because if

16 people start altering what you have added on to, it will

17 interact with what you observed as drug effective. But if

18 you designed it right, there is absolutely no problem, and

19 quite common to develop drugs as add-on therapy.

20 DR. SACHAR: It is not as common in the industry

21 protocols as we would like it to be

22 DR. SIEGEL: Well, it depends on the disease. In

23 HIV and cancer, typically, the three drug regimens versus

24 the three drug versus this new drug is a very common way to

25 develop.

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1 DR. HANAUER: Based on what it takes to get it,

2 sample size, et cetera.

3 I promised to end at 2:00. It is approximately

4 2:00. I want to take this opportunity to -- I think we have

5 come a considerable way. This is the beginning of a

6 process, so actually we are midway through the process. We

7 had a document to work from, and I think that that document

8 did suffice to gain the first drug that has been recommended

9 for approval for Crohn’s disease. So, I think that that had

10 a considerable success, but it was never meant to be the

11 definitive document, and the comments and instructions and

12 questions that were brought up today I think were very

E==. 13 useful for the evolution of this document into a formal

14 hopefully accredited guidance document that we will be

15 pursuing over the next time interval.

16 Specifically, I want to thank the consultants to

17 this committee: Dr. Sachar, Dr. Rutgeerts, Dr. Ki~s~hner,

18 Dr. Feagan, Dr. Simon, who have been extraordinarily helpful

19 in these discussions. It broadened the scope of this

20 committee which was necessary for this unique situation.

21 I need to thank the Agency, Dr. Talarico and her

22 group from CDER, Dr. Weiss, Dr. Siegel from CBER from their

23 invaluable drafting and guidance for the guidance, and Joan

24 Standaert for her continued tremendous assistance for this
.—-—__
25 committee.

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1 DR. ELASHOFF: I just would like to say that I
[---
2 think what I said in the beginning is that I would like to

3 have the opportunity to put these questions out there on our

4 web, so that other people can respond to these questions and

5 naybe add some additional things, and then, as I said in the

6 beginning, I think the next step is for us to assimilate all

7 ~f this into a very first draft that then we will put out,

8 perhaps take again to another meeting of the Advisory

9 2ommittee at a future. date.

10 DR. HANAUER: Thank you. Good afternoon.

11 [Whereupon, the meeting was adjourned at 2:00

12 2.m.]

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181

((—
CERTIFICATE

1,ALICETOIGO,the Official
Court ReporterforMillerReportingCompany,

Inc.,herebycertify
that1 recordedthe foregoingproceedings;thatthe

proceedingshave been reduced to typewriting
by me, or under my direction
and

thatthe foregoingtranscript
k a correctand accuraterecordof the proceedings

to the bestof my knowledge,ability
and belief.

@-

u
ALICE TOIGO
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee
May 29,1998
115:15, 19; 122:12,13,14, 24, 25; 66:4,6,9,9, 10,11,
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128:5,5 8-week77:16
4884:6;
103:19 74:1,5,8, 10, 13,17, 17,
0 2-week 88:8
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171:20 9545:11
;164:13,25 37:4,5,11,13,13, 14, 14;
2468:21; 78:16; 80:20 5-year-old 133:18 38:3,16,17,21, 24;89:2,
1,500161:9, 15; 175:2,3,
25125:13; 131:20; 50 48:9; 49:24; 67:10; ;,8, 10, 10, 12, 13, 14, 15,
3,13; 176:10; 177:1,22 150:14,21
54:17, 19; 90:7; 101:24; A 17,20,21 ;90:5, 12, 19;
1/2102:21,23; 103:6,10, 25091:4 140:18; 176:19 )1:1,2,3,3,4,4,5,19,20,
21;105:8, 24;110:9,17, a 4:9, 15, 23,24; 5:3, 21;
20,24, 25;111:9; 112:19; 2668:19, 25; 70:1;73:5 500175:20 13;92:5,7,9,10,13,15,
28-day 77:9 6:1,5,10,11,14,19, 23; !o,21;93:2,6,8,9,9,9,
123:7 7:1, 15,16 ;8:1, 11,14,19, 16,17,18,19, 22;94:5, 5,
1089:10;
101:25;
93:8;
102:3;
99:21; 295:12;
110:9,
42:24
17, 2:00179:3,4
6 21;9:3,5, 11,13,18,21, 1,10,13,16, 17,20, 22;
24, 25; 10:2,5,7,10,15, )5:8,19,24,25;96:3,6,9,
20,25;111:6; 112:19, 23; 18,18,25 ; 11:1,4,11,11,
) 73:6, 15, 16;74:6,7, 11, 0,12,17,17,24, 25;
121:12, 17,17,22; 122:9;
125:12; 128:2; 137:23; 3 ?0,22; 75:1,3, 22; 76:4,
15,19, 24; 12:4,5,9,11,
17,21;
17:1,2,5,
13:5,6,7,15,18, )8:1,
13,23,24,
8,12,14,18,20,
24;
20;
138:2;139:10; 149:18 12;77:3, 4; 78:13,19, 25;
19,20,21,23, 24;14:2,6, }9:14, 14,15;100:3, 5>9!
.-. 10,OOO-patient 98:20 ) 47:2; 48:21; 75:17; 78:4; ‘9[4,4, 5,6, 10,11,14,16;
12,14, 17,18,21, 23; 0,10,17, 22; 101:2,8,
10-year-old 138:6 10:14;102:13; 105:1,9, 10:6,6, 15,21 ;81:9; 15:13, 15; 16:4,22, 25; 2,18,24, 25; 102:2,3,3,
3;124:15 13:24;84:3; 94:24; 105:9, 17:25; 18:15, 19; 19:11,
100 27:14; 49:19, 25; 2,14,17,22,23, 24;
l-month 77:24 3, 15; 111:14; 127:22, 25; 12, 12; 20:2,5,6,9,10, 24;
91:10; 94:7, 14; 161:7,14 03:3,3,6,8, 10, 16, 16,
L491:2 43:7 21:4; 22:5, 14,21, 24;
10th 137:25; 138:7 ‘4,25 ;104:1,4,5,9,12,
L6 153:17 i-month 74:13, 17; 23:10, 12, 16, 25; 24:7,8,
5,16, 18; 105:9,20,24,
11 126:5,7; 137:24; 138:2
‘7:24; 78:23 10,11,22,
24;25:1,
18, 25; 106:3,5,6, 13,13,15,
1251:15 ;68:21; 70:13, 1047:2; 91:3; 96:16, 23;
i-MP 24:17; 55:18; 69:13; 24;26:1,2,3,5,6,7,8,21,
20,20, 24; 107:8,9, 12,
25; 73:2; 78:15; 80:20; 10:12 ;131:20; 150:14,
‘9:12; 146:7; 168:5; 25;27:2,9,9,
13,18;28:6, 17, 17,22; 108:1,3, 11,
100:19;
102:12;
105:14, 1; 176:15
70:8; 171:8 7,18;29:2,7,8,9; 30:5, 14,16,19,25, 25;109:5,
16;124:7;
126:5,
8;128:5, lo-minute 10:18 10,14,17,20;31:7, 10, 15,18,19;110:1,2,5,10,
7;131:6
;136:19;
137:10; O-point 98:14 i-week 88:8
16,18;32:6,8,9,10, 18, 12,16, 25;111:3,16, 19,
138:2;
143:6,
10;144:25; 10047:13, 15;48:13; 090:7; 115:17;150:13 ~l,21; 33:2,8,19,22; 21;112:2,3,5,8, 13,15,
145:2,
5;151:4,6;
162:17; 3:24;94:15 ;161:5,13; 0094:11; 164:19;16%2; \4:3,
5,10,13, 20; 35:1,5,16,24;113:5,5,6,8, 18,
172:13 64:9,12,18,24 75:20; 176:11,17,23,24 14,15,19;36:14, 23;37:4, 18,24;114:1,22, 23;
12-year-oid 128:2; 138:7 os 148:15 13,15,17,23; 38:1,3,4,9,
467:8 115:3,7,9,13,20, 25;
12A4:25 1047:15
15,22,23;39:2,3,10, 13, 116:8, 16,21;1 17:5,11,
65146:7,17, 23;147:5,6,~1,25;40:5,6,7,8, 24;
13128:15 3149:18 23;148:24 12,15, 17,21; 118:1,6,
14-year-old 128:16
~1:11,13;42:14; 43:7, 15, 11,11,12,15,16,21,25;
590:13 66-pound 138:1 13;44:2,8,10, 12,14, 16, 119:1,
14056:4
2)8,10,19,22;
5091:4 681175:18 17,19;45:7,11,14, 19; 120:1,4,10,15,18, 20;
15 102:3; 111:9 ;121:12; 6 67:8; 84:7 i6:14,21,24,24; 47:l,ll,121:1,3,4,4,8,12,17, 17,
6990:6
133:11 [2,12,13,16, 17; 48:6,8, 22;122:2,3,4,9,10, 14,
15018:15,18,
19,21; [z,18,18,22;49:3,4,5, 15,16,21,22;123:2, 25;
27:14
;32:11;
40:24; 4 7 :4,14,22,23; 50:15,18, 124:1,1,10,11, 15;125:7,
45:14;
49:19;
59:7;
89:7; !5;51:4,4,7,8, 13, 14; ),11,25;126:7, 10,14,
94:3,7 69:2,13,16,22,24, 25; 799:23; ;2:4,4,5,9,12, 13, 13,14, 15,16, 17,24;127:1, 10,
102:21,
23; .7,19;53:3,4,5,7,7,8, 21,25; 128:1,14,15,16,
1670:23;103:19 0:4,8,9,10,13,17, 18; 103:5,10, 21;105:8,24;
16-week 81:25 1:13,14 ;72:2; 73:24; I1O:9, !2,24;54:1,5,7,11,14, 19;129:2, 22;130:21;
17,20,24,25; !3,24;55:3,6,10,16, 19; [31:7;
184:18;137:9;
144:2s; 4:2,23; 76:1, 23;
77:16; 111:9; 112:19;123:7;
132:1,4,6,8,14,
1:7,12, 17;85:4, 11,
16, ;6:1,4,
7,8,9,9,11,12,[5;133:5, 14,15, 15,18,
.=———.1452,5;151:6
7,19, 25;88:2; 94:24; 127:25; 130:20;139:8,9 2,14,15, 15,24,24, 25; [9,22, 23;134:12,16,24,
18896:17 5:1,3;98:9; 102:13; 7.5103:21 ;7:3,7,10;58:1,6,8, 10, 25;135:4,8,9, 11,12,13,
19137:24 11:15, 17,25; 124:16; 7089:21;90:4, 11;1256; 2,25;59:7,9, 13; 60:10, [4,16,24;136:2,22, 25;
1990s7:3 72:3 L26:17; 147:11;171:6; 5,17, 20,24;61:1, 2,5,6, 37:17;138:1,3,7,24,24,
19956:25 4-week 85:1,3 L76:19 1,22;62:7,8, 17; 63:2,8,!5;139:3,8, 14,19,22,
19985:12 4.8153:17 7190:6 ~,
1 2,
1 2,15;64:1,5,7,9, !4;1 40:8,8,16,17;141:9,
0,12, 16,16,20; 65:9,9, 0,12;142:2,2,3,9. 11.
1:3010:20 40106:21:110:12: 75146:7 19,
19,20,20,21,22,23,
6, 25; 143:3,6:7:19, 2~,
Miller Reporting Company, Inc. Min-U-Scripti
Hearing Volume Number 2 Food & Drug Administration
May 29, 1$)$)8 Gastrointestinal Drugs Advisory Committee

‘,25;144:1,3, 14, 16, 23; 129:10;
130:2;131:19; act 125:2; 130:13; 131:3 132:8; 140:11; 141:21 23; 147:5,10, 10, 11,13,
145:1,2,14, 17; 146:4,13, 132:16;
134:2;135:3; acting 79:15 address 5:8; 90: 18; 97:6; 17; 148:8, 20; 149:8, 10;
+n2_23, 25; 147:1,9, 15, 136:1;
138:24;139:10; 150:13; 151:3,21; 152:11;
action 154:21 106:11; 135:21; 144:10,
18,23; 148:5,10, 11; 142:22;
144:11;145:8,9; 16; 151:7; 161:2; 164:9; 163:18
149:4, 23; 150:4,8, 12,21; 146:5,5,
12,14,17; aCtiVe 18:19; 23:3,5,9,
15,21 ;24:2, 10,19, 23; 167:12 age-related 152:17
151:1,9, 13, 18,20; 152:6, 147:18,24;149:17,21;
addressed 51:2; 105:2, agency 7:6; 19:6; 20:11;
18,22; 153:5,5,6,10,17, 150:13;151:1;152:1,3,7, 25:22; 26:1,6,16, 19;
27:3, 11; 30:3,8, 13; 32:3, 4; 167:21 34:18; 37:21 ;38:13;
21; 154:2,13,22, 23; 7,13,21,24;153:2,23;
addresses 4:8; 97:8 57:15, 20;86:16; 113:10;
155:2,2,3,5,16,19, 23; 154:5, 21; 5; 34:25; 39:5; 42:4; 49:16;
5,6;156:7,19,
130:12; 134:17, 22;
156:5,6,6, 12,16, 22; 157:2,3,25;158:2,3,4,6;50:5,19; 51:19,20; 52:1; addressing 124:15;
135:19; 141:9; 143:23;
157:1,2,9, 15,20; 158:10, 159:23;162:25;163:2,5, 58:20; 61:21, 23; 62:12, 166:24
166:25; 170:4; 178:1, 7;
10,14,14, 16, 17; 159:11, 11,14,18,20,25;164:6, 21, 22;63:12;64:20, 23; adequate 79: 13; 107:24;
179:21
13,22, 23; 160:8,9,10, 68:2o, 24; 69:13; 71:2; 143:17; 156:13; 159:2
7,25;166:18;169:16;
10,15,16, 19; 161:5,8, 75:10, 20; 79:15; 80:25; Agency’s 4:24; 132:22;
170:11,14,17;174:15; adequately 135:6
14,21; 162:1,4,7, 12,15; 62:5; 84:18, 20; 85:5; 88:5, 160:21
175:25;176:1,17 adjust 100:4, 9; 137:14
163:4,6,9, 22,22; 164:2, 6, 22; 101:18, 20; 109:2, agenda 4:11; 5:2
above 18:20;115:20 15; 110:3,21; 116:10,17, admirably 55:3
8,14,24, 25; 165:2,3,3,7, agent 72:6; 77:11; 81:22;
abscess 23:23;26:1; 19; 120:23; 123:21; Admittedly 73:25
9,11,12,19, 20,24; 82:7; 118:4; 122:1; 124:1,
30:11;47:16;48:13 150:19; 164:7; 168:11,12,
166:3,4,5,6,8,9,10,10, adolescent 128:16 8; 142:7; 155:18; 162:18;
abscesses 165:10 15; 169:20; 171:11; 173:3, 152:11
15,18, 23; 167:3,21, 25; 167:16, 19; 168:1,3;
absence 59:22; 64: 18; 5,6,8, 10,12, 19; 174:8
168:2,3,5, 17; 169:8,9, adolescents 128:6,8,9, 171:11
12; 170:2,5, 22; 171:1,3, 67:24 ~CtiVeiy 7:7; 37:23; 77:12 14, 18;131:1; 139:18; agent’s 135:8
13, 15,21, 22,23; 172:10, absentia 9:2 activities 20:24; 44:4; 140:5; 143:5 agents 24:21; 125:4;
15, 16, 18,20,20, 25; absolute 87:6 ?2:17
~duit 125:19; 126:16; 155:1; 172:8,9
173:2,3,9,18, 24; 174:1, absolutely 15:14; 34:14; activity 13:14; 14:18; 128:16; 133:4; 135:16; ages 132:17
2,4,5,6,7,9,12,13,21, 41:11 ;63:25; 86:10; 15:1; 16:4,10, 11;17:2, 138:20; 142:3; 143:3, 13;
[1;18:15,18,
20;21:8; aggressive 125:25
24; 175:15,20,23, 25; 14823; 176:21; 178:18 153:18; 155:3, 5; 160:2,7,
176:14,14,15,16, 18,21; }1:17;
32:10;
35:11,14, aging 149:13
absorption 14:19 [1, 17
177:6,8,9,10, 10,16, 17; [6;42:9,
14;44:3;
46:11; ago 75: 12; 79;7; 106:6;
absorptive 14:20 idults 96:19; 124:12,18,
178:1,7,10, 10, 11,24; [8:23;
52:22;
53:4;54:20; 135:14; 137:17; 139:9
!0, 23; 125:1; 126:16, 25;
179:5,5,7,10, 13 abstract 163:21 ;5:20,
22;78:5;
107:8,10, agree 30:25; 45:6 46:1;
[28:10 ;130:16; 131:12;
abdominal 13:19; 28:23 academia 139:11 [0,13;108:20;
111:13,22, 50:5;78:18, 23; 85:7;
[36:3, 25; 137:2; 139:20,
-.-~lity 12:24; 83:25; academic 34:18 12;120:19,25 39:12;97:7; 111:24;
!3,24;
140:23;
141:6,
13;
:14 Academy 130:23 Ictual 21:20; 93:24 .43:8;
144:1;
153:20; [12:3,9; 122:11; 123:15;
~u[e 11:11; 29:3; 37:18; ictual[y 1S.18; 21:21; 154:24;
155:9;
159:12; 136:17; 153:13,19, 22;
accelerated 141:23
41:18 ;42:20,20;44:17; !6:17, 20; 29:5, 24; 36:17, !72:14,
16 161:11; 176:23
accept 65:5, 24; 72:19;
52:2; 73:2; 82:25; 99:17; !0, 25; 40:19; 43:23; idvance 19:4; 20:11; agreed 37:9, 24; 102:25;
51:7; 85:9, 11,12,16,24,
105:8; 110:16; 120:24; i3:16;55:l,8; 57:13,15; .59:15 [77:11
24;92:10;
103:5;
169:19;
121:13, 21; 122:9; 152:15; .’9:7;93:21; 94:2, 2; 101:7; agreeing 122:8; 129:19
172:15 advantage 22:9
163:12; 171:7; 177:20 103:8; 104:15; 105:10; agreements 141:17
acceptable 20:1 I; 31:19; 114:14; 116:3,19, 25; adversarial 5:22
abnormalities 28:15; 51:16; 71:16; 74:2; 101:9; agrees 152:3
119:4; 120:11, 20; 122:8; ~dvice 136:6
29:14, 17;73:6 113:8; 115:2; 161:15, 19; aim 111:8; 120:2
124:15, 24; 136:2; 138:22; Bdvisory 7:14; 39:9;
abnormality 28:9 162:1; 169:13 airned 102:23
140:16; 154:20, 22; 157:8; 98:22,23
about 10:5; 11:1,7; acceptance 36:19; 72:1 163:21; 166:21; 168:9; air 177:5
ndvocate 9:25; 149:2
22:22; 23:10; 24:4; 25:22; accepted 35:22; 73:23; 170:15; 177:15; 179:6 dfect 14:19; 16:6; 36:1 ala 168:7
27:10,12,16, 17,18, 21; 74:13 actuarial.1 2:4
29:1; 30:23, 24; 32:3,5, Mfected 4:21 albumin 15:1
accepting 81:12; 85:8 acute 22:25; 23:5, 9;
13; 33:3,7; 34:16; 35:7; Bffecting 126:10 ali 4:12, 13, 19; 5:7, 24;
accordance 4:18 25:23; 30:23; 31:7,13, 16; 7:25; 13:16; 16:14; 18:21;
38:4; 39:2, 16; 40:13; 42:3, Bffirmative 111:20
according 15:19; 16:2; }2:4; 34:25; 37:16; 38:18; 23:25; 25:9; 27:17; 29:3, 5;
4;48:25;49:10, 15, 15; after 9:17; 10:2; 18:7;
51:24; 54:12, 13; 55:11; 17:10, 15; 4S24 39:5, 12;45:19; 64:13; 30:12; 32:3; 36:13; 37:10,
72:1;75:8; 81:12, 14, 17; ~8:8; 86:7; 110:5; 116:13;
56:6, 6; 58:19; 59:13; accordingly 10:23 14; 38:19; 39:6, 8; 42:8;
33:20, 22;84:10; 117:8 123:13; 147:14; 150:1;
60:13 ;61:10, 11,13;63:3; accredited 179:14 43:3; 46:9, 12;49:3; 50:21;
164:22
66:2,12;67:3,14,17; ~CUtely 43:25; 77:15; 55:20; 56:20; 57:18;
accumulative 38:3 78:4; 122:16 afterwards 151:9
68:10,11,14;69:12,14, 58:16 ;62:11;63:4;68:1o;
achieve 32:15; 39:1; ~dd 114:24; 178:10, 11 Rgain 8:2,6; 37:12; 46:4; 70:3, 5;72:17; 73:17, 18;
20,22;72:13;75:15;
52:19; 62:6; 101:13; 48:17; 63:8; 65:24; 66:6; 74:23; 79:9, 24; 82:10;
77:25;78:10;79:4,4,5,6; zdd-on 178:19
111:7,20 57:3; 78:10; 80:9; 81:10; 63:1, 4; 84:19; 87:9; 88:4;
81:3;
82:9, 14;83:1,11; added 37:14; 103:8;
84:9,
16;85:20, 21;86:23; achieved 42:23; 53:16; 35:18;86:14; 92:7,19; 89:lf$90:5;94:ll, 12;
171:8; 178:16
87:20,22;89:17;90:7; 70:23 )4:8; 97:2; 105:12, 18; 99:5,16, 23; 103:2, 4;
zdding 61:15; 107:17, 21; 107:16; 111:13; 130:2;
92:7;
93:10, 11;97:10,22, achievement 103:5 106:9; 107:25; 110:14;
[09:14 ;110:2 136:4; 142:21; 143:4 112:23; 114:2,4; 116:7;
22;99:6,11,12;101:17, achieving 38:4; 96:21
~q 102:11, 12;103:1,16; 4ddisonian 117:5,6,7; lgainst 21:8; 66:5; 95:12; 117:9; 118:1, 22; 119:7,
acknowledged 165:4 [20:7; 123:8,12, 13
“:24;105:16,19; )9:10; 129:3; 130:7; 11; 123:1; 125:8 ;127:14;
acknowledgment 162:5 iddition 45:21; 51:7;
.1:23;108:3,7,8; 165:9,13 129:3; 130:4, 11;131:24;
109:13,18;110:1,8,23, ACR40:11;43:22 19:15;90:9; 123:2, 3; ~ge 125:12; 126:4; 127:9, 132:13,
17;133:1;
135:2;
23;112:17;115:3,9,20; ACR-20 39:15, 23; 40:17; [33:2 ?1,23,25; 128:10, 21; 144:1
1;152:23;
160:4;
116:8;117:1,4;119:3,13; 53:25 ;54:2,4 additional 7:22; 20: 18; [30:20, 25; 136: 18; 137:8; 164:5,
21;168:22,
23;
120:10;123:8;125:7,14, across 132:17; 154:24; !1:16; 61:7,7,9,15; [38:4,8. 21; 143:10,17: 173:4,17
16;126:9,16;127:3; 155:1 ;3:22; 88:7; 89:25; 131:4; !44:25; 145:2,5; 146:14, I all-cause 77:9

abdominal - all-cause (2) Min-u-seript@3 Miller Reporting Com~anv. Inc.
Food & Drug Administration
Hearing Volume Number 2
Gastroi.ntestind Drugs Advfiory Committee
May 29,1998
a[!OW 7:21;
80:7;
118:9; amount 6:13; 36:22; 23;21:1,1, 10,20,21; 108:2,6,6, 11,14, 25; 63:21; 65:6, 10; 76:23;
138:5 96:6; 102:3; 156:8; 22:5,6,7,12,21, 25;23:L 109:15; 110:5,8,13,17, 77:9; 81:13; 82:7; 89:6;
.->
.—- allowed 120:21;
178:13 173:10; 177:17 12, 13; 24:6,11,22, 24; 18,20,22,23,24, 24; 95:13; 106:2; 113:19;
allowing 77:18;
123:6 amounts 135:24 25:4, 10, 19;26:2,6,6, 1: 111:2,8; 112:5,10, 12, 17 116:9; 117:3; 142:7;
diows 131:23 ample 102:9 20;27:1,5, 11;28:2, 11, 19,19,22, 23; 114:7,9, 159:5; 167:15; 169:6
14, 21; 29:2,3,4,9,9,10, 17,18, 23; 115:8,13,14,
aiMOSt 67:20; 76:3; amplify 54: 10; 77:8 answer 62: 17; 86:9;
12,13,19,23, 24; 30:8, 16, 17, 18,20, 25; 116:7,
114:4; 147:9, 14; 161:1; an 4:15; 5:3,22, 23; 7:22; 102:10; 111:20; 112:18;
166:2, 12; 168:8, 12; 13, 17; 31:5,6,17, 23; 10,14, 15, 15,21; 117:5, 118:1,2,3; 122:18; 123:5;
8:3; 9:5; 10:9, 11; 12:13;
178:5,9 32:22,25; 33:1,8,14, 14;8,10,12, 16,21; 118:1,
13:11,22, 25;15:7; 17:9; 34:9,10,17,18,18,20, 130:4; 133:16; 155:14, 19;
14,18,20, 21; 119:4,5,
alOne 62:5; 138:4 24:5; 25:23; 27:22; 29:6; 20,21; 35:3,19,23, 25; 157:23; 158:14; 170:12;
11, 16; 120:2,2,6,20,20,
along 41:23 ;73:17, 18; 30:11,18; 31:19; 33:19, 36:4,7,12,15,16,19,19, 175:8; 178:6
23,24,25, 25; 121:3,10,
132:12; 153:1; 167:11 20; 34:24,25, 25;35:1, 3; 21, 24;37:5,9, 11,14,17, 14, 16; 122:1,7, 18;
answered 133:4; 158:17
alongside 173:23 41:23 ;43:17,17;44:15; 20, 24; 38:4,11,13,22, 123:13,16, 17,18,19, 19; answering 140:13; 178:7
alpha-1 15:3 46:19; 48:15, 23;51:16; 23; 39:2,4,5,10,12, 13, 124:1,5,18,22,22, 23; 120:9;
answers 143:14
already 5:2; 18:24; 24:8,
52:8; 53:1,6, 10; 54:2; 15, 20; 40:2,8,8,13,14, 125:10,13,16,17,22,23,
57:20, 25;58:1 1;60:23; 15, 18,23 ;41:3, 10,12, Anti-metabolites
169:24
21; 25:7; 26:5,7; 54:11; 23, 25; 126:3,3,5,7,13,
anti-TNF 173:22
74:1,9; 84:25 ;102:11;
61:4; 62:3,16, 23; 63:13; 13,18,18,20, 23; 42:5,5, 14,17,19,20,21, 25;
150:21; 152:1,17, 19;
65:3, 13; 66:16, 20; 68:20, 6,13,18, 23,24 ;43:2, 5, 127:8,10, 11,13,22,23,
antibiotic 167:15
165:9; 166:5; 172:17 24;69:15; 71:25 ;72:1,6;10,15,18, 24;44:3,4,9; 23; 128:1,6,7,18, 23; Antibodies 77:7
A[s05:21; 6:18; 7:21;
73:17 ;75:14, 15;76:3; 45:2, 11,13,20; 46:1, 11, 129:5, 16, 24; 130:15,20, anticipate 174:25
8:10, 12; 10:11; 11:4, 10;
77:11, 16;79:13; 81:12, 25; 131:1,5,8,10,12,14, anticipating 63:24
17; 82:8, 15, 18; 83:16, 22; 12, 19;47:5,6,9, 13, 15, 15,20; 132:1,3,7,16,17,
12:13,21 ;15:11,25; 15; 48:5,13,15, 17,20, anticonvulsant 135:13
27:20; 29:18; 38:20;
$4:10; 85:13, 14; 88:24; 20,20, 25; 133:2,4,7,13,
23; 49:5, 10,16,19, 25;
41:16 ;42:11;43:7; 46:24;
S9:7, 25; 90:25; 92:2s; 15,18, 23,24; 134:4,18, antimetabolite 168:22
50:1,6, 17, 18, 19, 20;
>4:4,22, 24; 95:2; 99:7,8, 19, 19; 135:16,18,19, 25; antimetabolites 24:17;
51:6, 12; 52:3, 21; 56:2; Z2; 100:7, 14;101:9; 51:1,3, 10, 12, 13,20;
58:3; 60:12; 66:24; 74:12; 136:3,3,5,7,7,9,19, 25; 168:23
[03:2, 9;107:24; 111:20; ;2:2, 3,24; 53:1,4, 10,11,
137:11, 12,19,19,20,20, antitrypsin 15:4
75:4; 76:6; 92:11, 14;
101:2, 5; 102:17, 25;
112:25; 113:3; 116:22; !3,24,25,25;54:3, 13,
?1,24; 138:3,4, 19,21,
[17:6,8; 118:23; 120:24; [6,20,20,25;55:2,8,17, !1, 23; 139:7, 12, 16, 24; any 5:1,8,9 ;7:4; 22:10;
106:2; 108:19; 120:9; 17,19,20,22, 25;56:3,4, 25:16; 29:12, 13, 13;
L22:18; 123:2, 21;124:8;
125:7; 130:23; 133:23;
.26:16; 128:16, 16; 129:5, ~,16,19,24; 57:1,4,6,8, [40:10, 12,21,25; 141:1, 34:14; 37:17; 45:8; 46:5;
135:21; 139:21; 140:11; 19,16, 19;58:6,13, 14, J, 13, 17,21; 142:7,14, 52:17; 57:23; 58:7; 64:5, 6;
— 145:21; 159:16; 164:23;
.0; 134:21; 135:5,13; !5; 143:6, 10, 13, 14,24,
36:1; 138:6, 20;141:7; .5,15,16,20, 24;59:4, 68:7; 79:8; 87:25; 91:7;
165:14; 166:2; 168:14; !5; 144:4, 14, 17,25;
43:17,23; 146:14,15, 19; 9,25; 60:6, 1 4; 61:6,7, 93:1; 97:9; 103:22;
174:13; 178:14 0,11,12,19.22.24: 45:3,4,8,10, 24; 146:7, 113:25; 121:23; 123:5;
47:10,12, 24;149:2; 13, 16; 147:1,12, 23;
alter 158:10 53:13; 154:18; 155:3; 6’2:2,3,4,’7, 10,11, 13; 129:4;
130:4;
143:1;
148:8, 14,15, 17,17,18,
altered 15:19 57:13,17, 23;160:10, 25; 63:2,4,5,7,18,23, 25;
25; 149:3,7,8,9,14,14,
145:13;
155:23;
168:11;
altering 178:16 61:23; 162:12; 166:3, 13; 64:1,7,10,11,12, 14,20; 169:3
67:4, 14; 169:15, 20; 65:10, 25;66:6,10, 13,22,20, 25; 150:13, 20; 151:4, Anybody28:l;131:ll;
although 16:4; 20:8; 24, 2 4; 6 7:4,5,12,13,14, 4,14, 16; 152:2,5, 12,24;
62:8; 74:13; 82:24; 88:20; 70:1; 171:11 ;173:3,5; 154:7,19, 22; 155:3, 12,
139:15
74:8,9,25 24; 6 8:21; 69:24; 70:4, 14; anyone28:8;
32:4,
12;
90:4; 99:24; 105:1; 13,23; 156:1,4, 14, 14,
lnalogous 41:14
71:8,9, 13,14, 15, 1 7; 70:17;
144:15;
170:12
109:17; 152:14; 166:20 72:6,9, 25;73:5,7, 11,11,22, 23; 157:2,2,5,10, 18;
always 26:8; 28:7; 47:21, analyses 97:14; 98:2, 25; 158:10, 19; 159:3,14, 16, anything 22:9; 63:3;
13,13,17,18,19, 20; 71:17,18; 77:3; 91:5; 95:9;
24; 55:25; 56:3; 89:5; 99:1; 147:14; 151:9; 174:9,12,12,14,21,22, 18,24, 24; 160:5,7,9, 10,
90:17; 112:10; 114:24; 154:4,5 24;75:6,8, 11, 11;76:3,4, 12, 12,13, 15, 16,17, 18, 106:25; 113:13; 127:3;
147:9, 14; 151:8; 153:11; analysis 74:13; 87:18; 20, 22; 161:6,8,14,17, 156:23; 158:22; 178:9
5,5,7,7,9,15, 18;77:1,
155:14; 168:12 B8:11, 24; 97:12; 106:8; 10,12,14,15, 16,18, 18; 21; 162:11,22; 163:1,12, anyway 104:14
am6:12; 10:2; 1I:1o; 145:3 ;148:11; 151:2; 78:6, 9;79:19; 80:5,8,13, 17,20, 22; 164:6, 18; anywhere 139:1 I;
33:19; 34:7; 44:14 ;46:19; 166:23 17,25 ;81:6,11,11,13, 165:1,5,7,15, 15; 166:10, 162:17
50:20, 22; 51:23; 52:7,7, 22, 22; 167:9, 11; 168:1,
analytical 99:9 18,21 ;82:1 ,3,4,13,18, aphthous 16:13
23, 25; 56:3; 57:17; 58:17; anastomotic 19:9 18,19, 19;83:3,9,10, 24; 11, 19; 169:6,17, 18; apparent 34:14
61:1o; 67:14; 68:9; 75:5,6; 84:2,18,18, 19;85:7,8, 170:7,11, 14; 171:8,9;
anatomically 28:21 lppeal 33:19
80:23, 24; 81:9; 82:17; ~14,18,22,24, 25; 86:3,6,172:1,3,13,14, 19; 173:5,
86:3; 90:24 ;91:19; 94:15; ANCA 13:4 9,13,13, 16,19,20,21,6, 17,24; 174:1,1,4,5,6, ippealing 67:14
95:21 ;99:12; 100:12; md 4:3,9, 11, 14; 5:5, 15, 25;87:3, 12,15,21,21; 17, 20; 176:15, 17,20,21, Ippear 12:9; 13:6; 88:13,
109:23; 113:21; 118:23; 19,23,25 ;6:1,3,5,8,10, 88:2,4,8, 14, 21;89:10, 24; 177:11,18,21, 22; 13
123:5; 127:3; 128:25; 12,13,13,14, 19,19,20, 20;90:6, 10, 13,20,21, 178:3,4,9,14, 18,23; Appearance 4:10, 15;
129:2, 5,25; 133:8, 10; Z3; 7:8, 10, 12,20; 8:1,6, 23, 24;92:1, 2,4,6,8,14, 179:7, 11,11,11,21,23, .6:3
12,16, 20;9:5,6, 14,15, 16,19,20, 23
139:13; 140:12, 19; 21;93:2, 5,7, Ippeared 125:3
142:23; 143:9; 144:2, 5; 16, 18, 19; 10:2,11, 12, 13,17,19,23, 24;94:4, Anderson 98:3 I Ippears 28:20
146:3; 148:3; 150:9; 14,18,18,19,20,22,22, ‘11,15,22,25 ;95:2;96:1, anecdotal 146:8
154:12 ;157:12; 158:1,4; ~s; 11:44,8,9, 17,22,23, Ipplaud 131:15; 136:24
2)7,9; 97:11, 13,15, 16, Anemia 14:17; 29:23;
.—.=
_-— 159:3; 164:9; 166:13; ?5; 12:3,4,4,9, 10, 13, 16, 17,18,20,21 ;98:1,4,9,40:14 applicable 41:24 ;42:lo;
171:21; 172:6; 178:7 20,23; 13:1,8, 13,16,21;13,14,16, 17, 20;99:5,7,ngiogram 66:17 31:1; 151:3
ameliorate 23:6 14:1,4,8,13 ;15:4,7,11,14, 15; 100:10, 14,19; Implication 95:21;
ameliorated 27:3
12,13,14, 18,20,25; 101:2,7,10,18, 23;102:9,ankylosing 14:7 31:25; 141:17; 163:10,
16:5,7, 10,20,22, 24; 13,13; 103:2,5, 11;104:6,announcement 4:7 :2;174:25; 175:1
American 37:1 1; 41:5,8; 17:1,4,9, 15, 18,21; 18:1,6,13,16,21,
60:12; 96:15; 130:23
24;105:9, anomalies 158:5 applications 135:2
7,9, 11,13, 18,19; 19:10, 11, 15,22, 22,25; 106:21,Another 19:5; 30:19, 19; pplied 106:20; 133:7;
among 30:8; 96:15 22,22 ;20:10, 11, 11, 16, ” I 22,24; 107:15, 18)24; 43:21; 47:5; 48:22; 51:10; 66:13
Miller Reporting Company, Inc. Min-U-Script@
(3) allow - afmlicd
Hearing Volume Number 2 Food & Drug Administration
May 29, 1$)$)8 Gastrointestinal Drugs Advisory Committee

_SpplieS 130:17; 137:18; 90:15 ;91:13,21;93:16; argument 169:15, 16 152:3,4; 153:10, 20; 9,13,23, 25; 100:16,19,
157:8; 161:19; 166:23 95:4,6,8,9,10, 15; 96:4, arm 104:8; 108:8; 119:5; 157:5; 158:14; 160:25; 23; 104:23, 25; 105:12, 13,
~-~iy 110:2,6; 140:11; 8,9, 20; 97:2,14,16,17, 120:8,9 161:23; 162:1 1; 166:3,9; 14, 16; 108:15, 23; 109:7;
,24 19,20,21,21,22,24, 25; 168:5,6,6, 11; 169:21,21; 112:2; 113:25; 114:6;
arms 119:5
appreciate 39:4 98:1, 18;99:5,8, 10,16, 170:23; 173:17; 174:12; 118:20; 119:6, 10,12, 18;
around 33:2, 12; 86:13;
18, 20; 100:9, 13; 101:6, 175:12,24 ;176:21; 121:17, 18; 122:2,12,13,
approach 33:9; 44: 19; 87:22; 88:19; 94:12; 96:5;
18; 102:9,10, 16; 103:3, 177:18; 178:6,11, 17, 19, 23; 123:7, 14; 124:10;
64:2; 86:24; 118:25; 110:24; 127:25; 136:7;
16; 104:2,3,19, 23; 105:8; 20,21 125:3,8,12,15, 24;
137:1; 139:22; 141:2 138:15; 154:14; 156:9;
106:22; 107:11, 17, 23; Asher 46:7 126:20, 21; 128:13; 130:4,
appropriate 10:3; 80:20; 173:14 20,25; 131:14,21; 132:18;
108:1,2,3,4,6,7,8,16,
87:2, 10; 107:11; 114:15, arrangement 5:22 ashore 82:3
17,19,21,23, 24; 109:4, 136:23; 137:24; 138:3,17,
22; 129:1; 134:13; 135:5; arthritides 14:5 aside 108:3; 134:21; 19; 140:16, 18; 141:3;
6,12,14,18,21, 25;
143:11; 146:19; 160:25; 165:17 142:8; 143:1; 144:1, 11;
110:1,5,21,22, 23; arthritis 14:4, 6; 29:19;
175:5 ask 5:7; 10:2; 28:7; 33:12; 145:5; 146:14; 147:10, 20;
111:13; 112:12, 14;114:4, 34:8,12, 24; 35:16; 37:8;
appropriately 12:21; 72:2; 106:17; 111:18; 149:12, 16,23; 150:1;
5,7; 115:7,9; 116:5,8,11, 38:10, 21; 39:9; 40:2; 61:5;
36:13; 155:1 130:1; 136:16; 145:9; 151:4, 8; 152:16, 20;
12,13,22,25 ;117:1,5, 81:8; 82:16; 92:4; 163:3;
approval 19:7, 23; 20:3, 155:18; 168:17; 170:6 156:5, 8; 157:16; 158:23;
14,16, 19,24, 25; 118:3, 168:7; 171:12; 172:1, 19
17; 58:2,4; 102:18; 113:6; asked 9:12; 38:17; 86:12, 160:7; 161:6,7,8, 13;
7,12,15,16, 17; 119:3,8, arthropathies 14:9
124:6; 128:20; 132:21,22, 163:1, 9; 164:4; 166:12;
10, 16;120:1,10, 11,11, 16, 17; 109:24; 112:17;
article 45:10; 50:15; 168:6,15,20,22, 23;
22,23, 23; 141:9,13, 23; 20,23,24; 121:1,11,12, 120:10 ; 132:11,21;
142:5; 165:22; 167:24; 175:3 169:17; 17021; 171:19,
12,13, 14; 122:4,19, 22; 150:25; 155:12; 159:23;
179:9 artificial 129:5 20; 172:8, 10; 173:13, 14;
123:4, 11,11, 18,24; 165:15; 167:12, 17;
175:1; 176:11, 13; 177:21,
approve 11:1 1; 85:22; 124:12; 125:10, 16,18,20, as 6:14,25; 7:6, 15, 20; 175:23
22; 178:14; 179:3
165:19 20, 23; 126:2,6,12,13, 9:1,8,18, 19; 10:15; 11:4, asking 23:22; 38: 16;
11,17, 23; 12:9,13, 24; attached 122:2o
approved 70:8; 113:5, 15,16,17,17,19, 23; 71:24; 72:17; 73:10, 25;
20; 114:8,18, 19; 130:16; 127:16,21,21,22,23,24; 13:3, 16,24; 14:2,4,7,8, attachment 122:22
145:8; 157:23; 162:21;
131:15; 132:8; 133:23 128:12 ;129:3, 11,15,21, 10,20,22, 25; 15:16, 20; 163:12, 24; 176:6 attainable 67:21; 68:1
approving 115:3 24; 130:2; 131:11; 132:2, 16:4, 13; 17:2,2,4,4,9, attained 107:20
aspect 35:8; 86:16
5, 11,25; 133:3,6; 134:18; 13, 15; 18:16; 19:2,8,12, attempt 33:20; 64:8,10
approximately 4:3; aspects 9:4, 23; 20:8, 8;
135:1,18,23, 24; 136:8, 15, 16, 17; 20:8,8,15,15,
10:17; 12:15; 171:6; 179:3 21:12 ;35:13;67:2; 68:18; attempted 64:1
17; 137:23; 138:8,15, 23; 16, 19;21:12, 24, 25;
ARAMIS 34:8; 41:4 22:24; 23:10,21, 23;24:1, 86:23; 160:2; 167:8 attempts 84:4; 122:12,
139:1, 1; 140:13; 142:20,
arbitrary 75:22; 77:17; 21; 143:1, 15; 144:2; 4,9, 12;25:6, 17, 18; 26:1, assess 42:14; 46:24 13
‘Z12, 15; 90:7; 97:16 145:4,7,12,22,22,23, 2, 15; 27:3,11,14,18,22, assessed 47:23 attention 33:6; 130:6
.5:4, 19; 6:4, 20; 7:6, 24; 146:1, 12,13, 13; 23; 28:6; 29:8,9, 24; assessing 21:10 attitude 111:14
11,11,13, 18, 19,23 ;9:8; 147:4,5,5,15, 16,22, 25; 31:16,18, 22; 32:9,14, 14; attractive 93: 19; 138:11
assessment 46:1; 49:12;
10:25; 11:16; 12:21; 13:3, 148:6, 14; 149:2,12,13, 34:13,21,24, 25;35:8; 136:1 AUC 103:21
16; 14:5,8, 14, 25; 15:10, 17,19,20,21, 25; 150:7, 36:16; 37:13; 38:16;
21,25; 16:5,12, 12,17;
assessments 10:11 audience 22:18; 46:5;
3,13,16, 16,18, 19; 39:21 ;40:3,3,23; 41:14;
17:3,8, 18; 18:1,3,5,6, 42:19; 43:17,21 ;44:3; assistance 38:8, 12; 87:25; 151:1
151:10,13,14,14,18, 19,
12,21 ;19:15; 21:19,21; 20,22; 152:1,5,11,13, 45:4,11, 18,21 ;46:9,19; 179:24 author 6:25
23:5,15, 22; 24:15, 18,20, 13, 16,17, 17,21,24; 48:21; 49:6,6,18,22, 24; associated 57:21; 108:2 availability 135:4
22, 24; 25:2,4,7,9,10,13, 153:4,10, 14,20,21,22, 50:6; 51:15; 53:4; 54:5; Association 41:5, 8; available 6:4; 13:1 1;
17,20, 22; 26:9; 27:2, 15, 23; 154:4,5,8,11, 13; 55:3; 56:16,23,24, 25; 58:12, 14;92:19 53:22; 74:9; 97:14; 99:9;
15, 16, 17, 25;28:13; 155:10, 12, 12; 156:2,4, 57:6,9,20, 25; 62:12, 20; 141:16; 142:3; 166:5;
assume 23:14; 125:22;
29:11,11, 12,21 ;30:12, 10,19, 21; 157:21,23, 24; 53:2, 20; 64:6, 10; 65:13; 173:23
139:19; 142:25
16,17,20, 23;31:5,6,23; 1583,5,16,23, 23; 56:5,9, 10, 22; 69:19; average 95:3; 103:18, 20
assuming 85:17; 100:8
32:25 ;33:2,3,3,4,7,7,7, 159:10,11,14,15, 22; 70:3; 72:19; 73:23 ;75:14,
assumption 28:8; 100:7 averaged 103:21
8, 17;34:2, 11,15, 17,22; 160:1; 161:6; 162:7,8,21, 19; 76:8, 8; 78:7, 13,15,
35:7,11,12,20, 24; 36:3, 24, 25; 163:2,5,9, 12,13, 15, 16,24,25 ;79:16;81:7, assumptions 89:4 avoid 159:16
25; 37:4; 38:10,15,16, 17; 17,18,20, 23; 164:6,7, 22, 22;83:1, 12;84:13, 14, at 4:10, 16; 5:25; 7:13; avoiding 97:15
39:1,6,7,15 ;40:1,4,13, 21; 165:8; 166:9,10,11, 14; 85:4; 86:18; 88:15, 20; B:23;9:I, 13,22; 11:11; aware 5:4; 7:6; 16:18
16, 18;41:22, 22;42:3, 10; 12,18, 23; 167:1; 168:24; 90:18, 19;91:2, 13;92:3, 13:5, 10; 15:24; 16:14; away 35:22 ;41:8; 58:21;
44:8; 46:3, 12; 48:23; 169:18, 20; 170:17, 23; 10, 11;93:6, 17,19,22, 17:17; 18:15; 19:9, 12; 61:22, 24;90:2, 15; 114:6
49:10; 51:21 ;53:13,14; 171:5,5,8, 9; 173:4,6,15, 25;94:5,24;95:1, 1, 11; 21:5,19, 20; 22:11 ;23:22;
azathioprine 24:17;
54:2, 13;55:12; 57:7; 58:2, Z5; 174:7,15,17, 25; 3617, 25; 97:16; 101:22; 25:8; 31:7,8; 34:1; 36:15;
123:21, 25; 146:7; 168:5;
4,9, 23; 59:8,18,19, 24; 175:14; 176:1,1,6, 17; 102:2; 103:6,9, 15; 104:4; 37:23; 38:2; 39:8,11, 21; 170:7; 171:8
61:15, 20;62:13, 14, 25; 177:1, 19, 20; 178:11, 12; 106:13, 23; 107:20, 25; 40:25 ;41:19;42:8; 43:3,
63:5,9,17,17, 24;64:2,6, 179:6 108:1; 109:16; 111:3,9, 24;44:21; 45:2,7 ;46:2,
13,14, 14;65:11;66:8, 14; area 36:7; 46:24; 51:9, 14, 15; 112:5,6 ;114:19; 11,12, 16;47:25;48:13, B
68:23 ;69:5, 5,12,14, 17; 10;57:17; 72:10; 73:17, 115:14; 116:4; 118:1,6, 16, 19;49:3; 50:21; 55:4,
71:14,19, 24;72:3, 4, 13, 19; 103:15, 20; 104:23; 11; 119:2; 122:3, 4; 123:2, 20; 59:25; 60:1, 22; 64:5;
b 22:25;
49:9,
13,20;
17, 18, 25;73:3,3, 10, 11, 105:1; 137:18; 177:16 10, 25; 124:18, 19; 126:22; 65:1 ;66:13;67:21; 68:3;
63:10;
73:14,22;92:21;
~, 20,21, 25;74:7, 10; 127:10 ;128:4,9; 129:11, 69:25 ;70:4, 13, 18;72:9,
_= areas 7:8; 35:10; 36:7, 110:17
‘7, 9, 23;769, 11, 25; 25; 130:13; 131:1,2,2,12, 10;73:16, 16;74:4, 14, 20;
18;38:2; 61:13 ;110:12 B(268:13
.22, 25; 78:6; 79:16, 16; 23; 133:3; 134:4,4; 75:6, 22; 78:25; 79:9; 80:2;
80:13, 16;81 :5, 12;82:4, aren’t 34:14; 38:5; 87:25; 136:14; 138:7,7,10, 13; B12 14:21
81:25 ;83:22; 84:3, 5,16,
14,23,25 ;83:1,7,11; 97:16; 138:14; 150:20 139:16; 140:4,15, 15; 19; 85:3; 87:23; 88:7,8,9, back 9:21; 10:19; 36:8;
84:9,15,19,19, 25;85:4, arguably 54:22 141:13; 142:4,4; 143:8, 10;89:4, 7; 92:18 ;93:2, 47:6; 4&17; 61:24; 63:7;
4,5,8,17,20,21, 23; 87:2, argue 54:16;
55:2,
11; 16; 145:1, 20; 148:2,5, 23; 21;94:3,7; 95:22 ;96:1,2, 75:12; 80:3; 81:4; 82:21;
9; 88:7, 10; 89:5,9, 19; 68:25;115:17;
144:18 149:2:150:23:151:22: 20; 97:2,9, 18; 98:4,5,9, 86:7:87:14:100:24: ,

applies - back (4) Min-u-scripti Miller Reporting Company, Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,19$)8
126:18, 21; 144:14; 92:13,13,14,17,
18,25; 167:6; 169:10; 170:13; benefit 45:2; 77:15, 17; body 42:23; 65:22
150:25; 151:2; 153:17; 93:1,13,17;94:22;
95:1, 174:14; 175:24; 177:15; 91:21; 101:20; 102:1; body’s 12:3
.- 157:1;159:19;171:21; 3,13;
96:4, 10;
97:23; 178:7,15 107:24; 108:2,16, 17; bone 29:23; 110:23;
172:23; 174:11 98:7,
19; 99:17,
24;100:8,become 123:19; 129:10; 109:7; 111:18; 117:2; 111:1; 146:8; 157:6)9, 10;
background 9:10; 20;101:25;102:1,12,
14; 139:10 118:8, 10; 119:14, 20; 167:2
127:10; 165:9,13 103:1,1,15,15,
18; becomes 51:11, 12; 129:18; 132:1; 133:24;
104:25;105:15,
16,23; border 65:18
bad 44:24, 24; 156:10 121:16; 168:20 173:10,13,14, 15,17,18
107:12;108:12,
13;109:2; borderline 82:24
badly 58:14,15,16 benefits 108:4; 132:10;
110:20,25; 112:7, been 4:13, 19; 9:3,9,14,
111:8; 165:21 Boston 54:9; 154:13
balance 58:23 24,25;113:3,8,18,
19; 18,23,24, 24; 10:7, 16;
benefiting 97:25 both 12:8; 16:6; 20:16;
baldness 165:25 114:11,22,22;
115:6,17, 11;2, 12, 18; 16:22; 17:4,
29:8; 34:17; 37:21; 38: 13;
Barbara 9:21; 32:1; 18; 118:18; 14, 23; 18:24; 19:6, 15;
116:16,20; Berardi 10:14
43:14 ;90:20, 21; 109:1;
119:17;120:21;
121:6,12,20:21; 21:7; 22:8; 23:7, 7; best 54:16; 68:13; 70:23;
131:1,23; 138:13; 139:6 112:21 ;114:18; 118:18;
21;123:13;124:16; 26:8; 32:6; 33:5; 34:13, 20; ?9:8; 111:7; 114:3;
base 102:21; 133:5 119:5; 161:17; 178:14
Based 4:ll; 11:11; 19:4;
125:17,
19; 126:9,
16,25; 37:6, 22; 38: 12; 39:20; 138:23; 151:17; 173:16
bother 45:3; 119:1
127:5,8,9,9,12,17,21, 40:25 ;41:11;46:17,18, Oet 98:10
20:7, 9; 28:9, 13; 35:20; bottom 141:8;
147:3
44:18; 45:14; 58:3; 70:8;
22,23,
24;129:24;130:6, 25; 47:6; 49:18, 24; 54:11; better 12:5; 13:9; 17:19;
7,18;
132:3,9,14,
24; 64:1; 74:13,19; 77:24; bowel5:19; 6:3,11, 24;
71:22; 104:22; 106:6; 25:16; 29:11, 12; 36:20,
133:4; 13; 86:12; 93:25; 96:14;
134:2,3,4,5, Z5;43:I 1;44:10; 45:6;
3:5,7, 23; 10:1,9, 12;
124:6; 156:13; 157:13, 20;
135:2,
16;136:9,10,14; 98:11; 100:25; 104:12; 54:17; 55:1; 56:19; 59:20;
11:15,22; 13:7; 14:6; 15:6;
158:5,22; 164:19; 165:20; 137:3,4,6,
12;1381; 106:7; 112:10; 115:4, 24; 17:lq 18:9; 21:5,7 ;28:19;
173:11; 177:9; 179:1 $4:13, 24;65:1; 66:11;
139:13,17,23,
24;140:4, 117:13; 121:13; 122:8; 71:8,8,11 ;72:12;73 :1;
55:13 ;38:20; 40:15;
baseline 18:7; 47:25; B;141:5,
12,18,
19,20, 129:15, 18; 130:20; 131:2, il:12;46:21; 55:20;
L04:13, 14; 105:14; 108:4,
68:3; 88:2; 170:2; 173:21 22,23,24,25;142:2,5,7, 14, 22; 132:7; 144:8; 59:21 ;84:15; 93:8,9, 12;
~; 110:25; 112:22, 22;
baselines 94:11 3,13,22,25;144:3,6; 147:9; 150:10; 151:18; )4:20,24 ;95:5,6; 99:21,
[16:20; 118:9; 159:13;
bases 13:9 145:14,15;146:9,15,22, 153:11, 12; 157:16; 158:7; 12; 141:2; 163:3; 170:8
!60:14, 21, 22; 170:22
25;147:1,2,3,20;148:11, 159:7; 163: 16; 166:6; >OX 114:23
basic 33:14; 64:2; 152:25 )etween 8:11; 9:6; 10:20;
25;149:8,9,21,24,25; 168:2, 4; 170:14; 174:1;
basically 6:5; 44:7; .6:1o; 18:2, 11; 24:7; 26:4; 3radshaw 55:25; 129:23
151:19;152:15;153:3,6; 179:8,18
48:16 ;74:4;80:1; 114:19; 154:8,18,19,20,22,23; !7:10; 32:21; 39:5; 40.2; xain-wash 77:5
Before 6:7, 9; 7:9; 20:22;
135:2; 138:5; 139:12; 155:3,4,19;156:17; [2:18 ;43:14; 46:10; )reak 10:18; 86:12;
49:13; 66:7; 72:18; 75:15;
143:22; 150:4; 158:23 157:5,17;158:13,24; iO:17, 18; 52:24; 53:24; [00:18; 132:19
36:12;89:3;90:1; 101:17;
basis 9:4; 48:24; 51:14; 159:9,16,18,23;160:2, ;4:19; 58:13, 14;60:6; weakdown 150:1
_—_ 109:24; 119:3; 140:10, 23;
84:1, 2;92:25; 108:18; 12,17,18;162:1,6,14, ;6:22; 73:13; 80:24;
141:9; 144:9 3rian lo~ 54:10; 143:1
142:2, 10; 153:17; 156:6; 14,17;163:8,12,25; ]2:23; 83:18; 86:19; 88:2,
Degan 146:23 wief 10:2; 21:! 5; 22:1
165:4; 173:8 165:11;166:8;167:4,5, i, 14;90:5, 12;92:21;
Oegin 4:4; 17:17; 37:5; 12:19; 126:5; 133:22; >riefly 47:10
bathroom 55:21 18;169:13,19,23;170:4,
f;172:9,16;173:11,21; 104:13 ;124:11; 153:8 43:13; 154:18; 160:9 )ring 4:4; 33:20, 22; 47:4;
be 4:20, 23; 5:5, 14,23;
174:22,23,24;175:6,14, a;ginning 8:25; 40:25; leware 121:5 .06:10; 129:1; 130:5;
8:3; 10:20; 11:24; 12:25;
z5;176:1o,11,20,25; 96:2; 179:5 ~eyond 63:24; 70:8,9, .53:10; 155:21; 167:21
13:5,6,7; 14:1, 1, 18,20;
15:1,11, 13,25; 16:5,5, [77:4,
7,9,23;178:3,4,5, Oegun 12:9; 19:11 O;75:4; 79:15; 129:21 winging 78:10; 152:2;
11;179:10,14 ~ehalf 13:2 .60:21
11,13, 18; 18:5; 20:9, 23; ~ias 92:1; 117:19
21:19; 23:25; 24:23; 25:4, >ecame 130:14 ~ehave 124:19; 143:2; woad 7:15; 10:10 ;22:15;
lig 90:5, 12;92:2; 114:23;
25; 26:12, 18; 27:6, 9; >ecause7:4; 8:21; 17:5; 144:19; 145:9 36:25; 175:16 !3:3; 25:24; 40:8; 135:12;
28:9, 20; 29:2,3,10,15, ?0:6;21:1;22:18; 23:15; 50:5; 165:25
]ehaving 87:20 lill 47:10; 177:3
18,19,22, 24; 30:2, 9; ;5:14,17;26:13,25; ~roadened 179:19
>ehavior 143:5 liologic 8:20; 54:20;
31:14 ;32:6,19,20; 33:14; 18:18;32:18, 25;34:13; ~roader 33:20; 166:16
>ehind 160:20 15:4,5,6; 60:19; 78:2;
34:5; 35:4, 14, 24; 37:10, }5:11;38:5,22;39:9; 41:4, ]roadly 149:24; 156:1
leing 10:24; 22:9; 25:24; 11:22;154:19, 25; 167:22
10,13, 13,15, 18,25; ~;42:6,9;44:8, 11;51:24;
Z9:12, 14, 14;35:21; 39:7; tioiogical 99:18; 152:22; ~roke 41:20
38:1; 39:10,16, 17; 40:13, j3:21;54:5;55:9; 56:5, 11,
17;41:13, 18, 23;42:12; [9;58:24;59:8; 60:10; ;6:3, 17; 67:22; 82:7; 98:7, 55:15, 16; 157:19; 167:5, wought 19:6; 54:14;
43:24 ;44:10, 12,16, 16; ;2:3;63:16;68:1, 5;73:7; 13;104:22; 106:23; 108:9, .33:2; 179:12
45:7; 46:16, 24; 47:2, 17, 76:24;78:4;80:15, 24; [2;111:21,25; 112:1,7; tiologicals 65:21 lruce 54:9
23;49:5, 15, 15; 50:1,4,5, 11:16;82:4, 10,17,22, 25; L19:8; 120:1, 11; 124:7; lioiogics 6:10; 8:11; mdesonide 105:13
6;51:15; 52:2,5,14,20; $3:4;87:14,15;89:4; 90:4, 129:3,4, 11; 132:4; 137:1; 31:16; 163:15 ~uffer 156:8
56:10,11,12,14, 17; !1;91:12,19;93:3; 94:17, [55:12; 173:20; 177:6
liopsy 51:9 wild 37:5
57:20, 25; 58:11, 14; ~8;95:11;96:17; 97:6; 3elgium 9:14
lit
37:4;88:21;
115:13; luilding 4:25; 136:1
59:11,12,22, 25;60:10, 18:23;100:7; 101:3; >elievable 153:5
15;61:1, 13;62:1,6,23;
38:3,24;157:2;
160:19; luilt 78:7, 13
[02:10;103:2; 104:7; >elieve 54:15; 79:18; 74:13;175:15
63:10, 23; 64:2o; 66:17, .06:20,25;108:24; 106:3; 115:23; 132:11; wmping 107:19
19, 23; 68:24; 69:14, 15, I1O:21,25; 112:4; 114:5; tlack114:23;
154:1,2
L50:7; 151:1,14, 19; lut 6:25; 7:19; 12:16, 21;
23, 25;71:16;72:12, 14; [15:9;116:8; 117:7; danket 136:12
[52:10; 177:16 3:5; 15:13 ;1612; 18:16;
73:2,4,5, 10;74:20, 25; .18:8;119:7; 123:11; Ileed59:19 9:16; 20:18 ;21:5,11,22,
]elieved 102:21
.-. 75:9; 76:17; 77:10,13,16, .25:8,23;129:7, 10; Ileeding 13:20; 14:20; !4; 22:11; 23:9; 25:8; 26:9;
16, 19; 78:4,12, 13,17, .3620;137:2; 138:5; >elow 18:18; 27:14;
65:10 !7:3, 15; 28:10, 25; 29:21;
20,22, 22; 79:12, 14; 80:6, 140:2;142:3; 143:4, 6; 31:19; 32:11 ;49:19; 87:5;
>Iinded 64:8 31:8,10,19, 20; 33:5;
7, 15;81:18, 22;82:19, 22, 146:14,23;147:1, 25; 95:8, 8; 96: 18; 105:8;
]Iip 70:4 }4:15; 35:6, 15;36:10;
23,24 ;83:1,16;84:1,2,4, 148:1,11,25;150:8; 110:17,17, 18, 20; 119:8;
$7:23; 38:6, 20; 40:6; 42:7,
17; 85:18; 86:7,8, 17; 153:20;155:4, 22;156:2, 122:9,12,13 )Iood 31:5
[1; 44:19, 22; 45:7; 47:14,
88:16, 23; 89:9, 12, 23; 4.16;158:6.10.11.15. bend 88:16 )Ioody 93:8,9; 94:24 ?2;48:12; 50:19 ;51:1,8,
90:10, 23;91:11, 23; 16, 24; 159:1, 3; 15; 166:3; beneficial 22:22 due 39:25 [4; 52:8,11,13,18. 25;

Miller Reporting Company, Inc. Min-U-Script@ (5) background - Bnt
-Hearing Volume Number 2
Food & Drug Administration
May 29,1998 Gastrointestinal Drugs Advisory Committee
53:15, 17; 54:12, 15; 55:( C-reaCtiVe 14:24 carried 78: 12; 150:21 136:17; 142:14, 23; circumstance 115:6
56:2, 12, 15,18, 25; 57:1!
calculatable 96:7 carry 13:4 152:11; 160:5, 11; 163:1
__#%~, 11, 18; 60:7; 61 ;12, circumstances 76:20;
calculate 91:14 carrying 56:13 certainty 52: 17; 95:4; 114:24; 131:6; 133:20
;2:16, 19, 21;63:6,9,
LL;64:5,13; 65:5,22; calculations 94:1 case 76:21; 86:14; 93:2( 153:23
Claim 38:25; 45:17, 25;
67:20; 68:9, 15; 69:12,15 call 4:2; 25:9; 26:4; 51:5 108:3,7; 131:11; 139:16; cetera 26:23; 27: 1; 28:2 51:4; 61:6,6; 62:3,7
20; 70:10, 13; 71:6, 18; 58:8,10, 21; 59:6; 67:23; 140:5; 151:22; 152:21; 93:12; 135:16; 141:22; claims 22:21; 61:7, 12;
72:4,7, 13; 73:20, 25; 94:13; 105:21, 22; 135:7, 155:1; 158:21; 162:13; 179:2
62:2; 134:16
74:7; 75:10, 19; 78:4; 79:! 19; 172:20 167:5 chair 130:23 Clamp 129:23
11;80:3, 11,20; 81:18,2( called 6:22; 7:9; 26: 10; case-by-case 142:2 Chairman 8:25 clamped 99:25
82:12,20,24, 25;83:5, 14 28:19; 34:8; 37:7; 55:18 Cases 97:21; 162:1 challenge 169:19 clarification 20:19;
25;85:3,9, 10, 12,23; calling 79:13 cast 120:14 change 31:8; 32:10; 41:- 80:24; 134:16
86:5, 15; 89:12; 90:7,13,
calls 123:18; 161:5 catch 47:1 44:20; 46:21; 68:14; 78:3
18,24 ;92:8;93:21; 95:1, clarify 50:22; 145:7
Came 37:1 1;75:16; categories 22: 16; 23:3; 5;87:4, 12, 18;88:11, 24;
9; 96:13; 97:1,7; 98:8,12, clarity 45:12; 57:4; 67:12
98:14; 122:14; 124:5; 25:25; 49:17; 51:15; 89:8,15,15, 20,21 ;92:11
22; 99:9,11, 20; 102:2; classic 163:4
166:5 62:11; 63:20; 75:9; 150:3 20; 93: 10; 94:7; 96:6,7,
103:17, 19; 104:3, 10,23; classical 15:12
can 7:23, 24; 10:21; categorizing 52:5 25;97:5; 98:21 ;111:17;
105:5, 14; 108:2, 14;
11:19; 13:22; 14:2, 5; 138:21 classification 9:7; 11:23;
110:4; 112:2; 114:16; Category 25:24; 26:2;
15:11, 25; 19:10; 23:25; changed 90:6, 6; 104:20 12:5; 13:11
115:18 ;117:1,3; 119:4,5, 30:13, 15; 50:9; 62:9;
17; 121:5,20; 122:1,2,19 26:19; 27:5; 28:1, 21,22; 63:21; 105:19; 112:4 changes 9:20; 19:10; classified 74:9
21; 123:12,20; 124:9; 31:5; 32:6; 34:15,21; 35:6 35:24; 39:18; 93:4; 95:10; classify 11:19; 13:10;
Catholic 9:13
126:2; 127:7,20, 25; 36:13, 17; 37:5; 38:5; 99:18; 165:12 62:11,20
caucus 113:18
129:1, 19,22; 130:1, 12, }9:21; 40:13, 17; 42:2, 12; changing 16:5; 100:6 classifying 11:14
f3:l,4,24; 44:17; 45:5; saught 158:11
16; 131:19; 132:22; 134:8, sharacter 87:16 Clear 22:5; 45:8; 55:19;
135:11, 17; 136:17; 137:8, i6:16; 49:5, 19; 50:1, 25; :ause 92:16, 16
characteristics 36:21; 57:5
14, 18, 24; 138:4, 5; 139:7 $1:9, 13; 52:1,4,16; :auses 57:18 55:2;73:12; 87:20; 89:3; clearance 15:3
15, 23; 140:22; 141:24; ;3:16; 55:5; 56:14; 57:8; :ausing 21:21; 100:5 173:21
142:20,21; 143:16; 144:5, j9:22; 61:6; 62:I9; 63:23; Clearly 32:5; 57:24;
:autions 172:25; 178:12
characterized 54:25; 59:19; 99:10; 114:17;
5,14,20; 145:20,21; ;4:14; 68:1; 69:13; 72:24;
2BAI 64:9; 66:11 12:13 154:25; 178:13
146:24; 147:10,12, 16; ‘6:17 ;79:18; 81:17;
2BER 179:22 :harge 100:22 clinical 6:2; 9:4,9, 19;
148:8, 20; 149:2,11, 13, 12:19,19,22, 24; 83:7, 9;
!5:2, 15, 17;86:17; 91:1, 2CFA 127:15;138:18; :heck 153:10 10:8, 10; 13:8; 15:13; 16:6,
_ 19; 150:4, 19; 151:2,9;
i, 5; 97:17; 98:17; 99:14; 40:18;142:12 :hecking 151:15 11; 17:1, 17;18:21; 19:5,
.11, 13,23 ;154:4;
~>>:18; 156:12; 157:23; 01:19; 102:18; I1O:1O; X)AI 18:17; 39:24; :hest 58:8
27:13; 11, 11,21,25 ;20:7,9, 16;
12:21,23; 113:12,13, 19; io:ll,
13,22;42:7;45:14; Chicago 9:22 27:2; 32:12, 21; 35:6; 37:8,
159:10, 12; 160:1,5,6;
15:22; 117:18; 119:15; i7:6,
9,15;48:13,19; 11, 14; 42:18, 23;43:6, 15;
162:8; 163:5, 13,24; child 126:15; 135:16;
164:10, 21; 166:5; 168:14; 23:13,21; 124:17; 9:11,18;53:25,25;54:5, 5:2,20, 24; 46:11; 47;7;
138:1; 139:7; 142:22;
169:16; 170:16; 171:6, 11, 26:19; 127:3, 15; 128:12; 4,18;55:1,3,24;56:4, 7:16,22, 24;64:5:6;
144:3; 155:3
30:21; 131:1,7, 15; 8;59:7;65:19,20;66:3, 1:24, 25; 76:2; 90:18;
23,25; 172:5,23; 173:4; child’s 125:16
174:2,7,13, 16,20; 175:3, 33:4; 134:16; 135:16, 19, ,22;67:19;86:13;87:17; 5:15; 98:21 ;101:2;
23; 136:2,6, 10; 137:12, 8:2,3,13;89:8,11;91:3; children 13:24; 124:19, 05:9; 106:4, 8,9; 109:7;
5, 24; 176:10; 178:17;
179:10 14; 138:1; 139:13; 142:9, ‘3:17;
94:5;
95:21,22; 23; 125:1,5, 11,13; 126:1, 15:13; 116:4,8; 118:7,
13, 18; 144:7, 14; 147:24; 96:13,17;98:13;99:20, 25; 127:1,8,13,16, 24; ~; 119:14,19, 21; 123:3;
buttoning 35:23 128:1,5,7, 11,13, 15, 18;
150:25; 154:4; 157:22, 24; 23;111:17;117:7;129:17 24:8; 128:23; 129:13;
buyer 121:5 130:16,25; 131:2, 11; 30:24; 133:16, 25; 143:4;
159:21; 160:11, 17; cDAls 129:8
by4:12,14,21,24 ;6:12; 170:12; 171:18; 174:5; 132:2, 25; 133:7, 7; 47:6; 149:16, 23; 155:23;
9:2; 10:20; 12:12,12,13, CDER 10:15; 179:22 136:17,21, 25; 137:13, 19; 54:5; 168:8; 169:14
176:1, 13; 178:9
15; 13:21; 15:7; 17:14; Celgene 75:5 138:14; 139:18, 19; 140:1,
can’t 11:3; 19:1; 39:14; Iinically 55:10; 89:10;
18:12,21 ;20:22;21:11; cells 31:4 8, 11,21; 146:5 ;151:3,24; 1:25; 92:5; 94:15; 98:19;
40:13; 44:11; 45:3; 58:24;
22:4,9, 11;24:16,21; Center 4:14; 8:11, 12,14 154:24; 155:6, 10; 156:6; ):7, 18, 24; 171:1
73:7; 78:9; 91:14, 22;
25:6; 27:13; 36:25, 25; 157:4; 158:16; 159:13, 17,
121:23; 122:18; 123:5, 17, centers 60:12; 137:10; Iinician 93:6
44:21 ;49:19; 50:2; 54:14; 25; 171:5,20; 172:12;
20; 129:7; 137:2; 144:20; 138:24; 139:4,12 Iinicians 95:15; 120:4;
56:3; 57:20; 63:3, 15; 67:8, 175:25; 176:2
153:18; 159:6,7, 18; 174:5 :entimeter 46:23 i3:23
10, 13;68:7;73:1, 10; choice 114:24; 174:3
76:1 1;78:2; 80:6; 82:6, 13; ~anada 162:8, 10 centimeters 47:2,3 ock 157:1
choose 50:2; 120:23
86:17,20 ;91:10;93:25; :ancer 31:4; 52:12; ~entocor 13:2; 49:24; OSe 37:2; 47:13; 55:23;
j7:21; 58:6, 12, 13; 59:1; ;2:8; 70:17; 88:1; 98:4; chose 76:1, 23; 77;4;
94:19; 96:23; 99:23; L:21
100:20; 106:5,13,14, 16; [65:19; 178:23 L40:16 102:4; 110:19
osed 47:22; 48:2, 5;
108:4, 25; 114:16; 115:20; :andidates 150:18 :antral 14:6 chosen 112:20
k25,25;62:18
124:12, 15; 129:4; 131:10; :annOt 29:10; 57:20; :ertain 12:15; 58:2; Christine 31:1; 123:10
oser 70:14
133:4; 136:15; 138:18; .34:6 ;5:11; 67:23; 70:24; 73:1; ‘ chronic 20:25; 23:7; osing 62:3
147:17; 148:7,20, 20; 13:11; 86:7; 96:6; 118:16; 32:6; 35:1, 15; 65:6; 76:15;
:apable 32:19
~O:14; 157:19; 161:22, 80:21 ;82:12;83:23; 84:1, osure 30:10 ;48:20, 25;
-- ;apetOWn 129:24 .19:8; 127:21; 131:6;
164:17; 175:14 !:24; 63:1
50:3; 155:19; 163:5; 2,5,20; 101:17; 119:19;
:aptured 160:13 161:2; 162:25; 163:6,18, CiUeS 126:12
65:23; 167:1, 8; 177:10,
c :are 51:24 ;79:3;93:1o,
1;95:25; 96:4; 113:16;
1
:ertainly 6:3; 23:9; 27:5;
20; 175:13
chronically 35:2; 43:25;
clustered 94:12
clustering 97:22
14:19,21 ;119:13; 143:6
2:12;81:13,21 ;112:22, 85:5; 101:20; 164:20 co-complication 14:21
C 23:1; 27:24; 31:8; ares 56:6,6
2; 114:3; 128:1; 130:17; chronicity 21:1; 81:6 so-morbid 148:6,20,24
110:18 Carl %6:8 32:15; 134:21; 135:6; I circulatory 145:16 coefficient 67:6,7
buttoning - coefficient (6) Mifi-U-Scrip@ Miller Re~ortin~ Comoanv. Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1!)98

cognizant 16:5 commonness 175:11 152:7; 158:25; 163:11 consultants 127:1 1; 89:21 ;90:10;92:16,16;
Colitis
6:23;
12:9;
14:13; community 81:6, 8; 82:4; concerned 32:13; 67:14; 129:16; 179:16 96:1,4,10, 17;99:21;
-_ 15:15,1657
:1;79:20; 86:3, 4; 134:24; 136:6; 68:10; 97:22; 99:10, 12; consultative 6:1 101:24; 115:17; 131:16;
124:24 160:11, 17; 168:21; 172:1, 100:13; 110:21; 123:8; consume 28:17 136:16; 139:5; 141:10, 18,
collaboration 143:12 13; 177:24 129:2; 142:22, 24; 168:7 22; 154:17; 155:9, 10;
context 119:23; 130:11
companies 4:20; 30: 16; concerns 174:19 157:1; 170:6; 171:21;
collaborative 139:3; continual 103:4
38:24; 135:12; 174:21; 175:9
142:15 conclude 131:17; 161:1 continue 21:12 ;24:23; couldn’t 105:23; 140:3
COi[apSing 99:25 175:12 concludes 5:11; 134:17 27:1,3; 55:13 ;81:19, 19;
company 30:19, 19, 20; count 37:18; 48:1; 94:20
colleague 57:6 concluding 172:22 94:2
32:9; 74:25; 75:2; 174:24 counterpart 8:13
collecting 149:9 conclusion 56:16; 141:3; continued 24:10, 12, 19;
comparative 104:21; 145:4 counting 94:19
collection 135:7 26:6; 43:9; 49:1; 179:24
135:15 countries 111:3
collectively 36:4 concomitant 145:14, 15; continuing 26:6; 106:15
comparator 168:11, 12, COUntS 92:13
College 37:11 148:l,i; 178:2,4 continuous 54:1,6;
18; 169:20; 170:3 couple 27:9; 34:6; 106:6;
collegia[ 90:23 concordance 121:1; 87:13; 88:25; 93:18, 19;
compare 19:1; 40:12, 18; 159:22; 172:25
169:1 94:5; 97:10, 15, 19; 100:15
colon 59:24 169:6, 14; 171:18
CorlCUr 8:15; 38:12 continuously 42:12 course 19:11 ;33:22;
Coior 39:25; 59:14; 160:6 compared 98:14; 35:4; 42:12; 76:16; 85:13;
concurrence 150:10 continuum 103:3
colostomies 129:7 168:11; 169:12; 170:5; 87:9; 103:17; 107:25;
173:12 concurrent 136:25; contribution 135:8 125:21,25 ;133:25;
combination 55:7
137:8; 167:14; 168:2 control 52:21; 83:20; 134:11,12,17, 18,20,23,
combine 138:15 comparing 38:14; 40:14;
86:21; 168:15 condition 28:19 B5:5;86:20; 143:1,3,7; 25; 137:14; 155:14,20
come 6:11; 8:21; 10:19;
conditions 85:8; 148:1, 165:11; 173:3,5,6,8, 10, court 141:22
18:23; 19:19; 20:12; comparison 18:25;
43:21 ;86:18; 151:5; 20; 161:4; 166:7; 173:3 12, 19; 174:3,8 Covariance 87:19; 88:11,
21:24; 25:19; 34:19;
56:16; 62:9; 75:20; 79:9; 176:16 conducted 120:1 controlled 25:3; 109:19; 24
100:24; 103:13; 108:24; conducting 121:4 173:11 COX-2 157:11
Comparisons 87:2;
113:9; 122:18; 123:5; 147:17; 173:11,18 conference 33:5; 138:17 Controlling 52:22 create 29:7; 92:5; 155:10
141:21; 144:14; 179:5 compelled 168:10 confidence 164:13,25, Eontrols 53:5 created 92:14; 174:14
comes 12:11; 27:21; compete 69:1 25; 165:2; 173:14 sonundrum 77:9 creates 94:8
59:3; 68:13; 81:3, 13; confirm 131:1 conventional 113:7;
COmp!ete 10:19; 26:22, creative 138:3
82:20 ;91:6; 110:16; 115:4
22;27:12,16;29:11; Conflict 4:6,8, 16; 5:11 credit 6:10, 15
__—_ 152:12
30:10,10, 11; 32:13,18, confounder 120:19 conversation 152:6
comfort 36:19 crisis 120:7
20, 21; 42:5; 49:17,19,23, :onverse 28:12; 51:12
confounding 118:8, 13, criteria 11:19; 12:15;
comfortable 35:19; 25; 50:1,18, 23; 51:4, 5,5;
20; 119:7, 15; 121:3 zonvince 109:6 13:22; 18:21; 20:12;
95:10; 164:1; 176:24 58:9,10,21,22, 25; 59:2,
confronted 18:12; 89:9 :ooperate 136:19 44:19; 51:24; 56:8; 61:14;
coming 11:16; 26:5; 9, 20; 67:15, 20; 68:1, 10;
confused 80:24; 81:9; cooperation 137:12 56:13; 68:8; 73:2; 86:20;
61:24; 109:23; 131:14; 83:21; 101:9, 23; 102:8;
82:17; 174:18 :ope 82:25; 119:22 B9:14, 24; 107:9; 110:2,6;
137:22; 174:25 105:22,25
CO.tIfUSiTIg23:13; 30:5; 112:10,11, 12; 116:5;
comment 5:10; 8:3, 14; completed 76:3; 143:7; :opout 123:6
132:6
22:2; 25:21 ;33:24; 38:7; 150:2 72:4 20py 4:23
confusion 39:4; 174:14 criterion 27:13
40:21; 49:7; 53:23; 74:17; completely 8:16; 43:18; :ore 37:13,23
87:8; 89:25; 95:23; 96:11; congratulating 22:5 critical 12:2; 73:19
58:9,21, 23; 59:16; 60:2; Dornell 137:21
112:16; 115:23; 132:11; 96:8,9; 106:1; 112:1 connotes 31:4 criticisms 40:12
143:9, 20; 164:8; 171:3 :orollary 144:13
complex 166:23 consensus 37:5,20, 22; criticize 75:1
:Orrect 58:3
commentary 174:5 complicated 21:4 38:4; 40:9; 61:12; 65:25; ~riticized 17:5
commented 104:1 :orrectly 45:15
complication 13:8 92:5; 93:14 ;136:1; Crohn 82:3
comments 4:5; 7:21; 138:19 ;141:1; 170:16 sorrelate 9:10; 16:14, 19,
complications 12:12; Crohn’s 4:22; 5:20; 6:23;
8:16; 10:3, 5; 46:4; 50:11; ?0,21; 17:5; 55:24; 57:24
14:16; 165:7 consider 15:16; 21:11, B:4,18; 9:16, 17; 1J:7, 14,
68:1 1;78:16; 162:9; 16; 43:25; 44:2; 69:15; :orrelated 16:3; 46:12 22; 12:5,9; 13:13, 14;
component 14:3; 108:20
169:3; 179:11 86:8; 107:22; 11 1:25; :Orrelates 14:8; 16:10; 14:13, 16; 15:10, 14, 25;
components 17:3,3, 21; 17:20;18:16;43:5; 48:16;
committee 4:12, 19; 112:2; 117:13; 128:15; 16:17, 25; 17:2, 10, 11,24;
18:3, 10; 28:14 168:4; 176:15 54:25; 57:16 18:2,4,15,17;19:7,8;
9:24; 11:11 ;22:13,19;
28:18; 39:9; 53:18; 57:1; composite 20: 10; 29:2; considerable 20:2; correlation 18:13; 46:10; 21:8;
22:7; 25:5;28:8,11,
58:18, 19; 69:23; 76:8; 138:10 58:13; 60:6; 66:21; 67:4,5, 23;30:21;31:16; 32:1o,
65:22; 166:24; 179:5,10
80:20; 81:10; 85:24; 98:5, composites 17:16 7;87:21 15;38:18;40:2;49:3;
consideration 6:1;
10, 23; 100:16; 108:24; compound 8:20; 120:22 141:15 :orticosteroid 167:15; 52:10;56:24;57:1;58:16;
113:5; 119:18; 129:9, 16; compounds 12:23 170:4 76:2,9,17,23;78:21;
considerations 73:9;
132:18; 161:11; 167:17; :orticosteroids 42:22; 79:21;81:5;83:7,11;
conceivable 136:18 114:15 ;133:3
168:17; 179:17,20,25 f3:2; 60:22; 169:7,12 B4:17;101:1;108:25;
conceivably 146:22 considered 32:12; 113:1,4,7;114:12; 115:3;
committee’s 4:21; 130:5; :Ost 95:13
conceive 91:22; 121:23 47:17; 57:20; 66:1,7 118:24;122:19; 124:6,13;
132:22;
167:24
—*—. conceiving 37:3 consistency 99:3 >osts 108:2 125:5,11;126:5, 10;
committees 7:14; 98:22;
COnCept 11:16; 27:5; consistent 64:2; 155:5 >ould 4:20; 17:17; 20:9; 127:10,12, 16;128:1,7;
115:14
77:8; 92:4 Constitutional 28:13; Z3:18;30:18; 31:14,15, 131:3;144:17;146:17;
common 14:17,23, 25; 17;32:9; 34:16; 36:5;
conceptualizing 38:13 29;25 147:4;149:7,11, 11;
37:10; 54:15; 105:5; J9:1O;41:23; 47:23, 25; 154:2,12;161:12,15,18,
135:2; 154:22; 170:23; conceptually 34: 11; construct 41:13
[8:12, 13; 52:19; 55:2,2, 22;163:2,20;164:3;
178:19,20,24 54:3; 93:18 ;169:19 constructed 41:23 7;62:1, 5,9, 20; 69:1; 165:18;167:13, 18;175:1;
commonly 55:6; 167:18 concern 83:14, 17; consultant 9:12 70:18
;75:19;
78:19; 177:1;179:9
Miller Reporting Company, Inc. Min-U-Script@ {7) co~nizant - (%nhn’s
Hearing Volume Number 2 Food & Drug Administration
May 29, 1!3$)8 Gastrointestinal Drugs Advisory Committee

‘CrOSS-OVerS74:22 days 7:9; 75:17 degree 17:6; 20:2, 3; 34:10; 133:5; 175:12 159:11;
173:21,
22;177:2
cross-referenced 47:6 deal 6:1, 10;48:22; 91:1, 42:9; 52:17 development 5:19; 6:2; differential
147:18
— 2; 100:13; 117:8; 119:14,
‘~’ing 57:3 delay 165:22 7:7; 8:4, 18; 9:15,19, 25; differently 37:4; 77:6;
.mulative 35:8, 12 18; 143:23; 151:24; deliciously 77:1o 10:8; 11:8; 21:13; 26:17, 95:14, 16; 143:2; 144:20;
174:20 delta 94:5; 111:17 21;37:7,22; 38:11 ;83:3, 145:10; 159:18,20
curability 21:2
dealing 22:7; 54:2; 75:24 16; 101:3; 114:12; 131:5;
cure 67:2o demand 117:17 differs 50:14
84:19; 116:12; 118:15; 132:15,16; 134:11, 13;
cured 103:2 demonstrate 134:24; 137:21; 139:8; 148:5; difficult 32:15; 36:23;
152:1, 18; 154:8
curious 176:25 156:13 155:2, 4; 158:9, 13; 174:2( 43:18; 46:24; 104:17;
deals 143:24 122:17; 123:3; 127:17;
current 5:8; 15:17, 18; demonstrated 19:8; developmental 137:19;
dealt 95:13 BO:17;107:18 154:8; 163:21, 24; 169:25;
30:2; 68:22; 168:5 154:23; 156:17; 158:5;
death 36:10 demonstrating 17:12; 173:2, 24; 174:2,9
currently 132:18 159:6
decade 149:14 95:3; 126:24 difficulties 20:7; 40:22
curve 38:2; 72:10, 11; deviation 86:19; 93:22;
decades 23:8; 141:10 demonstration 60:16; 96:8 difficulty 51:23; 54:4
73:17, 19; 88:19; 94:8;
103:15, 21; 104:24; 105:1; decide 52:2; 88:10; 37:3 devil 133:21 digestive 28:19
122:24:135:22 departments 137:11,12
110:13 diagnosed 131:2 dilemma 78:1
130:20;
cut 40:22, 23; 59:3; 87:12; decided 92:4,6,9 depend 71:4; 76:6 dimensions 36:3,8,15
diagnosis 126:6
89:7; 90:4,8,9,14, 16, 21; decision 116:7,16 ~ependence 101:8 Diminished 15:1
diagnostic 11:25
95:8; 97:16; 160:19 decisionmaking 117:20 dependency 117:2 dialogue 159:22 directed 7:18; 34:7
cutoff 147:10 decisions 35:7; 65:25; iependent 25:10; 75:13; diarrhea 13:19; 23:6; iirection 61:11
cuts 103:5 66:8 [06:19, 23; 107:1,4; 28:22; 108:5 jirectly 96:6; 108:16;
cutting 91:9; 95:6 declared 39: 17; 106:23 [09:20; 110:5; 115:9, 11, 160:16; 161:1o
dichotomize 94:3
cyclooxygenase-2 declining 70:14 !2; 116:2; 119:4, 25;
dichotomous 93:18 ~isability 35:20; 36:10;
157:3,5 .20:11 ;121:9; 145:19,20
reconstruct 65:19 ;5:11
dependents 116:25 dictating 116:13
cyclosporine 79:11, 13, decrease 49:22; 64: 15; jisagree 67:25
18,20 ;114:16 Iepending 104:19; did 12:16; 20:8; 26:20, 21;
111:8 iisagrees 32:4
Cytokine 16:7; 29:23; 33:20; 143:10; 173:3 32:3; 33:24 ;43:11, 11;
decreasing 177:23 48:25 ;66:11; 73:16; iisappear 123:14
158:6, 11 Iepends 51 :9;60:17;
decrying 79:8 74:25; 85:23; 92:22; 93:3; Disappointment 20:25
cytokines 12:24; 158:9 ‘3:9; 108:1; 120:19;
~efending 50:21 >4:10; 100:24; 103:9;
25:15; 178:22 Iisaster 152:15
105:2; 114:21; 137:17;
.—. ~eferred 131:24; 141:18 Iescribe 22:24; 54:12; iiscern 120:24
D ~eferS 131:25 5:12
154:25; 155:8; 162:19;
179:8 discontinuation 27:22;
deficiency 14:19 leSetVe 158:17 02:1; 111:7
jidn’t 12:20;
42:7;
49:2;
damage 35:11,13, 17; iefinable 29:20 Ieserves 6:14 Discontinued 24:13;
$2:20; 65:16, 17;93:1;
92:15,16,16 iefine 13:13; 18:13; lesign24:17;25:l; }8:5, 23;103:12; 104:14; ‘9:20
Dan 57:9; 76:5; 115:22; }1:15, 17;36:2, 13;59:2; 17:11, 23,25; 121:5,23, 106:11, 18,25;110:8; Discontinuing 112:9
143:19 ;3:11, 18;64:8, 10;67:18; 4, 24; 124:1; 132:17; 131:20; 156:24, 24;159:1, Discordance 121:2
dangerous 155:19 ‘2:25 ;73:2O;87:1O, 12; 35:6; 137:13; 155:22; [,2,2
Discordant 120:20
data 22:10; 34:8; 41:12; )0:21, 22; 91:15; 106:18; 57:22 difference 24:7; 27:10;
09:16; 113:22; 115:12; Discouraging 153:7
46:2; 70:8; 96:13; 106:3; Iesigned 55:17; 72:14; )2:21; 50:17, 18; 53:24;
112:21; 124:6,22; 127:14; 22:5 78:18 J3:18;89:1O, 12, 13; Discovered 104:11
131:19,21,24 ;132:24; Iefined 13:4,7; 17:20; ‘esigning 38:14; 144:24 J2:20;98:18; 99:14; Discriminated 129:3
134:3, 19, 22; 135:5,6, 17; 9:25; 20:6, 9; 25:6; 29:24; 09:4; 131:7; 133:22; Discriminating 130:7
esigns 64:1
136:9, 20; 138:16; 139:17; ;0:6, 22; 49:18,21, 24; 34:24; 144:15; 152:24 Discrimination 129:11
140:4, 11,23; 141:10, 16, esirable 36:14; 52:20,
~O:l;64:5; 67:18, 23; 74:8; differences 24:24; 39:5;
1, 24; 101:10 Discriminatory 147:2
21; 142:3; 143:8, 25; ~6:10;111:6; 115:7; ;2:24;73:13; 98:19;
144:21; 145:1, 18; 148:23, 119:25, 25; 124:18; 128:4; Iesperate 8:19 iiscuss 5:18; 26:13;
138:22; 143:15; 147:25;
24, 25; 149:9; 152:10; 148:20 Iespite 107:18; 160:23; }6:17; 49:20; 62:25; 67:1;
151:19; 152:17; 169:18; ;8:12, 15; 124:4; 167:17;
153:4; 157:16; 165:23; ~efines 31:21 67:23 177:10
167:9, 23; 168:1; 169:17; L74:13
defining 19:3; 20:7; Ietaii 88:9 different 5:15, 21; 7:8;
173:24 22:12; 34:1 1; 40:23; 75:7; iiscussed 20:19; 21:6;
Ietails 49:10, 20; 133:21 12:11, 13;13:8, 15; 14:5;
database 41:14; 126:7; !3:19; 138:18;140:16;
16:20; 109:22; 115:4; IeteCt 75:4; 165:12 16:25; 18:3, 5,8; 23:14;
161:9, 15; 166:18 [66:4, 19
L70:13 leteCting 86:25; 89,20; 25:1; 26:14; 27:17, 18;
databases 135:25; Iiscusses 22:23
~efinite 162:4 77:10 }1:12,24; 33:13; 36:9,9;
165:20 iO:l, 16; 44:18; 47:7; 52:6, Discussing 35:1 1; 49:9;
lefinitely90:17 Determinant 21:4
date 11:13; 16:24; 19:19; 17; 54:7, 25; 59:13; 62:4; .21:21
~efinition 23:11; 27:18; Determinations 164:19
150:8 $4:12;65:8;69:25; 71:1; discussion 4:21; 5:23;
}2:9, 18;33:4; 41:1; 45:12, Ietermine 173:15
daughter 130:19 76:10;81:5;85:8; 87:23; ‘:19, 20; 10:13;13:17;
L3;63:15; 67:15 ;82:21;
David 8:25; 22:2; 49:7; 106:13,14, 16; 107:3;
Determined 4:13 38:6;94:1; 97:1; 98:11; !2:3; 29:4;31:25; 32:24;
_&6:15; 80:3; 170:19 .15:15,22; 121:9, 19; devastating 76:18,19 [07:8, 12, 23; 108:14; ~3:Z 23;34:4,6, 14; 39:4;
.46:12; 170:11 Ievelop 7:16; 8:1,3; 9:9; [09:5; 112:4; 113:9; [7:8; 54:12, 13;55:11, 13;
‘“vial’s57’:3
8:24; 126:5; 132:7; L16:17; 122:15; 123:4; ;9:15; 69:12; 107:16, 18;
~dy 71:8,9,11,12,13; Definitions 26:14; 27:17; 08:1; 124:12; 135:15;
78:19,25 [24:12; 126:12, 13;
72:1; 93:9,9; 95:1; 101:12, ;0:12; 33:13, 16; 52:3; 52:1; 164:14, 16;170:10;
[28:14; 130:2; 134:19,20,
24,25, 25; 102:3,3,4,22, ;7:6;66:6; 113:1o; 117:1; Ieveloped 7:9; 47:16; 77:15
!3; 137:2, 17; 139:18;
24; 103:11, 17, 18; 105:25; 28:4; 162:4 39:23; 178:11 .44:17; 145:17, 20; Discussions 5:1; 8:7;
111:10 ; 121:13,17,22; Infinitive 140:23; 154:6, evelopers 175:7 46:15, 24; 149:1; 150:3; 8:11; 39:8, 22; 133:12;
126:17 ‘; 176:1’6; 179:11 Wdopiflg 7:12; 17:23; 51:14; 154:23; 155:3; 64:1o; 179:19

cross-overs - discussions (8) M&U-Script@ Miller Reuortin~ Comnanv. Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1998
disease 4:22; 5:19, 20; distinguishing 117:6 138:20; 143:11; 158:12; DR4:3;5:14; 6:17; 8:8, 6,15,18, 20;128:3,9,12
6:3,11,23, 25;8:5, 18; distributed 96:5 159:3; 164:12 10, 12,13,15, 16,23, 25; 19,22,23,24, 25;129:14,
____ 9:5,8,16,17, 24; 10:1,9,
distribution 86: 19; doing 7:13; 31:z4; 55:16 9:3,3,8, 12; 10:6,6,14, 18,22;130:9,9, 10;
12; 11:7,9,15, 17, 22,22; 14; 11:17; 13:1; 19:8; 22:4
149:10 58:14, 15, 16;68:14; 132:19,20,21,24 ;133:1,
12:2,6,9, 12,12, 18; 13:7, 71:19; 90:3, 19; 108:7; 17; 23:2; 26:8,8, 10, 12;
disturbed 56:3 3,6,8,9,10,12,14,18
8,13, 14, 14; 14:3,6,13, 117:11, 16; 118:12;
disturbs 59:16
27:8; 28:4,4,6,17, 25; 20,22;134:1,4, 15;135:1,
16,18, 18; 15:10, 14, 25; 131:15; 139:2; 149:12; 29:15,18,21,25 ;30:1,1, 21;136:5, 12,16,23;
16:3,17; 17:1,2,4,9, 11, diversity 40:5, 10; 86:4 153:10; 172:2; 173:1 4, 16,22 ;31:1,2, 14,20, 137:7,10,16;138:9,9,10
12,21,24, 25; 18:2,3,5,8, divide 49:16 23; 32:2,5,23,23, 24;
dominant 35:22 17;139:3,6,14, 14,15;
10,15,16,18, 19,20; dividing 26:15; 51:14 33:24, 24; 34:1; 38:7,9,
dominating 35:16,17 140:6,9,9,14,22, 25;
19:3,7,8; 20:25; 21:5,7,
divorce 85:22 don’t 19:17; 23:8; 25:15, 15,17, 19; 39:7,23, 25; 141:7,11;142:1,11,12,
8,18,19, 22; 22:7, 25; 40:10,20,20, 21;41:2, 2,
DMARDS 172:3 16; 28:10,12, 17; 30:13; 20,23,25;143:16,16,19
23:4,9,15, 21; 24:2; 25:6, 3,7,9,25, 25;42:1, 16,16
do7:15; 13:1,10, 13; 31:9, 10; 32:4, 12; 40:1; 21,22;144:9,9,11, 13,
22, 23; 26:1,16, 19; 27:11; 17;43:20, 20,21 ;44:6, 13,
15:17; 16:1,14, 19,21; 44:13; 45:8; 46:2; 48:19; 16,22,23,23;145:6, 7;
28:2,8,11,11, 23; 30:3,8, 15,16, 25; 45:10; 46:4,6,
17:5, 24; 18:19 ;21:5, 10; 49:2; 50:23; 51:24; 52:9, 146:2,2,4,10,11,16,18,
13,21 ;31:7, 13,16, 17; 7,9; 47:18, 19, 20,21; 19,21;147:3,8;148:3,13,
22:2; 25:13,15, 16; 27:2; 10; 53:21, 22; 54:15; 55:6;
32:4,6,10, 16; 35:1, 17; 48:2,3,4,6,7,8,10,12, 21;149:6,10,12, 16,20,
57:16, 23; 59:6, 14; 65:5,
36:6; 38:18,18, 20; 40:3; 33:21; 34:1 1; 36:6; 37:4; 14, 15;49:7,8; 50:11,12,
40:18,19; 43:21,24;
21, 25; 67:1; 70:2; 71:7, 23;150:7,12,23,2s;
41:12, 19;42:4, 13;43:2; 14; 51:8,12, 18; 52:7;
44:11 ;45:3,6;46:3; 51:6,
17;78:18,21,23; 79:3; 151:12,25;152:2,6;
44:1,3, 17;45:19; 47:2; 54:8,8,9; 55:13, 14, 15;
24; 53:21; 55:6,17, 20;
82:2, 9; 83:3; 84:22,23, 153:1,9,11,18;154:10,
49:3, 16; 50:5, 19; 51:1,3, 56:13, 16,21,21, 22;
56:20; 59:2; 60:24; 63:4,
23; 86:14; 90:2,14, 19; 15,
17;155:11,21,25;
8,13, 19,20; 52:1,10, 11, 94:8, 15; 95:19; 97:7, 9; $7:11, 12; 58:2, 11, 18; 156:2,
12,21; 157:1, 12;
15, 22; 53:9; 56:2; 58:16, 17; 66:15, 24; 68:15; 69:2;
72:24 ;73:17, 18, 18;
100:17; 103:8; 105:2,4, 59:2,6, 10, 16; 60:4,4, 5, 158:1,3,4,19;159:5,10,
20;59:11, 18;61:21,23, 23; 106:25; 111:25; [5, 17,19, 20;61:1, 3,4,5, 21;
160:23; 161:16,17,20
25;62:12, 21, 22;63:12; 74:16 ;77:11;79:5; 82:3; 112:11, 14;113:21; zz,
25;162:7,7, 10, 15,
), 17, 18, 19, 20; 62:1,8,
64:11,13,20, 23;65:2,6, B7:8, 18, 19; 88:23; 89:14;
116:11; 117:12; 119:13, 16, 25; 63:9,15,22, 25; 19,21,
24;164:2,4,8, 17;
35:2; 96:24; 97:14, 17;
10; 67:20, 24; 68:2,5,5, 17; 122:21; 124:24; 125:2, ;4:16, 18, 19, 22, 23, 24; 166:2,
15,17, 19;167:11;
)8:20; 99:2,3,4, 11;
20,25 ;69:13;71:3; 73:4, 3,9; 126:1; 127:5,6, 17; ;5:2,4, 5,6, 12, 14, 15, 16, 168:9,17,18,19;169:3,3,
105:17;106:3,11,18;
6,7; 75:8, 10; 76:2,9,15,
110:15;112:11;113:9,12,
128:15; 130:4, 11; 137:5, 7,19; 66:9, 12, 18,21; [,8,
9,10, 15,23,24;
17,17,23, 23; 77:14; 78:3,
13;114:2;115:12;117:8,
13; 142:9, 23; 143:6, 11; i7:l, 3, 12, 12, 25; 68:4,7, L70:1,6,9,9,10,16,19,
21;79:3, 15,21 ;80:13, 14, 145:8; 148:10; 149:1, 18; ~,11,13, 17;69:l,3,4,5, ?1,25;
171:3,3,4, 13, 14,
[8;118:14,19,21,21;
17,22, 25;81:12;82:5, 12; 154:10; 155:23; 156:23; ‘,8,9, 10, 10,11,17, 19; 15,
16,17,19,21,23,24,
[19:11,16,17;120:6;
..-. 83:6,7, 12;84:3, 15,17,
[23:23;126:3;127:1,12;
158:22,25, 25; 159:8,15, ‘0:2, 5,6,7,9,10,12,16, !5;
172:5,6, 12,18,22;
18, 20;85:5;86:15; 92:16; [6; 161:19, 23; 164:23; 9,20,21,22 ;71:1,4,6, .75:8,8,9,10,15,17,18,
~28:3,6,10,10,13,14;
94:11 ;96:14, 18; 101:2,
[29:8;131:8;132:1;
[66:20; 167:6; 168:1o; 0,12,13, 24; 72:3,16, 9,19,20,22,22, 23;
18,20,21 ;103:1; 104:19;
[34:7;136:9,20;140:5,7,
169:16; 170:12; 172:19, :0,21,22,23, 24; 73:15, 76:3,4,5,5,6,8,9, 12,
109:1,2,2,15, 17; 110:3,
.0,11;144:16,19;145:2,
?4; 174:17 5,18, 23; 74:4,12,16, 2,13,22,22, 23;177:3,
21; 113:1,4,7; 114:5, 12; ione 10:5; 30:24; 34:10; 8, 25; 75:3,5,25, 25; ~,6,
13,14, 25;178:1,6,9,
115:3,8,9,10, 11; 118:24; !,3;147:6,14,17;148:10,
.8;149:14;152:10;155:2, }8:10; 41:15; 43:7; 90:3; 6:1;77:5,7,21,21,22; 1,20,22; 179:1,17,17,
121:9; 122:21; 123:4; J5:9;100:6; 105:23; 8:9,15, 18; 79:1,2,5,7, 7,18,18,21,22,22
124:6,20,23, 25; 125:5,
.7,24;156:1,1,15,23;
59:12, 20;162:23;
.06:25; 125:20; 135:13, 18,22,23,25, 25; 80:1, kdl6:4, 22;7:8;8:1,1;
11, 15,22,22; 126:6,11; .6; 136:14; 137:1, 12; 0,10,11, 19,21,23; 1:12;15:21;18:24;
127:13, 16; 134:18, 19, 20;
66:13; 168:6;171:13,15;
72:3; 173:4,
24;174:2, 9; .38:25; 139:13; 142:2; 1:1,3, 10, 16,24 ;82:1, 9:20;
22:23; 33:1;38:19,
135:3, 22; 136:2, 3; 47:15; 153:12 2, 16;83:5, 14, 18;84:7, :1;45:18;68:19;
75:6
139:18; 141:2; 144:17, 19;
77:18,21,23
Iose 42:22; 72:6; 102:23; ,11,11, 13;85:7, 16,20; Irafting 179:23
145:8, 20; 146:13, 14, 15, Ioability 148:4 6:2, 11; 87:9; 89:6, 16,
03:20; 104:17; 106:3; Irag 82:3
17,23, 25; 147:4; 148:8, 10CtOrS53:11; 76:13; 3, 25; 90:23; 91:9,12,15,
07:20; 111:4, 5; 112:2o; kaining 47:12
18; 149:7; 150:14, 21; ‘7:1 8,24,24, 25; 92:22, 24;
21:16; 122:24, 25;
153:1 ;154:2; 161:12; Iocument 6:22,23; 7:1, 3:6,6, 13,15,15, 16; kamatic 78:4
24:11 ;126:14; 137:3;
163:3,6, 20; 167:3,9,13, ,2,16 ;8:1,2,4; 38:9,21, 4:10,14,19, 21;95:15, dramatically 15:19; 78:6
40:7, 8; 159:17; 161:6,
18; 170:8; 175:1,4, 10, 13; :2;39:7, 20; 45:1; 83:23; 7,17, 19,23 ;96:11, 11,
3; 168:24, 24; 171:13, 15; draw 26:3
177:1, 7; 178:22; 179:9 01:1; 105:4; 140:25; 2,20,22, 24; 97:3,4,6,6;
76:15 drawback 66:25
diseases 6:14; 11:16,21, 65:5; 166:20, 20; 175:3; Iosed 84:7; 124:10 8:12, 16; 99:8, 12; 100:2,
driven 94:19; 114:16
24; 12:8; 13:10; 16:8; 18:1, 79:7,7,11,13,14 6,22; 101:15, 16; 102:5,
loses 88:6, 21; 126:13, driving 97:24; 117:6
14;39:24; 64:1; 79:24; Documentation 45:22, ,16, 20; 103:7,8,10,12,
4, 14; 137:2, 14; 153:14 drowning 82:2,4
145:9, 22; 148:6, 25; 3 ~, 20,22,24, 25; 104:9,
150:20; 160:12; 162:5, 25; losing 124:10 1; 105:4,7, 10; 106:2,5, Drug 4:14; 5:18; 11:8, 11;
documents 71:19
163:16; 165:15,16, 24; doubt 66:19; 139:16 ; 107:6,6,7,14,15, 22; 14:21;16:4;20:6;21:12;
does 16:18; 54:21; 57:15;
167:10 doubtless 80:8 08:19, 22; 109:8, 10, 11, 26:7,17,21;30:16;36:11;
59:4; 60:7, 21; 62:17; 71:4;
dismayed 93:25 down 7:4; 34:2; 49:2, 23; 2,21,23; 110:15, 19; 42;20;44:7;47:7;49:3,5;
72:17; 76:6; 85: 16; 88:20;
dismiss 99:17 59:3, 8; 71:15; 75:20; 11:2,2,5,9,11,12,23, 54:23;56:8,11,12,15;
B9:23; 115:6, 10; 116:7;
B2:19;83:21; 88:16; 91:4; 23,24; 112:16, 24; 113:2, 58:6;
60:16, 18,20;62:19;
disorders 136:14 129:10; 134:23; 136:z1;
101:24; 103:4, 10; 106:22; 3,12,13, 14,21,23,24; $4:7;
69:16;71:5, 10,14,
-
— dissimilar 58:25 139:12; 144:15, 19;
110:13,24 ;111:21; 114:2, 13, 13, 14; 115:1; 16,21,22;72:1;74:2,8,
dissuade 121:4 161:11 ; 165:1,2,7;
121:14 ; 138:12,21,23; 116:3,3,6, 25; 117:3, 24; 17;75:13,21;78:1,24;
177:18; 178:1 118:5, 12; 119:2,3,13,24,
distinct 14:1; 84:9 143:10; 150:15; 151:3; 79:13,17,24;80:6,16;
doesn’t 25:19; 41:20; 25; 120:13, 17, 17, 18;
distinction 26:4; 90:1z 152:11, 12; 156:7; 160:19 14:1,2;85:1,11;86:6,8,
i2:8; 44:11; 55:4; 63:3; 121:7,7,8,19,20, 23;
distinguish 18:11 ;73:11; down-regulation 78:5 [7;89:8,11;90:12;91:7,
$6:24;76:13, 13; 88:16; 122:6,7,11,13, 17; 123:6,
90:5; 154:18 [4,17,21;92:15;94:13;
~5~7;96:13; 112:11, 18; ~ownward 138:8 7,9,10,15,16, 24; 124:3,
distinguishes 88:4,5
~5i4;
104:6, 21;106:24;
[19:1;
122:15;
129:2; I jozen 30:16 [1, 14, 21; 126:22; 127:2, 07:17, 19,21;108:25;
Miller Reporting Company, Inc. Min-U-Scripm (9) disease - DIWQ
Hearing Vohune Number 2 Food & Drug Administration
May 29,1998 Gastrointestinal Drwzs Advisory Committee

110:2;
113:5,6,18,19,20, 75:15,16, 17;83:25; emphasized 13:3,16, equivalent 174:8 exacerbation 82:15, 18
24;114:1,11;115:3,10, 86:17, 18;87:4;90:25; 24; 19:15,17, 20; 2022; era 169:20 exacerbations 82: 13;
_=l.18:9;123:21;127:7; 96:21; 99:2,
3,4;107:13; 118:1 erosions 37: 18; 43:23; 84:18
!3;133:6;136:24; 111:22; 118:8;120:24,
25; emphatically 90:24; 44:20,20,21 exact 143:5; 144:18
1-,,:19,22,
24;141:9; 121:6; 166:3;168:2; 133:1; 136:13 esophageal 18:4 exactly 7:13; 39: 14; 40:5;
142:4;
143:11;145:14; 176:14,15,18,19 employed 169:13 essential 140:21 76:22; 88:10; 89:3;
148:5;149:25;154:3; effective 12:14;24:18; encapsulation’ 22:6 essentially 65:9, 20; 100:19; 140:13; 143:8;
155:23;
160:8,
9;164:20; 25:17, 20;69:16;135:15;
encourage 5:23; 46:4; 171:8
166:3,5,10,11,
13;167:3; 139:25; 141:13;148:17; 84:20;
96:25;
109:3;
168:5,
6;169:6;173:2,
16; 53:17 126:20;
128:16;
172:16 examination 159:4
171:11; 178:17
174:12,18;176:14,18,20; encouraging 74:14 establish 68:20; 72:16 examine 89:2
effectively27:25
177:17;178:7,10,12,17, effects 22:22;29:23; encumbered 22:9 estimate 173:9, 10,16 examined 77:16
23,24,24;179:8 66:24; 84:23;
86:25; end 54:23; 56:4; 74:23, estimated 127:16,18 examining 89:1; 167:24
drug’s 134:12,18 97:18,22 ;111:1,1; 24; 80:2,
3;94:8; 95:22; estimates 163:25; example 12:14; 17:9;
drugs 4:22; 8:12,14,18, 120:19, 25;126:3;127:4, 96:2; 147:5; 176:17; 179:3 164:11 26:24; 29:22; 31:19;
20; 16:6; 26:18; 32:17, 19; 4;134:18; 166:12 endoscopic 9:15, 20; 33:1 O;34:23, 24; 35:21;
estimation 38:6
39:17; 44:24; 46:3; 60:24; efficacious 153:15; 15:10,14, 17; 16:2,7,10, 36:22; 47:8; 65:7; 72:6;
et 26:23; 27:1; 28:24; 75:14; 81:24; 89:1, 7;
66:24; 70:22 ;74:6; 75:9, 15917 20, 20; 17:19, 20; 18:13;
93:12; 135:16; 141:22; 116:19; 117:15; 137:23;
19;77:18; 80:7; 81:19; efficacy 70:10, 23; 75:4; 19:5; 20:8, 12; 23:17;
179:2 162:2, 15; 163:4
82:10 ;83:16; 84:22; 78:22; 85: 19; 87:3; 2622; 27:1, 4; 309, lx
85:22; 103:2; 114:4; 124:18; 127:1, 14; 131:19; 42:2,13,18, 24;43:4, 13, ethnic 150:1 examples 24: 14; 26:14
127:14; 130:15, 17; 133:13; 134:7, 8; 135:8; 15;45:1, 5;46:10, 15; Europe 17:15 exceed 165:1,3
131:15 ;132:8,12; 133:15; 136:3,4, 10; 139:17; 49:11; 51:23,25; 57:13, European 169:11 excellent 75:16
142:15; 145:11, 17; 140:3,12,14, 21,23; 23; 60:6,8,9,11,13, 16, Europeans 115:17 except 108:8; 157:s
150:17, 18; 153:14,16, 19; 141:4,6; 142:17, 21; 24
evaluate 167:19; 177:20 exception 121:9
165:19; 166:15; 167:18; 148:25; 152:9, 12; 156:1, endoscopicaliy 43:9,
Evaluation 4:14; 22:7; exceptions 4:17
168:16; 169:5, 11; 174:22; 13; 159:12; 160:14; 168:6; 11;47:1
112:4 excessively 94:19
178:4, 11,19 171:17; 172:14; 173:8; endoscopies 60:12
174:8,20 evaluations 161:1 exclude 5:4; 129:6;
due 7:3 endoscopy 47:5; 58:23,
?fficiency 55:9; 93:24; even 4:10; 14:9; 33:13, 148:6; 152:15
duly 80:19 24
)7:12; 100:14 17;43:23, 25; 45:3; 58:22; excluded 129:4, 12;
duodenal 18:4 mdpoint 43:17, 17; 45:7, ~O:l; 63:24; 64:23; 69:2;
dficient 93:20; 94:2, 17; 150:6
d,,~abil~
-- . 56:9; 68:3,
18; 11;46:19;48:21,24; 33:19; 88:15 ;90:13,15;
)7:15 57:22; 60:9, 21, 24; 66:15; excluding 129:24;
25;72:7;81:14; )4:16; 104:18 114:6;
Mciently 97:19 S9:20;70:12; 76:3; 77:17; 146:22, 25; 150:8, 10;
e-.i5;10l:ll; lO8:l5 122:20; 124:24; 129:19,
dfort6:13;8 :ll,ll;9 :5, 97:9; 98:5,6,8,13, 24; 165:6; 177:1o
duration 56:3, 14;68:19, 25; 147:15; 148:15; 153:7,
24;69:21;70:20; 72:14; ~; 87:13; 122:2 116:22, 23; 118:7; 119:10; 18; 155:9; 156:6; 157:8, exclusion 5:5
74:14, 19;81:4;84:24; dforts 7:3; 115:24; 132:4 122:4; 123:2; 124:2 20; 159:22 exclusive 36:4
87:1;99:2;102:16; eight 37:19; 56:12 endpoints 9:1 5; 16:25; event 5:1; 154:19, 22; exclusively 147:7
105:12; 107:23;109:25; 19:3; 20:1; 37:10, 12;45:4; 155:5; 160:10; 164:11,13 exclusivity 131:5,6,7
sighties 25:4
115:16 48:18; 57:25; 58:3; 135:4
sither 14:15; 19:4; 21:11; mrents 116:12; 156:20; excretion 15:7
durations 169:18 England 106:6 160:11; 163:23; 164:20,
24:1,11,23 ;31:5; 49:24; Excuse 8:10; 78: 18;
during 47:14; 123:18 50:1; 61:21 ;62:12; 63:7; enhance 55:8 22; 165:2 153:12
dying 149:20 65:18; 67:9; 86:17; 92:15; ENL75:14 eventually 13:9; 16:7 Executive 56:25
104:5; 119:5, 23; 121:25; enormous 99:22 ever 35:13 eXt?I@fkd 17:2; 107:16
146:18, 19; 150:15;
E 167:14; 178:10
enough 59:12; 62:4;
73:24; 78:10; 90:12;
every 60:16; 71:15; 85:2;
101:25; 102:4; 105:19;
exemptions 166:11
Elashoff 40:20, 21; exhaustive 36:4
99:17; 105:18,21, 22; 111:9; 126:7; 127:7;
each 30:17;
48:16,
17; 68:13; 87:9; 89:16, 25; 112:13; 118:22, 23; exist 46:3; 159:3
129:6; 130:12; 160:9;
96:22,24;97:1;117:11; 95:23; 96:24; 145:6; 135:22; 147:22; 151:21, 168:8 existing 8:1; 22:23
122:8; 174:18 146:2 ;151:12; 159:5; 23; 156:13 everybody 6:6; 98:2, 9; exists 28:10
earlier 76:6;
106:7; 161:16; 164:8; 177:6 enrolling 140:1 11921; 121:25 eXpeCt 77:23; 85:9;
120:10; 138:13;144:7; elderly 145:1o, 12, 13; ensued 29:4 everyone 10:16; 152:3 139:21; 175:13
152:7; 159:23 146:7; 148:7; 149:3, 8; expectation 44:23, 24;
enter 143:10, 12 everything 27:7; 36:5;
early 7:2,13;25:4;
38:11; 150:9 84:21 ;92:1
entered 47:13 45:8; 61:10 ;81:21;
142:17; 174:23 element 107:2 100:18 ;115:1; 126:13; expectations 44:7; 93:7
enteric 29:15
ease 142:13 elements 29:1; 54:19, 20; 130:20; 178:4 expecting 73:3; 84:25;
55:4; 135:1 entering 168:25
easier 22:15; 57:10; evidence 23: 17; 44:22; 85:4,8
140:22 elevated 30.14; 121:16 enteropathy 15:2
45:8; 52:15; 53:8; 57:23; expedite 142:13
easily 57:5; 63:23; 138:7 elevation 14:23 enthusiasm 100:17 65:14; 151:15; 154:3; expedition 156:22;
easy 37:21; 51:21; eliminates 123:7 entire 35:3 1561 157:15; 158:18
=7:18; 156:5 elimination 101:10 entirely 90:2; 146:15 evidence-based 144:21 expeditions 156:22
“> 170:10 else 10:1667:11,11; entirety 86:3; 90:15 evident 77:19 experience 25:9; 106:9;
etinoed 67:13 70:4, 17; 82:7; 92:14; entity 61:2; 146:24 evolution 34: 13; 36: 19; 122:23; 143:4, 5; 144:13,
economic 36:12 110:9; 178:4 entry 116:5 179:13 19; 145:13; 160:7; 166:16;
ecstatic
78:22 elsewhere 79:1 epidemiologic 160:10 eVOIVe 38:5 177:22
effect
36:11;54:23; embarrassed 92:7 equal 47:24 evohring 125:10 experienced 36:25
55:10;
62:6;
68:2o;74:7; emerging 163:17 equivalence 173:8 exacerbating 167:8 experiencing 87:6

drug’s - experiencing (10) Min-U-Script@ Miller Reporting Company, Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1998
experiment 157:9 164:25; 177:15; 178:13 finalizes 89:3 follow 7:ll;38:19; 46:21, 155:4, 9; 156:25; 157:8;
experimental 150:16 fairness 5:8; 124:14 Finally 37:2; 67:24; 135:9 69:22; 70:1; 71:22; 78:8; 158:19; 159:12, 12;
.-= expert 10:9 fairy 142:17 139:21 160:14; 161:3,3,5,7,8,
financial 4:12; 5:3,9
experts 76:11, 24; 136:5; fail 112:3; 134:23 follow-up 46:24; 75:1; 12, 12,13,14,15,16,18,
find 22:14;
23:12;
32:24;
137:20, 21; 168:24 144:23 20; 162:2,15,16,18,21,
fallen 36:9 78:1;
111:16;
128:13;
followed 46: 16; 70:13 22,23, 25; 163:4,6, 11,
explained 67:8, 10 false 100:10 139:25;
143:14;
153:18;
13,16,20, 24; 164:3,13,
explicitly 118:13; 119:23 familiar 130:1 156:23,
24;159:1,9,17 following 4:7,16 50:7,8;
19, 19; 165:6,8,14,19,
explored 114:8 far 11:22; 20:15; 40:3; finding 176:15 87:2; 158:19
21; 166:3,6,8, 10, 11;
exposed 36:22; 168:1 78:15; 102:22; 160:8; findings 13:1, 23; 46:16; follows 42:19 167:13,19, 24; 170:2;
extend 6:18; 68:21 168:6, 9; 169:21 49:11,11 for4:ll, 14,15, 22; 5:2,5, 171:9, 11,17, 25; 172:8,9,
farther 35:5 fine 83:15; 93:13; 11024; 12,16,18, 19;6:6, 19,22, 10,16, 25; 174:15; 175:13;
extended 63:23; 70:9
fashion 117:7; 153:5,5 156:16; 157:12, 18; 165:6 22;7:7; 8:2,4, 11,12,14, 177:17, 18, 24; 178:7;
extending 138:8
fast 77:11 finished 10:20; 100:18, 18, 22;9:15; 10:17,21, 25; 179:9,9,13,20,23,24,24
extension 61:4 11:23; 14:12, 13; 16:21,
father 56:24 20 foresee 142:6
extent 76:6; 108:8; 160:6 25; 17:24, 25; 19:6, 12;
favor 62:4; 65:15, 17; fire 83:8,10,12 forget 80:3
external 66:5, 13 20:12, 17; 22:5,13, 24;
143:9 firm 5:9; 135:13 form 131:5
externality 66:15 23:7; 25:5, 14; 29:22;
favorably 70:3 firms 4:14; 5:2; 177:19 formal 7:1; 20:22;
30:18; 31:24; 32:6, 14;
extra 29:15 167:19; 179:13
FDA 5:3; 7:1, 23; 8:3; fkSt 7:15; 8:1; 17:24; 33:10, 19; 34:9,9, 23;
extraintestinal 14:3; 113:16; 130:12; 131:14, 22:4,12,17, 19; 23:20; format 8:9
35:3, 21; 36:6,9, 22;
170:23 17, 25; 132:7; 141:4; 32:3; 37:7; 38:19; 43:4; formed 48:12
37:21; 38:10, 17,20, 21;
extraordinarily 78:20; 143:24; 169:19 46:9; 49:16; 81:4; 88:4; 39:11, 15;42:19; 43:2, 3, forming 48:8; 165:10
179:18 FDA’s 38:7 39:18;90:5; 101:8; 16;45:12, 17;46:14,20; formulate 136:7
extrapolate 124: 17; FDAMA 13013 104:11; 106:21; 107:1; 47:1,7,7,8, 10;48:17, 21; formulation 114:16;
126:18; 134:6; 135:23; 114:8,8,8; 116:6; 125:17; i9:5,14; 50:4; 51:16,21;
Feagan 10:7; 32:23, 24; 132:4, 5; 135:5; 144:4
137:3; 139:17; 140:3; 139:23; 164:21, 23; 53:1,6,9, 10; 54:1,4, 14,
39:25; 54:10; 59:2, 10; formulations 132:16
145:1; 159:18; 173:18 168:22; 172:15; 173:4; 23; 55:3,8, 11; 56:4,7,8,
65:15, 16; 66:12; 67:3;
[79:8 $11,12,15,15 ;57:4,15;
forth 47:6; 129:24;
extrapolation 131:18; 69:4, 7; 93:15, 16;94:14;
‘irst-line 113:25 58:1; 60:11, 16, 20;61 :6,
150:20; 173:24
132:17; 151:5 95:17, 19; 107:6, 7;
111:12; 120:17,18; 138:9, ishing 156:22, 22; ~, 14;64:6, 16, 21;65:7,8, fortunate 11:18
extreme 97:21
10; 143:1, 16; 149:16; [57:15; 158:18,23 [0, 14; 66:9,10, 15; 67:7; forward 8:6; 54: 14;
extremely 39:20;
132:2;
—- 162:7, 10; 168:18, 19; istula 14:2; 23:23; 25:25; 58:24; 69:24; 70:22, 22; ~l:ll; 133:2
174:9 71:2,8,9, 12, 13, 14;72:1,
169:15, 24; 170:9,10,19, }0:10, 18; 40:24; 46:15; found 139:24; 143:8
extremes 138:1 ~4;73:4,6; 74:2,4,5,6,6,
25; 176:12, 13; 179:18 [7:9, 11,12, 14,23;48:8, Foundation 57:1
exudation 15:5 [1, 17,23 ;75:1,10, 11;
Feagan’s 111:3; 129:18 !9,
20;49:1;
55:19,23; Iounded 169:16
;1:14,
22,23;62:3,
24; ?6:2, 12, 14, 23; 77:13, 24;
fear 97:7,8 78:12, 19,20,21, 24; ‘our 43:5; 108:13; 115:16;
F Feasibility 138:11 ;3:1,8;
64:9
~9:11, 13,24, 24; 80:7, 14, 128:4; 132:6; 139:9
istulae 23:6; 40:14;
feasible 137:14; 148:10; !6,18,21; 81:10,11,11, ‘our-week 84:24; 119:1
153:5; 176:24
i5:16; 49:23; 59:8; 62:15,
faced 133:14 .2, 17;82:10;83:12, 16, ‘rank 10:14; 32:2; 59:16;
8; 105:20; 170:24
facilitate 7:20 feature 14:13,23 .9,20, 24; 84:22; 85:22, $5:19; 70:2,6,9, 19;75:3;
iStUh 47: 14; 59:23;
fact 7:1; 23:18; 25:12; Features 11:21; 14:12, !5; 86:1,6,6, 20; 87:3; 78:9
25:13,14
27:23; 37:15; 42:11, 20; 14; 15:4,8, 10,15, 17, 24; )8:1,3,7, 13,25 ;89:1,7, ‘rankly 18:20; 117:25;
istulizing 19:1 ‘,20, 22; 91:7; 92:20;
46:3; 47:22; 49:8; 59: 17; 16:7, 15,20, 21; 17:4, 16; [44:18
73:3; 80:5,7 ;83:14; 84:4; 19:5; 21:24; 57:24; 147:18 istulous 59:10; 61:25 J3:13;94:7; 96:18,19;
%edd 6:25; 175:2
87:19; 92:7; 95:2; 96:4; it 96:13; 138:6 .00:17; 101:12,16, 17;
Iecal 15:3 ‘ree 20:23; 44:18; 46:5
98:25; 104:3; 118:14; its 110:14; 165:18; .02:12, 13,14,16, 18;
!eel 46:5; 53:1,9; 69:13; ‘reedom 4:24
123:24; 127:20; 133:3; 76:18 03:7; 104:20,21; 105:1,
71:8;81:17; 89:21 ;95:16;
134:2; 139:15; 154:19; }; 106:15,21 ;107:3,9, 11; ‘rench 42:21 ;43:7
112:19; 120:22; 122:21; ive 37:6; 75:12; 125:6,
155:22; 156:4; 157:12; 08:11, 13; 109:22; 110:3, requency 137:3
136:13; 168:10; 170:22 3,17,21
158:22,24; 160:4; 165:20; i,22; 111:25; 112:4, 12, ‘requent 51:14
beling 71:7, 14; 73:1; ixed 124:11 5, 25; 113:3,6,6,9, 10,
169:5 requently 151:10;
141:11 Iare 28:3; 64:21, 22; 8,25; 114:12,22 ;115:3,
factor 13:25;
100:14; [56:17
‘eels 17:6; 42:14; 44:5; ~3:7,
22,25;84:10,
10; !, 11,15,20, 22; 116:3,
119:15 %ieS 33:24; 34:1,7;
54:22; 56:19; 80:20; 04:8;
106:21;
117:8; 9; 117:15,17; 118:18;
factorial 117:11 159:19 22:9,
21;170:22 19:17, 19; 120:14; }8:17; 41:4,7, 10; 56:13
factors 12:22, 24; 13:3; ‘en 32:11 Iare-ups 82:14 21:14,22 ;123:11; 124:6, rightens 151:25
21:21 ;95:11; 99:23; i, 25; 125:10; 126:3, 10, rom 5:5,21,24 ;7:14, 14;
‘elt 55:17; 56:1; 58:11; Iares 65:8
123:1; 174:19 5; 127:7, 10; 128:13,14, 10:7, 15; 11:24, 25; 12:2,
~40:20; 163:8 Ieshing 135:17,18
facts 22:10 4, 19; 129:4, 18; 131:3,3, L,3,4,6; 13:18,20, 22;
‘ever 13:23; 28:12; 29:22 Iexibility 162:11
failed 84:25; 94:13; 4,15,15, 24; 132:6,8, !0:5; 21:16,22, 23; 22:22;
‘evers 23:6 Iexible 90:23 9,23,23; 133:1, 11;
104:7; 113:19; 114:18; !3:15; 25:1; 28:4; 29:6,8;
---—.. 121:10 ;132:5; 133:15; ew 10:5; 65:21; 108:11; 9Ca[ 15:12, 25;51:8 34:6; 135:19; 136:18, 19; J1:15;34:7, 24; 35:14, 15,
172:3,5 L2O:1O;147:4 LJCUS5:20; 86:14, 15 37:13, 23; 139:4, 14; !2; 36:24; 38:15, 23; 45:7;
failure 64:8,10, 16; ibrosing 125:23 ~cused 38:23; 83:25; 40:2,19, 20; 142:3,5,8, [6:5; 47:15; 50:14; 52:7,8,
102:2; 148:2,2 ield 6:6; 54:14; 177:20 55:17 8; 145:11,13, 17; 146:6, 1;57:4; 60:10; 61:24;
igure 89:19; 175:20 1,13,22,25 ; 147:1,21; ;4:12; 67:7; 68:2, 21; 69:6,
fair 74:25; 82:1; 127:25; )cuses54:21
48:17; 149:11; 150:6,9, !5;70:16; 71:25; 73:22;
142:11 igures 164:15 >cusing 157:21 4,16, 18; 151:6,16, 21; ‘5:5; 76:7:81:5:82:8:
fairly 58:13; 152:13; I inal 167:11 )Iks 160:7 .52:16; 153:10,13, 16; 3:3; 84:9; 16; 85:14 ;86:2,
Miller Reporting Company, Inc. Min-U-Seripm (llJ ex~eriment - from
Hearing Volume Number 2 Food & Drug Administration
May 29, 1998 Gastrointestinal Drugs Advisory Committee

9;87:11; 89:17; 90:3,15; geriatric 144:15; 145:18, 156:7; 157:24; 163:4; grade 19:16; 48:20; 125:8
91:2,3,4,21 ;93:7,8; 21,23,24, 25; 146:3 171:21; 174:21 graded 46:16 H
&M:14, 16,17, 24; 95:3, 17; geriatrician 148:22; goal 8:3; 26: 1; 30:8; gradual 36:18
7,7,9,12 ;99:21; 149:4 44:12, 14; 51:16; 52:12,
AuI:2,2,21,24; 102:2; gradually 70:14; 114:9; H 57:17,18,19,19,19,
geriatrics 144:10,17 12, 13; 53:18, 21; 55:22,
103:18, 19; 106:2; 107:8; 149:13 20; 58:15
get 7:15; 10:21; 12:20; 23;56:1,4; 83:13 ;96:21;
110:6, 12; 113:9; 115:25;
102:15; 103:2,6, 24; GRAFFNER 51:18, 18; had 7:2, 9; 32:8; 40:5;
121:4; 123:4; 126:18; 30:18; 31:15; 33:13,15, 41:7; 42:24 ;43:12; 44:8;
104:9; 112:5; 116:4; 82:1; 119:24; 177:14
127:2, 4; 129:4, 12; 17; 35:8; 36:13; 37:3, 16; 46:15; 47:8,11,21,22,23,
39:21; 49:10, 20; 55:4; 118:11; 119:14; 173:5,7; granted 4:19; 33:4
134:21; 136:23; 137:9,22, 24; 48:2,4,7,10,10, 18;
60:2; 61:6,7, 10; 62:19; 177:9,11 grappled 92:3
23,23,24, 25; 138:3,11, 52:19; 53:7; 55:19,22, 25;
12; 139:11, 11, 11; 141:24; 63:17; 68:1, 16; 70:1; 75:7; goals 19:20; 21:16; 30:9; gratified 34:17 58:7; 60:12; 66:16; 68:11;
143:25; 144:4, 25; 145:1; 77:9; 79:22; 80:22; 81:17, 35:5; 55:18,22, 22; 56:17, great 6:1, 10; 22:9; 38:12; 69:22; 70:10; 79:1; 80:4;
148:4; 151:1,6,22; 162:8, 19, 21;82:18;85:2, 17; 18
44:16; 48:22; 71:14; 86:4; 98:8; 99:2, 3,3; 105:20;
16, 17,23; 165:17, 25; 90:1,2, 15; 91:3; 93:4, 23; goes 18:18; 45:22; 53:23; 114:6; 120:6 113:24; 114:6, 18; 115:23,
167:9; 168:14; 170:1; 95:7; 99:15; 100:18; 76:4, 15; 82:21; 93:8; 24, 25; 122:12; 125:13, 13;
greater 47:24; 48:9;
173:18; 174:9,12,14, 17; 101:24; 102:23; 103:10; 94:24; 98:16; 107:10;
133:5 140:9, 16, 17; 141:2, 17;
176:10; 177:16; 179:7,22, 105:24, 25; 106:24; 116:16; 124:19; 151:2;
146:12, 25; 149:4; 150:14,
22,22 110:16; 111:2; 117:12; 164:14; 177:12 group 15:15; 37:7, 25;
17;155:15, 16; 159:13;
front 80:2 118:8; 119:7; 120:5,9, 12; going 5:14, 19; 10:2; 86:18,20, 20; 87:4; 88:21;
171:3; 175:23; 179:7,9
123:18,20, 22; 126:21; 11:24 ;15:21; 18:3,5,6; 90:25; 91:22; 92:23;
front-line 114:10 hadn’t 109:24; 115:20
127:13; 128:19; 129:2; 21:19 ;29:10;33:17; 36:8; 96:16, 20; 116:17, 18;
full 30:15; 45:24; 64:4; Ialf 10:18;
47:24;
95:7;
132:1,4, 20; 134:4; 136:8, 39:1, 8; 42:15; 48:23; 129:2; 136:14; 139:4, 6;
100:18 [17:11,12;165:3,12
20; 138:3, 15; 140:22; 51:15; 56:6; 57:12; 59:19; 140:20; 142:15; 143:18;
fulminant 46:20 142:17; 143:25; 146:1; 145:1, 5; 148:9; 151:21; lalf-empty 67:9
53:10; 72:25; 73:3, 11;
functional 44:1; 135:3 147:15,18, 24; 149:2; 78:24; 80:13; 81:22; 83:1, 156:15 ;165:11; 179:22 Ialf-ful[ 67:9
fundamental 53:24; 151:9; 153:4,7; 154:24, };88:10; 89:2,9, 19;91 :1, groups 100:1;
117:12; lalt 26:21
124:17 z5; 167:9; 169:15; 172:23; 13,21,22 ;99:21,24; 127:9;128:10,21;
130:25; +ANAUER 4:3; 5:14; 7:3;
fundamentally 76:9; 174:18; 176:13, 20; 179:1 100:2; 102:2; 103:4;
139:1;174:3 k8, 12, 23; 22:17; 26:8,
152:10; 174:16 Jets 56:4; 93:23; 121:2, 106:10; 108:23, 24; 109:2,
~5 growing 58:8;
59:1 .2; 28:4, 17; 30:1, 16;
further 8:2;83:17; l15:5, [,6; 110:11, 13; 115:7;
117:20; 118:17, 18; 121:6, yown 35:19 ~l:l,14,23; 32:23 ;33:24;
7; 147:20 letting 27:7; 49:19, 23;
12; 122:16; 127:9,12,17, growth 13:24; 110:24; k8:7,15; 39:23; 40:20;
i9:25; 63:7; 64:13; 78:25;
fl~ure 5:18; 8:21; 12:18;
_.—— Z3, 24; 129:24; 134:2, 5, 111:1; 134:21; 137:21,25; il:2,25; 42:16 ;43:20;
16,18;70:16;71:18; 10:24;82:17; 101:12; i4:6, 15; 46:4; 49:7; 50:11;
[02:12; 108:4; 125:20; !2; 136:8,9; 137:3,4,6; [57:4,6
.):14 ;1:12; 54:8; 55:13; 56:21;
[26:10 ;132:6; 141:14; ~38:15; 143:19; 144:2; ~uard 99:1o
50:7; 156:8; 163:22; [47:5,6; 148:11; 149:2,6, ~7:ll; 60:4, 15, 19;61:1,
Juess 33:1, 19; 34:9;
G 65:23; 169:20 1,8,25; 151:19; 152:12,
[2:1, 3; 53:17; 72:3; 82:20;
,9, 18;63:9, 22;64:18;
;5:2, 5, 12, 17;67:1, 25;
~1136:5; 137:11 !3; 153:3; 154:8; 155:24;
15:2;91:15 ;101:21; i8:7, 11, 17; 69:3, 5,8, 10,
.56:7,10, 10; 157:17;
Gain 144:13; 179:8 Jive 6:9; 10:2; 24:14; 113:15, 17; 120:18; 7; 70:5,7,10,16, 20;
.59:16: 162:17:164:9:
gained 160:17,18 L4:5;38:17; 42:21 ;43:1; .38:12; 141:5,7,8; ‘1:1, 6,12,24;72:20, 22;
71:4; 174:7; 175:14; ‘
gaining 20:17
gamble 120:21,22
;1:4; 53:18,20; 57:15;
i4:7;74:5; 85:14 ;91:12;
102:19; 112:18; 136:6;
76:1, 17,20
gold41:ll; 66:5,16;
.55:15; 157:14; 162:24;
.65:17 I
4:4,16,
,1;78:15;
25;75:25; 77:5,
79:1,22,25;
134:5; 168:12,18; 171:10 guest 8:24 10:10, 19;81:1, 10,24;
gaStritiS 57:20; 58:15 164:15; 167:3
guests6:19 14:11
;85:7,20; 86:11;
gastroenteroiogist qiven6:l; 24:ll; 45:15;
Goldstein 56:21,
22,22;
19:6,
23; 91:24;93:6, 15;
28:6; 46:8 ;7:14;64:5; 65:7; 66:18;
57:13;79:25;80:1; 130:9, guidance 4:21; 7:l,4,7,
J5:15;96:11;
98:12;
gastroenterolog ists 14:2; 108:16; 130:6; 10;133:1,8, 10,14,20; 10, 10, 12, 16;8:2,4;
[00:16,22;102:5, 16;
33:12; 140:19; 143:13, 14; I34:1O; 172:13; 173:23;
134:1;135:1; 136:12; 22:23; 38:9;45:18; 68:19;
103:7,10,20,24;104:9;
153:19 [75:10, 11; 176:9
137:16; 139:6,15;143:19, 71:24 ;72:8;74:5; 101:1;
105:7;
106:2; 107:6, 15;
Z2;159:21 102:19; 113:10; 116:4;
Gastroenterology 9: I Jives 164:24; 165:2 108:19;109:8,11, 21;
gone61:23; 73:4;80:5; 117:22; 119:18; 136:7; [10:15;111:2,23;112:24;
gave42:22;85:ll; 113:5 3iVing 72:5,6; 84:15;
[47:12;168:9 145:11 ;161:20,25; 113:3,
13,21,24; 114:13
geared 139:1 [00:10; 126:17; 177:13
Sood 7:10, 10;37:15; 162:23; 163:7, 19;166:10; .16:3;
117:3,24; 120:17;
general 4:18, 21; 10:10; Jlass 67:9 173:25; 174:1, 2;175:3,6, .21:7;
}9:2;
56:11, 12;58:13; 123:6;124:3;
16:3; 22:3; 34:15; 36:1o; Jlimpse 47:1 50:6;
66:18, 21;72:5; $;179:14, 23,23 .26:22;127:6,18;128:3,
38:15 ;61:10, 12; 148:7; ~lobal 52:5 T3:24;75:18;81:22, 24; guide 123:16 9,23;129:14; 130:9;
149:21; 163:8,24; 164:2 12:10
;91:7; 104:23;
jlobals 66:6,13,14 ~uided 142:9 32:19;133:6,9,12, 18;
generally 14:15; 37:15; [12:13;120:4; 124:1,1; 34:15;
137:7; 138:9;
]Iucocorticoid 104:13, ~uideline 18:24; 31:21,
41:24 ;87:11; 150:20; [37:11,11;141:12; 40:9;
141:7;142:1, 20;
6,18 ?1;71:19; 74:5; 161:5;
161:11; 163:1; 169:13; !44:20;166:24; 167:9; 43:16,
2 1;144:9, 13;
173:12 Jucocorticoids 104:20 [62:12, 13; 164:18;
.71:23;173:7; 175:20; 165:14; 166:10; 176:21 46:2,10,16, 19;147:3;
generate I41:1o; 160:13 ~naWing 76:15 .77:20,24 48:3,21;149:12, 20;
108:2;11:2; 23:21 ;35:5; ~uidelines 5:18; 6:5, 22;
~—flerated 134:3; jot6:20; 32:20;37:19; 50:7,
23;153:9; 160:23;
,9:11;41:20;48:17; 49:2; }:25; 11:12; 15:21; 17:24;
:14, 16 [4:25;109:4;114:23; 61:17,22;162:7,15, 21;
,6:7; 58:21; 61:22; 72:9; .9:21 ;21:25; 26:15;
genetic 9:8, 10; 12:1, 22; 15:18; 127:11; 174:11 64:2;166:2,17;167:11;
‘4:6, 10; 75:12; 78:21; !7:15; 33:1, 1;74:5; 75:6;
13:9; 14:8, 10; 21:20 Iotten 35:10;68:4 68:17;169:3,8,10, 23;
~1:4,18; 99:6; 102:6; .02:19; 126:21; 161:1;
gentlemen 131:12 Government 71:7
70:1,9; 171:3,13, 15,17,
05:15; 112:11; 116:20; 74:21; 177:21
4;175:8,17,19, 22;
George 56:22; 67:13; 26:13, 14; 135:24; 144:4; %abowsky 125:10 luinea 144:3 76:3,5,8,12, 22;177:3,
108:25 50:25; 153:16; 155:23; Irabs162:23 lUyS 93:7; 104:10; 118:3 - 25;178:6;
3, 179:1
front - HANAUER (12) Min-u-script@ Miller ReuortinQ Comoanv. Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1998
hand 11:10; 25:13 ;32:17; 19:11, 13,16,17, 19; 20:5, 24:22; 28:11,15, 23; 33:18 162:4
43:7;59:21; 163:9 19; 21:5, 10; 22:8,13, 18; 29:13, 14; 51:23 ;63:8; heterogeneous 12:10; huge 66:16; 126:7; 155:7;
_.———.handle 43: 16; 86:11 23:7,7; 24:21; 25:9; 27:1, 84:22; 95:5; 108:10; 18:1; 104:19 176:18
handled 97:19; 100:25 2,3, 10,23; 28:2,6,7,11, 109:17; 117:25; 120:1,3,
high 42:22; 95:22; 125:5; Human 139:8
12, 18, 22; 29:2; 30:6; 8; 121:21; 133:15; 150:19;
hands 37:18 156:4; 164:25 humanistic 35:18
31:2,4, 10; 34:9,19,20, 152:6; 163:22; 175:1;
Hans 51:18 high-dose 69:15 hundred 154:11; 176:4;
23, 24; 35:6,10,18,19, 177:19
happen 91:22; 130:23; 21, 22; 36:2,9,15, 20; higher 59:25; 93:23; 177:5
He 10:9, 10;65:17, 17, 18;
139:24; 156:10 37:17; 38:12 ;39:16; 126:15; 140:8 hundreds 84:14; 95:2;
79:2, 9; 97:4; 98:4; 116:4;
happened 34:6, 16; 37:5; 40:12,25; 42:2,7; 43:1,4, 121:21 ;129:19; 137:8; highlight 50:16 143:24
81:11 ;99:13; 147:1 7; 44:6,19, 25; 45:8,8; 143:19; 171:9,10 highlighted 11:9 hung 39:3
happening 34:22; 63:7; 46:1,2,5,18, 18;47:16,
head 98:3 highly 94:20; lo4:7; hurting 123:19
116:13,14 22, 24; 48:7,9,10,12, 13;
head-to-head 169:8,9 127:21; 139:25 hypertension 166: 1;
49:8; 50:9,25, 25; 51:1,3,
happens 18:17; 103:12; heading 10:25; 102:6 him 82:3; 97:7; 143:21; 177:18
6,9,13; 52:1,4 ;53:1,3,5,
149:19; 170:20 heal 43:2; 170:24 175:23
6,10,11,12, 15,22; 54:3; hypocritical 166:12
happy 77:10; 85:19; 55:25; 56:16; 57:6,16,18, healed 44:8 his41:16; 116:4; 141:1
hypothesis 98:7; 157:13,
110:20 23; 58:4, 25; 59:20; 60:1, histologic 15:24; 16:7;
healing 23:12,17,18, 23; 17,20; 158:21; 159:13
hard 36:23; 40:12, 18; 13,16,17, 20;63:4;64:1, 25:24, 25; 26:1, 22; 27:18; 45:1; 49:12; 57:14, 24;
71:5, 19,20; 113:18; 155:6 20; 65:7; 66:22; 70:3,8,
30:10,14,18, 19; 31:22; 58:15
hard-to-deal-with 90:19 24;71:17;72:18, 18;
32;14, 20, 22;33:10, 11; histology 16:2 I
harder 36:21; 165:12; 73:15 ;74:1,12,13; 75:1; 42:21; 43:4,17, 22; 44:10, historical 173:17, 23;
167:9 76:2, 3; 77:10,15,17, 23; 20;45:1, 5,22, 23; 55:19; 174:19; 177:15 i4:3;5:15,22; 6:7,7,9,
82:10 ;83:2,7; 84:17,18, 57:19; 59:20, 21; 60:3,6,
Harlan 52:7; 57:6; 141:1; historically 76:1; 144:8; 12, 18;7:2;8:6, 10,12, 15,
20, 25; 85:3,3, 22; 86:13, !3,14,21, 23;61:14;77:19
178:14 173:11 15, 23; 10:2,2,4,5,12, 16,
15; 87:13,22, 24; 89:14;
harmful 173:7 health 112:8; 132:10; history 135:25 24; 11:8,10, 17; 19:16, 22;
90:11,11,19,20,20, 22;
Harmonized 145:11 139:7 20:2, 19; 22:1,8,9,14, 24;
92:5,24, 25; 93:2,7,11, HIV 178:23
Harry 130:18 14;95:1, 1,7,16, 19;
hear 48:25; 58:19; 61:12; 23:2,4,8,11, 12; 24:4, 14,
HLAB-27 14:8
30:8; 85:23; 146:8; 153:9 15; 25:21, 23; 26:4,12, 13;
Harvey 55:24; 129:23 96:13, 14;97:1, 14;98:11, HLQOL 50:3
12,21,22 ;99:13,21; heard 8:18; 9:1; 11:7; 27:8, 20; 28:6,7, 17; 30:4,
has 4:5, 13; 5:3; 9:3,9, 14,
100:4,6,9; 101:4,19,20, 12:14; 18:14; 19:2; 40:13; holding 159:10 5,13,23, 25; 31:2,2,7,8,
18,22,24, 24; 10:7, 10,
22; 102:1,11,20,23, 25; i5:8; 50:25; 56:13; 67:3; home 26:21; 27:6 8,9,10,10, 11; 32:4,12,
16; 15:20; 16:22; 19:6,8, 20,24, 25; 33:11, 19, 19;
.+=% 104:12, 25; 105:5,10, 17; $9:21; 73:20; 74:23; 76:7; homogeneous 18:25;
15; 20:21; 21:7; 26:7,8;
106:9,17,20, 25; 107:17, 30:8; 81:22; 83:2;85:7,9, 19:13; 20:1 34:2,3,5,7,7,9,17, 23;
28:8, 8; 29:7; 30:1; 32:6,
20, 25; 108:10, 16, 25; 12;86:2; 95:16;108:10; honored 141:20 36:21; 37:24, 25; 38:7, 12;
20; 33:5; 34:6,13, 16;
109:23; 112:13,17, 20; 111:16
;113:15;
115:1; 39:2,3,4,7,13,21, 25;
37:5,6, 21; 38:7; 39:20; hope 8:16, 20; 21:18;
113:17,19; 114:24; 115:1, 119:21;
134:19;
138:19; 40:1,3,9,12, 17,21 ;41:3,
41:10,10,11,15 ;46:17; 37:25; 39:21; 151:16;
12; 116:13; 117:4,13,15, 154:6 12,16, 22;42:1, 2,3,3,8,
47:5; 48:22; 49:18, 24; 176:6
21,22; 118:1; 119:14,21, Iearing 36:16; 59:17; 17;44:6,9, 13, 14;45:3,6,
54:11,11,14 ;55:1; 56:8, hopefully 10:20; 11:1; 11,12, 14;46:1,4,19;
10; 59:18, 23;61:23;
22; 120:6, 22; 121:10, 13; 113:21; 118:23; 174:17 13:9; 68:17; 129:21;
122:8,21 ;123:1,16,20; 47:4; 49:13; 50:12, 12, 15,
72:16; 74:19; 78:13; 79:9; Ieavily 38:21; 39:8 179:14
124:15, 17; 125:20, 25; 20,21,21,25 ;51:19,22,
80:12,14,15, 17;81:25; Ield 77:16 hoping 116:25 23; 52:4,7,7,9, 10, 18,18,
126:7, 18; 128:4,13, 14;
83:21 ;84:13;86:12, 16; Ielp 10:12; 11:19 ;44:22; Hospital 9:1; 46:8 20,21,22,23,24,25,25,
129:14,17, 17; 130:4, 4;
87:19; 93:25; 99:22; 36:6; 102:10; 104:14; 25;53:1, 1,3,4,5, 10,13,
131:2; 132:5; 134:3,7, 19; host 160:15
100:25; 105:17; 106:7, 11, 159:6; 165:7 17,17,19,20, 25; 54:3,6,
20;107:12;
112:9;113:17; 135:3, 12; 136:3,8,9; hour 100:18
137:2, 11,11,20; 138:15, Ielpftd 39:20; 41:13; 10, 10,15,16, 18; 55:6,
115:3,17,
18;116:15; hours 10:18
22; 139:8,14, 16; 140:15, 179:18 11,15, 15, 17,17,25;
118:14
;125:11,22; how6:20; 8:19; 13:13; 56:3,7,10, 14, 15, 16;
23; 141:20,21, 25; 142:20; Ielps 88:9
127:15;
129:19;130:6,20; 17:6, 19; 18:14; 31:12;
143:17,17, 22; 144:8, 19; 57:1,3,7,12,17, 22;
131:14,
22;132:7,24; Hemoglobin 99:15 40:13, 15; 42:14; 43:16;
146:4, 12; 148:14; 149:1, 58:12,17, 19; 59:3,6,7,
134:5;
143:7;147:9,
12; Iepatic 148:2 44:4; 52:25,25; 53:15, 21;
24; 150:2,4,10, 14,15, 10,11, 13, 14, 17;60:2, 5,
151:18;
153:11;157:16, Ier 6:9; 179:21,24 54:12, 22; 55:17, 20;
17,20; 151:23; 153:12, 14; 5,9; 61:3, 10; 62:4,4,7,
16;158:11;
160:4,5; Iere 6:20, 20; 7:23; 8:8; 56:19 ;59:2;63:11; 71:3; 10;63:1,4; 64:2,25 ;65:6,
154:11 ;155:2; 156:1,2,3,
161:21;
162:4;166:6; 10:22; 22:8; 23:21; 27:23; 72:6,8, 17; 73:11, 25; 16,21, 23;66:6, 10,12,
12,15, 23; 157:7,18, 20;
167:4;
173:10,16,17; 28:7; 32:25; 34:22; 36:16, 80:18 ;82:2,6; 85:20,21; 14,23, 25; 67:3,5,6,14,
158:6,7,8,10,14, 17;
174:1,
19;176:10,11,14, 22;50:2; 62:25 ;66:17; 86:22; 87:19; 88:10; 89:3, 17, 25; 68:9, 15, 20; 69:11,
159:2,7, 13; 160:4;
18;179:8 57:4;69:11, 19;72:4; 19;90:10,22; 99:11; 11,12,19, 21;70:2, 22,
161:22; 162:15; 163:9, 16;
hasn’t 46:25 31:24;85:21;89:5; 93:16; 100:13; 105:18; 106:18; 24, 24;71:17, 18,22, 22;
164:14; 165:9, 21; 166:15;
hat 148:22 107:24; 117:9; 121:25; 109:5,8,8; 116:7; 117:8, 72:3; 73:20 ;74:1,18; 75:5,
168:2,4,9; 169:11; 170:2,
125:20; 128:4; 130:4; 23; 119:18; 123:17; 6,12,13,19, 22;76:5, 20,
hate 170:10 14; 171:1,13, 15,25;
137:18; 141:8; 145:21; 126:18; 127:17; 130:6; 22; 77:1,8, 10; 78:9, 18,
haunted 116:15 172:2,8; 173:9,13,13,15,
150:13; 153:10; 159:6; 132:1; 135:22; 138:25; 18,21,23,24,25 ;79:1,1,
hav 115:7 18,22, 22; 178:1, 12, 16;
-—.= 177:15,19,23 145:21; 148:10; 154:10, 3,4,5,18, 23; 80:19,23,
179:4,18
have 4:19, 20; 5:25; 6:10, heretofore 130:15 12; 156:23; 157:22; 23, 24;81:9;82:1, 17,19,
13;7:18; 8:18, 19, 24; haven’t 11:12; 30:22, 24; 161:19, 23; 162:22;
leSitate 172:24 20; 83:2, 23; 84:9,15, 21;
9:12; 10:5, 14,21; 11:2, 68:4; 73:20; 86:2; 95:8; 166:22; 175:19, 22; 176:3, B5:2,7;86:3, 11,13, 13;
18, 19,21,23; 12:9; 13:1, 103:22; 104:10; 106:22; Hesitations 160:24 8; 177:3 B7:11, 24; 88:8, 25; 89:16;
10; 14:7, 10; 15:19; 16:3, 112:15 leterogeneic 40:5; however 24: 17; 58:3; 90:17,23, 24;91:15, 19,
24; 17:4.9.9.11.14.20. havent; 107:18 }9:12; 170:14 63:18; 67:18; 77:22; 22, 25; 93:6,7, 18; 94:8,
23: 25; 18:2,3,4:8, i9, 24; I having 15:16 ;22:8; heterogeneity 12:10, 12; 80:13:97:20:102:25:
-. –, 15,15,21 ;95:19,20,21,

Miller Reporting Company, Inc. Min-U-Scriptt3 {13J hand - I
Hearing Volume Number 2 Food & Drug Administration
May 29, 1998 Gastrointestinal Drugs Advisorv Committee

23;97:6,7,7,9;98:2,10; 59:9, 10;67:17; 84:3; illnesses 12:10; 166:1 25:1,3,5,6,7,7,12,15, 18,20,23,24, 25; 140:1,
99:7,11,12,16;100:2,12, ?2:15, 15;93:3; 126:18; imagine 130:21; 155:9 17,18, 2Q 26:5,5,5; 27:9, 4,21,23; 141:1,2,6,13,
=U]6, 17,24; 1o1:3,21, 141:12, 15; 147:24; 150:4; 13,21,23, 25; 28:20; 30:6; 14, 19,21; 143:3,4,5,8,9,
imbalances 116:14,21
03:8,14;104:4,24; 157:7; 158:6; 163:2 31:5,16, 20; 32:10,12,13, 22; 144:4,15,17, 17,24;
immediately 31:4 145:10,12,13,18,22,23,
.~>:l,4,5,15,23;106:3; ideal 35:2; 102:1 15,22 ;33:1,3, 11,16,20,
107:2,7,9,15;108:19; immortal 130:18 20; 34:6, 10,10, 11,12, 25; 146:2,5,7, 17; 147:6,
ideas 177:20
109:12,23,25;110:9,19, immune 12:23; 126:10 12,14,17,19,20, 23; 11, 13; 148:4,5,7,9,14,
identified 105:10, 11 15,17,19, 24; 149:13;
19,20,21;111:6,12,13, immunoiiflammatory 35:1,2,6,15,16, 24; 36:2,
17,24,24;112:1,2,3,3,5, identify 15:5; 21:17, 18, 12:23 3,5,7,7, 10; 37:5,8,10, 150:7; 151:13,18,20, 21;
6,9,10,16;113:2,14,17, 21 14,15,22 ;38:1 ,10,11, 152:7,14, 16,18, 18;
immunomodulatory
21;114:3;115:1,14,23; idiosyncratic 154: 18; 11,13,14, 16;39:7, 12, 153:4,5,5,5,7,19,21, 24;
125:4; 167:15; 168:1,3
154:1,7,19,19,23,23,
116:25;117:4,13,21,21, 156:20; 167:2 immunosalicylate
17, 24; 40:4,7,8, 11, 17,
22,24, 25;41:4, 12,14, 24; 155:1,3,3,4,6,19,22,
24;118:5,14,23;119:2, if 11:1; 20:10 ;22:11; 23:5; 167:14 23, 23; 156:3, 4,6; 157:4,
17,21;120:4,13,13,18, 24:12, 15; 25:8; 29:6, 18; 20; 42:4, 19; 43:8,11, 22;
immunosuppressive 45:10,10,17, 19,21 ;46:3,
4,10,10,12, 17; 158:13,
21;121:3,8,10,20,23; 31:7; 32:6; 33:12; 34:23;
171:18 15,22, 24; 159:8,9,12,
122:6,7,11,11,17,17, 36:13 ;41:23; 42:3,21; B,21, 24;47:4,9,9, 11,17,
impact 12:18;18:10; 14,15, 17,19, 25; 160:4,
18,19,25;123:2,5,5,10, $3:17; 44:8; 45:5; 46:5; 20, 22; 48:4; 49:3,8,8,22,
11, 21; 161:25; 162:5, 13;
13,15,17;124:4,11,15, i7:12, 21, 23; 48:4,10,18, 26:19;36:12;99:22; 24;50:14, 15,21,24 ;51:1,
113:17;132:13;145:16 163:9,15,15,21, 22;
16,17,21;125:7,8,9,25; 22; 50:24; 51:3, 25; 52:3, 7; 52:10, 14; 53:8,8; 54:2,
164:5,10,12,14,21,23,
126:1,7,7,13,18;127:2, 19; 53:3, 5,7; 54:20; impairment152:23,23 23, 25; 55:7,15, 16; 56:1,
24;165:2,4, 11,11,18,
6,15,17,20; 128:12,15, 57:22; 58:5,9,20, 22; impetus 176:19 2,3,7,10,17, 17; 57:4,17,
23; 166:5,6,7,9,17,21,
25;129:2,5,9,11,14,15,59:8,20, 23; 60:1, 12, 17, 18; 58:4,5,6,8,16, 25;
Implication 83:6, 8; 23,24,24, 25; 167:3, 18;
21,25; 130:4,4,5,10,11, ~o, 22;61:21, 23;62:5, 17; 59:13, 17,21, 24; 60:9,11,
168:14 168:21; 169:4,10,13, 17;
21,23,24 ;131:14,20; 55:9, 19; 66:16, 23; 69:12, 24;61:5, 11, 20;62:19, 20; 170:8, 12; 171:5, 20;
implications 14:25;
132:11,11;133:8,10,10, !2; 70:3, 17; 72:24, 25; 53:15,22 ;64:1,4,5,9,11, 172:2,3,10,12,14,18,
io:16
14,17;134:15;135:3,7, 73:2; 77:17, 22; 78:7, 19, 18;65:5,6,7, 13,15,17, 19,22, 24; 173:2,19,20,
,mplicitiy 118:13; 119:23 21; 66:4; 68:3, 5; 69:2;
12,23,23;136:4,12,15, ?4; 79:15; 80:16; 81:13, 21, 23; 174:8,17,22, 25;
16,16,23;137:7,10,14, 16; 83:8,10, 14; 84:2; ‘replies 64:19; 67:15,20 71:11,13, 18;72:6; 73:3, 175:2, 12; 176:2; 177:1,2,
17,20;138:11,19,24; 15:11, 14,16, 19;86:5; mportance 5:17; 11:14; 5,7,8; 74:1, 2, 10, 19; 6, 14,20,21; 178:15,20,
139:13,14,16;140:6,7, 17:10; 89:1,6,10, 21; $0:25; 90:18; 92:11; 99:1 75:14,14, 16,21 ;76:2,20, 22; 179:19
12,14,19,23;141:5,7,8; )0:11, 13;91:15; 93:3; mportant 5:16; 11:24; 24; 77:3,14, 19; 78:5,7,
inactive 109:2
142:9,11,12,15,22,23, )4:10, 14, 23; 95:2, 8,9; 12:25; 13:25; 24:5; 40:6; 13, 22; 79:20, 20; 80:5, 7;
31:3,5, 12,13, 20; 82:3,
inactivity 108:21
=2+43:6,9,12;144:1,2, >6:4, 24; 98:8, 20; 100:3, fl:22; 50:15; 54:23;
11,18,20;145:25; ZO,22, 25; 83:2,11, 23; inappropriately 100:7
i,9; 101:24; 102:10,25; 55:16; 56:2; 60:8, 22;
.:3,4,7,16,19;147:8, 106:13,20, 25; 107:10; 77:14; 80:18; 83:6; 89:5, 34:3,4,4,4,6,9, 24; incentive 81:18; 83:16
11,12,22;148:3,10,21, [10:15; 111:17; 113:24; ~2;90:4; 92:12; 93:2; 98:6; 35:15, 23; 86:3,14,21, 25; incentives 131:3,8
22,22; 149:1,1,2,3,3,6,~14:6, 21; 115:7,20,23, )9:5; 101:1; 105:11, 12; 37:19, 25; 88:9,14,15,20,
incidence 152:14; 158:2;
14,18;150:7,9,12,25; ?5; 116:11, 19, 22; 117:15, 20, 21;89:2, 11, 15;90:3,
108:11; 116:23; 118:24; 165:1,8; 167:4
151:1,12,12;152:2,5,6, 18; 118:12, 15; 119:2; 134:21; 135:9; 139:25; 5,5,9, 20; 92:9; 93:22;
inclination 118:18
10,20;153:3,9,9,12,16,[20:6, 22, 22; 121:2, 5; 144:1, 5; 147:17,19, 25; )4:6, 10,22, 22; 95:2,7,
18,22, 23;154:1,2,6,10, [22:8, 12, 20; 123:20; 20; 96:4,10,16, 18;97:9, include 15:3; 17:1; 29:3,
148:13, 18; 155:4; 157:5;
11,11,12,12,17,24,25; [25:14; 126:22, 23; 127:9; 17; 98:14, 25; 99:15; B;36:4; 43:22; 60:23;
159:25; 165:7,8,21
155:15,17,25;156:8; 100:12,22,22, 25; 101:1, 129:19; 134:17; 147:9, 23;
[32:5; 133:14; 135:11; mpossible 46:13;
157:12,14,14,18,19,24; ~37:20, 24; 138:15; 48, 12,18,20, 22; 102:5; 151:3,16
127:12; 132:2
158:1,4;159:3,5,10,11, 139:15,21,22 ;141:12,15; 103:23, 25; 104:3,4,6,7, included 25:25; 37:14;
lmpraCtiCai 132:2 18; 105:19; 106:2, 5,8; 56:17 ;60:10
19,20,21,22;160:16,20; [42:17,21; 143:11, 14;
161:19,23;162:11,12,24; [44:25; 145:4; 148:13,16, Impressed 6:12; 41:3, 16 107:1,8, 14; 108:3,6, 15, includes 29:5; 139:4
163:1,3,3, 19;164:8,9, z2; 149:1,3, 12, 16; reprove 6:4; 26:20; 22; 109:19; 110:1,3, 16; including 13:19, 23;
10;165:5, 16;166:13,19, 150:13; 151:3, 13, 18; 55:23 ;91:14, 17 111:3, 17; 112:24; 113:16, 16:12; 19:21 ;45:3; 57:13,
20,21,22 ;167:4,21; 153:17, 24; 155:15,16, 18; improved 43:8, 10; 44:9 19; 114:2,3,4,8, 15; 25; 143:9; 160:12
168:19,19,20,21, 25; 156:12,16,17, 19; 157:20, 116:14,17,17, 25; 117:5,
itIIprOVt?nK?M 19:21, 25; inChISiOn 136:18; 137:8;
169:6, 15,16,18,24; 21, 23; 158:21; 159:6 6,7,10,11,11 ;118:8,15,
27:13; 30:9; 42:25; 43:6; 149:18
170:6,10,11;171:4,21, 160:6; 163:19; 164:11, 12; 20,22,24, 25; 119:4,19,
56:8; 60:7, 14; 64:1 1; inclusive 15:7; 61:19
21,25;172:1,6,8,9,19, 165:9; 166:5, 9; 167:3; 23,24, 24; 120:1,3, 15;
65:12; 67:22, 23; 85:12;
20,22,23,24 ;174:11,12, 168:16, 20; 169:17; 121:1, 12,14; 122:3,23; incomplete 27:12, 16
105:21,22, 24,25; 110:11;
14,16,17;175:2,15,20, 171:19; 172:20; 173:4,4, 123:1,3, 20,24; 124:8,9, inconsistencies 111:14
130:14
21,23, 24;176:6,9,10, 7; 174:7, 25; 175:25; 14,18,23,23, 24; 125:1, inconsistent 107:7
improves 58:6
13,17,23,23,24,25; 176:14, 18; 177:8; 178:15, 5,6,11,12, 16; 126:1,4,6, incorporated 92:18;
177:4,6,8,9, 14,16,18, 17 improving 27:14; 91:10 7,9,12,16,19,23,24, 25; 102:20;
168:8
21,21, 22;178:7;179:3,4, ignore 118:21; 119:16; in 4:13, 18, 20; 5:1,7 ;6:2, 127:1,6,7,8, 13; 128:2,6,
incorporating 61:16
4,7,9,12,16,21 24, 25; 7:1,2,7, 9; 8:13, 7,10, 17, 18,20; 129:3,
158:12 incorrect 47:18, 19
IBD 132:12; 139:4; 143:3; 21;9:2,4,9, 13,14,19, 23; 13, 14;130:11, 13,14,16,
II 141:3 10:8,8,9, 11,12 ;11:18, increase 64:9; 117:6;
16,18, 25; 131:4,5,7,11,
177:18,24
111176:16 22; 12:11, 15; 13:15, 16, 23; 132:9,10,14,14, 143:12
15,
_A~Q 50:2; 54:16, 21;
ileal 43:2 23; 14:6,16, 18; 15:5, 15; 15,16, 25; 133:2,4,7,7,
increasing 107:19; 149:7
,8; 56:17, 18;66:10,
ileitis 46:20 16:3, 24; 17:15,18,19, 23; 10,15,21,23, 25; 134:8,
incredible 71:16; 126:6
~L, 23; 67:2,7; 89:1;
18:1,2,21,23 ;19:1,3,9, 11,12, 14,24; 135:9, 15;
128:13; 129:25 ileostomies 129:7 incredibly 6:12
12,20, 23; 20:7, 11,24, 136:3,4,5,7,14,14,17,
iceberg 121:11 ileum 46:23 25;21:1,5,
16,18,20; incurring 109:18
20,21,25,25 ;137:1,9,
ICH 161:1; 174:1 ill 165:21 22:6,9,
18,21;23:2,
18, IND 174:23
10,12, 17; 138:6,14,17,
idea 37:16; 38:25; 51:19; illness 35:4, 15 25;24:7,8,
10,15,20,24; 15,18,18, indeed 57:9; 82:1 2;
22,23;139:12,

IBD - indeed (14) Min-U-Script@ MWer Reuortim Comoanv. Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1998

160:17 17:7, 16; 50:24; 51:1, 7; 158:6, 9; 168:6; 174:12 iron 14:19 22;90:2,7,25;91:6,7,16,
independent 29:16; 57: 18; 58: 16; 75:20 interactive 97:18 irrelevant 46:13; 59:22 18,19,21,25;92:7, 8;
———_ 122:23 inflammatory 5:19; 6:3, 93:9,10,11,19,20,20,
Interest 4:6,8, 16; 5:3,8, irritable 17:10; 28:19
indeterminate 11:20; 11, 24; 9:4,7, 23; 10:1,9, 11; 10:11; 154:8; 172:22
22;94:2,4,6,15,16,17,
is 4:3,9; 5:14, 17, 18, 22;
15:16 12; 11:15,22; 12:8; 13:7, 19,20,21,23,25;95:6,9,
interested 41:4; 57: 17; 7:6,10,12,15,16, 20; 8:8,
25; 14:6; 15:1; 16:18; 17:8; 10,12,18,20,24;96:3,6,
Index 17:2, 11; 18:15, 18; 144:4; 174:17 16,17,19,21,25, 25;9:5,
20:10 ;21:8; 32:11; 39:14; 18:11; 19:10; 21:5,7; 18,25;97:4,8,11,13,20,
interesting 43:8; 47:22; 11, 13,21; 10:3,9,15,17,
41:23 ;43:22;44:1; 48:15, 38:20; 41:12; 45:19; 21;98:1,3,17,18,22;
155:21 22; 11:1,4,15, 16,24;
16;54:2,6; 71:15 ;87:5, 48:23; 84:15; 125:14,15, 12:2; 13:4,21, 24; 14:17,
99:8,23;100:2,3,4,5,5,
17; 141:2; 163:3; 170:8 interests 4:12, 13, 20; 7,10,12,14;101:1,5,6,8,
13,14, 18; 100:3,4; 156:7 23; 15:7, 13; 17:24; 18:8,
10:1 8,9,11,11,12,13;
indexed 108:6 infliximab 12:14; 15:18; 14;19:7; 20:21 ;21:4,22;
16:4; 43:3; 60:11; 83:4; intermittent 161:3 102:21,21,22;103:2,3,4,
indexes 36:15,16 22:14,20, 21;23:8,9, 14,
117:15; 124:5; 152:22; internal 73:12 18;24:5,6,6,8, 10,10,11,
21,24;104:9,12,18,23,
indicate 96:17 24;105:5,18,22,24, 25;
153:21; 154:1; 156:5; international 9:6; 37:7, 12,13 ;25:1,11,21;26:25;
indicated 62:22 167:23 20 106:3,7,10,13,15,16,
27:23, 24; 28:2,12, 16,18,
indication 22:2o; 23:11, influence 12:22 internationally 37:24; 25; 29:6,10,11, 19; 30:5, 17,18,20;107:2,2,4,7,9,
20; 27:22, 24; 30:5,14, 15, 145:11 6,8, 14;31:3,6, 11,12,12, 11,15,23,24,24 ;108:11,
inform 22:21
18;38:25;44:10,15; 12,19,20,20,24, 24; 13,14,20,24;109:2,4,5,
Information 4:25; 9:16; interpret 176:21
48:17; 49:4, 6; 50:4,5; 32:5,8, 15; 33:5,10, 22; 6,13,15,15,16,18,19,
22:10; 41:6; 88:9; 91:6,13, interpretation 94:5;
53:6, 10; 57:21; 58:1; 61:2; 34:8,9,13, 20; 35:1,4,8, 20;110:3,4,10,10,11,
16, 18; 132:9; 141:6; 121:3
62:22, 23; 63:2, 14; 64:12; 17; 36:7,18, 22; 37:2,8, 11,13,20,21,22,22,24,
142:16, 18; 146:11; 154:6, interval 164:13; 173:14;
65:3, 13; 66:2o; 80:16; 20,23,24, 24; 38:9,25, 25;111:5,7,9,11,18,21,
7; 160:16 179:15
82:20; 83:23; 85:14; 25; 39:2,3,7,13,14,14, 21;112:5,13,18,18,19,
101:9, 10, 13; 102:18; informative 97:16 intervals 85:3 22,22,23;113:8,8,14,
15,18,19,19,21,23, 25;
103:9; 107:11; 110:7; inherent 80:12, 15; intervening 19:12 40:1,3,4,9,10,11,17, 18; 15,16;114:3,6,11,20;
112:25; 113:3; 115:8; 154:20 41:5,6; 42:5, 20;43:3, 17, 115:11,23;116:3,7,14,
intervention 9:18; 44:3;
120:16; 122:4; 153:8 inhibit 155:2; 156:18 18,18, 23;44:10, 13,15, 17,24,24;117:2,4,9, 12,
78:2
indications 22:12, 15, inhibiting 78:6; 158:5 17, 18,21,23,23, 24; 13,13,16,18,20,25;
into 6:13; 12:20; 21:24;
24; 23:2, 22; 30:2, 21; inhibition 43:23; 154:21 45:11,13,25,25; 46:13; 118:5,13,18,19,23,23;
29:11 ;33:15; 35:10,21,
38:16,17, 23; 47:7; 49:15; 47:4,6,18,
25; 36:10, 14; 38:8; 45:2; 19; 48:14, 15; 119:11,14,21;120:2,4,5,
inhibitors 157:3
53:14, 15; 56:11, 14; 49:10, 16; 50:20, 23; 49:5, 21; 50:2,7,16,17, 15,18,20;121:1,2,2,6,6,
57:15; 63:23; 64:18; 65:8; initial IO:22; 64:23; 18,18,23,24 ;51:1,2,3,4,
51:15; 77:9; 78:19; 79:22; 9,10,15,16,18,19,24,
83:19; 102:6; 126:2; 71:22; 72:8; 84:4; 137:9 8,9,10, 15,21 ;52:10,11, 24,25;122:1,2,2,5,6,9,
_—_ 87:13, 14; 93:24; 99:6;
137:23; 166:22; 175:13 initiated 141:5 12, 13, 15, 17, 18,21,22, 17,22;123:6,7,21;124:3,
100:1;
105:6;
111:14;
indicators 14:25; 17:8; initiation 119:6 112:3; 117:19,20, 23; 53:4,14,19,24,24,
116:16; 4,16,16,17,22,22,23,
29:7 initiatives 160:15,21 21;121:3; 133:18; 25;54:1,1,2,5,6,7,7,11,
125:21; 25;125:9;126:1,2,8,8,
indices 17:1, 1, 12, 14; input 7:14, 15,25 ;40:8; 135:24;
145:3;
150:23; 15,17,18,22, 23,24; 12,22;127:2,7,8,17, 20;
18:20; 21:6, 11;86:14 134:4; 146:1 164:18;
168:8;
169:20; 55:4; 56:4,5,6,9,10,18, 128:3,6,16;129:1,2,9;
19,19, 23; 57:3,15, 21; 131:1,11,12;132:3,13,
individual 5:25; 13:15; insight 6:13 173:19;
174:11;
179:13
58:3,11,11,12,16,18, 13,15,17,18;133:16,21,
35:3; 61:13 ;62:2,3; 63:13; insights 9:8 intraocular
121:15
19, 24; 59:1,9, 12, 17,19, 22,23;134:1,2,5,10,11,
65:13 ;67:2;86:21; 94:22, intravenous 69:15
insist 71:7; 149:4 23; 60:6,8,20,21, 24; 16,19,20,21,22,23, 25;
25; 96:22
insisted 90:11 introduce 6:7, 8; 8:23; 61:5,22,23,24, 25;62:1, 135:11,12,16,19,22;
individualized 92:25 25:15; 46:6; 67:6
instance 46:14, 20; 3,4,8,10,13,14,14,14, 136:4,9,15,18,21; 137:1,
individuals 28:21; 95:2 introduced 9:2; 10:6,16 17,22, 25;63:1, 4,5,6,7, 3,4,6,7,8,9,14,21,22;
47:10; 60:11; 70:23; 89:7;
induce 42:21 ;60:21, 23 124:25; 125:11; 136:19; introducing 5:16 10,12,15,16, 19,21; 138:11,12,24,25;139:3,
induced 26:7 146:6; 150:6; 151:6; 64:2,12,12,16,24,25, 6,8,10,15,18,22,22;
introduction 11:2; 22:1;
inducing 26:20, 22; 153:16; 163:12; 166:6 24:7; 25:6
25;65:1, 2,4,5,9,9,12, 140:5,7,7,10,22;141:4,
50:19 ;75:10; 117:4 14, 15,17,18,19,20,21, 7,9,12,15;142:1,11,12,
instances 46:13; 90:21 introductory 4:5; 5:13
22,23, 24;66:3,4,4, 15, 14,21;143:3,5,8,25;
induction 19:21; 22:25; instead 89:1; 103:4 intuition 157:21 15, 19,21, 25; 67:8,9,10, 144:1,2,3,5,14,16;
23:10, 13; 26:16; 27:11; Institutes 139:7 intuitive 53:1, 9; 124:21 11, 14, 15,19,21,21,25; 145:14,15,19,20,20,22,
30:3,4,6 ;31:11,17,22;
institutions 139:5 invalidated 21:6 68:3,5,7,18,18, 25; 69:3, 25;146:2,9,19,21;147:9,
39:5; 42:5; 45:17; 83:21, 16,19,20,23, 24; 70:5,7,
instructions 179:11 invaluable 179:23 10,12;148:10,11, 13,16,
22; 169:21; 170:1
instrument 54:17; 66:19; 7,20,21,21 ;71:2,3,5,6, 16,18;149:8,10,13,17,
industry 5:24; 34:18; invariable 94:20
143:17 15, 18,20,25 ;72:1, 1, 1,2, 18;150:2,2,4,4,12,21;
37:21; 51:14, 22; 52:8; invariably 20:25; 29:8, 9;
instruments 34: 10;
5,8,13,17, 24; 73:7,11, 151:2,6,13,15,16,21,
53:5, 20; 57:5; 82:8; 101:4; 155:20 12, 15, 19;74:2,7,8, 12, 23;152:1,18,21,22,23,
135:19; 139:11; 153:7; 138:14 invest 131:4 18,19,21,22, 22;75:1, 25;153:3,13,13,17;
160:4, 5; 177:13, 16; insufficient 69:14 investigators 17:14; 13,18,19, 22;76:3, 12, 154:8,13,13,16;155:6,
178:3,20 intellectual 37:3 12,14,14,15,17,19,21, 11,13,14,18,20,20,21,
36:9; 95:16; 153:21
industry’s 176:25 intended 7:19; 8:8; invited 8:24 22; 77:4; 78:1, 1,7; 79:3, 22,24,25;156:2,5,7,8,9,
ineffective 25:5, 14; 40:18 ;84:1,2; 161:7; involve 5:1; 167:8
15, 19, 19, 23; 80:6, 14, 10,13,14,14,16,16,19,
_—___ 132:3 162:2 18,20,21 ;81:5,6,16,21, 21;157:3,4,7,7,15, 15,
involved 7:7; 9:3, 23; 24, 25;82:1,3,4,8,9, 12,
infant 128:5 intending 113:25; 173:4 17,17,19,21;158:1, 15,
37:22, 23; 39:8; 50:21; 13,14, 16,17, 17, 21; 17,19,20,20,21,21,24;
infants 127:23 intents 74:24 Yl&53:7; 158:13; 83:10,11,14,15,15,17, 159:3,4,5,17,19,21,24,
infection 57:19 interact 178:17
18,21,22,22, 24; 84:2,8, 25;160:8,10,20;161:1o,
inflamed 15:6; 51:3, 10, interaction 160:9; involvement 5:5, 9; 17; 85:13; 86:4,23, 24; 12,15,17,18,20;162:2,
10; 58:23 167:20 14:10 87:3,5,19,21, 25;88:14, 3,4,10,12,12,17,22;
inflammation 14:15; interactions 145: 15; involving 160:5 19, 20;89:2,9, 10,13,21, 163:1,2,4,7,7,11,13,21

Miller Reporting Company, Inc. Min-U-Scripti (15) inde~endent -is
Hearing Volume Number 2 Food & Drug Administration
May 29, 1998 Gastrointestinal Drugs Advisory Committee

23;164:2,2,4;165:4,6, 71:1,4,5,9,13,18, 19; items 37:9, 19; 38:5 Kevan 98:3
10,11,14,18,22,24; 72:1,1,2; 73:8,9,12,16, itS 7:2; 13:13; 21:20; key 40:9 L
4zzK,2,
17,23;167:9,17; 22; 74:2,6, 19; 75:3,13, 66:2o; 81:6; 85:19; 162:4; kg 126:17,18
2,7,7,12,14,14,17, 18, 22; 76:3,3,4,6,13, 22; 173:21; 174:19,19, 20;
kick-in 80:2 142:22
Au,169:4,6,7,12,16,24; 77:1,2 ;78:1,6,7,19; 175:10, 11; 177:6
170:5,7,16,17,19,21; 79:7,12,15,16, 23; 80:4, kid 144:3 label 17:25; 22:21;
itself 63:3; 95:24; 131:3 113:18
171:6,8,10,11,24;172:1, 6,9,13,17,17,17, 18; kidding 146:3
6,7,8,10,16,18,19,20; 81:14,20, 21;82:1, 13,17, labeled 62:21 ;l13:16;
kidney 145:16
173:2,5,7,7,15,20,
174:2,4,6,9,
24; 18,21,22 ;83:15,21,21,
17;175:5,5, 22, 22; 84:5; 85:2,3,11,
J kids 84:14; 101:17;
161:22; 162:8
labeling 130:15; 160:14,
124:12; 125:25; 126:5,13,
5,11,15,20,23,24,24; 13,17, 19;88:10, 13,15, 22
Janet 68:1 1;86:23; 87:8 19; 144:17; 175:22; 176:3
176:20,25;177:2,16; 20, 20; 89:4,13, 20; 90:11, laboratory 14:12, 14;
Jerry 75:5 kind 42:11; 52:4; 82:4, 7;
178:13,18,20,24;179:3, 13,20,20,22, 25; 91:12, 15:4, 8; 16:6, 15; 17:16;
14, 19;92:3, 5,7,11,24,
Jim34:7;41:4,6, 10,15 83:9; 84:15; 88:9; 95:25;
5 19:5
isn’t 42:15 ;77:4; 80:11; 25;93:17, 19, 19,23 ;94:1, Joan 4:5; 179:23 96:3; 151:5, 15; 153:4;
162:23; 164:11 lack 14:12; 17:12 ;21:1
83:9, 13; 94:1; 100:8; 2,4,16, 17,19,23, 25; job 57:8; 149:13
kinds 34:15; 38:3; 52:6; lacked 11:21
113:20; 122:16; 152:22; 95:7, 20; 96:1,14, 25; John 10:15
97:13; 98:7,16, 21; 99:23; 87:21 ;99:5; 117:9; 130:1; ladies 131:12
154:15; 169:1; 170:16; join 9:12
173:6; 178:13 100:10; 101:1,5, 22;
joining 10:15 163:25 Laine 10:14; 30:22;
102:1,2, 11,21,21; 103:1, Kirschner 9:21; 41:25; 44:25; 57:12; 58:1 1;
isolation 97:9; 135:8 joint 8:11; 9:6; 14:9;
3,4, 24; 104:18,21,23, 42:1; 64:23; 69:9, 10, 11; 61:17, 19;62:1; 64:24;
issue 4:8; 25:23; 27:20; 92:13
25; 105:5,13,14,21, 22; 84:12,13 ;85:16;96:11, ~6:18; 71:4, 10, 13;72:16,
33:1O;40:1,3; 50:8, 22; 106:16; 107:7; 108:1, 12, 10intS 123:18 21;73:23
65:23; 68:14; 73:19; 12, 22; 97:3; 101:15, 16;
13,14, 15; 109:5,6; Journal 6:24; 106:6
110:19; 111:11 ;121:7,8, landmark 73:16; 74:13
78:10,11 ;84:11;85:13, 110:11,24; 111:7, 11,18, Joyce 125:10
23; 86:1 1;87:15, 18; 90:3, 20; 122:6, 11;124:11,21; large 14:9; 92:2; 93:3;
21; 112:5,11,11, 18; JRA84:14
15, 18;92:1, 3;93:17, 25; 127:2,15,
20;128:12,22, 118:21; 135:24; 156:13
113:12, 18; 114:6,6,23,
94:4,4 ;95:13;99:8; 101:1, iudge 98:17 24;132:25;
134:5;136:5, largely 7:3
25; 115:4,6,12,17,18,
4,6; 105:2, 18; 109:25; 19; 116:17; 117:16, 18; Iudged 98:7 23;139:3,
14;140:6,14, larger 94:7; 166:8
111:13; 112:17; 113:17; 118:13,14, 14,21,22,25; iudgment 99:6; 100:3; 25;142:12,
23;144:16;
‘ast 37:6; 46:23; 49:7;
117:4; 118:6; 120:18; 119:1,11,11, 14,16,17, 134:25 146:4;
149:6;153:11;
~9:22;74:7; 84:ll;88:l;
121:24; 123:7; 129:10; 17,25 ;120:18; 121:1,2,5, iudgments 99:9; 16o:6 154:10;
156:2;159:10;
>6:11; 111:24; 119:22;
134:22; 137:17; 138:11, ~, 16; 122:17, 18; 123:22, 171:3,4,
19;175:22,23;
iumped 158:8 130:14;136:12; 177:13
--—-4; 141:2,8; 143:24, 23; 124:8,10,10,15,16, 176:4;
179:17
iUSt 6:19;
8:13,15;10:24; astly 132:4
44:10; 150:12, 22; 22; 125:3,15, 19; 126:1,2, Kirschner’s 132:20
1>3:13; 156:16, 17;
22:17;23:21;24:14; asts71:13; 72:7; 81:7
3,12, 25; 127:2,7,12, 17;
25:21;27:8;29:1,4;30:6; knew 86:6
157:18; 166:22; 172:24 128:3,6 ;129:1,11; 130:1, ate 25:3; 130:14
}3:14;34:5;37:2;40:21; knock 75:20
issues 11:8; 28:13; 29:3, 5, 14; 131:25; 132:3; ater 30:23; 39:19; 43:24;
f3:21;44:ll,14;45:23; know 10:5; 11:3, 3,4;
5;42:10;46:9; 75:4,4; 133:16,17,23, 25; 134:2,
47:21;
49:13; 50:16, 22; 78:4; 125:13,18, 23;
78:12;92:19; 93:16; 4, 13; 135:12,13,14,16, 23:8,11;27:3; 33:13;39:7; 147:20
53:21;54:3;57:12; 58:11; 40:12; 44:18; 49:2; 52:9,
100:23;
114:17; 116:6, 24; 16, 17, 24; 136:9, 18, 21;
latter 86:24
63:5,
20;68:9; 69:23; 72:4;
117:9,
10,19,22;149:17; 137:18, 19,22, 22; 138:3, 13,16,25, 25;53:15,15,
73:9;
75:6;76:1; 78:7; laudable 52: 12; 103:6
152:5;
160:5; 167:7; 20, 25; 139:10,13,15, 17, 21;55:5; 57:18 ;60:23;
80:23;
81:9; 83:5;93:3; Laughter 26:11; 144:12
174:16;
175:4; 178:15 21; 140:4,6, 22; 141:12, 74:19,21;75:23; 79:4,5,
94:1;
95:20; 96:25;97:11, laundry 30:17, 20; 102:5
h 4:3,13;5:22, 22;8:13; 23;142:1,16,21,21; 6,6;84:22,23, 23;86:5;
13;98:3,5,23;99:12;
9:19;10:3;11:1; 12:20; 143:11; 145:19, 20; 146:2, 91:20;97:7; 98:2; 99:11; hW 130:14; 131:22;
100:15,22;101:12;
13:5;20:25;21:20,24; 21,23; 147:11, 16; 148:10,
102:19;107:19; 111:2,12; 100:3; 101:3;106:25, 25; 132:10
11,13, 16,18,25; 149:1,
22:13,15;23:9, 12;24:4; 112:16;117:17; 118:21, 108:16; 114:3, 5;121:20; lead 22:4; 83:9
2,17, 18; 150:2,21; 151:2,
26:20;27:5,24;28:9,10, 21,22;119:13, 16;121:8, 124:24,25 ;125:3,7; leader 9:19
18;29:5,18;31:3; 32:2,
6; 16,18, 22; 152:12,22; 126:1; 127:5,17;130:11;
20,25;122:4;123:22; leaders 6:14
34:5,13,25;35:1,4,4; 153:3; 154:3, 25; 155:3,4, 131:23; 136:8; 137:5;
124:14;126:6;127:10; leading 9:5; 120:8
36:18;37:15, 20;39:14, 6,8,13,18,20,21, 24; 142:9;144:11; 146:8;
129:1,9;130:5;131:11;
19;40:11,18;41:7, 12,23; 156:5,9,16,17, 19; 157:5, 134:7;137:25;138:14,20, 148:5,10,13, 21;149:1, leads 20:25
42:6;43:3,5,16, 17,24; 9,21; 158:15, 19,21,25; 25;142:25;144:9; 145:4; 14,17, 18;152:3, 25; leap 65:22
44:2,4,10,11,11,13,15, 159:1,2,2,3,4,9,14, 18;
146:3,11,16,21;147:1,8, 153:20,24, 25;154:10; learn 17:18; 60:10; 82:6
16,17,23,24, 25;45:6, 160:20; 161:21; 162:3,12,
23;148:4,7,15;150:25; 155:23; 156:10,24, 25; learned 112:13; 130:21
11,20;46:2, 13;47:22; 12, 14; 163:21,23; 164:4; 157:22; 158:22; 159:1,8,
151:14;153:3;154:1; learning 14:9
50:2,12,12, 12,23;51:5, 165:2,4,11,11,18,22, 157:13;158:21; 163:7,19, 15;161:19, 23;167:2;
8,10,15,21 ;52:12,13, 25; 166:2,2,21, 24; 167:3, least 11:11; 17:17; 21:5;
24;169:10;171:4, 21; 172:20; 174:22; 177:18
16,18,23; 53:21, 23;54:1, 4,4, 5,9; 168:14,15,16, 37:23 ;39:11; 46:2, 11;
177:4,
17;178:7 knowing 71:20; 95:6;
5,7,18,20,24, 25;55:1,2, 19; 169:4,7, 14; 170:11, 74:20; 78:25; 84:3,16, 19;
@stHy 68:21 151:10; 158:15
4,6,19;56:10,12, 13; 13, 17,25; 171:11; 172:5, 93:2; 105:1; 112:2; 114:6;
19,20, 20; 173:2, 17,22, knowledge 22: 10; 46: 18; 119:18; 122:23; 125:4;
57:21;58:3,10,11,11;
i5~13,16;60:15,17,20, 22, 24; 174:6; 175:11, 24;
— K 65:22; 102:20
known 60:13, 21; 130:13;
130:25; 144:1; 152:21;
156:5; 161:7,8; 163:1;
‘1:22,
24;62:4, 5,10, 176:2, 10, 11; 177:4,7,9,
...14.14,14;63:4,6, 7, 15, 16,17,18, 23; 178:16, 146:9 171:20, 20; 172:8, 10;
Karen 6:8,14, 16; 165:15 176:11
12,15;64:24, 25,25;65:4, 18,20,21,22; 179:1,1,3, knows 43:16; 100:13;
5,5,9,14,20,21,23, 24; 10,19 keep 35:6; 83:2;126:21; 116:15; 117:4; 156:2 leave 10:21; 13:5; 68:2;
66:4,15,18,23, 24;67:11, It’s 26:10; 62:15; 72:4, 5; 143:22 Kornbluth 46:6,7,7; 71:9; 100:25; 138:1;
18,21,25;68:7, 13;69:2, 103:11 ;111:22; 129:23; keeping 85:23 47:20; 48:2,4,8,12, 15; 146:16; 172:24
4,19,23,25;70:7, 18; 169:8,9 Kerwin 106:5 144:22,23 Ileaves 144:9

~n~t - leaves (16) Min-U-Script@ Miller ReportinQ Comoanv. Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1998

lecture 11:5 141:5, 23; 143:23; 148:15; 8;153:25;
160:7; 164:4; 24:2,3,5, 16; 25:5, 14, 17, matching 29:4
Ied 9:16; 15:20; 104:3 149:10; 150:1, 6; 152:3, 168:6,
15,20; 173:13,14 20; 26:3; 27:24; 31:8,9, material 130:11
_—- ieft8:25; 14:14; 16:2; 20; 160:6; 163:2, 19; looked 43:24; 48:16; 11; 39:6; 78:24; 79:13, 23;
matrix 33:3,7
118:3 164:8, 10; 172:23; 174:11, 70:3; 81:25; 98:25; 115:11; 118:12; 168:5
matter 4:18; 64:25;
13; 177:9,9; 178:21 105:12; 126:20; 168:22, major 9:25;
10:8;
16:22;
leftover 90:19 94:23, 25; 95:7, 24; 167:3
likelihood 17:17; 93:11 23;177:21,22 56:1;
66:25;
83:9;139:12
Iength71:21; 72:14 ;74:2; MATTHEWS 47:21; 48:3,
166:24 likely 95:1; 116:20; 125:1; looking 22:11; 38:2; mSjOrity
25:12;97:24;
6, 14;80:23;81:3, 16;
127:21; 132:3, 14; 145:14, 66:13; 75:6; 80:16; 88:9; 123:12;
148:14
leprosy 75:14 82:16 ;83:14
15; 172:9 96:20; 97:2, 17; 100:23; make 8:14; 10:3; 26:21;
lesions 16:12,12, 13; maximum 69:18; 161:6
Likewise 53:7 105:15; 109:7; 116:3; 30:4; 41:23; 42:7; 45:6, 24;
27:1,4 ;43:5, 10;44:9 may4:23; 5:10, 12; 12:16,
limit 7:19; 11:1; 147:13 118:20; 119:10, 19; 48:23; 50: 16; 56: 18; 57:8;
less 66:4; 73:8; 77:3; 126:21; 128:13; 132:18; 61:22; 65:25; 71:15,21; 18,22,25; 13:5,7,18, 25;
86:24; 87:15; 96:13; limited 44:21; 114:17; 14:1,1, 1, 1,7, 10, 17, 18,
145:5; 150:9; 152:16, 16; 87:13; 88:17; 89:16, 25;
101:25; 102:3, 21,22,23; 124:25 19,19, 20; 15:1,4, 14;
156:25; 157:16; 158:23; 93:14; 96:1; 99:9; 100:3;
103:5, 21; 105:25; 108:5, line 33:20; 54:19; 82:9; 165:8; 166:12; 174:15 16:4; 22:18 ;23:7,7; 24:15;
112:16; 123:2; 131:7;
5,9,10, 12; 109:5 132:12;
141:8;
147:3 26:18; 27:9; 28:9; 29:15,
lookout 147:21 136:1; 143:19,21; 151:5,
lesser 112:10 linear 15:12; 88:13; 100:9 15, 20; 152:23; 159:7; 21, 24; 30:9; 32:19; 35:14;
looks 15:24; 169:17
let 22:4,7, 17; 71:1; 80:3; lines 41:24; 141:20; 160:14; 164:8; 177:7,8 46:3; 52:14; 56:11, 12;
[OOSe 113:8 58:14; 59:25; 60:1; 64:2o,
89:25 ;112:11; 121:5; 153:1 ;167:11 makes 30:24; 50:13;
132:19; 136:7; 137:16; Loren 75:12 20; 71:18; 73:2, 5; 75:9;
linked 162:3 71:10; 159:14
141:12; 143:10, 11;145:7; loses 85:19 78:4,8 ;80:7;81:18; 82:23;
list 13:21; 15:7; 30:17, 20; making 33:19; 35:7; 84:17; 89:11 ;93:13;
169:10 37:14; 102:5; 132:8 [OSing 15:2,3
40:22; 53:20; 90:9, 10;
let’s25:2;
71:10,15; 94:22,23, 25; 95:1, 3;
lists 132:12,13 [0SS 13:23; 51:6,7 96:6; 103:5; 116:22;
79:22;116:9;119:13; 97:23; 98:19, 21; 108:12,
literature 24:15; 96:19; lot 6:14; 33:2; 34:3, 10; 155:25; 159:3; 165:5; 13; 109:16; 114:24;
158:20,20,24;168:17 35:19; 38:22; 39:3; 50:25; 166:11
101:19; 131:16 115:17 ; 116:16,21;
letter141:1 51:13 ;52:13; 54:11; malabsorption 15:2
little 5:21; 23:13; 33:6; 118:10; 125:17, 19; 126:3;
leukemia 31:4 57:10; 60:10; 86:13; maldistribution 100:5 132:9; 134:4; 139:23;
35:22; 37:4; 54:12; 64:12;
leukocyte 15:6,6 67:13; 88:16; 93:16; 140:8; 142:5, 7,8; 146:9,
56:4, 11; 71:5; 76:4; 81:9; man 82:2
leukocytes 15:5 104:1, 12; 112:13; 117:21; 15, 23; 147:3; 154:19, 20;
32:17; 88:17; 92:7; manage 33:21
126:10; 128:1; 129:22;
Leuven 9:14 111:15; 121:8; 134:16;
manageable 160:19 155:2,3,4; 158:10, 13;
130:21; 135:24; 142:16; 159:18; 162:1,5, 14;
level 12:25; 14:15; 16:18; 135:11; 138:3; 157:1;
.—
—— 145:14; 154:13; 155:2; managed 47:13 165:11; 167:3,4; 168:2,4;
18:15, 19; 19:10 ;26:19; 174:12, 13; 175:15
160:16; 165:8,12,19, 20; Management 41:5,9
27:14; 31:19; 33:23; liVe41:18 172:16; 173:21,22, 22;
174:21; 178:11 mandated 132:7
41:20 ;64:24;65:1; 67:21, lived 28:7 174:22, 23; 176:20; 178:4
lots 44:18; 97:17; 121:12; mandates 130:14
22, 23; 83:22; 86:22; 95:4; maybe 43:18; 49:4;
kr 145:15; 152:23 135:18
108:20; 119:8; 136:24; manifestations 14:4; 53:23 ;54:1;72:4,4; 81:7,
living 58:7 10Ve 117:22
174:20 29:16; 170:23 19; 103:18; 105:13;
local 142:9 IOW 44:8; 93:7; 106:3; 124:14, 14; 125:23;
levels 87:23 manner 19:9
location 12:12; 13:8 152:13; 158:2 126:12; 138:2; 147:20;
liability 160:5 manufacturers 131:4,8,
logarithmic 100:11 low-incidence 157:25 148:15,19
life 10:11; 20:21; 21:4,10, 21
logic 50:20, 22; 164:18; lower 88:15, 21; 94:8; me 8:10; 11:3; 22:4,8, 17;
12;23:24; 28:14 ;39:19; manufacturing 174:21
165:6 122:9; 136:18; 144:25; 31:3; 32:2; 44:25 ;45:5;
50:1; 54:17, 20; 57:10; many 7:7, 8; 9:4; 16:12;
logical 40:8; 111:13; 147:9 52:11; 53:3; 59:16; 62:5;
65:13, 20; 66:19; 67:19; 17:9; 18:6,8; 21:11; 28:20;
165:4 lowered 176:10 66:18; 71:1; 72:4; 75:3;
79:8; 82:25; 101:13; 33:22; 34:12; 42:9; 55:20; 78:18; 79:12; 89:25;
125:16; 130:2; 160:8, 8; long 25:18; 32:6; 34:13; lowering 137:8 74:21; 86:22; 89:19;
165:14
91:18, 23; 104:3; 106:10;
35:5, 5,9; 36:2; 42:12, 22; lucky 114:5 90:10,22; 94:1; 95:5; 116:15; 132:19; 137:16;
life-threatening 83:8; 43:11;72:7,8, 17;74:1; 99:21; 101:4, 17; 109:10;
lunch 10:18; 100:18 143:20; 145:7; 151:25;
76:16; 77:13; 79:9; 80:18;
163:16; 165:16
109:5,8,8; 110:12; 112:8,
klf3US 38:12; 104:1,4,18 111:3; 114:7; 123:17; 155:8; 169:10; 170:25;
lifetime 79:2, 3; 163:6 125:19; 128:15; 136:14; 176:6
15; 118:25; 119:19; 138:6, 17; 139:5; 140:18;
light 107:8 mean 31:11 ;40:1;44:11,
like 4:4; 6:8; 8:12; 23:2;
135:13 ;146:13; 147:1 M 145:16; 147:11; 148:6;
13;58:12; 59:11, 13, 17;
long-term 41:14 ;42:15; 153:14; 156:23; 160:12,
29:22; 33:16; 35:3, 23; 60:7; 63:3, 4; 64:25; 67:5,
56:14;84:23; 112:5; 12; 162:22; 163:15; 166:7,
37:16; 39:14; 40:14; made 4:9; 45:23; 66:2, 8; 6, 16;68:14; 69:12 ;71:17;
161:2, 16, 17, 20; 162:19, 7; 167:7, 25; 169:11;
42:17 ;47:4; 49:3,14; 75:12 ;87:13; 90:14; 74:1; 76:13,13 ;80:12;
22; 167:23, 25; 168:3,4 175:12,19,22, 24; 176:3,
50:12, 16; 51:19, 23; 52:4, 104:21; 116:7; 132:4; 83:2; 85:17; 86:18; 87:4,
longer 29:12, 13; 38:2, 3; 6;177:1,3
14; 53:6,10,11,12, 17, 159:23 18; 88:10, 24; 89:8,15,20,
20,25;54:10 ;66:16; i3:12; 58:7; 73:25; 78:13; margin 19:9 23;90:19; 91:2, 3,3,4,4,
magnitude 99:4
67:17 ;70:22; 71:8,17; 31:14;86:25; 105:15; mark 22:14; 32:11 5,9,10, 22; 92:2; 94:9;
161:3; 168:11 mainly 73:7
72:5; 74:18; 77:8; 82:22; marked 124:15 95:21; 96:7; 97:2, 24;
longitudinal 78:8 maintain 41:13 ;43:12;
85:10,25 ;86:1; 88:12; marker 21:18 98:13; 105:5; 107:9;
54:14;75:8, 18,21 ;77:12;
.—.= 89:16; 90:23; 95:23; ook 8:6; 19:12; 21:20; 110:21; 121:10; 126:4, 13;
79:18 market 133:23; 141:14,
97:1O; 99:20; 103:3; Z3:22; 25:8; 31:7,8; 48:19; 127:20; 135:23; 136:23;
maintained 24:12, 12, 24; 148:16; 175:14
111:12 ;112:6; 116:1; 50:22; 72:10; 73:16; 74:4, 138:24; 140:7; 142:15;
22;41:10; 119:8 marketing 141:16; 163:9
120:13,14; 121:8; 122:23, 14;84:5; 88:10; 89:4; 146:8; 153:12, 16; 154:11,
24;123:21; 124:4, 11; ?2:18;93:21; 97:9; 98:5, maintaining 28:1; 75:1 1; marrow 29:23; 146:8; 12; 158:12; 159:11; 163:2;
125:6, 8;126:8; 128:20; ?3;108:15, 23; 122:2; 108:20, 22; 117:2; 121:17 167:2 168:20; 170:13
129:9; 130:10; 134:15; 137:24; 138:3; 147:20; ?IiZtitItWItirrCt? 19:22; mass14:1 meaning 15:18; 80:16;
135:7; 136:5; 137:1; . 149:16, 23; 150:1; 151:4, 20:15, 17, 18; 23:1,4; master26:8 67:4; 164:15

MWer Reporting Company, Inc. Min-U-Script@ (17) lecture - meaning
Hearing Vohune Number 2 Food & Drug Administration
May 29, 19$)8 Gastrointestinal Drugs Advisory Committee

meaningful 5s:10;76:19, mentioning 53:25; models 34:21 Most 11:3; 22:6; 24:18;
25; 77:4; 78:20; 94:15; 178:15 moderately 148:18 26:25; 35:21; 46:20; N
&’”8, 9, 18; 99:7; 108:11, mentions 175:4 modern 97:8; 100:12 54:23; 55:16; 56:2; 62:7;
11:16; 112:7; 132:1 76:20; 89:12; 104:25;
met 9:11; 10:14, 15; 20:2; Modernization 130:13 n 63:13
l,~eaningless 80:14; 90:8; 162:14 112:19 ;120:4; 121:11;
modest 176:14 naivete 55:15
91:1;
99:24 123:20; 125:20; 131:21;
metabolic 29:24 modification 44:2; namely 23:17; 53:9;
means 13:21;
15:7; 136:13, 15; 160:1; 164:20,
metabolized 159:18 99:25; 154:20 107:4
20:17;
21:10;
29:13; 20; 167: 18; 172:9
31:24;
52:11;
53:2;
67:10; metaphors 26:9; 29:4 modifications 129:17, narrow 88:21
mostly 114:16
81:1;
95:20,
20,21; method 40:8 20,22 National 34:8; 139:7
mouth 127:7
106:15;
107:4 methodologic 117:9 modified 19:23; 27:6; natural 77:19; 135:25
meant 76:25; 77:1; 92:5; 30:2; 63:23 move 10:22; 35:15; 37:3;
methodological 116:6 49:13; 68:17; 94:14; 95:2; nature 71:20; 76:14
157:19; 179:10 modifier 78:2; 96:17;
methodology 144:24 114:9; 174:11 nausea 13:20; 28:23
measurability 68:12 157:2
methods 42:13 moved 34:23, 24; 35:21, nay-sayer 142:25
measurable 28:13, 14; modifiers 154:25; 167:6
methotrexate 168:7, 13; 22; 49:8; 174:13 nearer 72:11
29:19; 68:7, 9; 73:1; 92:8 modify 21:25; 68:22;
171:9; 172:3 movement 35:18; 61:11; necessarily 5:25; 16:1;
measure 17:25; 23:16; 129:16
metric 59:13 92:1 17:5; 21:23; 23:8; 25:23;
30:7; 31:5; 33:14; 36:23; Modigliani 115:18
42:12 ;43:24; 44:17; mg 101:24, 25; 102:3,3, movements 18:9; 40: 15; 45:3, 15; 52:8; 54:15 ;64:4;
21,24; 103:6,10, 21; molecular 152:25; 153:1 72:22; 121:4; 127:4;
46:13; 49:4; 52:16, 25; 93:9,9, 12; 94:20, 24;
53:16; 55:5; 64:11 ;65:20, 105:8, 25; 106:21; 111:3, Molndal 51:18 148:19; 150:2
95:5,7; 99:21,22
23; 67:9; 69:25; 72:9; 73:8, 6; 115:16; 121:12,17, 17, moment 13:6, 10;42:19; necessary 101:14;
moving 9:8; 36:20; 38: 1;
21;74:14; 80:13 ;87:19; 22; 123:7; 126:16,17 43:16; 57:2; 60:1; 143:1; 126:25; 127:7; 128:3, 6;
61:9, 11;160:25
92:17,22; 107:24; 108:14; mgkg 42:23; 115:18; 149:12 136:17; 165:22; 179:20
118:7; 143:17; 170:15 MP 143:8
124:10; 126:14, 21; moments 56:23 necessitating 19:25
measured 35:2, 3; 49:6; Mr7:3; 154:2
153:17; 171:20 money 177:17 necessity 42:2; 74:17
54:5; 66:5; 69:20; 73:10; microscopic 16:1 monitoring 9:15; 43:9 MRI 44:22
need 5:4; 8:19, 22; 11:2;
93:1; 103:15; 104:22; MS 4:7
middle 148:7 monotherapy 178:2,5 12:5; 16:5, 17, 21; 17:18;
108:4
midget 131:13 month 56:7, 9; 75:15, 23; Mt 9:1;46:8 18:11, 13;20:12; 21:11,
measurement 54:24;
midway 179:6 83:8,10, 13; 85:2; 86:6; much 5:23; 7:20; 9:3; 15, 17; 26:3, 12;32:18;
55:7; 73:13; 80:5; 88:25;
109:9; 111:19; 115:20; 11:9; 12:20 ;35:5; 41:3, 24; 42:11; 48:19, 20; 55:9;
_~16, 17;97:11;
100:6; might 34:5; 35:24 ;46:24;
122:16; 123:22 55:24; 60:13; 72:2; 76:13, 57:4; 62:16; 66:9, 10; 67:1;
‘“12 47:1,2,16; 78:1; 90:11;
months 39:ll; 43:2; 14;78:13; 83:25 ;88:14, 70:24, 25; 75:3; 78:12, 21;
-surernents 35:20; 92:13,13, 14; 100:8;
56:10 ;68:21;73:6, 15, 16; 15; 94:6; 96:13; 105:18; 80:23; 82:6, 9; 83:9; 89:14,
46:19; 79:9; 92:18; 93:5 107:22; 108:14; 114:22;
74:6,8,11,21, 22;75:1, 3, 112:6; 119:16; 125:1; 19;90:9; 110:15; 112:14;
measures 23:20; 24: 1; 116:20; 118:2; 133:24;
23; 76:4, 12; 77:3, 4; 113:9, 21; 115:6; 127:9;
143:14; 146:21; 147:2; 126:15; 127:24; 131:20;
35:23 ;36:10,11,11,11, 128:10; 136:4, 14; 137:13;
148:25; 151:22; 154:18, 78:13,16,19, 25; 79:4,6, 134:5; 143:9; 145:19;
20, 21; 38:3; 40:4; 58:4; 138:3, 22; 140:10, 11;
22, 23; 155:5; 157:5; 10,11,14, 16;80:7, 14, 149:20; 152:3, 24; 166:1
67:5; 86:15; 99:20; 108:6 15,20, 21;81:9;83:24; 144:5, 16; 145:2; 151:20;
160:19; 162:13; 166:7; mucosa 36:22; 50:24;
measuring 16:17; 36:21; 84:3; 102:12,13, 13; 153:14, 22; 159:12;
171:10 51:1,3
54:19; 59:5; 73:20; 105:1,9,13,14,15, 16; 161:23; 168:6; 173:9;
108:17; 118:6, 10; 159:7,9 mimic 15:14; 117:7 mucosal 23:12, 17, 18; 179:21
109:9,10, 11; 111:14,19,
mechanics 138:25 mind 35:6; 83:2; 85:23; 20; 116:1,2; 123:13, 17; 25:23; 27:18; 28:1 1; 30:9, needed 48:9; 112:15;
109:22; 143:23 131:6,7; 137:17; 144:6; 10, 14; 31:22 ;32:14; 132:5
mechanism 154:20;
158:23 mindedness 22:14 161:3,7, 14; 162:17; 33:1O, 11;42:21; 43:17; needs 10:4; 20:18; 76:7;
mine 41:ll 163:1, 5; 164:19,21,22, 44:10; 45:22,23 ;49:21; 79:11 ;95:13; 142:2;
mechanisms 153:1
mineralization 110:23 23 59:17,18, 21; 60:3, 23; 145:12
Medera 56:22
more 5:23; 18:8; 19:12; 105:20
median 86:19 minima146:15; 71:2,25; NEEMAN 47:19; 48:7, 10;
72:13 ;89:15,24;92:10; 21:22; 33:17; 35:18, 19; multi-dose 137:1 61:5; 74:12; 84:7; 103:14,
mediators 16:18
163:8 37:17; 38:6; 39:23; 40:10, multifactorial 29:2 22; 171:21, 25; 172:6, 18
medical 24:4; 50:8; 81:6 17; 41:24; 47:3; 48:2; 52:9;
minimize 148:9 multiple 65:7; 176:11 negotiated 166:21
medication 24:9 55:11; 57:17; 59:24;
minimum 69:17; 70:20; multiplicity 118:2 neighborhood 175:2
medications 148:1 60:13; 64:15; 67:16; 76:4;
71:6; 74:19,20; 78:16; multiply 99:23 neither 16:1; 54:21;
84:25; 85:4,9,10,13,13,
Medicine 9:13; 106:6; 85:25; 102:12, 18; 161:5; 69:21
14, 25; 86:1; 88:25; 93:20; must 23:14; 74:6,7, 10;
131:13 163:13
94:2; 97:15, 19; 102:22; 131:17 neonates 128:5
meeting 4:4,9, 10, 11, minus 149:18 111:11 ;112:2; 114:10; mutually 36:3 net 77:17
16;5:14,15,17,21,23; minute 6:19; 11:5 115:16; 116:20; 118:9;
6:8; 7:17; 8:17; 20:23; my 6:18; 8:8, 13, 25; never 103:12; 153:12;
minutes 34:6; 75:12 125:1, 22; ’130:19; 134:4; 10:17, 22; 22:14; 25:21; 179:10
9SS2; 138:20; 140:16, 18; 136:13; 142:22, 23; 143:9;
miserable 122:22 28:25; 46:17; 49:14; 50:4; new 8:18; 24:7, 7; 25:6;
145:14, 15,21, 25; 147:8; 55:15, 17; 57:6,12, 14;
member 9:24; 10:15; misperception 84:16 26:5; 32:17; 46:8; 47:14,
148:16; 149:8,8, 20; 59:9; 61:20; 63:15; 81:16;
=-4; 56:25 missed 69:12; 113:2 16,23, 25; 48:8, 12; 64:7,
152:5, 8; 159:25; 160:19; 83:14, 17;84:16; 105:16;
missing 107:2 9;74:6,17; 84:22 ;85:11,
nbers 5:25; 6:7, 18; 163:11, 13; 164:15; 112:10; 120:14 ;121:19; 22; 106:5; 107:17, 19, 21;
22:18; 129:16 mixing 26:9; 27:9; 29:4; 165:23; 166:1; 169:24; 122:23; 123:18; 127:2; 114:15; 119:6; 127:7;
mention 6:21; 8:10 109:12 170:6 130:19; 142:1, 22; 143:4; 131:22; 134:1; 135:8;
mentioned 11:17; 46:17; mixmaster 26:10 morning 49:9; 100:17; 144:3; 148:22; 152:7; 141:11,14; 148:5; 154:13;
57:7; 65:12; 80:3; 107:25; model 19:5,7, 12; 20:16; 123:20; 170:11 158:1 166:3,8,10, 11; 172:9;
118:15:139:7 144:24 mortality 36:10; 77:10 myself 95: 17; 140:20 178:10,24

meaningful - new (18) Min-U-Script@ Miller Reporting Comoanv. Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29, 19$)8

newly 25:15 69:16,17, 20;71:16, 18; 173:3; 175:15, 17,25; 13, 14,16, 22; 30:2,3,4,6 15,23,25, 25; 100:7;
next53:23
;95:1;
116:4; 72:9, 22; 74:7; 75:1, 11; 176:14,23, 24; 177:12,23 7,8,8,9,10,11,13,14, 101:10,11,13,17, 18,21;
____ 124:4;
127:8;
134:10; 76:21; 77:8, 16; 78:7, 8; numbers 40:15; 55:10; 15,20,21 ;31:3,7,8,9,9, 102:1,2,5,6,7,11,14, 18,
162:18;
164:15;
167:19; 79:12,15,16,20,22, 24; 67:6; 84:6; 93:5; 100:1; 11,11,13,16,17,18,22, 23;103:1,1,5,5,16, 17;
179:15 80:3; 81:20, 21; 82:23, 25; 149:7;
150:3;
152:18; 24;32:3, 13,18,19,19, 104:1,4,12, 16,17;105:8,
nice 36:23; 97:13; 103:1 83:1,4,5,10,20, 24; 155:7,
8;162:5;
163:8,
25; 22;33:1,2,5,6, 10,11,13 12;106:6,6, 16;107:3, 14,
nicer 39:25
85:13, 20; 87:12; 89:13; 164:15,
18;174:14;
177:8 15,16,16,19,22, 23; 15,20,24,24, 25;108:15,
90:20; 91:9, 21; 93:2,5, 34:1,3,6,6,6,10,11,15, 18,20, 20;109:5, 15,25;
night 88:1
NIH 34:9; 137:20
10; 94:16,17,22,23, 25;
95:8,10, 21; 96:8; 97:25; 0 21, 25; 35:4,8,10,
20; 36:3,12,14,14,18,
14,17, 110:2,3,6,7,12,12,14,
16,17;111:1,7,13, 14,
no 4:15; 11:4; 13:21; 15:7; 98:19,21 ;99:12; 102:14; 19, 22; 37:2,3,7, 12,13, 18,18, 19;112:4,5,8,13,
30:3; 43:11, 12;44:16, 16; 103:16, 18; 104:2, 23; 0116:4 15, 18,25; 38:1,3,12,19, 21,25;113:4,6,6, 14,15,
46:15, 18;51:3, 13;52:11, 105:11, 14; 106:7; 108:7, 22, 24; 39:3,17, 19; 40:5, 16;114:4,7,7, 11,16,19,
o’clock 4:3; 10:20;
15; 53:8; 59:6, 17; 60:6; 13, 16; 109:18; 110:11; 10,12, 15,16,22,24,24, 21,25;115:11,16,16,19,
100:19,20
62:6; 64:25; 66:19; 68:7; 111:5,8,22 ;113:16; 25;41:12,17; 42:1,2,3,4, 24;116:1,7, 15,24; 117:2,
objective 13:22; 17:4, 21;
69:9; 70:6,8,10, 19; 114:6, 18,21; 115:10,21; 4,5,9,9,11,13,22,23, 4,6,9,10,10, 12,19,21,
29:21
71:13 ;80:12,14;81:18; 117:14, 18,20; 118:2; 24; 43:4, 23; 44:1, 1,3,3, 21,24;118:2,6, 11,16,
91:12; 103:9; 105:13; 120:11, 19; 122:8,13, 25; obliterate 118:10 4,7,12,14,18,20,20,20, 20,23, 24;119:3,6,8,10,
111:11 ;113:10,11,23; 123:13; 124:8,10, 19,22, observation 93:5; 22,23, 24; 45:9,12,13, 15;120:5,7, 18;121:3,5,
115:18; 120:6; 122:13, 13; 22; 125:24; 127:3,23, 24; 157:13 14,17,18,20,22,23,24, 11,12,19,23,24; 122:15,
126:18; 130:4, 19; 131:12; 128:25; 129:18, 25; 130:6; Observations 106:7; 25; 46:9; 47:1,5,6,9,13, 21,24,25 ;123:1,2,4,6,
132:1; 139:16; 143:5, 22; 131:11; 132:21,22; 133:1, 158:12 25; 48:20,22, 25; 49:1,2, 11,12,25 ;124:3,21,23,
146:10 ;150:18; 151:13, 10; 134:7; 135:13, 17,22; 4,5,8,13,16,18, 22; 50:1, 25;125:3,4, 11,12,12,
Dbserve 158:25; 159:1,2
15; 156:7; 157:7,8, 18; 19,20, 21;126:3,4,6,6,8,
136:2,3,18, 21; 137:7; 5,6,8,15,25 ;51:7,7,13,
158:6; 159:14, 21; 165:1; Dbserved 133:12;
138:4,4, 25; 139:6,23, 25; 16, 19, 19,20,20; 52:1,3, 10,15;127:2, 11,23,25;
168:19; 169:4; 170:5; 163:23;
178:17
140:12, 20; 141:12, 16; 4,5,6,12,13,13,15,17, 128:1,4, 15;129:3, 10,17,
171:14; 176:8; 178:6, 18 Dbserving 157:10; 22;130:1,2,8,15,22, 23;
142:7; 144:2,6; 145:8, 19; 21, 22; 53:4,8,13, 19;
Nobody 43:16; 159:19 164:24; 165:1 131:5,8,21,24 ;132:8,9,
146:24; 147:5,6,10,12, 54:3, 11, 17, 19, 19, 20;
nodules 58:8; 59:1 16, 25; 148:3,7, 19; obstruction 23:24 55:4,9, 10, 18, 22; 56:1, 1, 13,13,14;133:15,25;
noise 59:4; 118:22 149:11,20; 150:2,8, 16, ~btained 4:23 5, 15, 18,23, 24, 25; 57:1, 134:1,11, 11,12,17, 19,
non 18:7 18; 153:6; 154:4,5, 12,17, obviously 20:18; 21:25; f, 5,8, 19, 22; 58:2,5,12, 20;135:3,4,8,9, 15,17,
25; 155:4, 6,7; 156:10,15, 36:2; 89:21; 105:5; 13, 20; 59:8,9,10,13,22, 18,18,24,24, 25;136:14,
non-fistulizing 19:2 15,23,24;137:14, 19;
———. 19; 158:1,7,11, 17,21; 133:21; 159:25; 163:21; 25;60:2, 25;61:21, 23, 25;
non-inflammatory 138:4,4,13,17,24, 25;
160:2; 162:3,5,8,12, 14, 165:25 52:9,9, 11, 12, 12,21,24,
18:10, 12 19; 164:6,9, 21; 165:1,3, 24;63:1, 10,12,12, 13, 139:5,7,8; 140:16,18;
>ccur 14:6; 39:18; 125:1;
nonbiologic 157:2 7, 22; 166:17,21; 167:3, 13,16,16,19,19,20,20, 141:3,8,9, 22;142:3,7,
164:20,21,22,23
nondisease-specific 24, 24; 168:1,22, 24; 21;64:1,13,18; 65:2,10, 14,16;143:6,9,24, 24;
)ccurred 42:6; 116:1 144:6,7, 10,24;145:2,4,
167:1 170:23; 171:5; 173:16; 13,15,20,22, 24; 66:1,3,
174:4; 176:6, 21; 177:20; >ccurring 165:10 7,9,10,19, 24; 67:2,5,8, 5,13,16,17, 18;146:6,6,
nonetheless 28:10
178:4,20 >f 4:6,8,8,9, 10, 15,16, 10,12,15,17,19,20,22, 11,14;147:5,10,11,17,
nonlife-threatening
22,23,24, 25; 5:4,8, 11, 24;68:2, 3,4, 14, 15, 18, 18,19,25;148:1,4,5,7,8,
161:4; 165:24 note45:12;69:21; 156:24
~7, 18,22.23.24:6:1.2.8. 19, 22;69:21;70:1, 12, 16; 9,11,14;149:2,7, 11,25;
nonspecific 14:14 noted 5:5; 45:15; 133:4
IO; 12:13: 14; 15: 24;’7:3, ‘ 71:2,9,20,21,22, 25; 150:3,3,5,5,9,11, 15;
nor 129:18 notes 161:25 7, 12,17, 25;8:1,4,
17,177 72:7,11, 14;73:1,4,4,6, 151:5,8,9,15,22,25;
normal 28:21;
93:12; nothing 55:19; 70:4; [8, 24;9:1,4,7, 13,15, 17, ?, 9,12,12,22, 24; 74:7, 152:16,21,25 ;153:1,4,
121:16 164:24 ~2, 22,23,25, 25; ~o:7, 8, 17,20,21,23,24, 24; 14,20,25;154:7,13,20,
normality 100:8 notion 111:3 10,21, 25; 11:2,3,14,15, 75:7,8,8, 9; 76:3,8,14, 21;155:1,14,16, 20;
novel 44:7; 142:4 ~9,21, 24, 24; 12:1,5,10, 15,16,18,19, 24; 77:9, 156:1,6,8, 15;157:9, 10;
normally 71:21; 137:9
[1, 15,16,17,22,25, 25;
13,17, 19;78:5, 5,5,10, 158:8,9,15,16, 25;
normative 77:19 now 7:13; 8:8, 19; 10:24;
[3:2, 5,6,6,8,15,19, 23;
12, 15; 79:3,8,8,10,13, 159:14, 22;160:2,4,8,8,
North 96:15 11:14; 12:8; 14:4; 27:15;
14:3,5,14, 15,16,21,23,14,15, 16;80:4, 5, 11, 25; 15,16,20; 161:2,5,9,13,
30:22; 37:20, 23; 43:3;
not 5:2,22, 25; 7:19, 23; ~5; 15:2,3,5,7, 10, 11, 15,
31:1,4,6, 14;82:4, 5,7, 15,23;162:1,23; 163:5,7,
44:22; 63:10; 80:24; 81:9,
10:18; 11:17; 12:16; 13:4, ~5,21,24; 16:7,11,18, 15,21,22 ;83:5,6,6,7,9, 15,23,23, 25;164:4,5,9,
13;87:17; 102:1; 108:10;
10, 16; 14:1, 1; 15:17, 19; 15;17:3,3,6,8, 12,12,15, ), 16, 21,24; 84:3,9,14, 11,11, 18;165:5,6,8,17,
109:23; 110:8; 131:22;
16:1,3, 14, 19, 19,21; [6,16,17,21;18:2,3,6,8,15, 16,24 ;85:5, 11,13, 17,19,24;166:4, 22;
133:7; 135:17; 140:12;
17:5,8, 25; 19:6; 20:5; [0,14,15,19,25, 25; ~5; 86:3,4,7,9, 15, 16, 18, 167:1,4,7,8,12,25;
141:15; 142:23; 146:13;
21:23 ;22:8,9,18; 24:12; ~9:3,4,7,10,11,13,21, 22, 23; 87:2,3,5,6,9,9, 168:2,3, 13,22, 24;169:1,
147:1, 12; 150:14; 160:4;
26:21,21, 25; 27:15; 28:2, 12;20:1,7,15,17,21,23, 11,13,14,14,15,18,19, 5,12,20,21,22 ;170:1,7,
162:15; 163:17; 168:12;
6)9, 18;29:12,12, 12,13, 14;21:1,2,4,10,10,12, ~l;88:4,6,9, 11, 16, 17, 11,17,20;171:1, 16,17;
171:10; 174:22
21,24 ;31:6,20; 39:16; ~2,18,19;22:3,6,7,9,14, 24; 89:7,7,8,8, 12, 17, 18, 172:22,25; 173:1,3,4,8,
41:19; 42:10, 20;43:2, 12, Nowhere 48:25 ~o, 21;90:5,8, 13, 25; 10,10,12, 16;174:3,16,
~5,20,22,25, 25;23:1,
2,
18,21,25 ;44:13,15,23, nuclear 13:4 },4,10,13,15,17,19,19,)1:3, 3,4,4,13,16, 16,18, 20,21;175:1,2, 25;176:9,
23;45:11, 13,13, 15)24; number 12:21; 16:25; !0,20,21,24,25;24:1,2, ?0,23;92:1,5, 11, 15,22, 13;177:4,6,10, 17,23;
_m—. 46:1, 12, 19;48:2; 50:20, 19:11 ;36:14; 46:12; !,3,5,5,7,14,16,16,18, Z4;93:3, 5, 16, 17,21, 24; 178:6,8,11,13, 14;179:5,
21;51:1,10,24; 52:8,16, 47:25 ;50:15;63:14; 64:1; !0;25:2,3,5,6,8,9,12, )4:4, 5,8,18, 25;95:2,4, 13,19
17, 25; 53:14, 18; 54:6; 92:2,2; 101:18; 104:15; ,4,17,20,23,24, 24; 11,12,21,22,24,25,25; t#f22:4, 11;25:19; 39:16;
56:5,12, 24; 57:15; 58:14, 126:4; 128:1; 132:14; !6:1,1,3,3,9,14,14,15, )6:1,3, 4,5,6,9, 12, 14, 52:10;63:17; 89:7;
24; 59:9; 60:1,7,8, 21,21, 133:15; 136:8; 145:13; .6,16,19,22,24, 25; [5, 16, 21;97:4, 10, 12, 100:25; 101:12, 13;
23, 25; 62:10, 20; 63:5, 18; 147:24; 150:9; 161:13; !7:6,6,9,11,11,13,14, [7, 17,23, 24; 98:1,3,10, 102:12, 17;103:1; 106:1,
64:4,11, 13;65:17; 66:3; 162:1; 163:5; 164:2; 8,23,23,24,24, 25; !3,22; 99:1,1,2,2,2,3,3, 22,24;108:12; 111:25;
67:21, 25; 68:7, 7,9; 166:4; 169:5:171:6: !8:12,14;29:3,5,7,13, [,5, 5,8,13,13,14, 14, 112:1,7; 120:5,8,11,12;

Miller Reporting Company, Inc. Min-U-Script@ (19) newlv - off
Hearing Volume Number 2 Food & Drug Administration
May 29, 1998 Gastrointestinal Drugs Advisory Committee

123:22; 124:15; 129:17 mcology 114:3,4 126:25;
142:1 organizations 4:20; 9:7 30:7; 34:10, 12; 35:1;
offer 130:10 one6:14;7:12; 8:17; opinions 132:20 originaI 27:5; 55:18; 37:13; 38:3; 40:3; 58:4;
‘Te4:25 11:17; 15:24; 22:20; opportunity 129:12; 131:10 66:22; 98:10; 104:15, 17;
23:18, 19;25:13, 24; 179:4 Originally 131:16 108:6; 170:13,15, 19;
. ..cially56:25
27:24; 29:6, 7; 30:6,12, 171:2
often 18:15 ;23:5; 24:6; opposed 24:9; 27: 14; orosomucoid 14:25
17, 18;31:14, 19;40:21;
45:18,21 ;81:8; 83:12; outcomes 35:2, 18; 36:2,
49:4; 122:19; 139:24; orphan 161:23, 24; 162:3
42:1, 20; 45:2; 46:12; 3,5, 14; 37:8
167:8; 178:2 90:24 orphans 130:19; 161:19
47:21 ;48:7, 11; 50:15; rmtside 5:24
Oh 70:7 opposite 51:2; 166:3,11 osteoarthritis 38:11
51:9; 53:13,19, 23; 55:2;
opposition 57:13 mtsider’s 29:6
Okay 68:17; 69:8,23, 25; 56:8, 23; 59:11; 63:19; other 5:2, 7; 11:10; 14:8;
80:21; 101:12; 103:11,24 optimal 139:23 15:4; 16:12, 14; 18:21; mrer6:ll;8:13; 33:21;
65:8,9; 67:14, 19, 22;
old 124:7;
131:2;
137:24; 21:11; 23:22; 28:12, 14; 34:16, 19;35:3, 14; 37:6;
70:12; 71:11,12,13; or 4:20; 5:2,8; 11:20;
138:2,2,2;
147:1;
166:13 32:8, 17; 34:12; 36:7, 25; 38:5; 41:11 ;42:12; 72:10;
72:10; 76:22; 80:5; 82:1, 12:17,24 ;14:1,1,2,3,7,
43:1,7; 46:12,23; 48:4; 74:15 ;76:15, 18; 103:16,
older 146:12,13,
14; 13, 19;86:9, 11,16, 23; 13,15,18,21,24,24, 25;
50:1 1; 53:23; 56:17; 58:5; 17;110:12; 111:17,19;
147:23;166:15 87:3,10, 17; 88:11, 17; 15:2,3,4, 5,6; 16:2, 14;
59:21,23; 64:18; 65:14; 112:8; 146:7,7,17, 23;
OMERACT 37:8 89:1,3,4,8; 91:25 ;92:2; 17:25; 18:4; 19:5; 21:20;
67:4; 72:8; 73:4; 74:22; 147:4, 6; 148:24; 150:4,
93:1; 94:25; 95:9; 97:8,10, 22:10; 23:8,16, 19, 24;
on4:ll,21; 5:2,20 ;6:5; 75:21; 76:5, 8; 77:18; 78:7; 14; 158:8; 179:15
24; 98:22; 100:24; 102:17; 24:1,2,8,9,12, 17,23;
7:4, 22; 8:4, 25; 9:3,7,8,103:18; 104:24; 107:15; 25:16; 26:1; 27:22; 28:12; 80:7; 84:25; 86:11, 14; overall 86:18; 87:4;
20,24; 11:10; 12:18, 22;
108:3,14, 17; 109:4, 9; 29:14, 19, 22; 30:3,7,10, 87:17; 90:20 ;95:11; >0:25; 91:5; 92:23; 96:20;
13:2,7;16:2;19:4;20:7; 111:19; 113:14, 15; 10,11 ;31:5,8;33:21; 97:18; 100:4, 12; 101:22, 127:19; 151:4; 154:15;
22:2,15;23:21;24:11, 18, 115:24; 116:9,15,24,24, 35:4,7,12, 23;37:17, 21; 25; 102:4; 105:19; 106:8; 164:5
23;25:10,10,13, 18;26:7; 25; 117:10, 24; 120:2,8,8, 38:18; 39:16, 16; 42:13, 108:6, 8; 109:18; 111:9; mrerlap 15:13
28:9,13;29:23;32:17; 12; 121:2; 122:1; 124:3, 20,21 ;43:9,22,25;45:1; 113:20; 116:24; 117:10;
mrerlooked 24:6; 129:2;
33:25,25;35:9,20;37:12; 21; 127:11; 128:14; 131:2; 46:13,14,15,16, 23; 47:1, 122:1,8; 126:23; 129:16;
160:3
38:21,23;39:4,8,11,13, 132:19; 134:6; 136:2,8, 24; 49:1,4,17,22, 25; 134:15; 140:12; 145:17;
overpower 98:17
16;41:17;42:17;43:7,24; 12; 139:19, 21,25; 140:3; 50:1,2,2,3,3,7, 20; 51:5, 147:17; 148:6; 152:20;
160:15; 166:6,7,9, 22; mferview 10:2; 21:15;
44:18;45:14;46:21,25; 142:4; 143:21,23, 23; 6,15, 16; 52:2,16,16, 17;
167:9; 169:1 1; 175:12; 56:7; 135:12
49:2,7,8,13;51:14; 52:3, 145:12; 147:9,11; 151:25; 53:9, 22; 54:4,6, 16;
4;53:18,21;54:22; 56:7, 153:20; 154:12; 155:9,9; 55:24; 56:7,7,9,9, 11; 176:18; 178:8 own 22:14; 48:18; 62:2;
13;58:3,24;59:21 ;61:9, 157:8; 160:13; 161:8, 14; 57:13,16,22, 23; 58:15, others 7:23, 24; 38: 10; 56:2o; 126:20, 20; 162:4;
15;62:2;64:6;65:18; 164:11,12, 24; 165:5, 25; 22; 59:22; 60:19, 22; 110:14; 111:6; 136:5, 15; 174:19
_ffi:20;
68:17,20;70:3; 166:8, 23; 168:23; 169:17, 61:15,15,21 ;62:12,13, 151:3 Dxford 129:23
‘,7,22;72:8,9;73:9; 25; 170:6; 171:23; 174:16; 18,23, 24; 63:8, 13; 64:7, otherwise 18:9; 42:6
~,11,17,21;75:13;
76:8,15, 25;79:10;
176:4
80:22; one’s 73:9
22,23, 24;65:1, 24;66:10;
67:9,19, 19; 68:2o; 70:17;
ought 37:17; 57:2; 77:15; P
90:10; 159:9; 160:18;
81:18;82:7, 24;83:3,6, 72:4,9, 10; 73:2; 75:10, 174:24
one-third 12:16
25,25;84:1,1,2,11; 23; 77:16,16,24, 24; 80:6, paid 33:6
One-time 83:20 0ur7:20; 8:16; 15:17;
86:14, 15;87:8;89:3; 6, 15;81:20;83:19, 20; pain 13:20; 20:23; 23:6;
18:16; 20:22; 25:12;
91:14, 17;92:25;95:4,23; one-year 102:17, 18; 84:17; 85:18; 86:6, 20; 28:23 ;36:11; 40:15;
32:17; 36:7; 39:1; 44:23,
96:24;97:1;99:23; 100:9; 118:15 87:17, 18;88:3, 11,11, 24; 93:12; 108:5
24; 55:9, 12;68:22; 74:5;
102:19,23;104:2,3, 12, ones 30:23; 47:25; 99:1; 89:1; 90:11 ;91:10; 92:16, painful 14:2
76:11,24 ;77:5; 84:21;
22;106:6,21,24;107:13, 121:11 18,23 ;93:18;94:24;
86:1; 93:7; 96:15; 98:5,6, panel 6:7; 9:12, 24;
17;108:1,7,9,12, 17; OIIgOhg 14:21; 119:24 95:12 ;96:21;99:15, 18,
109:1,14,17,19,21, 25;
23, 25; 99:1; 100:22; 10:15 ;70:2;76:25; 86:12;
only 30:23; 42:24; 43:3; 22; 100:1; 101:9,12,20,
110:2,4;111:1,1,21; 113:14; 126:13,14,20,20, 149:4; 167:22
69:22; 72:24; 76:12; 79:7; 25; 102:3,4,7, 13; 103:21;
21; 132:21; 136:7, 23; panelists 8:24; 86:9
112:14,21;113:17; 114:9, 85:11,19 ;90:7,13; 91:15, 104:5 ; 105:13,14,25;
139:5; 142:14, 18; 148:24;
24;115:2,10,23;116:21; 18, 20; 108:17; 113:19; 108:12,13, 20; 109:2; paper 7:4; 106:5; 125:11
149:12; 150:23; 153:13;
117:15,17,22,23; 119:4, 114:17 ;115:6; 121:2; 112:2,6; 115:10,16, 19; paradigm 77:14
160:6; 163:15; 178:2
5,5,18;120:9,12,19,19,131:15 ;135:17; 136:21; 116:1, 10; 118:21 ;119:16, paragraph 22:17
23,24,25;121:22; 122:1, 138:12; 139:6; 140:20; 23; 120:19; 121:12; ourselves 77:9
paraliei 39:20; 40:5;
2;124:6,10;126:14, 14; 122:22; 123:22; 124:19, out 7:22; 8:2; 10:13, 21;
144:4; 153:25; 154:12; 88:23 ;92:18
127:12,14;129:19; 22; 126:1,8; 128:15; 18:17; 22:8; 26:18; 30:17;
159:12; 162:21; 164:7,22, parallels 38:22; 40:2, 4;
130:20,24;132:12,12, 20; 22; 171:22; 174:22 129:7,23,23, 23; 131:6, 34:2; 35:5; 36:9; 37:9;
133:12,20,23;134:16; 39:1; 45:11 ;46:10; 47:4, 65:11
20,24, 25; 132:2, 3;
onset 125:12, 24; 146:14; 11;48:15; 56:13; 57:10; parameter 159:7
135:11;137:17,21; 134:25; 135:7, 22; 136:2,
149:11, 13
141:14;142:2,9;143:23; 10; 138:6,6, 25; 139:9,9, 59:16; 70:13 ;75:18; parameters 43:14;
145:19,21;146:1; 147:20, Ontario 10:7 15, 18; 140:1, 11,12; 78:12,21 ;81:19;83:9,10, 57:14; 159:8
20;148:16,22;149:3,4,4,open 5:23; 22:1; 31:24; 144:6; 145:16; 147:19,20, 12; 84:6; 87:24; 89:19; paramount 143:25
9;150:10,15,16; I5I:12; 63:8 20, 25; 148:1, 15; 149:18; 91:25 ;98:4;1OO:15;
parent 144:2
152:4,8,9;153:17; 156:5, open-ended 155: 13; 150:14, 17,,21; 151:5; 101:21; 103:21; 118:22;
121:5; 135:18,18; 137:16, parents 172:14
14;157:13,20,21; 158:5, 157:24 152:23; 153:17, 17,24;
22;159:6;160:14,25, 25; open-label 124:9 154:17, 21; 158:22, 25; 20, 22; 138:1; 141:14; Parklawn 4:25
–~l:l;163:4, 17;164:19; 159:2; 160:14; 161:2; 142:16; 143:14, 16; parlance 130:13
opened 47:14
2,19,20;166:13; 164:9, 10; 165:10,10,12, 146:16 ;149:19,21; Dart 4:9; 7:12; 25:6;
:14,25,25;168:3,4, Dperated 46:25 22; 166:10; 167:15, 24; 152:20; 156:9; 159:17; 27:23; 49:9, 20; 81:4;
23;169:3;173:3,8, 11,25; Dperating 33:6, 15; 55:1; 168:5; 169:11; 170:3, 5; 162:11; 164:11; 165:16; 104:6; 114:11; 121:19,24;
174:2,5,13,23;177:9, 11; 56:1, 2,7; 67:4; 87:20; 171:7; 174:5; 175:2, 11; 167:21; 168:20; 172:17; [34:1, 12; 165:17
178:1,4,8,12,16, 22; )3:21 177:10; 178:10 173:1; 176:20; 177:4,19 Oartial 42:4; 49:17, 18,
179:1 ~perations 150:17 0rder4:2,4; 101:12; out-of-the-blue 26:4 21, 24; 50:1, 18; 101:23;
once 115:9; 171:7 ~pinion 40:6; 86:4; 99:7; 136:20; 159:9 outcome 23:16, 19; 24:1; 102:7

offer - partial (20) Min-U-Script@ Miller RC?DOrtifM2
COmnanv. Tnr.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1998

participant 5:3 91:7,13,16,21;92:23, 24; 93:2, 10; 96:16, 23; 125:6, 118:19; 160:10 142:8;
143:16;
159:22;
participants 4:13, 19; 94:12;96:21;97:5,23,25; 12, 13; 126:8; 131:20; physician’s 52:9 165:5
__—_ 5:4,7 99:21;102:23;104:2,5, 153:25; 164:13, 25; 165:1, policy 145:18
physicians 21:1; 62:7;
participate 129:12 12;105:8;107:17; 108:4, 3,12, 12; 167:12; 171:7; 85:4; 112:11; 125:19 pent 137:16
7,10;110:16,17;111:16, 176:15, 19; 178:8
participating 156:3 physiologic 57:16,22 poor 18:12
18,25;112:7;114:18; percentage 92: 19; 95:17
particular 7:8; 23:16; 116:9,20;117:11; 118:16; physiological 40:11 population 10:4; 59:1 1;
24:21 ;29:5;44:1; 72:11, percentile 137:24, 25;
119:3,8,25;120:3, 10,15, pick 66:23 77:20; 94:23; 97:23;
15; 89:20; 117:22; 126:9; 138:5,7 106:14,15, 19; 107:3;
23;122:19;123:12,19, 20; piCtUre 51:25
133:24; 136:24; 154:7; petfect 26:14; 38:6; 119:2; 130:7; 144:15;
124:3;125:8,21;127:19; piece 50:20, 23; 157:9,10
163:23; 172:3 44:23 145:23,24, 25; 146:3;
129:3,5,7,25;130:3,8;
particularly 9:5,19, 25; perfectly 117: 16; 124:1, pig 144:3 148:8, 12; 149:21; 151:4;
142:19;143:2,3,10;
15:20; 17:19; 22:12; 146:12,17,22;147:4,6, 1 PK 134:7; 135:5; 148:24 152:18; 153:6, 22; 154:16;
32:13; 52:3; 54:21 ;84:21; 22;148:8,9,14,24;149:7, perforation 59:25 phCt? 107:1; 155:6; 155:24; 156:6, 12; 158:16;
95:11; 118:5; 135:9; 11;150:9,11;154:1,11, 172:10 160:1; 161:7; 162:2;
perform 20:24
137:1; 152:4; 172:12,25 14;156:15,23;161:5,9, 172:7, 7,8; 173:19, 20;
performed 60: 12; placebo 24:24; 64:7;
Partly 35:10; 87:14, 15; 13,14,15;162:1,16, 22; 176:10
126:24; 142:13 70:15; 88:4, 21; 89:8, 11;
92:7; 95:24 164:5,7,7,12,24;165:21; 90:13 ;98:14; 104:5,8; populations 54:25; 92:2;
perhaps 12:22, 23;
parts 73:4 166:4;167:13,25;168:23; 105:14; 108:25; 116:17; 93:4; 94:6; 109:1; 124:18;
32:17; 42:2; 44:21 ;67:16; 132:10; 134:9, 14; 148:19;
passed 87:24 169:22;170:17;171:1; 120:8, 12; 122:2; 164:6;
72:11; 105:11; 146:24; 154:11; 165:23
172:2;175:2,14;176:8, 168:10; 173:12; 174:5,6,
past 16:24; 163:15 148:2; 150:18; 163:6;
11,11,17;178:8 7; 178:10,12 PORTER 77:7,7
pat 34:14 167:6; 174:14; 177:23
paul9:11;112:9; 137:7; placebo-controlled posed 22:19; 126:22
pathognomonic 14:12; perianal 46:14; 47:12
138:10;143:9 24:16; 116:1o; 123:25; position 178:1
17:25; 21:17 period 6:12; 35:14;
Paulus 54:4 140:2; 172:2, 10,15,20 positive 34:20; 148:3
pathologic 15:15 56:15; 70:24; 72:1 1; 73:4;
peak 149:13 76:18; 77:13,24, 24; plan 7:20; 10:17,22 possibility 107: 16;
pathologically 28:21
pediatric 9:23; 10:1,
4; 34:24; 86:7; 103:7,9, 16; planned 173:20 136:22; 158:13
pathophysiologic 12:17 96:12,15, 17;101:19; 110:12 ;111:19; 112:8; plans 116:4 possible 11:1; 30:7;
pathophysiology 124:18; 128:4,19,21; 123:23; 141:19 62:10; 67:22; 78:2; 152:4;
135:15 plausibility 155:15, 16;
130:15 ;131:17; 132:9,10, periods 123:11 155:13,18, 20; 156:9;
157:19
pathway 158:22 15,16;134:1,3,8,14, 16; 174:6
peripheral 14:9 plausible 157:20
patient 17:6; 18:2; 19:16; 135:2,4;136:5,9,
13; possibly 69:14
-- 137:11;138:19,23;139:2, Dermit 131:18 play 10:8; 21:24
—- 24:8, 10;25:18; 26:5,7; post 88:14
3,9,12;140:17,19;141:4, oerplexed 66:17 playing 6:5
35:15,20; 36:5; 41:17, 17,
16,21;142:2,8,14,17; Serson 44:17, 18; 93:8; post-op 50:8
18,19, 20; 42:14; 44:4, 4; please 46:5; 51:17
45:6; 46:14, 25;47:11, 12, 143:2,13;145:20;150:11; 122:3; 126:18 post-randomization
pleased 11:10
16, 23;48:17, 18, 22; 152:8;153:12,
21;160:17, Personally 44:6; 66:2o; 116:12; 117:19; 178:15
21,22;172:13,18 plot 88:3, 4,5; 126:4
51:21, 25; 53:8; 54:22; 111:6 postmarketing 141:19;
pediatrician
56:24; plots 88:7 160:9
55:17; 56:5,6,19, 24; Perspective 10:10; 28:5;
59:18, 23; 62:9; 63:17; 84:13;136:20;
143:7; Z9:6; 174:10 plus 86:18; 104:17; postoperative 19:7;
66:5,13 ;69:24; 72:18; 148:23 130:21, 21; 149:18; 20: 16; 63:20
Oertains 101:5
73:1; 76:8; 77:20; 78:20; pediatricians140:1; 159:16; 176:16; 178:12
Oertinent 167:4 postoperatively 24:9
86:1,3,4 ;92:11,25; 93:1; 142:6 plus-minus 135:14
~harmaceutical 51:22; potential 4:15; 19:12;
94:6; 96:22, 25; 97:1; Pediatrics 9:22; 42:8; pOint 8:23; 18:17; 22:8;
101:3; 131:4 20:17; 22:24; 23:19;
102:12; 106:12,14, 15,20; 124:5; 130:24; 131:19, 23; 28:2, 25; 38:1, 24; 40:22, 30:12, 20;74:16; 112:4;
107:5; 108:17; 109:13,15, ~harmacodynamic 23; 45:7, 22;47:4, 5;
132:14; 134:6; 135:9; 121:14; 142:6; 158:4
19, 20; 110:1, 3;114:22; 127:3; 140:20 53:24; 57:4; 59:4; 64:1o,
136:4; 148:15; 150:6; potentially 121:18; 158:2
115:25;117:5,15, 17; 151:2; 153:5,24, 25; ~harmacodynamics 16; 66:2, 14; 67:14; 72:10;
118:18;122:5,9,10, 15; 159:24 73:13,14,22, 22;75:12, power 89:18,19, 22;
159:11,19
123:16;124:7,10;133:14, 19, 22; 79:10; 80:2; 81:16; 141:8; 145:4 ;151:21;
penicillin 49:3 ~harmacokinetic 127:4;
24;154:2;156:12; 160:10; 34:11, 16;87:11; 88:8; 159:2
penuhimate 150:24 128:23; 140:10, 15; 156:3
161:7;176:9 39:11, 17;90:5,8,9, 14, powered 135:6; 147:16
people 7:6; 10:21; 23:14; ~harmacokinetics
patient’s12:3;36:24; 126:23, 24; 159:24 21;91:25; 92:21,21 ;95:8; powerful 86:24; 87:15
45:16;48:18,21;57:10 24:20; 34:17; 50:25; )6:9, 12; 97:8; 98: 16;
~harmacology 130:22, PPRUS 139:9
57:18; 59:8; 64:20; 76:5; 29:15; 100:16; 101:21;
patients 11:20;12:15, 16; ~4; 139:9; 152:25 practical 164:4; 175:5
89:19; 90:14, 22; 95:4; 106:10; 113:25; 123:14;
13:16,18;15:16;17:9, 18; practice 133:10
97:10; 99:11; 104:21, 25; ~hase 35:16, 17; 37:16; 126:9; 127:2; 129:1;
18:4,6,17,19,20;19:1,2,
112:14, 19; 113:19; 71:22;84:6; 141:3; 134:10; 136:23; 138:4; Practices 7:10, 10;
2,13;20:1,22,23 ;21:19;
115:16; 117:14; 121:22; 174:23; 176:16 142:14; 144:1,6; 146:11; 166:25
22:22;24:22;25:7,9,12,
126:17; 128:12; 140:17, ~henotype 57:7 148:22, 22; 150:17; practicing 57:9
15;27:1;28:22;31:18;
18; 146:14, 25; 148:17; ~henotypes 9:10 152:20; 154:15; 155:25;
32:11;36:1;37:1;40:16, pragmatic 165:17
149:9,19, 25; 150:5,13, 158:1; 159:3; 160:4;
24;41:14;42:15;43:8,9, >henotypic 52:4 pre88:14; 174:22
19,20; 151:16; 158:16; 169:4, 6; 170:21
---- 10,12;47:9;49:2; 51:24; ~henotypically 146:15, pre/pOSt 87:21; 88:22,22
163:25; 168:25; 176:1;
52:6,23;53:11;55:10; 24 pointed 98:4; 162:11;
177:11, 19; 178:16 precedence 102:9
58:6,7;62:7,19;64:4; 165:16
per35:25;45:23 phenotyping 115:14 precedent 110: 14;
70:13;71:8;76:7,9,14, points 27:14; 46:10;
per-patient 156:5 Philadelphia 138:18 162:16
20;77:1,5;78:22;79:6; 49:19, 22; 53:19; 57:10;
81:11;82:6,23;83:4; 84:7, percent 42:23, 24; 48:9; phone 123:18 64:9; 73:16,18; 80:1; preceding 15:18
21,24;85:6,21,22;86:1,49:25, 25; 67:8, 10; 84:17, phrase 155:12 87:12; 89:16; 90:16; precise 26:13
21,22;87:5,6;90:8, 10; 19;90:8, 11, 13;92:9; physician 57:9; 66: 14; 91:10 ;94:14; 97:16; ,
rxeciselv . 164:17
Miller Reporting Company, Inc. Min-U-Script@ (21) Darticiuant - m-eciselv
Hearing Volume Number 2 Food & Drug Administration
May 29, 1998 Gastrointestinal Drugs Advisory Committee

preclinical 21:20 priori 91:20 proportions 54:3; 96:21; randomization 117:10;
preclude 4:9 prioritize 132:7 150:11 Q 178:14
randomize 24:23; 116:11
-— defined 20:1,11 probably 7:6; 11:15, 16; proposal 18:24; 49:14,
.tict
12:17;
17:17; 22:14; 35:21; 36:24; 15; 50:4; 58:22; 59:11; qualify 105:18 randomized 24:15; 25:3;
19:10
;71:19,20 40:10; 56:18; 59:24; 67:13; 130:5; 134:1 C@itdk 33:23 116:8,9, 13; 136:10;
predictable
19:9 68:13; 84:14; 103:14; proposals 57:3; 141:11, quality 10:11; 20:21; 140:12; 153:6; 155:22;
predictor 13:5; 66:9,10 111:11 ;118:17,25; 15 21:4,10, 12;23:24; 28:13; 172:21
121:10; 126:15; 127:22, 39:19; 49:25; 54:17, 19; randomizing 140:2
predictors 17:15 propose 50:6
24; 129:15; 138:14, 23; 65:13, 20; 66:19; 67:18; range 121:12; 128:2
prednisone I02:21; proposed 19:19; 45:25;
140:6, 22; 152:14, 14; 79:8; 130:2
108:12, 13; 115:16; 115:14; 121:25; 140:10 ranges 67:7; 127:21;
157:22, 25; 159:25; quantitate 36:24
121:16,22 ;126:15 165:25
160:12, 20; 165:22; proposing 74:10; 102:16
predominantly 145:22 quantitative 33:8, 23; ranked 99:1
171:10; 172:7 prospective 46:18;
prefer 23:4; 81:9; 87:12 36: 17; 38:6; 173:9 rapidity 142:7
problem 16:22; 31:2, 10; 106:8; 135:6; 146:5, 6;
preferable 33:4; 87:3 quantum 65:22
54:18; 66:16; 79:19; 94:8; 171:5 rapidly 6:10; 77:11, 15;
premarketing 160:8 question 22:19; 28:7; 158:8
95:19; 106:7; 112:18;
Prospectively 48:19 37:3; 49:14; 51:2; 52:17;
prepared 135:19 121:3; 127:22; 141:3; rare 56:23; 57:2; 154:19;
protein 14:24; 15:2,3 54:7; 59:17; 62:1, 16; 68:3;
prescribers 22:21 153:13; 155:11; 168:20; 165:7
69:19; 70:21; 81:3; 82:20;
178:18 protocol 138:21; 144:25 rarely 145:24
presence 58:12, 13; 86:5; 98:1; 101:6, 11;
59:22 problems 14:20; 17:23; protocols 171:25; 178:3, 105:12, 17; 106:17, 18; rate 14:24; 37:16; 70:15;
present 4:15; 9:3; 13:18, 22:6; 33:2, 4; 42:1,7; 44:6; 21 109:5,9, 24; 113:2; 127:5; 170:7; 177:10
22, 25; 14:2; 37:13; 42:20; 89:9; 117:24; 140:1; prove 45:5; 46:2; 85:15; 118:19, 24; 122:15; rates 24:25; 35:24;
45:2; 48:16; 55:14, 15; 145:3,16 91:5; 136:3; 173:2 124:15,16, 17; 126:22; 152:14; 156:4; 164:11, 13;
78:18; 79:5,8,18, 23; procedure 7:12 127:8; 131:19; 134:10, 12, 169:17
proved 24:21; 169:1;
80:21; 110:11; 111:23,24; procedures 7:11 15; 135:17,21; 139:14; rather 22:16; 23:3, 4;
172:16
123:9,10,
16;128:9; 140:7,8,9, 13; 144:14, 23; 25:1,22, 24; 26:2; 32:4;
proceed 6:9; 21:25 proven 141:13
142:25;
144:9,11;148:6 145:7; 146:4, 20; 147:8, }3:23;56:18;
84:1;105:7;
PROCEEDINGS 4:1 provide 119:18; 160:15 22; 151:1; 155:16, 18;
Present’s 79:2 135:14
process 19:23; 20:3; provided 130:12 156:7; 157:24; 158:15, 17;
presentation 14:17; ‘ationale146:22,25
21:13; 33:9,20,20, 25; 159:23; 164:9; 165:15, 17;
15:5; 70:3 provides 81:14; 131:3 ‘each43:18;90:22;97.5;
54:25, 25; 35:1,23; 37:22; 167:12, 21; 169:22; 170:5,
presentations 12:11
38:1,14 ;40:4,4,6; 41:21; providing 32:19; 54:14; 7, 12; 175:8,9, 23; 176:7 103:3
--sented 20:22 51:16; 77:19; 148:4; 175:6 ‘cached 40:9; 86:22;
Questionnaire 21:7
s-sure 121:15 174:1; 179:6,6 proximal 47:3 141:17
questions 7:18,19,22,
presumably 108:23; Orocesses 40:11; 125:10 24;22:3,6; 101:7; 102:10; ‘eact ive 37:16
proxy 107:9
140:3 Orocessor 138:21 105:11 ;113:14; 118:1,2; ‘cad 22:17; 69:19; 130:11
~sychological 122:22;
presume 108:19; 145:10 ~roduce 12:24; 132:9; 130:1; 155:12,13, 16; ‘eading 100:10
123:1
presumes 145:11 177:17 172:23, 25; 179:12 ‘cads 140:25
~uberty 126:3
presuming 108:17 m’educes 13:15; 28:20 quick 24:14 ;43:4; ‘eady 133:6,8
~ublic 7:14 143:21; 144:23
pretend 52:11 woduct 22:21, 23; 81:13; ‘eagent 19:16; 125:8
12:18;83:5; 118:11; wblication 7:8 quicker 136:20
pretty 34:17; 78:17; eagents 19:17
81:21 ;90:7; 126:2; 134:5; 141:14,24 ;152:21; mblish 132:8 quickly 142:16
eal 5:17; 77:17; 151:13,
152:18, 19; 173:6,7,9,16 [56:14; 158:10 wblished 6:21, 24; quiescent 17:18; 82:24 9
prevalence 149:15 ]roduction 29:23 11:12;18:24; 31:21,21; ~Uiet 82:18 ‘eality 98:17; 153:10
prevent 61:24; 62:13; ]roducts 5:2,9; 38:24; }8:20; 45:10; 96:18; quieted 83:21 ‘eally 7:2, 16; 8:21;
82:8; 83:3; 106:16; 110:5 13:1;161:12 123:24; 131:10 ~Uite 11:18;
15:11,25; !3:25; 24:18; 25:22; 27:6;
preventing 61:21; 65:8, %ofessor 9:13, 22 lulling 177:4 18:1;115:2;
120:10; i2:24; 33:11; 35:17, 19;
10;82:10 ]rofoundly 165:21 wrpose 6:8; 7:16; 22:2o; 129:25;144:2;155:9,
10; ;6:19;37:6; 42:8,8 ;46:15;
prevention 31:9; 50:6, 7; prognostic 12:4,6 ?6:15;33:5 178:19 il:2; 54:21; 55:7; 56:5;
51:20; 52:2; 61:25; 62:9, ]rogress 41:19 quoted79:1 i9:12;62:16; 64:25 ;66:3,
mrposes 74:24
12;63:10, 13, 16,19,20, 3;71:4; 72:17; 73:10,19;
progression 44:20; ]ursuing 179:15
21;65:2; 68:22 ;78:15; ‘5:13 ;79:9, 16;82:14;
81:1; 102:6, 11; 107:14;
;5:10; 124:25
.]ush 70:21 R 14:8;87:25; 89:2; 90:24;
110:7 prolong 85:18 95:7; 96:13; 97:21; 99:8,
put 6:5; 7:4,22 ;41:lo;
previous 5:9; 15:21; prominent 9:9,14,18 RA 38:16;39:7;65:5; 24; 100:17; 105:2; 107:23;
43:17; 53:7; 56:2, 10;
79:2; 100:23 promised 179:3 78:19; 81:20; 82:7; 83:9, 74:4,
10,19;76:3,9,14, 112:14; 114:l;125:8, g,
promising 8:20 10;86:5; 88:1; 105:6; 14,20;77:3;81:5;
83:12, 25; 131:20; 134:23; 137:5;
previously 11:20
106:21, 24; 126:7; 127:6; 23;103:23;106:2;172:11 139:1; 142:1; 143:15;
primarily 17:15 promote 61:8
133:18 radiologic 42:13; 46:19; 151:22; 152:5,16, 24;
primary 14:2; 16:13; promoting 50:20 153:3; 155:17; 163:5;
putative 122:1 49:11 ;58:5
17:8; 45:4; 70:12; 98:5,6, properties 33:6, 15; 169:18
_& + 13, 24; 100:6; 1o4:15, 56:1, 2,7; 67:4; 93:21 puts 166:2 radiology 46:17; 47:5
realm 30:21
!1; 116:22; 118:11; prophesy 91:19 putting 83:12; 121:18; raging 47:2
reason 32:15; 54:5;
I,+1O; 120:2, 5, 12, 16; 166:11 raise 106:18; 131:20;
wophylaxis 50:8 107:22; 110:19, 25; 126:4;
122:3,4; 160:1; 170:13 puzzle 43:16 167:8; 175:24
woportion 31:18; 86:21; 129:5; 139:16; 151:13,23;
principally 131:5 pylOri 57:17,18,19,19, raised 105:17
37:5, 6; 91:13,16, 20; 158:19
principle 110:10; 115:19 >2:22, 24; 96:6, 24; 97:4; 19, 20; 58:15 raising 66:14 ‘easonable 6:5; 45:7;
prior 7:5; 125:4 105:8; 110:16.17:118:16
., ~yoderma 112:6 ramifications 78:9 ;3:14; 59:14; 117:13, 16;

preclinical - reasonable (22) Min-U-Script@ Miller Reporting Companv, Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29, 1998

132:4, 5; 151:16; 162:6; reflective 168:24 remember 39:14; 152:6; resealing 95:25 142:3; 166:24
163:8; 164:3; 165:2; refiects 9:20; 115:2; 160:7 Research 4:15;
96:16; reviewed 171:25
.-. 175:11; 177:5,7 168:21 remission 18:14, 21; 137:17;
139:4,
10;142:15; reviewing 163:9
reasonably 87:10; 88:19, refractory 112:25; 113:4, 19:22, 22; 20:5,7,9, 13, 160:15;
173:1;
177:21 revisit 111:12
23; 96:5; 135:23 9,22; 114:5,9; 115:4,8, 15;22:25; 23:1,4, 10, 13; researchers 131:8
rheostat 77:13, 18,23,
reasonably-sized 15; 122:14; 169:22; 172:7 24:2,3,4,4,6,8,11,11, resection 16:22;
18:7; 23
152:15 regard 4:8; 24:3, 18; 16, 22; 25:5,7,10,14,17, 19:14
18, 20; 26:3,6,7,14,16, Rheumatism 41:8
reasons 54:1; 94:25; 27:20; 34:19; 40:17 Reset 77:13,24
20,24, 25; 27:2,6,11,13, rheumatoid 34:12, 24;
98:22; 101:16; 107:15; regarding 9:16; 10:3; resetting 77:18,22
19, 24; 28:1; 29:11 ;30:3, 35:16; 37:8; 38:10,21;
133:2; 145:13, 17 61:12; 86:12; 100:23;
5,6, 24; 31:3,6,8,9,11, resistant 109: 16; 110:1 40:2; 61:5; 81:8; 82:16;
rebounds 78:6 114:15; 118:3; 123:8;
12,18, 22;32:12, 13, 18, resolution 26:23; 30: 11; 92:4; 123:19; 163:3;
recall 115:14 139:15; 148:3; 173:25; 168:7; 171:11; 172:1,19
21, 22; 33:16, 17; 38:18; 45:20,21, 24; 58:5, 21;
receive 7:21 175:4
39:13, 17; 40:23, 25; 42:6, 68:2; 81:20 rheumatologic 11:21;
received 104:5 regardless 110:12 6,18, 19,24 ;43:12, 13, 28:4; 100:25
resolved 40:7; 58:9
receiving 149:25 regards 123:10 15, 15;45:12, 14,15,17, Rheumatological 41:5
Resource 34:8
recently 143:7 regimen 135:10; 150:16; 17, 25; 50:7,9, 19; 51:5;
rheumatologists 11:18;
resources 6:4
169:13; 170:2,4 52:1O, 11; 53:9, 17; 59:7,
Recess 100:21 respect 5:7; 80:21; 33:21; 34:2, 2;76:12;
regimens 169:11, 12; 9;64:5, 19;67:18, 19, 24;
recognize 5:24; 13:14; 107:8; 115:12 170:2
178:23 68~20; 72:16,18,19,22,
14:4; 26:18; 32:9; 118:14 25;73:24;75:9, 11,19, 21; respective 39:24 rheumatology 34:7, 19;
regular 20:24 37:6, 12; 39:17; 73:5;
recognized 78:17 77:12; 78:19, 23; 79:14, respects 138:6
regulated 4:14 102:19
recommend 122:25; 19;80:12, 12, 25;81:1,20; respond 7:23, 24; 12:16;
137:5; 142:18; 162:19; regulation 12:25 82:21,25 ;83:21;85:18; 27:8; 42:8; 114:21; rid 60:2; 68:4; 75:8
170:3 regulatory 19:6; 21:23; 89:7; 103:1; 110:4, 22; 115:10; 122:15,16 right 7:13; 19:17; 28:25;
recommendation 113:6; 38:8, 24; 60:15; 141:8 115:11; 119:4; 120:3; responded 83:4; 115:20 30:22; 31:23; 41:6; 44:22;
177:9 reinstitute 119:6 169:21; 170:1 48:3; 73:16; 97:3; 102:9;
responder 43:22; 48:6
reiterate 57:12 remission-maintaining 108:22; 122:7; 123:11;
recommendations responders 168:4
79:17 144:2; 157:22; 162:21;
161:12 reject 65:24 responding 104:2;
remissions 82:13;84:18 168:12; 172:6; 178:18
recommended 74:20; relapse 17:15, 18; 24:25; 118:16; 170:18
remit 77:12 rile 143:20
124:6; 129:17; 132:23; 25:11, 19;31:9; 50:6,7; response 12:13, 22;
___ 142:5; 161:6, 13; 179:8 51:20; 52:2; 61:21, 25; remits 80:17, 18 rip-roaring 48:18
15:20; 17:19; 23:16, 19;
recommending 167:24; 62:9,10, 13; 63:10,13,16, remitted 80:6 24:1; 29:1,7,8, 9; 30:7; risk 21:19; 34:1; 59:25;
168:25 18,19, 21,21 ;64:17, 19, 32:9; 42:14, 15; 43:25; 120:6; 121:18; 125:3,4;
remove 111:19; 115:25
record 4:9; 5:6; 80:22; 22; 68:22; 78:15; 81:2; 44:1, 2;46:11; 49:9; 51:5; 148:9
renal 148:2; 152:23
114:7; 149:3 82:8, 11; 102:7, 11; 55:5, 5,6; 58:9,10, 25; risks 108:2; 123:8; 142:6;
106:16; 107:14; 109:19; render 99:7 152:13
records 99:14 59:3; 67:5,15,20, 22;
110:5,7; 115:25; 120:15 repeated 161:3 68:10; 69:6; 70:14; 72:7,7, risky 139:17
reCtal 13:20; 18:2
relapsing 65:10; 101:21; replacement 55:3 9,20,21, 22;73:10, 24; robust 33:14
rectovaginal 46:15 102:13,14 replicate 15:4; 28:22 74:8; 81:7, 12,14,17, 25; role 143:1
recurrence 9:17; 20:16; relate 14:19, 19 85:1,10, 25;92:6,9; 93:2;
report 35:21; 69:24 Room 4:25; 33:12;
123:4 95:12; 100:23; 101:11;
related 10:1; 11:8; 14:18, reported 4:12 170:12
recurring 65:9 20;15:1; 16:11; 20:6; 105:9;
106:4;
107:20;
reporting 108:5 117:3;
126:10;
127:5; roots 7:2
recurs 19:9 35:12 ;45:13;92:3,8,11; reports 146:8
redefine 86:15 147:19;
156:4;
157:2; round 10:12
93:4, 5;96:9, 10;101:5,7;
135:4; 167:22 represent 14:15; 35:13; 167:5;
168:3,
10;169:17; rule 131:10;
156:9
reduce 25:1 1; 39:10;
146:23 170:7,
11;176:25 rules 164:11
107:10; 122:20; 171:7 relates 44:4; 157:5
representation 150:5 responses 42:5; 54:12; run 26:21;
27:6;
117:19;
reduced 47:25; 87:5; relating 100:22
representative 149:24; 55:12; 167:7 145:3
108:18 relationship 12:17;
162:8 responsive 33:8; 109:20; Rutgeerts9:11,
12;19:8;
reducing 91:2; 96:22; 42:18; 43:14 ;60:13;
representing 56:25 110:4; 115:’21 42:16,17;
46:10;
49:22,
120:7; 148:17 87:23; 88:2,14,22,23
reproduced 129:18 responsiveness 66:4, 23;60:4,5,17,
20;61:3;
reduction 31:3, 16; relative 46:9; 137:18
reproducible 94:22 12;80:4 70:22;
111:2,
5;136:16;
39:12 ;41:17;45:19,21; relatively 36: 14; 37:21;
48:9; 49:1,18 ;89:11; request 4:24 rest 71:9 137:10;
143:9;
144:24;
123:12; 145:24; 147:4;
95:18; 96:16; 98:13; restate 175:9 169:3,4,9;
175:19,
20;
148:11; 156:5; 163:17; requesting 132:25
101:8; 102:7,8; 103:15, restoration 80:4
179:17
177:7 require 58:5; 92:19;
17; 120:20 relevant 43: 19; 89:10, result 158:14; 173:5
reductions 87:7
refer 23:13
13; 97:20; 156:7; 160:16;
161:1o; 171:2
121:22 ;131:23; 133:16;
134:22; 140:8; 153:24;
155:7; 166:7; 178:3
resulted 35:14; 157:16 s
results 8:17; 38:14;
referenced 47:10 reliable 33:8; 54:24; required 45:18, 19, 20; 69:24; 78:4; 108:23; Sachar 8:25;
9:3,9;
22:4;
-_ referral 125:21 92:20; 94:21 165:11; 166:4 126:20 23:2; 26:8, 10;27:8;29:15,
referred 154:2 reliably 36:16 requirement 134:3 resume 100:19 21;30:1,4; 31:20 ;32:5;
referring 122:6; 129:5; relief 32:22; 76:18 requirements 166:12 retaining 67:17 49:8; 61:20; 62:8,25;
134:2 rely 38:21; 58:24 requires 86:25; 102:17 ret reatment 84:6 63:15; 64:16, 22;66:9;
69:1; 79:7; 82:12;83:5;
refers 23:11 remains 43:15; 68:6 requiring 42:13 retrospective 171:6
90:23; 91:12, 18;92:22;
reflect 45:15 remarkable 83:1 requisite 60:15 return 49:14 94:19; 95:17; 96:20;97:6;
reflected 36:24; 37:12 Remarks 5:13 requisites 142:8 review 15:22; 66:1; 99:8, 12; 102:9; 105:
10;

Miller Reporting Company, Inc. Min-U-Scrip@ (2s) reasonable - Sachar
Hearing Volume Number 2 Food & Drug Administration
May 29, 1998 Gastrointestinal Drugs Advisory Committee

106:9;
107:14;
109:12,23; 159:6; 166:14; 168:19; 155:8 severity 16:11; 96:14 signal-generating 160:2
111:9;
113:23;
115:1; 171:4, 10,20; 172:1; seems 29:6; 32:2; 44:25; SF-35 50:2 signals 147:19; 160:13
_#%l; 119:3,25;
120:13; 174:4; 176:1 59:14; 75:3; 78:16; 79:12; share 93:6 signed 129:19; 131:22;
.9,23;122:7,
13; saying 58:25; 69:23, 25; 82:22 ;96:14; 115:2; 166:20
she 6:9; 156:2
.-_/.24;
128:25;
129:22; 76:5, 5; 81:5; 95:6,9; 97:4, 126:9; 139:24; 176:24 significance 98:21;
146:11,
21;150:12;
164:4; shitf 37:25
20; 100:12; 105:24; seen 8:1X 11:23 ;46:1; 99:16
170:16,21;
171:16;
175:8, 107:12; 142:21,21; 144:5; Shirkey’s 130:18
84:13 ;90:12; 103:22; significant 78:9; 92:6;
9,15,18;178:1,9,
20; 153:4, 23; 157:15; 159:11; 145:25; 156:17; 169:11; shopping 150:16
179:17 98:15,19, 20; 99:18;
171:9; 172:6 172:8 short 6:12; 76:18; 83:19; 105:21,24 ;112:1,2;
Sachar’s 67:13; 93:6 says 51:4; 56:16; 62:23; 123:11; 135:11; 161:17;
segue 112:24; 160:25 145:21; 146:2; 150:9, 11;
sacroiliitis 14:7 55:14;80:17,21;81:13; Segueing 150:23 162:22; 163:17 165:9; 171:24
safe 139:25; 141:13; 33:15;113:11;171:9; St2iZt? 57:2 shortened 35:13 significantly 13o:16;
144:6; 148:16 175:3 shorter 85:10; 160:8 133:15 ;145:12,23
SeleChd98:12
safety 75:4; 78:10, 25; scale 88:16; 92:14, 15; shortly 139:10 Signs 15:2; 20:10;29:9,
selection 150:12,22
84:22; 133:3,5, 13; ?7:1; 100:9,10 13;39:10,12; 44:3;45:21;
Self 35:20 should 10:19; 23:22;
140:10; 142:22; 143:25, scanning 15:6 61:6; 72:25 ;73:5;
83:24;
self-fulfilling 91:19 25:25; 30:2; 37:10, 13;
25; 144:5; 146:6; 147:19; 148:17
scatterplot 88:3 39:11 ;45:12; 56:17;
150:23; 152:4,5,8,12, 13; Senior 10:15; 41:2, 3,9;
scenarios 77:10 58:21; 59:12, 14; 60:9, 15; Similar’ 35:25;39:6;
153:13; 156:1; 159:24, 25; 57:12; 68:4, 9; 172:12
61:1, 13;62:23; 65:6; 44:10; 88:19; 89:2;
160:14, 25; 161:1,8, 14; scene 10:24; 11:7 sense 23:25; 27:9; 33:3; 56: 19; 68:24; 71 :7; 72:9, 126:23, 24;127:5;135:22;
165:19, 23; 166:18, 23; science 112:18; 157:8; 34:20; 42:7; 50:13, 17; 14;74:20;89:14,23; 152:12; 171:9
167:7, 9; 172:14, 23; 158:8,11 57:14;74:1; 80:11, 15;
174:19 )0:17; 93:17; 102:11; similarity 131:18
Scientific 21:17, 23; 31:5; 105:5; 130:12; 111:8; 112:24,25; 113:3,
said 32:5; 41:4; 54:11; Simon 10:6; 11:17; 28:4,
S6:23;40:7; 44:19; 147:15, 18; 151:9; 159:14; 3; 114:11; 120:21; 121:21; 6, 25; 29:18, 25; 39:7;
56:13; 60:5; 62:2, 3; 72:17; 134:24; 174:9 172:19 130:18; 132:21; 135:2;
73:5, 23; 74:1, 6; 90:4; 43:20, 21;44:13, 16;
scientists 36:19 separate 23:11; 26:2; 141:9; 147:23; 149:1, 9; 72:23, 24;73:15, 18;
102:11; 110:9,9, 20; 30:5,15 ;43:23; 45:11;
sclerosis 65:7 155:17; 156:17; 158:12; 77:21,22 ;80:10,11;
115:23 ;122:12; 127:11; 51:1,2, 14, 17, 18;62:11; 160:2; 161:18; 163:12; 91:24,25 ;92:24;93:13;
128:9; 134:5; 139:16; Scope 179:19
56:22; 96:8; 112:24; 172:1; 174:7, 24; 175:6,25 102:20; 103:8, 12; 104.11;
143:19; 175:3 storable 46:21 127:1; 128:10, 20; 134:7, shouldn’t 44:11; 53:20; 106:5; 112:16; 114:13, 14;
salient 22:6 Score 16:2; 29:2; 30:9; 3; 137:13; 138:24; 139:1; 57:25; 100:15; 104:12; 133:4; 152:2; 153:2;
salvage 114:1 )1:17, 18;47:13, 15; 151:23 119:7 154:17; 155:21; 156:12;
---e 13:16; 19:1; 34:21; i8:24; 49:22, 23; 59:13; separated 29:10 show 26:13; 27:25; 157:1; 158:1,4; 168:9;
); 62:6; 64:24; 65:1; >1:1,5,
10,22;93:17; 170:6; 171:14, 23; 172:5;
Separately 108: 15; 39:11; 51:6; 55:10; 56:8;
8u:2; 84:14; 87:22; 88:14; )5:24,
25;96:23;111:17 176:5, 6,9; 179:18
151:24 70:17; 78:22; 83:25;
94:9; 96:25; 101:16, 22; Scores28:14;47:9; 39:10; 92:20; 98:20; simpIe22:14; 32:14;
sequential 139:22
105:23; 107:20; 109:3; f9:l
1;92:23;
93:23,24; 29:14; 136:3; 143:2, 4;
sequestration 135:7 57:5; 109:8
111:9, 18; 119:12; 124:19, >4:7;
95:21,
22;96:4 147:16; 170:25; 173:5,7;
SerieS 10:25; 11:15, 19, simpler 68:18
23; 125:2, 24; 126:1; SCOrhg 40:14;42:2 174:7
128:9; 143:5,8; 144:18; 23; 12:10; 13:6, 23; 14:14; simplicity 57:4; 67:12
se35:25;45:23 showed 70:14; 121:15
148:21, 23; 149:5,6; 46:22; 139:8 simplify 63:9
second 22:7; 88:5; 90:2; showing 64:14
169:4; 177:17 serious 121:11; 163:16; simplistic 52:9
101:11; 105:17; 110:13;
sample 93:25; 127:13; 165:7; 166:1 shown 25:4; 43:1; 86:17
120:13; 132:19; 134:11; simply 23:15 ;31:14;
145:4; 157:23; 166:8; seriousness 175:10 shows 58:23; 62:18, 18, 88:8; 93:8; 151:16
149:14; 171:21
179:2 serologic 11:19; 13:1,3 18; 88:2; 170:25
secondary 14:3; 98:2, Sinai 9:1; 46:8; 154:2
sanctions 141:22 serum 14:24 sick 29:12, 12,14,14;
25;99:1; 116:23; 118:7 since 19:8; 23:5; 45:2;
Sands 54:8, 9,9; 56:16; 60:1
Secondly 46:17; 90:7 serve 34:21; 55:2 66:21 ;96:13; 103:12;
65:14 sicker 94:6; 98:9 121:15; 132:11; 140:3;
SeCtiOn 23:21 ;27:21; session 6:19; 10:19;
satisfied 69:5,6 100:23 side 34:18, 18, 18;36:11; 151:23
39:13; 49:9; 130:24
satisfy 42:15 66:24 ;84:23; 111:21, 22; single 47:12 ;72:6;
sections 22:13, 13 set10:24;
11:7;32:25;
138:12; 147:9; 152:5,8,9 103:16; 143:3; 160:9
saw 43:10; 69:6; 70:4, 5; sedimentation 14:24; 37:9,13,
23;39:1;40:7;
72:5; 75:15, 16; 99:6; 59:13
;93:7;110:15; sides 112:21 SIP 50:3
35:24; 37:16
167:22; 178:7 111:3,6;
112:10;116:24; SIEGEL 38:9; 40:10; sit 59:8
see 7:14; 8:20; 30:13; 45:10 ;47:18; 50:14; 58:2,
say 6:20; 8:15; 22:9; 126:14;
139:8 site 18:2
42:2; 43:3; 44:17; 51:13; 18; 59:6; 62:16; 63:25;
23:18; 24:10; 25:2, 13, 16; setting 14:16; 20:24; sitting 66:17
71:18 ;75:19; 89:2; 64:19; 65:4,6; 69:19;
34:15, 16; 35:16; 48:20; 101:21; 105:7, 23; 109:4; 23:16; 52:5; 114:3,4,9;
70:21; 83:18; 84:8; 86:2; situation 91:23; 151:13,
50:23, 25; 51:22; 53:1; 112:21 ;116:21; 125:17; 140:17
91:9, 15;94:10, 21;97:4; 18, 20; 162:13; 166:18;
57:22; 58:20; 62:20, 22; 128:1, 17, 18,20; 129:11; settled 150:15 179:20
63:1; 65:7, 16, 17;71:10; 103:25; 107:22; 108:22;
133:6; 141:5; 152:12; settling 49:14 113:14; 118:5; 119:2; situations 83:11; 166:7
72:25; 73:2, 3; 74:7; 75:22; 155:5,6; 156:6; 164:10, seven 42:22 139:14; 140:9, 22; 145:7; six 37:9; 39:11; 56:9, 11;
76:6, 22; 79:3; 80:14; 85:2; 12, 12; 165:16; 172:14
_&$ 90:10, 17; 94:23; seventies 25:4 146:18; 149:10; 161:20, 109:11; 131:6; 135:3;
seeing 72:6; 93:25; several 8:24; 14:5; 19:19; 25; 162:19; 164:17; 161:3,7, 13; 162:17;
100:2; 103:19;
116:14; 118:17; 125:23; 24:15 ;31:23; 46:17; 166:15, 19; 172:22; 163:1; 164:19,21,22, 23;
.10; 110:11 ;112:12,
127:25; 147:5; 164:1 107:25; 112:17; 121:14; 175:10; 178:11, 22; 177:5
23; 115:17, 18; 116:1o;
119:13, 16; 128:17; seek 147:23; 150:2 154:11 179:22 size 89:20; 94:1; 127:13,
139:18; 144:2,25; 145:2; seeking 16:5; 19:15 severe 17:11; 46:20; sigmoidoscopy 91:1 13; 137:19; 145:4; 157:23;
149:6, 14; 150:13; 151:12; seem 16:11; 33:14 ;62:5; 59:18,23 ;82:23;94:11; signal 59:5; 160:13; 160:20; 164:4, 5; 175:4;
153:24; 158:20,20, 24; 66:18; 88:16; 143:11; 96:18:126:3:148:18
-. 163:22 i 176:9,14,15, 19, 19;

Sachar’s - size (24) Min-U-Script@ Miller Reporting Companv, Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1998
177:11; 179:2 178:2, 9; 179:6,9 sophisticated 99:17 stages 7:14;21:20 27:20, 22; 49:5; 50:9;
166:8
SiZt?S so-called 106:11; 172:7 sorry 80:23; 123:5 stance148:23 55:25 ;61:14; 62:5,8; 63:3,
——.-
skew 93:22 Society 96:15 sort 27:23; 30:14; 33:19; Standaert4:5, 7;179:24 4,6,10,11,18,19, 25;
skewing 100:5 soft 37:15 37:2, 25; 49:8, 13; 57:22; 91:10;101:7,8,9;102:7;
standard7:11; 66:16;
68:15; 74:24; 79:14; 103:14,18,22,25;104:4,
Slide 11:6; 12:7,
19; softer 36:20 86:19;93:22;
96:7;
82:22; 87:14; 88:17; 96:5; 9;106:19,23;107:1,3,4,
13:12;
14:11;15:9,23; Softky 129:23 107:13;113:16;114:19,
106:16; 114:7; 115:19; 8,9,10,12;108:18;
16:9,16,
23;17:22;
18:22; 21;134:6;159:11;161:18;
SOftly 99:25 134:11 ;150:15; 152:25; 109:16,20,20;110:1,2,4,
19:18,
24;20:4,14,
20; 168:13,18;169:1;170:4;
sole 49:4,6 163:7; 165:6; 176:13 4;115:8,8,15,22;116:2,
21:3,9,
14 171:10
solid 173:9 5,11,22;117:2;118:6,9,
slides 10:25; 11:4 sound 173:9 standardized 170:2 11,17;119:4,10,12,15,
slight 97:1 solutions 18:23 sounds 151:22; 177:5 standards 32:25; 66:5 19,24;120:10,20,25;
slightly 19:23 some 4:5; 6:21; 7:4, 18; space 115:24 standpoint 11:25; 12:2, 122:2,14;123:25;166:6;
10:3; 13:1,3,5; 15:21; span 101:13 169:13
S!Oppy 93:23 3,4,4,6; 13:18, 21; 20:5;
17:14; 18:18,20, 23; 20:2; spare 120:14 21:17, 23,24; 31:15; steroid-dependent
slow 170:17
21:5; 26:9; 28:8; 29:22; 106:12, 14; 120:15;
SIOW[y 120:6 Spating 23:23; 27:20, 22; 38:15; 51:14; 52:8,9; 68:2;
32:11,19; 33:1; 34:15,21; 70:16; 85:14; 93:8; 94:16, 121:13
;122:3,5,10
small 36:14; 46:21; 84:5; 49:5; 50:10; 55:25; 61:14;
36:7,18, 25; 39:15; 40:12, 17; 101:2, 3; 106:2; steroid-induced 26:24
62:5,8, 24; 63:3,4,6,10,
95:25 ;97:23; 98:21; 22; 42:11; 49:2; 50:14;
11; 19, 25; 103:22, 25; 138:13; 148:4 steroid-sparing 106:19
131:11 ;134:7; 148:12; 56:9; 57:21; 61:9, 12; 67:6;
151:6; 152:14,18, 19; 104:5,9; 107:3; 116:5; standpoints 11:25 steroid-t rested 25:12,
68:11, 17;71:15;75:21;
154:7,9,10, 12, 16; 155:9; 119:11, 12; 124:1 Stanford 34:7 18
76:6,8, 24; 77:16; 78:12;
156:6; 162:3; 166:4; 79:24; 80:15,16, 23; speak 9:2; ll:3;65:18; start 22:11; 38:23; 39:21; steroids 15:20; 25:2,3,4,
169:18; 177:16,19 82:22; 83:9,15, 22; 87:17; 90:4 46:16; 59:4, 4; 64:25; 7,10,11,13, 16,20; 28:1,
smaller 55:9; 95:10; 88:9; 92:19; 95:3, 17; 99:1, speaking 81:10; 87:1 1; 106:22; 109:1; 116:14, 16; 2; 35:7, 12; 46:11; 49:1;
136:11; 162:1, 10; 165:20; 2,3, 13,25; 100:5; 101:13, 140:19 118:17; 119:2; 124:14; 56:11; 62:6,10,19, 24;
177:8 19, 22; 102:3, 14; 105:5; SpeCial 148:19 127:25; 134:13; 144:7, 7; 63:5,6; 64:7, 11, 15;66:9;
smallest 173:15 106:7; 113:17; 114:7; SpeCifiC7:22; 10:3; 32:8, 170:22, 24; 178:16 69:1; 75:14 ;91:2; 101:5,
116:6; 117:7, 22; 118:20; 18;39:13; 61:13 ;63:2; started 47: 11; 86:8; 10, 13,19, 24; 102:13, 17;
SO 7:16, 19,23 ;8:12; 9:2;
126:2; 129:16; 130:6, 10; 36:14,16, 22; 95:20; 96:3; 114:4,8; 142:17; 144:8; 104:2, 3,6,7; 105:24;
10:4, 19, 20; 12:21; 13:13;
131:14,16,20, 24; 132:12; [15:7, 10; 136:13; 141:19; 151:7 106:3,16, 24; 107:11,18,
16:17, 24; 17:23 ;21:15;
134:19; 135:1, 14; 137:16, 145:14; 150:3; 158:10; 20; 108:9, 21; 109:5,14,
25:21; 26:24; 27:5; 28:10, starting 49:10; 91:20;
17,22; 138:13, 22; 141:6, 159:13; 161:21; 163:22; 17, 19; 110:6; 111:7,19,
–—- 22; 29:5; 30:24; 31:7; 32:4, 103:18,19
22; 142:5; 144:7, 13; ~64:9; 166:17; 177:8 21; 112:3,7,9, 14; 115:21,
20; 36:4, 18; 37:18, 24; Starts 6:9
145:22,23, 24; 146:1; 25; 117:17; 119:5,6, 22;
41:10,24 ;43:3, 14, 16,24; specifically 9:16; 23: 12; state 18:8; 42:17; 53:8,
147:17; 148:2, 19; 150:10; 120:2,6,9, 12,14,23, 24;
44:23; 45:22; 47:23, 25; }1:22; 40:23; 50:16; 16;71:1; 77:14 ;80:19;
151:5; 160:6, 20; 162:1, 5; 122:20,24, 25; 170:21;
48:4; 51:8,10, 25; 53:3, 52:23;88:13; 95:24; 12:2; 133:16
168:3; 170:16; 172:14,14, 171:7,19
13;55:11,22; 56:14; [27:10; 131:25; 132:20;
19; 173:25; 174:14 stated 26: 15; 89:6; SteVe 22:4; 27:8; 34:1;
57:22; 59:25; 60:2, 23; [38:18; 139:2, 4; 145:8,9;
somebody 29:10;62:17; 151:18;157:13; 158:21; 53:19; 56:23; 72:17;
61:1,3,6; 62:10; 63:18, [46:17; 150:6; 161:2, 25;
50:14;
90:6,
6;94:10,
23; 160:23 73:23; 77:7; 106:18;
22;64:9;65:11, 18, 21,23; [62:3; 167:17; 179:16
66:6,21 ;67:8,11; 69:11; 97:11;
104:1;
110:9,9; ;tatement 5:11; 41:16; 116:15; 128:25; 131:19;
specificity 17:12
70:16, 20; 72:16, 25; 73:9; 121:17;
150:25;
168:16 13:15; 111:24; 114:20; 133:21; 135:21; 136:16;
;peCifics 39:15; 79:22; 136:12; 142:11 170:6
74:1, 10;76:22; 78:3, 13, somehow 36:5 L35:11
23; 79:9, 23; 80:4; 82:9, someone 56:4;
78:19; ;tatements 4:23; 22:20 Ni[l 19:15; 20:5, 12, 18;
14,16, 16,23 ;83:24; ;p.ecified 32:1o; 171:13, States 9:6 29:19; 30:3; 34:3; 47:14,
93:25 [5
84:17; 85:3; 88:24; 90:14; 16; 50:24; 55:17 ;61:25;
something 7:9; 20:21; statistical 87:1 1; 89:12,
92:13 ;93:24; 94:10; ;peCify 178:13 f8:5; 79:14; I05:16;
26:5; 39:9; 52:18, 22; 54:6; [7; 95:4; 96:3, 9; 97:13;
98:20; 100:8, 9; 101:21; ;pectrum 165:18, 24 )9:16; 101:6; 117:18 109:12, 13; 119:14, 17;
55:18; 56:10; 57:7; 58:22;
102:5,16, 22; 103:3,10, ;peculation 134:20; 120:2; 129:24; 153:16;
67:11, 11;77:1,1,11,12; ;tatisticai[y 93:20;
16, 24; 104:9,14,19, 23; [57:4 172:2,10
B2:7;84:8; 87:25; 88:12; )8:15, 18; 99:17
106:17,23; 107:2, 11,14; 92:14; 99:15, 22; 100:1; ;peed 6:11 ~timUlate 7:20; 8: 17;
108:22; 109:5, 14; 110:22, statistician 31: 15; 151 :7;
106:11; 107:4; 109:14; ;poke 13:2; 109:13 26:17
24; 113:21; 114:7, 17,23; 171:22
112:6; 114:6, 11;115:6; ;poken 137:20 stoma 130:2
115:17; 116:24; 117:18; statisticians 18:16
116:1; 125:6; 126:8; stomas 129:6,25
118:22; 119:22; 120:8, 12; ;pondylitis 14:7 ;tatistics 97:8; 98:4;
129:9; 133:23; 136:10,15, stop 28:1, 2; 63:5; 70:18;
121:3, 17; 123:1; 124:10; 16;137:16; 141:12; ;ponsor 58:1; 81:25; 100:7,13
125:14, 22; 126:8,12, 14, 112:12; 178:4
147:19; 148:14, 16; .10:16, 17;113:24; status 42:19; 64:6
18, 19; 127:9, 17; 128:6, .20:21; 121:4; 126:23; stopping 75:10
153:17; 154:19; 155:13; ;tay 117:17; 121:22
19; 129:1,21,24; 130:21, 156:10, 24;157:20, 24; .27:18; 128:19; 132:24; straddles 54:19
;tayed 48:13
24; 131:15; 135:23; 136:6, 158:24; 164:14 .41:4, 10, 18 straightforward 117:20
21; 137:21; 138:2,7, 14; ;taying 64:24; 65:1
sometime 141:18 ;pOnSOr’s 127:11 street 112:21
139:13; 142:16, 17; 143:8; ;tays 25:18
sometimes 23:12; 49:21; ;ponsored 129:6; stressors 157:10
144:6; 145:19, 21; 147:4, 38:18 STEINBERG 177:4
24; 148:6, 15, 16; 149:18, 70:23; 114:8 strong 151:15
;ponsors 5:16; 38:13; ;tenosing 125:15, 18, 22
21;150:1,20; 154:12; somewhat 5:14; 65:15; Stronger 176:20
57:25; 76:4; 84:8; 136:10; ‘4:14, 16;81 :17; 136:7; ;tep 7:15
155:9; 156:4; 161:23; structural 28:9, 15;
163:24 48:5 Nephen 6:25
162:3,21; 164:14; 165:9; ?9:16, 18, 22; 39:18;
166:17; 168:5,9, 25; somewhere 56:7; ;pontaneou$.dy 24:8 ;tepping 117:21 i3:22; 73:6
169:23; 170:1; 172:9; 112:19; 115:19; 132:12; ;pread 87:22; 88:19 stereotypic 149:17 ;tructure 29:8, 14, 24;
173:24; 175:17; 177:1; 175:1 ;tage 64:5; 82:22 ;teroid 23:23; 25:10, 19; ;1:6

Miller Reporting Company, Inc. Min-U-Scripti {25) sizes - structure
Hearing Volume Number 2 Food & Drug Administration
May 29, 1998 Gastrointestinal Drugs Advisory Committee

struggled 162:24 subsumed 23:25 surrogate 58:3 taking 24:20; 38:3; 63:5, terms 32:13, 22; 33:11,
struggling 53:13 subtext 108:1 survival 58:6 5; 86:9; 96:16, 25; 155:6; 16;34:11; 36:3; 38:1; 39:6;
157:9 42:4; 47:5, 9; 66:6; 84:9;
s-+ied success 23:20; 24:21;
127:17; 133:7; susceptible 59:24
47:17; 49:4; 86:21; 179:10
; 172:9; 173:19,20 Talarico 8:13, 15; 179:21 97:17; 108:15; 126:6;
suspect 33:12; 44:9;
131:8; 144:24; 145:18;
successes 86:22
studies 24:18; 25:2, 3,8; 160:20 talk 23:10; 24:4; 27:21;
152:16; 159:14; 163:22
42:21 ;43:1; 55:9; 56:3;
successful 104:7 sustain 105:9; 106:3 30:23; 32:3; 49:15; 58:19;
60:9, 11;69:21; 70:17; 63:2; 68:14; 86:23; 110:8; terribly 58:24
successfully 20:6; sustainable 106:8
71:22;
72:8;
88:2;
99:13; 41:11 ;62:17;64:15 115:3; 117:1; 125:7, 14; test 117:18; 167:19
Sweden 51:18 146:4, 17; 157:2; 175:25
101:18;
125:20;
126:20; succinct 22:5 testable 157:14
128:3,6,17,
18,20;129:4, Swedish 43:1; 57:6 talked 27:10; 42:4; 61:10,
such 4:10; 5:5; 7:5; 8:22; tested 98:7; 127:8, 9;
14;130:25;
131:9,23; swim 82:2,6 11;86:13; 101:16,22; 157:17; 166:6
11:4; 12:24; 13:3, 10; 14:4,
132:2,
14;134:14,17; Swiss 135:13 119:3 testing 159:14
7,8,20, 22; 16:4, 13; 17:1,
135:14;
136:13,17,19,21, 2, 13; 22:5; 23:23 ;41:13; symptom 18:13; 36:11 taking 25:22; 27:12, 16, th 146:25
25;137:12,
13;138:19; 51:15; 66:5; 86:18; 95:11; symptomatic 13:20; 16, 17;29:1; 30:23 ;33:3,
139:11;
140:12,15, 15,21; 106:13; 125:9; 131:12; thalidomide 75:14,16,
26:23; 32:14, 22; 33:17; 7;42:3; 59:12 ;66:12;
18
141:18;
142:13;143:10; 132:6; 137:12; 142:4, 4; 49:17; 59:3, 19; 60:7, 14; 69:12,14, 17;72:13;
144:7,
17;146:5,6; than 5:15; 18:4, 9; 22:16;
146:25; 148:2; 166:3; 65:9; 109:14 76:24; 77:25; 82:14;
147:11,13,15,
16;148:19;168:5 23:3; 25:16,22, 24; 26:2;
symptomatology 56:15; 83:11 ;84:9; 85:20,21;
152:8;
154:1;
160:2,14, suffice 174:4; 179:8 87:20; 96:15; 98:3; 31:12 ;32:4;33:23; 35:5;
119:7,9
21;163:4;
164:5,6; 102:10; 103:16; 105:19; 36:21; 39:23, 25; 40:1 1;
sufficient 65:13; 69:3; symptoms 13:15,19; 43:12; 46:23; 47:24; 48:2,
167:20;
170:14;171:5; 107:23; 108:3, 7,8;
127:13 ;131:17; 133:16; 16:14,19,19;18:1,3,5,
172:10 109:18; 110:1; 115:9; 9;56:18; 66:11 ;67:16;
134:18; 147:24; 162:18 12;20:10;23:6,
9;27:2; 73:8; 76:4; 77:3; 78:7, 13;
study 4:22; 39:1, 10; 28:12,20,22;29:9,13; 116:8;125:16; 126:16;
suggest 20:9; 44:13; 65:1,4 ;95:13, 16; 101:25;
43:8; 46:25; 55:16, 18; 68:19; 94:21; 126:2; 39:1O,12;41:18;
44:3; 146:12,13;150:13;
102:3,21,22,22, 23;
56:5; 60:11, 24; 62:17; 152:11; 168:10 45:20,20,24;49:17;51:7, 152:13,21,24 ;153:2,22;
68:19, 24; 69:20, 23; 70:9; 103:5; 105:14, 15; 107:13;
suggested 18:25; 19:3; 13,20;52:21;55:23;58:7, 154:5, 5,6;156:19,21;
72:14, 15;73:25;74:10, 108:7; 110:25; 112:22, 23;
20:15 ;30:1; 120:1; 9,20;60:1;61:7;
62:14; 157:25; 158:1, 3,4;
21;78:7, 16;81:4; 83:17; 116:17; 124:12; 125:1;
129:15; 138:10,13 63:7;
73:1,6;75:8;76:19; 162:25; 163:2,5,14,18,
84:5; 86:20, 25; 88:3; 126:15; 128:14; 130:2;
83:20,24;105:20;108:11; 20;164:6, 7;166:18; 176:1 136:11; 144:7; 149:21;
89:18,22 ;90:12; 94:10; suggesting 30:17, 20;
117:5,7;123:4,5,
14; talks134:2 152:8; 154:24; 155:3;
98:15, 20; 104:5; 121:23; 38:18 ;44:14; 58:17,18,
148:17 tangent174:12 159:20; 160:8; 161:3;
19;64:3; 101:19; 137:7,8
syndrome 17:10; 28:19 taper 62:19; 64:10; 105:8; 162:10; 163:13; 165:20;
suggests 65:23; 154:3
synonym’ 64:16,21 116:16; 117:14; 119:5; 166:8
Sulfasa[azine 14:22
synovitis 35:25 170:22 thank 5:15; 6:17; 8:6, 8;
studying 127:23, 24; SUmmariZe 25:21
133:25; 153:21 system 29:2, 7; 36:6; tapered 104:6; 117:12 78:9; 177:25; 179:16,21
superb 75:1o, 17
41:6,9 tapering 104:7,14, 16; Thanks 34:1
subcategories 61:20 superior 66:3
subcategory 63:12, 13, Systematic 118:21 116:7,21, 22; 117:5; that 4:13; 5:l,8,11,24;
superiority 173:5 118:17; 119:15 ;122:12,
16 systematically 118:25; 5:4,23,24, 25;7:2, 5, 11,
support 6:2; 57:3, 8; 129:4, 12; 130:7; 133:25; 14 12,16,18,21,23,23, 25;
subdivision 24:5 88:24 134:13 Targan 13:2 9:10,15, 16,21 ;9:10;
subgroup 124:3, 4; supported 67:13; 10:5,13,19, 22; 11:10,12,
SyStemiC 104:18 target 154:21; 155:2;
145:2, 3; 147:14, 17; 135:14; 136:15 16, 18, 19; 12:10, 14,16,
148:10 ;151:1,6,8; 154:4, 156:14, 18; 158:11
supporting 131:17; 18,21, 22; 13:3,4,5,6,7,
5 135:5 T targeted 155:10
tastiest 144:4
), 14; 14:4,5,7,9, 15;
subgroups 13:5,6; 15:12,16,20,21, 25; 16:4,
supposed 124:16
18:25 ;20:1; 25:8; 128:5; teach 82:2 5,6,14, 18, 19; 17:13, 20;
suppressing 112:6 T16 88:3,15, 20;90:4
151:10, 14; 154:7; 177:2 team 166:21 18:9, 24; 19:20; 20:9, 21;
suppression 146:9; T20 40:24; 47:11; 88:7,
subject 100:24 techniques 10:11 ;97:14; 21:6,7, 15,21,22 ;22:1,2,
152:4; 167:2 15,20
subjecting 157:9 99:9 3,13,14,19, 20; 23:8, 11,
SURAWICZ 31:2; 50:12; TA 99:13 14, 14, 14, 18; 24:6,6, 10,
subjective 13:18; 17:3, technology 28:10;
51:8; 66:21 ;109:10; table 5:24, 25; 33:2 11,14, 18,23 ;25:1,11,
21;51:11 44:21,24 ;92:8
122:17; 123:15; 176:22, tables 137:25; 138:5 13,16, 23; 26:2,7,18,19,
subjects 161:8 23 tell 123:13, 17; 127:3, 15;
tackle 101:4 19; 27;8, 9,21,22, 25;
submission 131:24 128:12; 175:12
sure 46:20; 50:16; 52:23, 28:8,8,10,13,16,19,21,
take 6:19; 7:21, 25; 10:18; telling 67:ll; 124:12;
submit 131:16; 135:20 25; 53:10; 54:14 ;86:3; 25;29:1,4,6,6,7,9,10,
34:3; 47:8; 62:11 ;64:4; 174:24
submitted 4:11; 131:21 94:16; 95:21 ;127:3; 18, 19; 30:1,18,22, 24;
75:15; 89:6; 95:25; 98:1;
128:25; 139:13; 140:12; tempo 124:23 31:2,3,5,6,12, 12, 19,20,
submitting 4:24; 144:3 100:17; 106:22; 109:6;
151:15,20; 159:7; 173:6, temporally 139:22 24,24, 24; 32:2,6,8,9,10,
suboptimally 169:5 114:5; 120:21; 121:8;
16 tends 15:12; 167:5 15, 15; 33:3,3,5,7,9,12,
subpopulation 155:19 122:25; 136:2; 137:20;
surge 132:14, 15 13, 25; 34:3,15,16, 17;
138:20; 141:10; 142:16; tens 99:13
subsequently 128:7 35:2, 25; 36:4,6,18, 25;
surgeons 68:1 143:6; 148:21, 22; 168:16; tenth 99:15
s’%et 19:13; 40:16
-. 169:10; 176:14; 178:9; 37:15,17,24,25, 25; 38:1,
surgeries 130:21 term 23:5; 31:3; 36:3; 20,22, 25; 39:2,6,10, 11,
tance 135:17 179:4
surgery 18:7; 66: 10; 43:11 ;76:16; 77:17; 15, 15,20, 20; 40:6,7,9,
substantial 131:7; 140:4 82:24; 83:7, 10; 125:5; take-over 79:11 80:12; 83:19; 107:14; 17,21,23,25 ;41:1,6,9,
substantially 86:24; 165:10 taken 45:ll;84:l; 96:4; 113:8; 119:1, 20; 125:7; 12,22 ;42:5,11, 12, 19;
171:7 surgical 9:17; 16:22; 139:22 162:22 43:1,3,4,5,8,10, 18,23;
substantiate 144:20 18:7; 19:14; 24:4; 50:7; takes 108:15; 123:22; terminology 68:22; 44:1,7,8,9,13,14,15, 18,
substitute 55:8 68:2 139:11; 177:17; 179:1 113:10 22,22;45:1,3,5,9,
10,12,

struggled - that (26) Min-U-Script@ Miller Reuortirw Comnanv. Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1998

16, 16,22,23,25, 25; 20,24 ; 114:1,2,11,11, 18;178:3, 5;179:7,7,8,9,23;55:1,3,4,7,8,8,11, 13,14, 14,19; 111:1,1,8,
46:1,2,3,3,16,18, 2W 14,14,16,17,18,19,22, 9,12,14 16,17,21,22,23,23,23,9,12,14,18, 24; 112:4,
_—_ 47:3,4,5,14,16,17,18, 24;115:1,2,3,12,14,19, That’s 29:25; 68:10; 24,24;56:1,1,2,4,4,5,5, 17, 17,18,20, 21; 113:5,
19, 23; 48:14,16,20,21, 19,21,21,23,23 ;116:1, 156:16 6,8,10,16,17,17,19,23, 6,10,15, 24; 114:2,2,4,9,
23, 24; 49:2,5, 16; 50:1,4, 2,2,7,12,13,24, 25; The4:7,8,9,10,11,11,
25;57:1,4,8,8,9,10,13,15,15, 19,20; 115:6,10,
6,9,14,15,16,17,20,20, 117:3,4,8,13,17,17,19, 12,14,16,21,22,24, 25;
14,15,17,20;58:6,9, 12, 11,13,15,17,19,22,24,
22, 23; 51:4,6,9,10,15, 25; 118:2,5,8,14,14, 18, 13,20,22,22, 23;59:3,4, 25; 116:4,5,7, 14,15, 16,
5:1,1,2,3,4,6,8,11,15,
15,21 ;52:5, 11, 14,16, 20,23, 24; 119:22, 23; 16,17,18, 18, 24;6:2,4,4,
10,17,18,21,21,22,23,17,17,19,24, 25; 117:1,
18,19,19,19, 23; 53:1,3, 120:1,2,4,5,6,9,10,11, 8,8,10,12,14,18,21,24,
23;60:1,9,11,12, 1 3; 2,2,4,6,10,11,12,18,
4,5,5,6,7,9,10,11,12, 13,20,21,22,23 ;121:2, 25;7:2, 3,6,7,9,10,13,
61:23;62:1,6,9, 16,19, 19,20,23,24, 25; 118:1,
16, 18,19,20,21,24, 25; 5,6,9,9,10,12,13,13, 14,15, 16,25 ;8:1, 3, 12,
19,21;63:1, 17,18,19, 2,6,9,10,16,18,18,19,
54:1,5,11,13,15,16, 18; 15,19,22,24, 25; 122:6, 17, 19) 21,24, 25;9:1, 7,
23;64:1,11,12,18,24; 19,20,22, 24; 119:6,12,
55:2,5,12,13,16, 19; 7,8,9, 11; 123:2,2,6,7, 65:1,8,18,23;66:1,2,2, 15, 17,25; 120:3,9,14,
10,12,13,14, 17,22;
56:2,4,5,6,9,10,16,19, 10,14,16,17,18,21, 22; 10:4,7,8,15,19, 21,24; 3,3,4,10,11,14, 19,21; 18, 19,21,22; 121:5,6,9,
19; 57:7,14,16,23,25, 124:3,4,8,17,19,22, 24;
11:7,8,10,12,14,16,18,
67:1,2,3,5,6,7,8,9,10, 11, 11,11, 12,24,24,24;
25; 58:4,4,5,8,14,16,19, 125:3,7,7,9,16, 19; 12,15,17, 18;68:1,3,4, 5, 122:1,1,2,3,5,9, 14;
23,25 ;12:1, 1,2,3,6,13,
21,22,23,24, 25; 59:9, 126:2,3,9,9,12, 14; 16,18,23,23, 24; 13:6, 5,12,14,18,18, 24; 123:3,4,6,7,8,12, 20;
11,11,12,13,14,14,18, 127:3,4,5, 12,15,20,21, 10, 16; 14:9,15,16, 24; 69:19,20,20,21, 22;70:2, 124:4,5,7,8,9,9,11,16,
19,23 ;60:5,7,7,21,21; 22, 22; 128:9,13, 17; 15:5,5,7,10, 11,14,18, 9,12,15,16,20,21,23; 19,21,22,23, 25; 125:2,
61:8,12,22,22,24, 25; 129:2,9,11,14, 15,16, 21;24; 16:1,2,6,11,11, 71:2,4,6,6,8,9,18,20, 3,4,4,12,12,12,16,19,
62:4,4,6,18,18,18,23, 21; 130:1,6,7,12, 17,22; 18,21, 24; 17:2,3,6,6,6, 20,21,22,22, 25;72:7,7, 20,21,24 ;126:1,3,4,4,5,
25; 63:2,3,16, 20; 64:6, 131:3, 19; 132:12,23, 24; 10,12,17,19,21,23, 24; 7,9,10,10,11,13,14,24, 10,22,22, 23; 127:4,5,8,
12, 14,20 ;65:15, 16, 23; 133:2,3; 134:1,2,3,4,4, 181,5,10,12,14, 17; 25;73:1,4,10,11,12, 12, 11,15,18,20, 25; 128:2,
66:3,18,23,24, 24; 67:8, 6,6,10,15,16,17,20,22, 19:1,3,4,7,9,9,10, 10, 17,19,19,21,25 ;74:6,7, 9,13, 25; 129:9,12,17,
10,10,14, 25;68:3,6, 15, 23,25 ;135:1, 11,12,18, 15,17,20, 23; 20:3,7,8, 7,8,17,22,23,24, 25; 22,25; 130:1,2,5,11,12,
15, 16,21,22 ;69:3,5, 12, 24; 136:4,6,6,8,13,15, 11,16,22,24 ;21:1,6,8, 75:1,3,4,13, 19,20,21; 12, 15, 17,23; 131:3,5,
15,16,21, 23,24 ;70:2, 5, 17,18,19, 22; 137:14,22; 12, 16,17, 18,21, 22,23; 76:6,8,8,8, 13,14,16,16, 10,10,18,24, 24; 132:9,
7, 12, 14,21,21,22 ;71:3, 138:1,5,7,8, 12,15, 18, 22:6,8,12,13,15, 17,18, 18,19,21,25;77:8, 13, ), 12,13,14,15,17,21,
6,10,14,16, 17;72:2, 3, 19,19,20,22, 24; 139:1, 18, 19, 19,20,20,22,22, 18,22;78:1,3,3,5,5,5,8, 22,23, 24; 133:1,3,4,12,
10,15,19, 24;73:3, 5,7, 6,12,16, 17,19, 19, 21; 23, 24; 23:3,4,11,15,19, 10,10;79:6,8,10,10,10, 16,20,21,21,23, 25;
11,19,21,24 ;74:1,2,10, 140:5,8,9,13, 20; 141:2, 19,20, 20;24:1,6,7, 12, 14,15,19;80:1, 2,2,3,3, 134:1,2,5, 10, 11>11, 12,
12, 18,20, 24;75:1, 12, 10, 12, 14, 15, 18,20; 13,15, 17,18,20, 24; 5,5,12,19, 22;81:3,4,4, 15,17, 17, 18,18, 19,20,
.~ 13,18, 19;76:7, 12, 12, 142:1,4,6,9,11, 14, 18; 25:1,3,5,6,9,11,12,13, 5,6,8,10,11, 22;82:3,6, 20,22,22,23, 24; 135:3,
14,15,21,25,25,25, 25; 143:2,3,4,12,17,20, 23; 13,17,18, 19; 26:10,14, 9,14,20,21 ;83:5,6,6,8, 4,7,9,15,17,19, 22;
77:4,8, 11,12, 15,15,19, 144:5,11, 16,18,19, 19, 15, 19; 27:5,6, 10,13,14, 10,12,14,23,23, 25; 136:2,5,18,19, 24; 137:3,
23, 24; 78:1,2,3,7,13, 16; 20; 145:4,7,11,12, 25; 15, 15,20,24,25 ;28:1, 1, 84:3,4,6,11,14,20, 23; 3,5,8,9,17,18,19,24,
79:8,12,14,19, 23; 80:2, 146:9,15, 21; 147:2,3,5, 2,2,4,7,11,17,19,22, 85:18,21;86:2,3, 5,9,9, 25; 138:1,3,5,10,11,12,
5,13,13,16,17,18,19, 12,23, 24; 148:4,4,6,9, 25; 29:3,13, 23; 30:1,8, 12,12,15,16,17, 18,19, 12,13,16,17,19,21,21,
22;81:4, 5,6,7, 14,16, 19; 11; 149:3, 25; 150:2,7,10, 13,14,21,23 ;31:2,3,5, 21,23,24;87:2,4, 5,6,14, 22, 25; 139:6,7,16, 17;
82:2,3,4,8,9, 16,19, 23; 15, 17; 151:6,7,10,12, 15,16,20, 21; 32:8,9,10, 15,17,18,19,21,22,22, 140:5,7,7,9,17,18,19,
83:2,3,7,10, 14,15,15, 14,19,21, 25; 152:3,7, 11,14,17; 33:1,1,2,2,3, 25;88:2,3,3,4,5,5,6,7, 25;141:1,3,3,4,4,8,9,
16,17, 24;84:3, 3,6,8,17, 10,11,16, 22,24; 153:1, 3,5,6,7,10,12,15,15, 7,7,8,13,14,14,15,16,11,11,14,15,16,17,19,
20,22, 24; 85:3,12,12, 4,4,6,9,10,11,13,14, 20,21,21,25 ;34:1,3,7,9, 19,19,20,20,21,21,22,23,24; 142:3,4,6,7,7, 12,
16,17,17,22, 23; 86:7,8, 14,19,22,23, 23; 154:15, 9,16,18,18,18,19, 21; 25;89:1,3,4,8,9,18,22,13, 14; 143:5,8, 11,12,
13,16, 23;87:8, 10, 25; 19,22,23, 24; 155:1,1,2, 35:2,3,4,4,6,7,8,9,13, 23;90:2,3,4,8,9, 11,12, 13,13,14,23, 24; 144:1,
88:8,9,12,13,17, 25; 6,8,9,10,11,12,13,14, 14,15,17, 17,21,25; 13,18,20,21, 24;91:7,7, 3,4,6,7,10,13,15,18,
89:2,9,11,12,17,21,22, 17,18, 18,21,22,22,24, 36:1,5,5,6,12,14,21,24; 9,10,14,15,16,17,18, 19,24, 25; 145:1,1,2,5,
23, 23;90:1, 2,3,8, 10,14, 25; 156:6,7,8,9,9,11,13, 37:1,2,6,6,7,11,14,18, 22;92:1,1,1,4,7,9,10, 10,10, 12,13,18, 18,19,
15,17, 19;91:6, 11,18, 15,18,21,24, 24; 157:4, 21,24 ;38:2,7, 13,13,16, 11,15,15,15, 16;93:3,4, 22,23, 25; 146:3, 6,7;
23;92:4,6,7,9, 10, 13,13, 5,7,7,8,8,10, 10,12,13, 19,21,25,25, 25; 39:4,4, 5,11,16,17,20,21,22, 147:3,4,8, 11,15,20, 22;
14,15,17, 17,20 ;93:1, 1, 14,15,15,16, 16,17,17, 7,8,10,11, 12,14,14,23, 24;94:4,5,6,7,7,8,9, 11, 148:3,4,5,5,7,7,9,14,
3,3,4,10,13,14, 20;94:3, 18, 19,21,23; 158:1,5,6, 23;40:1,2,3,3,4,4,4,11, 12,18,25, 25;95:12,22, 14,16,,17,21, 22,23;
4,8,13,15,21 ;95:4,6,8, 10,15,15,16, 17,17,20, 11,12,17,22,22,23,24, 24,25;96:1, 2,4,7,7,13, 149:2,3,4,6,7,10,12, 13,
9,10,13,17,23, 24;96:3, 20,20,21, 24; 159:3,5, 24, 25; 41:4,5,7,9,17,17, 16,19, 25;97:4, 10,11, 13, 14, 16,21,24,25, 25;
5,21; 97:9, 10, 14,18,21, 13, 21; 160:19, 23; 161:15; 18,19, 19,19,20, 20; 13,15, 18;98:3,4,5, 10, 150:1,4,4,5,8, 14,17,18,
23,23 ;981,1,1,4,6,7,8, 162:5,14, 17; 163:1,7,8, 42:1,2,3,7,9,9,11,12, 16,17,22, 23;99:2,3,4,6,19,20,21; 151:1,4,10,
16, 17,19, 22;99:11, 18, 9,13,13, 23; 164:2,8,11, 15,17,18,19,19, 20,21; 8,13,20,23, 24;100:4,9, 14,17,22,24, 25; 152:1,
23; 100:3,4,5,8,8,9, 15, 17,18, 19,20,22,22, 25; 43:4,7,7,8,11,14,16, 22; 16,25;101:6,6,8, 10,10, 4,5,7,7,8,9,10,11, 13,
24, 25; 101:3,5,11, 19, 165:2,4,6,6,13,15, 18, 44:4,4,8,21,21, 22;45:2, 11,13,16, 17,18,22, 24; 15,20,21,21,25 ;153:1,
20, 25; 102:3,17, 18,21, 20, 22; 166:5,6, 19>21, 6,10,12,13,13,17,18, 102:6,20;103:4,5,14,15,4,7,7,11, 14, 16,20,22,
22, 25; 103:2,2,9,12,12, 22; 167:3,4,7,7, 21; 22;46:1,2,5, 10,14, 16, 17,17,18,20, 20,21; 23,25 ; 154:1,3,3,12,15,
21; 104:2, 12,15,16,20, 168:1,2,10,14, 14,16, 20,23,23, 25; 47:1,2,4,6, 104:3,6,8,11,12, 12,16, 15,20,21,21 ; 155:1,4,8,
24, 25; 105:1, 2; 106:3,5, 16,21,25; 169:1,1,4,5, 7,8,9,11,11,13,15,15, 16,17,20,21, 24;105:1, 11,11,12,12,14,18,19,
_ 7, 10,14, 15, 18,20; 10, 16,17, 19, 20; 170:5, 22,23, 25;48:16, 17, 19; 4,7,11,12,12, 17,18,23, 25; 156:3,8,14, 14, 16;
107:2, 12,17,19,19,19,
23; 108:2,2,3,10, 12,16,
12,19,21,25, 25; 171:10,
18, 24; 172:1,6,6,8, 13;
49:4,5,6,9,22,
14, 17,17,19,22,22,
24; 50:8,
24;I 25;106:5,7,
17,19,21,24
10,11,17, 157:1,22, 22; 158:8,11,
;107:1,2,3, 12,14, 19,20,21; 159:3,
16, 20; 109:6,6,14,15, 173:2,6,7,10,13,14,15, 51:1,2,3,6,12,19,21,21, 3,4,9,10,11,13,15,19,17;160:1, 1,6,7,7,8, 11,
19,21,23, 25; 110:10,14, 18,19, 19, 23,25; 174:1, 22, 25; 52:3,5, 12,15,18, 20,21, 22;108:1,4,5,6,8,17,20; 161:1,2,5,6,6,11,
15;111:6,7,7, 16;112:6, 4,8, 16,24; 175:5,5,6,6, 22, 24; 53:13,14,17,19, 8,17,20,23, 25;109:1,3, 13, 18,20,22, 25; 162:2,
12, 13,13,16,18,20, 23; 13,23, 24; 176:1,6,13, 23; 54:1,4,4,5,13,13,14, 4,13,15,18,24, 25; 3,10,11,13, 18; 163:2,4,
113:7,8,8,9,
14,15,19, 14, 18, 25; 177:12, 12,14, 16, 16, 18,18, 19,21,22, 110:2,2,3,4,6,6,8,9, 13, 7,7,9, 13, 15,19,21,23,

Miller Reporting Company, Inc. Min-U-Script@ (27) That’~ - The
Hearing Volume Number 2 Food & Drug Administration
lMay29, 1998 Gastrointestinal Drugs Advisory Committee

25;164:4,5,5,6,6,7,9, 19:4, 20; 21:16; 44:2; 77:7; thereby 160:18,18 things 8:22; 10:23; 27:9; this 4:4,9,10, 16; 5:14,
11,13,13,15,17,17,18, 118:3; 130:19; 137:18 therefore 44:23; 79: 12; 29:22; 33:16; 34:15,16, 17, 25; 6:5; 7:8; 8:11,17,
__&qI,23;165:1,4,5,5, Therapies 6:22; 8:4; 102:22; 104:13, 19; 21; 35:12,23,24, 25; 36:8, 23; 9:24; 11:9,16, 23;
4,17,17,20,24; 12:13; 15:18; 17:20; 108:14; 116:21; 145:19; 25; 37:15; 38:2, 5; 39:2,6; 12:3; 13:21; 15:7; 16:22,
...x11.20,20,21,22,23, 22:24; 44:7; 84:25; 155:5 40:1,14 ;41:22; 51:21,23; 24; 17:25; 18:23; 19:6, 12;
25;167:5,7,8,11,12,17, 114:19; 163:15,17, 18; these 4:23; 6:13; 7:22; 52:1,3, 13; 53:13; 54:3; 20:6, 18; 21:19, 22; 22:1,
19,22,22,23;168:3,11, 167:14; 169:21; 173:22; 8:6; 12:8, 25; 13:10; 15:17; 57:15; 61:8, 9; 72:3; 74:14, 18; 23:8; 26:13; 32:5, 24;
11,12,14,17,20,21,21, 178:8 16:8; 17:1; 18:6, 14; 19:22; 22; 77:14; 87:21; 90:3; 33:5, 22; 34:9, 14; 36:2, 7;
22,24,24,25,25;169:1, therapy 14:21; 15:19, 19; 21:11,24, 25; 23:6; 30:12; 91:25; 96:8; 97:10,17, 18; 37:3,22, 25; 38:1, 7; 45:7;
4,5,6,16,17,17,18,18,20:6; 21:1; 24:7, 10, 11, 32:19; 34:20; 35:8; 36:17, 98:17; 99:5; 101:22; 46:9; 47: 10; 48:20; 49:7, 9;
19,22,24;170:2,3,4,7, 12,13,19, 23; 26:4, 6; 18; 37:11; 38:4; 39:8, 21; 104:11 ;109:13; 113:15; 50:21,21 ;51:1,8; 56:23;
10,11,13,14,14,20,21,30:8; 44:8,12, 14; 52:13, 41:22; 52:3; 57:23; 60:10, 114:7; 116:12, 15; 135:24; 57:2, 4; 58:18, 19; 59:3,
23,24,25;171:1,4,6,10, 14, 19;53:3,5,7, 11,12, 24;61:13; 62:11 ;66:6,7; 150:1; 151:9, 25; 157:25; 14;61:1; 62:22 ;65:12;
17;172:1,7,8,8,13,22, 22; 55:19; 56:18; 65:14; 72:8; 78:12; 84:24; 85:5; 160:16; 163:2; 165:8 66:22; 67:21; 68:18;
23,24;173:6,8,10,12, 76:12; 79:11; 84:4; 101:7; 99:25; 113:1O; 114:7; think 7:2; 10:4,12, 16; 72:16; 74:1; 75:22 ;77:14;
14,15,16,16,16,19,23; 102:2; 106:20; 113:8,16, 117:22; 123:1; 125:10; 11:8; 12:21; 19:22; 20:2; 79:3; 80:8; 81:24; 82:12,
174:1,14,16,22;175:1,2, 25; 114:10; 115:4; 163:6; 127:14; 131:9; 142:13, 15; 22:15 ;23:2; 24:5; 25:22, 20;84:11;85:15,24 ;86:3,
2,3,6,8,9,14,15;176:9, 169:2; 170:3; 172:16; 150:19; 154:10, 13; 156:4; 23; 26:3,12, 13, 25; 27:9, 23;91:21; 92:3; 93:22;
9,10,18,18,19,20,23, 178:2, 19 159:15; 161:11; 162:5; 95:4,5, 20; 99:8; 100:16;
21; 30:4,5, 23; 31:2, 10;
24;177:1,5,11,13,17, there 6:21; 7:4; 8:21; 164:10, 15; 174:20; 177:8; 101:4, 17; 102:6; 104:23;
32:4,12, 20; 34:3,3, 17;
21,22,22,23,24;178:1, 11:4; 12:21 ;13:3,6; 14:5; 179:19
36:22; 37:24; 39:2, 2,3; 105:6; 107:16, 25; 108:22,
6,7,14,15,20,22,23,24; 15:13; 16:12 ;23:7, 11; they 5:8, 10; 6:1o, 13; 24; 111:5; 113:16, 17;
40:1,3,9,17; 41:12,22;
179:5,6,8,10,11,13,15, 24:5,15, 24;25:2,21; 7:19; 11:4, 18; 13:4,16, 114:22; 115:13; 116:15;
42:3; 45:11, 14; 50:17;
16,19,21,23 26:18, 18; 27:10; 29:2, 15; 22, 25; 14:2; 15:11; 16:1; 117:20, 21; 118:23; 124:5,
52:4,14,20, 21; 53:1,4,
30:16, 17; 31:23; 32:6, 20; 17:4, 5,8; 18:9; 20:10;
their 5:5; 14:3; 18:7; 11,13,19, 20; 54:10, 18; 20; 129:1, 10; 131:14,22;
33:2,4, 5;34:14, 15,20; 23:7; 24:20; 25:10,11,15, 132:13,18, 22; 133:6;
20:24; 24:21; 27:2; 39:24; 55:6; 56:7,10,14, 15;
35:1o, ll;37:2,20, 23; 19; 26:15; 27:2, 3; 29:10,
40:16; 42:14; 43:10, 12; 57:1,7; 59:3,6,7,10, 14; 134:12; 136:7, 14,24;
38:9,10, 22; 39:3,9,13, 11,11,12,21,21 ;30:18;
49:3; 58:8; 59:24; 62:2; 60:9; 61:3; 62:4,7, 10; 137:21, 21; 138:8; 139:8,
14,15, 18, 19;40:6,8, 10; 31:5,6,18 ;33:7,8,8;
81:12 ;84:22,23; 85:4; 64:2; 65:21, 23;66:6, 10, 22; 140:16, 25; 141:3;
44:9; 45:13,25 ;46:2,12, 34:21 ;35:12;37:9, 14, 18; 142:1,4,9, 18; 143:1;
88:1; 96:23; 97:1 1; 14,23, 25; 67:3, 17; 70:2,
18;48:15,15; 50:11,18, 40:1,9,18, 19;42:23, 24;
111:17; 121:16 ;122:20, 22,24, 24; 71:18, 23; 145:8; 148:8; 149:4;
24;51:2,4; 52:14,15; 43:9,10, 11;46:3; 47:21,
21; 125:21, 22; 148:15; 74:18; 75:22; 76:20; 77:2; 151:2; 152:1,7; 156:2;
53:8, 24; 54:11; 55:18; 21, 24;48:2; 51:24; 59:18,
_L-9:22 78:18, 21; 79:23; 80:19; 157:4; 159:12; 160:13, 19;
56:14; 57:3; 58:2, 12, 14; 19,20, 24,”25;60:1;61:20;
1 18:8; 25:15; 36:6; 82:1; 83:23 ;84:9, 15, 21; 161:1o, 12,18,18,19,23,
59:1, 17;60:5; 61:5, 13, 63:23; 64:13, 14; 68:4;
4u:15; 44:9; 47:22; 52:25; 86:13; 93:7, 18; 94:9, 15; 24; 162:13; 163:13, 17;
22;62:23;65:11,11,22; 70:18; 71:7,9, 24; 74:5,
53:1; 62:11 ;64:7; 74:21; 95:20; 97:7, 9; 99:11, 16; 164:2; 165:5, 20; 166:9,
66:19; 68:5; 72:3, 5;73:13; 10, 25; 75:10; 77:17; 79:6;
81:20,21 ;85:11,14,23; 100:14, 16; 102:25; 103:8, 13,17, 17; 168:15; 169:3;
74:19,20,21, 22;75:9; 81:12, 17; 82:4,23, 24;
87:9, 10; 95:12; 99:2,2,3, 14; 104:25, 25; 105:2, 4; 170:11, 12; 172:24; 173:4;
80:11, 15;81:18,19; 84:18 ;85:2, 3,4,9,9,10,
6; 101:12; 103:10; 104:2, 107:2,7, 15; 109:12, 25; 174:4, 12; 175:6,10, 25;
82:22; 83:7,15,16, 18; 10,12,15,16,17,17, 18,
14; 106:21,22,24, 24; 110:9, 19; 111:6,13, 17; 176:21; 177:14,20, 21;
84:17, 19;86:4; 87:24; 24;86:17; 90:3; 93:10,11;
108:12 ;112:14, 15; 120:5; 112:1,2,3,5,7,10; 178:5, 24; 179:4,5,13,17,
88:16; 92:17; 93:16,22; 94:9; 95:1; 96:8,8, 10;
121:18; 122:19,20; 123:6, 117:24; 118:5; 119:3, 17; 19,20,24
94:1; 95:15 ;97:17,21,23; 98:25; 104:3, 13; 106:22,
22; 125:17, 23; 126:8; 22; 107:1; 108:24; 109:1;
120:4,4, 21; 122:17, 19; those 7:21, 24; 11:21;
98:18; 99:20; 100:7,8, 14;
131:15; 140:19; 142:18; 123:2, 10; 124:16, 21; 19:13; 23:25; 24:20; 25:8;
101:6, 18; 102:9; 103:25; 111:3 ; 112:1,11,12,14,
143:6, 10, 12; 144:7; 20; 113:25; 114:1,9;
125:9,9, 25; 128:15; 26:25; 29:3, 5;30:9; 31:10;
104:1,4; 105:5; 106:3,13,
149:9; 159:16; 164:12 129:10, 14,15, 21; 130:24; 35:19; 36:8; 37:19; 39:6;
15; 108:9; 110:10,10,21, 115:20; 117:16; 120:1,11,
themselves 5:4; 106:23; 131:20; 133:24; 135:12, 41:14, 24; 43:9; 45:4; 49:2,
22,22,25 ; 111:13,21; 22,23, 24; 121:14; 122:20,
122:24 23; 136:4, 15; 137:7,10, 20; 51:21; 52:1, 24; 56:23;
112:24, 25; 113:3; 115:24; 21,21,22,23,24, 24;
15; 140:5,6,14, 24; 61:15 ;62:1,20,20; 63:1;
then 6:9; 8:2,3, 13; 10:19; 117:1,9; 121:2, 11; 123:11,19, 19; 125:1,17,
142:11, 12; 143:12; 144:1; 65:25; 69:24; 75:7, 8;
23:13 ;24:22; 25:19; 122:18, 22; 123:24; 125:9; 18,22, 23; 126:5, 15;
145:25; 146:19; 147:8,11, 76:19; 92:18; 99:5;
33:15; 36:15; 37:4, 11; 126:2,8, 12; 127:16, 20; 128:10; 129:11; 136:8, 9;
12, 22; 148:16; 149:1, 2,3; 101:20; 109:22; 114:18,
39:18,19; 43:24 ;45:6; 129:2, 15; 130:18; 131:12; 140:18; 144:8; 145:9;
150:12; 151:12; 152:2,5; 23; 116:20; 120:25;
50:19; 61:7; 62:8; 63:6; 132:11,13, 15,19; 133:3, 149:4, 13, 19,20,21;
153:3, 23; 154:3; 155:17; 123:14; 126:17; 127:22;
64:7, 8; 67:24; 69:13; 22; 135:1,18,23, 24; 150:14,15,16,16,17, 17;
157:2, 24; 159:5,10, 19; 132:5; 138:23; 140:23;
70:13 ;71:9,21; 73:21; 139:1,3, 20; 140:3,8, 18; 151:19; 152:8; 156:15;
160:16; 162:11, 12; 163:3, 141:18, 20; 142:8; 149:19;
75:20; 77:23; 78:3; 79:2, 141:7,19,21, 24; 142:5,7; 158:7,13, 16; 160:1;
10;81:3, 18, 18;82:6, 20; 165:21; 170:22; 171:5;
4, 19; 166:20, 22; 167:5; 153:19; 159:7; 16o:11;
143:1,3, 15;144:5, 14, 16;
168:19, 21,25; 169:6,15, 162:25; 164:14; 167:11,
85:2, 17; 89:14; 94:4; 97:2; 145:13,15, 22; 146:21, 24; 172:3,5, 15; 174:22,23,
16,18, 24; 170:12; 172:9, 25; 168:4; 172:13; 173:1
102:13, 14; 105:22; 147:3,9, 10,12,22, 25; 24, 25; 175:14; 177:20;
24; 174:16; 175:2,15,20, though 27:12; 29:16;
107:12 ; 114:9,21,23; 149:8,17, 19,22; 150:12; 178:3
21, 24; 176:9,10, 13, 17, 71:5; 88:15; 100:2;
115:1, 12;116:11; 117:18; 151:13,15, 19,21,23; thing 7:5; 11:4; 32:8; 24; 177:1,6, 14, 22; 179:4, 147:15; 148:13; 172:12;
118:10; 119:5; 123:19; 152:17; 154:3,4, 13,13, 35:22; 36:13; 52:4; 55:16; 7,9,12 174:11
_~7:8; 128:3,6; 133:24; 13; 157:3,7; 158:20, 24; 56:2; 59:23; 67:20; 68:15;
m–- - 10; 136:6; 137:13; thinking 34:25 ;79:16; thought 16:13 ;34:5;
159:5, 19,21, 22; 162:4; 69:25; 72:8; 88:18; 94:9;
21; 144:25; 145:3; 83:5; 104:24; 132:16 37:1 0;55:16; 76:15;
163:11 ;164:21; 167:1; 95:9; 96:3, 5; 100:4;
151:4,4, 16,20 ;155:17; 168:2, 17,21; 169:1, 12; 105:21, 23; 106:13; third 26:2; 40:24; 67:21; 92:12; 93:1; 114:1, 14;
156:16, 19; 157:14,17,21, 170:16, 17; 172:9,16, 17, 111:18, 25; 117:3, 13; 105:11; 106:10, 17; 107:2; 122:7, 11; 130:6; 135:3
21; 164:6, 13; 169:6; 18; 173:1; 174:2; 175:25; 125:9; 131:12; 149:6; 109:24; 149:14 thoughts 105:16; 124:22
173:17; 176:19; 177:11 176:20; 177:1, 18; 178:3, 152:16, 20; 159:5; 173:24; Thirdly 132:3 thousands 99:14;
therapeutic 12:2:16:25: -, 12, 18 174:2,9 thirds 170:20 143:24

their - thousands (28) Min-u-script@ M~er Reporting Comoanv. Inc.
Food & Drug Administration Hearing Volume Number 2
Gastrointestinal Drugs Advisory Committee May 29,1998
threatening 165:15 17,18;40:12, 16,18, 18, 16,22,23, 25; 118:3,3,7, together 7:25; 25:25; 116:10
three 22:16, 23; 23:3; 21;41:7, 13,14,18, 18, 14,17,18, 19,25 ;119:11, 27:17 ;40:14;41:10; 88:1; treatments 36: 12; 75:7;
..-. 25:2, 24; 30:2; 48:5, 10; 19,20;42:8, 14,14,15, 14, 16,18, 22; 120:2,3,5, 109:13; 119:11; 139:5 88:5
56:7; 104:11; 111:20; 15,17,20, 20;43:16, 18; 13,14,14,21, 23,24; told 76:11, 24; 77:3; treats 53:3
116:1; 123:13,17, 22; 44:2,4,10,10,13,16,17, 121:6,8,12, 13,21; 122:2, 117:13
139:8; 178:23,24 19,19, 25,25;45:5, 13, 4,6,9,15,16,18,20,23, Tremaine’s 47:10
tOmOrrOW 132:24
threshold 87:6; 97:5; 15,18,21, 22;46:2,4,9, 24; 123:3, 16, 23; 124:4, tremendous 99: 16;
too 27:10; 72:2; 75:22; 179:24
105:18; 110:8,10,13, 15; 13,17, 24;47:3,4, 13,15, 11,14, 16,18, 19;125:1,
111:4 ;112:17 22,24, 24;48:7,9,10,17, 4,14;126:2,9,17,18,19,115:23; 119:16; 129:19; trends 154:6
Thrombocytosis 14:23
17,19,23, 24;49:9,10, 21;127:1,6,8,9,9, 12,12, 135:13; 136:21; 142:16; trepidation 117:21
13,14,14,15,16,19,20,13,17,21,23,24, 174:18; 175:16,24
25; trial 10:10; 19:1,4; 25:3;
through 40:7; 98:2;
23;50:16,16,22, 23;51:4, 128:2,3,5,5,6,7,10,13, 138:12; 158:14
tool
40:24 ;41:1;47:11, 12,13,
107:25; 116:21; 123:17;
6,7,15;52:2, 10,11,11, 14,17,18,19, 20;129:1, tools 55:12 15, 17; 49:24; 64:6; 74:17,
166:1; 174:8; 179:6
14,25,25;53:3,6,10,11, 5,10,12,15,19, 24; top 95:22; 110:2; 114:24; 23; 76:2; 88:7,15, 15,20,
throw 59:16; 100:15 12,15, 17,18,20,21,22, 130:5,5,6,7,10,17, 23; 159:21 20; 102:18; 103:17, 25;
thrown 65:21 23;54:10; 55:10, 12,20, 131:4,8,18, 19;132:1,3, tOpiC 5:16; 150:24 104:4,6; 105:13; 108:3,
thus 11:22 21;56:4,6,8, 10,16, 20; 4,7,11, 14;133:3,6, 16;
tOtal 13:21; 142:3; 161:8, 23; 116:4,8, 14; 117:23,
T147:1 57:2,12,13,16;58:11, 25; 134:2,2,3,5,7,12,13, 22, 25; 118:2,13,15, 22;
14; 166:18
time 6:1, 12; 7:5, 22; 32:7; 59:3,6,8,8,16,19,22, 24; 24; 135:2,7,8,19, 21;
totaiiy 13:4; 28:18; 59:22; 119:1,1, 19;123:3; 124:9;
34:4, 17; 35:5, 15; 38:5; 60:2,16,23;61:9,10, 24; 136:1,1,3,6,8,8,9,9, 14,
71:4, 11;112:3; 122:14 127:1; 132:17; 133:19;
43:4; 44:21 ;45:2; 56:15; 62:5,7,10,13,14,17,22, 19,20, 2 0;137:3,4,5,6,9,
135:5; 138:11; 140:17;
67:21 ;72:11, 14;73:4, 16, 22,25;63:4,9, 10,17, 1 7; 10,13, 1 8,20,23,24,25, touched 83:6
143:3, 7; 149:24, 24;
18;74:15;76:18; 77:13; 64:10,10; 65:18; 66:18; 25;138:3,7,15,15,20, tough 153:3
150:1,4; 156:3; 157:22;
80:2,5,7, 11; 84:20, 24; 67:1,6,7,8,17, 23;68:2, 22;139:1,10,16,17,19,toward 9:8; 35:18; 36:20;
159:8,8; 168:8,21, 25;
86:7; 103:7,8, 16; 106:21; 12,15,16,17,17,19,19,21,24, 24;140:4, 11,11,
37:3; 38:1,4,6; 92:1 169:8, 9; 170:25; 172:15,
107:9; 110:12; 112:8, 15; 21,21,22,25 ;69:1,15, 13,22;141:2,5, 10,13,
20,21, 2 5; 142:2,12,17, towards 70:15 18,20, 21; 173:3, 20;
114:2; 115:21; 119:12; 22,23,25 ;70:1, 1,13,17,
25;143:2,4,10, toxic 102:22 174:8
123:11, 18,22; 125:16; 21,24;71:8,9, 15,19,20, 18,20,
17, 17, 19,21,22,25; toxicities 156:1 5; triaiist 10:9
126:7,9; 131:14 ;141:20; 21;72:2,11,16,18,18,
146:13; 147:1, 11; 150:15; 25;73:2,3,4, 10,11,21, 144:1,2,3,6,6, 10,14,15, 159:15; 167:2 trials 6:2; 10:8; 12:18;
163:9; 175:1, 14; 178:14; 22;74:2,4, 5,7,14, 16,18, 16,25;145:1,1,2,2,5, 14, toxicity 36:12; 56:1; 19:11; 24:16; 35:6; 37:9,
179:15 25,25;75:1,3,4, 12,18, 15;146:1; 147:1,5,6,8, 79:19 ;95:12; 110:22; 11,14, 17; 38:14 ;46:18;
-~. times 35:23; 46:17; 21,22;76:4, 5,6,13,19, 11,15,15,16,18,18, 19, 112:5 ;114:17; 121:15; 74:6,7, 21; 103:23;
23,24;77:1, 1,4,8,10,15, 20,20,23, 24;148:9, 10, 159:14; 163:11 119:22, 24; 123:24, 25;
55:20 ;94:1; 112:17;
121:14; 160:12 16;78:7,12,13,16,16, 11,13, 18;149:2,6,8,19,
TPN 130:21 124:9; 127:12; 129:13;
21,22,22, 24; 79:3,4,5,6, 21,24, 25;150:2,8, 17; [33:25; 134:7,8; 136:10;
tip 121:11 151:2,3,3,4,6,7,9,9,13, 114:7 track
6,12;80:4,7, 12,12,13, 137:9; 139:2; 140:2, 2;
tissue 41:19; 68:5 23;152:3, tract 28:20
14,15,20, 21;81:4,7,8, 15,16, 19,20, 141:5; 142:8, 17; 143:2;
TNF 12:24; 152:4 18,19,21, 22;82:2, 2,6,6, 11,12,12, 15,20,23; traditionally 49:18 147:6; 149:16; 150:8;
to4:2,4,4,4,8,9, 19,22, 9,10,21,25 ;83:1,2,3,4, 153:3,4,7,7,8,9,9,19;trails 134:8 151:23; 152:15; 153:12;
24;5:4,7,10, 14,15,18, 3,12,20, 25;84:1, 2,5,7; 154:2,8, 20,24;155:2,6, transferred 24:24 155:10,23; 169:11, 14;
20,22;6:2,3,4,8,9,11, S5:1,3, 11,22;86:7, 11, 8,10,14,23, 24;156:6,7, 172:2;173:11
transformation 100:11
18,18,19,19, 21;7:3, 3,3, 14,15,23;87:8,10,12, 9,10,10,13,23, 24; tried 18:23;
36:2;
76:5;
157:6,8,9,17,22,23, 23; transiently 78:3
5,11,13,15,15,19,20, 13,19;88:10, 10,16,23; 101:4; 121:10;
154:24
21,21, 22,24;8:3,6, 13, 39:1,2,2,4,9,15, 16,19; 158:11,14, 17;159:9,9, translatable 76:22
triggering 21:22
13,14, 15,17,20, 23;9:2, 90:1,7,9,9,10,22,23, 24; 11,12,16,16, 17,23; translated 38:8
trivial 99:19
9,12;10:1,2,2,4,4,17, ?1:2, 3,4,6,6,13,13,18,160:6,13,13, 14,15,17, translates 45:1
trouble 121:21
17,21,24,24 ;11:1,2,7,8,20,21,22,22, 23;92:3,4, 18,19,25;161:10,19,24, transmural 15:13
9,11,12,16, 17,24; 12:5, 5,8,11,18,25, 25;93:4, 5, 24;162:3,17, 17;163:8,8,
treat 4:22; 51:25, 25;
troubling 32:25
9,13,24; 13:6; 14:18,19, ?,11,14,19, 24;94:2, 2,7, 12; 164:8,9,10,14,15, true 28:16, 18; 29:25;
15, 15,19; 165:12,22, 25; 61:22; 62:14, 22; 69:13;
20,20; 15:1,13, 17,19, 11,14,23,24 ;95:1, 1,3,7, 48:14;51:12;66:3; 74:12;
166:13, 14; 167:5,9, 12, 85:21; 107:7
20,20,21; 16:2,5, 11,11, 13,23;96:14; 97:6,14, 14; 118:5; 157:7
13,18;17:10, 16,17, 18, 17,19,22, 22; 168:6,9, treated 90:8; 124:7, 9;
38:2,3,7,14, 16;99:2,3, truly 53:7
19,20; 18:3,5,6,11,13, 4,7,9,9,10,11, 17,17, 10,11,15, 15;169:6,12, 161:6,8,9; 162:16;
13,14,14,19, 19;170:3, 167:13; 175:14 try7:3; 10:22; 25:11;
17,23;19:2,6,11, 19; 21,24;100:2,9,13, 17, 33:22; 39:1; 118:19;
20:2,2,6,11,12,23, 25; 18,22,24, 24;101:4,5,5, 4,4,7,10,20,22, 24; treating 50:19; 61:21;
119:11; 136:1; 147:15,18,
21:11,15,17,18,19, 19; 7,12>25;102:1,3, 10,23; 171:4,6,7,9, 19;172:9, 83:22 ;84:10;91:7; 94:4
24; 151:4,9; 157:23;
22:2,11,15, 19,21;23:2, 103:1,3,9,10, 19,21; 14,23, 23,24;173:2,4,5, treatment 22:25; 23:3,
159:22; 174:7
5,5,12,13, 13,21;24:3,9, 104:2,3,13, 25;105:6,8, 5,7,8,9,11, 11,12,13, 15,20,23, 24; 24:2; 26:1,
trying 9:9; 23:5; 32:25;
10,23,23, 24;25:4,11, 2,15,17,18,21,22,24, 13,15, 18,24; 174:2,4,6, 16; 27:11; 30:2,7, 13;
34:11; 37:4; 50:22; 61:10;
21;26:3, 12,17,21;27:1, 24,25; 106:10, 10,11, 17, 7,7,9,11, 13,17,21,24, 31:7,13, 16;