Tuesday, April 23, 2002

8:00 a.m.









Holiday Inn Bethesda

Versailles I and II

8120 Wisconsin Avenue

Bethesda, Maryland








M. Michael Wolfe, M.D., Chair

Thomas H. Perez, M.P.H., Executive Secretary



Byron Cryer, M.D.

George S. Goldstein, M.D. (Guest Industry


John T. LaMont, M.D.

Robert A. Levine, M.D.

David C. Metz, M.D.

Joel Richter, M.D.


Gloria Anderson, Ph.D. (Consumer


Jurgen Venitz, M.D., Ph.D.




William H. Campbell, Ph.D.

Michael R. Cohen, R.Ph., M.S., D.Sc.

Stephanie Y. Crawford, Ph.D.

Ruth S. Day, Ph.D.

Jacqueline S. Gardner, Ph.D., M.P.H.

Peter A. Gross, M.D. (Chair)

Eric S. Holmboe, M.D.

Brian Leslie Strom, M.D., M.P.H.


Carlar Blackman


Thomas Fleming, Ph.D.

Arthur Levin, M.P.H.

GUESTS (Non-Voting)

Alex Krist, M.D.


George S. Goldstein, M.D.

John T. Sullivan, M.D.


Julie Beitz, M.D.

Florence Houn, M.D., M.P.H.

Victor Raczkowski, M.D.

Paul Seligman, M.D.









Call to Order, Introductions:

M. Michael Wolfe, M.D. 4

Meeting Statement: Thomas H. Perez, M.P.H. 9

Opening Comments:

Florence Houn, M.D., M.P.H. 13

Paul Seligman, M.D., M.P.H. 20

GlaxoSmithKline Presentation


James B.D. Palmer, M.D. 22

Burden of Illness & Efficacy of Alosetron:

Peter Traber, M.D. 30

Safety Assessment and Benefit-Risk Overview:

Eric Carter, M.D., Ph.D. 41

Risk Management Plan:

David Wheadon, M.D. 66

Clinician's Perspective:

Robert S. Sandler, M.D. 82

Summary and Conclusions:

James B.D. Palmer, M.D. 96

FDA Presentation


Victor Raczkowski, M.D. 98

Lotronex: Clinical Trial Experience:

Thomas Permutt, Ph.D. 99

Postmarketing Experience with Lotronex:

Ann Corken Mackey, R.Ph., M.P.H. 110

Lotronex Risk Management Program:

Toni Piazza-Hepp, Pharm.D. 120

Summary and Conclusions:

Victor Raczkowski, M.D. 135

Questions on Presentations 156

Open Public Hearing

Sidney M. Wolfe, M.D. 163

Public Citizen's Health Research Group

Nancy Norton 170

International Foundation for Functional

GI Disorders

Jeffrey D. Roberts 177

Irritable Bowel Syndrome Self-Help Group







C O N T E N T S(Continued)


Corey Miller 182

Lotronex Action Group

Gary C. Stein, Ph.D. 189

American Society of Health-System Pharmacists

William Brown, Esq. 194

Lisa Kenney 197

Maria Zargo 202

Julia R. Alberino 207

Terry Olifiers 210

Diana Hoyt 213

Kathleen Kelly Ghawi 217

Bob Morris, Esq. 221

Brenda Compton 224

Dennis K. Larry, M.D. 228

Paul Stolley, M.D. 228

More Questions on Presentations 232

Introduction to Questions and Charge to the


Victor Raczkowski, M.D. 291

Discussion of Questions 295







1 P R O C E E D I N G S


2 Call to Order, Introductions

3 DR. WOLFE: I am Michael Wolfe. I am

4 Professor of Medicine and Chief of the Section of

5 Gastroenterology at Boston University. I would

6 like to start with introductions around the table.


7 We will start at this end.

8 DR. SULLIVAN: John Sullivan, clinical

9 pharmacology, Amgen, industry rep for the Safety

10 Committee. DR. GOLDSTEIN: I am

11 George Goldstein, industry rep for the


12 Gastrointestinal Advisory Committee.

13 DR. KRIST: I am Alex Krist, Assistant

14 Professor, Virginia Commonwealth University, Family

15 Medicine.

16 MR. LEVIN: Arthur Levin, Center for


17 Medical Consumers in New York, and a consultant.

18 DR. COHEN: Mike Cohen. I am from the

19 Institute for Safe Medication Practices. I am on

20 the Drug Safety and Risk Management Subcommittee.

21 DR. CRAWFORD: Good morning. Stephanie


22 Crawford, University of Illinois at Chicago. I am

23 a member of the Drug Safety and Risk Management

24 Subcommittee.

25 DR. CAMPBELL: Good morning. Bill







1 Campbell. I am from the University of North


2 Carolina at Chapel Hill, and Director of the Center

3 for Education and Research in Therapeutics there,

4 from the Drug Safety and Risk Management

5 Subcommittee.

6 DR. GARDNER: I am Jacqueline Gardner,


7 University of Washington in Seattle, School of

8 Pharmacy, Drug Safety Committee.

9 DR. DAY: I am Ruth Day from Duke

10 University. I am a member of the Drug Safety and

11 Risk Management Committee.


12 DR. STROM: Brian Strom, Professor of

13 Biostatistics and Epidemiology, and from the Center

14 for Education and Research in Therapeutics at the

15 University of Pennsylvania, and the Drug Safety and

16 Risk Management Committee.


17 DR. GROSS: I am Peter Gross. I am Chair

18 of the Department of Internal Medicine, Hackensack

19 University Medical Center, Professor of Medicine,

20 New Jersey Medical School, and I am Chair of the

21 Drug Safety and Risk Management Subcommittee.


22 MR. PEREZ: Tom Perez, Executive Secretary

23 to this meeting.

24 DR. METZ: David Metz, University of

25 Pennsylvania, Division of Gastroenterology, and on







1 the GI Committee.


2 DR. FLEMING: Thomas Fleming, Chair of the

3 Department of Biostatistics, University of

4 Washington.

5 DR. LEVINE: Robert Levine, Division of

6 Gastroenterology, State University of New York at


7 Syracuse, Upstate Medical Center, and I am member

8 of the GI Committee.

9 DR. LaMONT: I am Tom LaMont from Harvard

10 Medical School, Chief of Gastroenterology, Beth

11 Israel Deaconess Medical Center, and I am a member


12 of the GI Committee.

13 DR. HOLMBOE: I am Eric Holmboe from Yale

14 University. I am a general internist. I am a

15 member of the Drug Safety Subcommittee.

16 DR. VENITZ: I am Jurgen Venitz,


17 Department of Pharmaceutics, Virginia Commonwealth

18 University, and I am on the Drug Safety and Risk

19 Management Committee.

20 DR. ANDERSON: Gloria Anderson, Callaway

21 Professor of Chemistry, Morris Brown College in


22 Atlanta, and I am on the Drug Safety and Risk

23 Management Subcommittee.

24 DR. CRYER: Byron Cryer. I am from the

25 University of Texas Southwestern Medical School in







1 Dallas, Associate Professor of Medicine, member of


2 the Gastrointestinal Advisory Committee.

3 DR. RICHTER: I am Joel Richter, Chairman

4 and Professor of Medicine, Department of

5 Gastroenterology at the Cleveland Clinic. I am on

6 the GI Advisory Committee.


7 DR. RACZKOWSKI: I am Victor Raczkowski,

8 Director of the Gastrointestinal and Coagulation

9 Division at FDA.

10 DR. HOUN: Florence Houn. I am Director

11 of the Office of Drug Evaluation III, FDA.


12 DR. SELIGMAN: Paul Seligman, Director of

13 the Office of Pharmacoepidemiology and Statistical

14 Science, FDA.

15 DR. BEITZ: I am Julie Beitz with the

16 Office of Drug Safety, FDA.


17 DR. WOLFE: Thank you. I failed to

18 mention I am Chair of the GI Advisory Board for GI

19 Drugs.

20 This meeting will be hopefully calm, but

21 it is a meeting which has a lot of material to


22 cover, so I am going to ask that persons who speak,

23 try to be succinct and make their point as

24 economically as possible.

25 We are going to start with the opening







1 statement by Mr. Perez.


2 Meeting Statement

3 MR. PEREZ: I wish I could be succinct,

4 but please bear with me.

5 Good morning. The following announcement

6 addresses the issue of conflict of interest with


7 regard to this meeting and is made a part of the

8 record to preclude even the appearance of such at

9 this meeting.

10 Based on the submitted agenda for the

11 meeting and all financial interests reported by the


12 committee participants, it has been determined that

13 all interests in firms regulated by the Center for

14 Drug Evaluation and Research present no potential

15 for an appearance of a conflict of interest at this

16 meeting with the following exceptions.


17 Dr. Thomas Fleming has been granted a

18 waiver under 18 U.S.C. 208(b)(3) for his unrelated

19 consulting for the sponsor, for which he receives

20 from $10,001 to $50,000 per year; and for his

21 unrelated consulting for four competitors, for


22 which he receives less than $10,001 per year per

23 firm.

24 Dr. Brian Strom has been granted a waiver

25 under 18 U.S.C. 208(b)(3) for unrelated consulting







1 for two of the competitors. He receives less than


2 $10,001 per year per firm.

3 Dr. M. Michael Wolfe has been granted a

4 waiver under 18 U.S.C. 208(b)(3) for his membership

5 on an Advisory Board, regarding unrelated matters,

6 for one of the competitors. He receives less than


7 $10,001 a year.

8 Dr. Jacqueline Gardner has been granted

9 waivers under 18 U.S.C. 208(b)(3) and under 21

10 U.S.C. 355(n)(4), an amendment of Section 505 of

11 the Food and Drug Administration Modernization Act


12 for her Individual Retirement Account with a

13 competitor valued between $5,001 and $25,000.

14 Dr. David Metz has been granted waivers

15 under 18 U.S.C. 208(b)(3) and under 21 U.S.C.

16 355(n)(4), an amendment of Section 505 of the Food


17 and Drug Administration Modernization Act for

18 ownership of stock in a competition valued at less

19 than $5,001 and for his spouse's stock in a

20 competitor valued between $50,001 and $100,000.

21 Dr. Byron Cryer Gardner has been granted


22 waivers under 18 U.S.C. 208(b)(3) and under 21

23 U.S.C. 355(n)(4), an amendment of Section 505 of

24 the Food and Drug Administration Modernization Act

25 for ownership of stock in a competitor valued at







1 less than $5,001. Included in the waiver under 18


2 U.S.C. 208(b)(3) in his writing for a competitor.

3 He will receive less than $5,001 a year.

4 A copy of the waiver statements may be

5 obtained by submitting a written request to the

6 Agency's Freedom of Information Officer, Room


7 12A-30 of the Parklawn Building.

8 In the event that the discussions involve

9 any other products or firms not already on the

10 agenda for which an FDA participant has a financial

11 interest, the participants are aware of the need to


12 exclude themselves from such involvement and their

13 exclusion will be noted for the record.

14 With respect to FDA's invited guests,

15 there are reported interests which we believe

16 should be made public to allow the participants to


17 objectively evaluate their comments.

18 Carlar Blackman, a patient representative,

19 would like to disclose that her supervisor at the

20 University of North Carolina is a consultant of

21 GlaxoSmithKline and Novartis. In addition, a


22 division of the University of North Carolina's

23 Functional GI and Motility Disorders Center has

24 done drug studies on alosetron and tegaserod. Ms.

25 Blackman is not a study coordinator or investigator







1 and the money received does not directly affect her


2 salary.

3 In addition, Ms. Blackman is the Executive

4 Director, on an independent contractor basis, of

5 the Functional Brain-Gut Research Group, an

6 international society which receives 90 percent of


7 its financial support from unrestricted educational

8 grants from pharmaceutical companies, including

9 Novartis and GlaxoSmithKline.

10 Further, she is an Administrative

11 Coordinator working on an independent contractor


12 basis for the Multinational Working Teams to

13 Develop Diagnostic Criteria for Functional

14 Gastrointestinal Disorders, which is also supported

15 by pharmaceutical companies.

16 Lastly, Ms. Blackman received a job offer


17 from the International Foundation for Functional GI

18 Disorders to become their Executive Director. The

19 Foundation works with all of the pharmaceutical

20 companies.

21 We would like to note for the record that


22 Drs. John Sullivan and George Goldstein have been

23 invited to participate as non-voting industry

24 representatives, acting on behalf of regulated

25 industry. As such, they have not been screened for







1 any conflicts of interest.


2 With respect to all other participants, we

3 ask in the interest of fairness that they address

4 any current or previous financial involvement with

5 any firm whose products they may wish to comment

6 upon.


7 Thank you.

8 DR. WOLFE: Thank you, Mr. Perez.

9 We have now opening comments from Drs.

10 Florence Houn and Paul Seligman for the FDA.

11 Opening Comments


12 Florence Houn, M.D., M.P.H.

13 DR. HOUN: Thank you. First, I would like

14 to welcome Dr. Michael Wolfe, who is chairing

15 today's meeting. I would like to welcome Dr. Peter

16 Gross, members of the GI Advisory Committee, and


17 members of the Drug Safety and Risk Management

18 Subcommittee, and other guests and consultants for

19 this joint meeting on the risk management of

20 Lotronex.

21 I want to thank the staff of GSK,


22 GlaxoSmithKline, and the staff of FDA for preparing

23 for this meeting. I thank members of the public,

24 the patients, the public health advocates and

25 others for their interest in this meeting and their







1 desire to contribute their views to help FDA make


2 the best possible public health decisions.

3 This meeting is to obtain advice on the

4 drug

5 Lotronex. Lotronex was approved in February of

6 2000 for women with diarrhea-predominant irritable


7 bowel syndrome, IBS.

8 The drug was found effective in providing

9 adequate relief of IBS symptoms. It was associated

10 with constipation and ischemic colitis. During

11 postmarketing in the year 2000, there were cases of


12 severe constipation leading to serious adverse

13 events, such as colonic obstruction and surgery, as

14 well as serious adverse events from ischemic

15 colitis.

16 A Risk Management Advisory Committee


17 meeting was held in June of 2000 when the initial

18 adverse event reports started coming in. The

19 committee recommended education and communication

20 about safe and appropriate use of Lotronex.

21 In the fall of 2000, death reports were


22 received. The FDA asked GlaxoSmithKline to either,

23 one, suspend marketing pending another Advisory

24 Committee meeting, or, two, withdraw the drug and

25 for patients with severe disabling IBS, to provide







1 IND access, and that is a type of access through


2 research noncommercial means, or, three, to

3 severely restrict the distribution of the drug.

4 GlaxoSmithKline chose to withdraw the drug

5 in November of 2000. GSK did not allow IND access

6 to this drug. FDA and GSK subsequently received


7 hundreds of letters and communications requesting

8 access to this drug by former users who had

9 benefited from the drug's effects.

10 During the year 2001, FDA and GSK met to

11 see if there was a way to provide access for


12 Lotronex to severely disabled patients. GSK was

13 interested in the restricted marketing of Lotronex.

14 To this end, FDA and GSK worked on labeling,

15 patient and physician agreements, and the

16 medication guide, but we never came to any


17 agreement on the overall Risk Management Program,

18 and therefore, the pieces we did work on were

19 without context.

20 I think the main hurdle has been the

21 nature of the marketing restrictions and how they


22 are implemented and checked. In the middle of last

23 year, FDA asked GSK to submit all the clinical

24 trials experience with Lotronex, so we could have a

25 full understanding of the risks to better guide







1 what restrictions in the form of risk management


2 are needed.

3 This submission was made in December of

4 2001, and we are here today to review the findings.

5 This Advisory Committee meeting reflects FDA's

6 responsibility in two fields that can be


7 conflicting at times - our responsibility to ensure

8 drugs are safe for marketing and our responsibility

9 that the public has access to drugs that have

10 clinical benefit.

11 Safe does not mean no risks. All drugs


12 have risks. Some risks are minor and a nuisance,

13 others are life threatening or life ending. Some

14 risks can be managed easily, others are more

15 difficult to manage.

16 FDA's major means to manage risk is to not


17 approve marketing for a drug, or rarely, we

18 restrict marketing. Restricted marketing under

19 regulatory authority has occurred with four drugs -

20 thalidomide, mifepristone, fentanyl transmucosal

21 delivery system, and bosentan.


22 Each of these drugs have a risk, such as

23 teratogenicity or predictable need for surgical

24 intervention, or the need for proper disposal to

25 prevent accidental use by children, such that a







1 program is established to ensure safe drug use


2 through restrictions on patients, restrictions on

3 physicians, and sometimes pharmacists.

4 Restricted marketing usually means only

5 certain patients get the drug, and only certain

6 physicians can prescribe. The drug is not carried


7 in all pharmacies. If restrictions are not carried

8 out, FDA can withdraw the drug more rapidly than in

9 situations of normal marketing.

10 In contrast, the major way FDA provides

11 access to drugs with clinical benefits is by


12 approving them for marketing. We also permit

13 investigational access to research drugs in a

14 noncommercial setting called IND access. Contrary

15 to public belief, FDA cannot provide access to

16 drugs by any other means. We don't stockpile


17 drugs, we don't manufacture drugs, we don't conduct

18 drug research trials, we don't run drug access

19 programs. We just don't have the drugs.

20 We can't force a pharmaceutical company to

21 manufacture or market or conduct research or


22 provide drug access programs. Thus, access to

23 drugs that have clinical benefits, but also possess

24 risk for serious adverse events generates complex

25 tensions between wanting to ease a disease burden







1 and wanting to protect the public from drug risks.


2 This Advisory Committee meeting is to help

3 FDA respond to that tension. FDA has been

4 criticized that we don't take IBS seriously. Well,

5 we take all disease and suffering seriously, IBS is

6 no exception.


7 FDA has been criticized that we have

8 secretly come to an agreement with GSK on the

9 return of Lotronex. This is false. There is no

10 done deal. The Company has made a decision about

11 what they wish to propose for restricted marketing.


12 We have worked with the Company and discussed many

13 of the controversial issues about Lotronex, such as

14 labeling, but is the labeling final? No. New

15 labeling has not been approved and we need your

16 input on several aspects of this and other issues.


17 FDA has been criticized for treating

18 Lotronex differently from other drugs. Well, let

19 me say again all drugs have risks. These risks are

20 different in frequency and type. The drug's

21 benefits differ, too. Some very frequent risks are


22 acceptable to the public. Some infrequent rare

23 risks are not acceptable. Risk acceptance and

24 perceptions of risks and benefits are value

25 judgments. Values differ.







1 There is no uniform absolute way to manage


2 drug risks for different diseases, different drugs,

3 different adverse events, and with different risk

4 tolerances by different people.

5 The input we seek today is over Lotronex.

6 What is unusual is that Lotronex ceased marketing


7 under safety concerns. GSK has proposed restricted

8 marketing as a means to allow access to this drug.

9 This meeting is to discuss should Lotronex return

10 to marketing, if so, under what conditions, in what

11 patients are the risks of the drug diminished


12 compared to the benefits, who should prescribe the

13 drug, with what expertise, what responsibilities

14 should patients and prescribers assume, what limits

15 and controls are feasible, acceptable, and

16 verifiable, who is responsible for ensuring


17 controls and that the limits are followed, what

18 happens if these controls are not followed, how

19 will success of the program be defined. These are

20 many complex issues.

21 We hope to hear your best advice. Not


22 only must it be your best advice, but it must be

23 pragmatic if you want if you want it implemented in

24 real time, real life.

25 Ultimately, FDA will have to make a







1 regulatory decision and try to negotiate a position


2 with GSK. GSK will have to make decisions, as

3 well. Today, your responsibility is to provide

4 advice to FDA on these important points for

5 negotiation mentioned above - should the drug be

6 marketed, and if so, under what conditions.


7 Today's discussions do not bind the

8 Agency. It is not a decisionmaking meeting for

9 FDA, it's an advisory meeting. You will be voting

10 on what is your best advice to FDA. The goal for

11 today is to obtain your best thinking on these


12 tough topics to help guide sound decisionmaking.

13 Thank you for taking your responsibilities

14 and duties to help us seriously.

15 Now, Dr. Paul Seligman has a few words.

16 Paul Seligman, M.D., M.P.H.


17 DR. SELIGMAN: Thank you, Flo, and good

18 morning everyone. I am Paul Seligman, the Director

19 of the Office of FDA's Office of

20 Pharmacoepidemiology and Statistical Science, and I

21 want to welcome all of you to the first public


22 meeting that includes the recently chartered Drug

23 Safety and Risk Management Subcommittee, a

24 subcommittee to the Advisory Committee on

25 Pharmaceutical Sciences.







1 The purpose of the Subcommittee is to


2 provide expert input in a forum for open public

3 discussion on a wide range of drug safety and risk

4 management issues.

5 Today, we have convened a special joint

6 committee comprised of members of the


7 Gastrointestinal Drugs Advisory Committee and the

8 Subcommittee members to obtain advice on viable

9 risk management options for the drug alosetron

10 previously marketed under the trade name Lotronex.

11 The issues we are asking you to tackle are


12 among the most challenging in the world of

13 effective pharmaceutical risk management, and to

14 this end, I look forward to a lively discussion.

15 On a somber note, I also wish to

16 acknowledge the recent sudden death of Dr. Kenneth


17 Melmon, a member of the Advisory Subcommittee, and

18 a giant in the field of drug safety. His

19 contributions, experience, and wisdom will be

20 missed by all of us and impossible to replace.

21 Finally, I want to thank you the FDA staff


22 who worked so hard to make today's meeting happen,

23 and want to thank everyone in advance for your

24 input into today's discussion, members of the

25 Advisory Committees, those who have been treated







1 with Lotronex, and members of the public here to


2 express their concerns and considered views. Thank

3 you all for coming and for being so willing to

4 bring your respective resources and expertise to

5 bear on this important public health issue.

6 Thank you.


7 DR. WOLFE: Thank you, Dr. Seligman, Dr.

8 Houn.

9 I would like to introduce Dr. James Palmer

10 now from GlaxoSmithKline, who will introduce the

11 Company's presentation and also will be introducing


12 all the various speakers for the firm.

13 GlaxoSmithKline Presentation

14 Introduction

15 James B.D. Palmer, M.D.

16 DR. PALMER: Good morning, ladies and


17 gentlemen, Dr. Wolfe, and members of the Advisory

18 Committee, Dr. Houn, Dr. Gross. My name is James

19 Palmer, Senior Vice President of New Product

20 Development at GlaxoSmithKline.

21 [Slide.]


22 I have worldwide responsibility for

23 medical, regulatory, and product strategy for the

24 Company. We are here today to discuss the possible

25 reintroduction of Lotronex to the U.S. market.







1 Before we begin our formal presentations,


2 I would like to give a brief overview of the

3 history of Lotronex.

4 [Slide.]

5 The original NDA was submitted in June

6 '99, and was granted a priority review. The drug


7 came before the GI Advisory Committee in November

8 '99, and received a unanimous approval

9 recommendation. At that time, the issues of

10 ischemic colitis and constipation were discussed

11 very thoroughly at the meeting, and, in fact, the


12 review clock was extended in December to further

13 discuss four cases of ischemic colitis.

14 [Slide.]

15 The original NDA was approved on February

16 9, 2000, with an indication that read, "For the


17 treatment or irritable bowel syndrome in women

18 whose predominant bowel symptom is diarrhea.

19 There were two prominent product label

20 warnings relating to constipation and ischemic

21 colitis. Specifically, for constipation, this was


22 noted to be frequent dose-related side effect, and

23 resulted in study withdrawal in approximately 10

24 percent of patients. You will hear a lot more

25 about constipation and ischemic colitis in the







1 subsequent presentations.


2 For ischemic colitis, it was noted that it

3 occurred infrequently with a rate of 1 in 100 to 1

4 in 1,000, and at the time of the drug approval, the

5 rate was, in fact, about 1 in 700, a rate which has

6 remained constant throughout the time the drug was


7 on the market from the clinical trial cases.

8 It was noted also that a causal

9 relationship between treatment with Lotronex and

10 ischemic colitis had not been established, and

11 specific risk factors for the development of this


12 condition also had not been identified.

13 [Slide.]

14 The drug was launched on March the 13th in

15 2000 in the U.S., and had a very rapid product

16 uptake with about 130,000 prescriptions written by


17 June of 2000.

18 It was in May that we had the first

19 request for a Risk Management Plan from the FDA

20 following reports of new cases of ischemic colitis.

21 In fact, at that in June, when we met with the


22 Agency, we had 8 cases of ischemic colitis, 3 from

23 clinical trials and 5 spontaneous reports.

24 We also had cases of complications of

25 constipation, 2 from clinical trials and 4







1 spontaneous.


2 [Slide.]

3 These concerns led to a GI Drugs Advisory

4 Committee in June of 2000, and the primary issues

5 discussed at that time were ischemic colitis and

6 the complications of constipation.


7 A Risk Management Plan was proposed at

8 that time, and was broadly accepted by the

9 Committee with also the inclusion of a Medication

10 Guide.

11 Now, from the period from July to October


12 2000, quite a lot of things happened. First of

13 all, we sent out Dear Physician and Dear Pharmacist

14 letters following the Advisory Committee and the

15 labeling changes relation to ischemic colitis and

16 constipation.


17 The labeling changes and Medication Guide

18 were introduced, and the elements of the Risk

19 Management Plan were being rolled out into the

20 physician and pharmacist community.

21 Also, during that time, additional serious


22 adverse events occurred including those with fatal

23 outcome, and we will discuss those at some length

24 in the later presentations.

25 [Slide.]







1 This led to November 2000, which was at


2 the time that the drug was withdrawn. We had had

3 multiple discussions with the Agency to explore

4 potential risk management options. These ranged

5 from restriction of the drug, as you have heard

6 from Dr. Houn, all the way to product withdrawal.


7 I think it is fair to say at that time

8 there was also uncertainty regarding the etiology

9 of the serious adverse events, and there was a

10 great deal of debate at that time about whether

11 there were primarily two entities, constipation and


12 its complications, and ischemic colitis, or whether

13 the paradigm of adverse events that we were seeing

14 was being driven by a single entity, ischemic

15 colitis.

16 This point is very important in the review


17 of the cases that you see and the overall data

18 during the day.

19 It is also fair to say that the concerns

20 really at that time had raised about the

21 benefit-risk ratio and how we could have a suitable


22 risk management strategy to manage what were the

23 perceived problems at that time.

24 We were unable to reach agreement on a

25 viable risk management plan and the product was







1 withdrawn by GlaxoSmithKline on November the 28th,


2 2000.

3 [Slide.]

4 Following the product withdrawal during

5 December and January 2001, there were thousands of

6 patient testimonies to the drug, both to our own


7 company and to the FDA. Also, many physicians

8 lobbied the FDA and lobbied us about the fact that

9 this drug was very effective, there was a clear

10 unmet medical need for IBS, and I think again many

11 people raised the question that the appreciation


12 and significance of IBS as a disease as it affected

13 sufferers had been underestimated.

14 That led in January 2001 to the reopening

15 of discussions between GlaxoSmithKline and the FDA

16 about possible market reintroduction.


17 There were many, many discussions during

18 2001 about how that might happen, and you have

19 heard some of the details of those from Dr. Houn,

20 but all those discussions culminated at the end of

21 2001, in December, with a supplemental sNDA


22 submission seeking market reintroduction of

23 Lotronex under restricted access.

24 [Slide.]

25 So, we are here today, in April 2002,







1 looking at the potential product reintroduction for


2 Lotronex, and the question that a lot of people may

3 have is what has changed.

4 Well, two things have changed, and I would

5 like to go through them very briefly. One is that

6 there is a substantial body of new data available,


7 a lot of data that was not available at the time

8 the drug was approved, and a lot of data that

9 wasn't available at the time we were having all the

10 discussions about the viability of continued

11 marketing of the drug.


12 On the benefit side, we have a clear

13 understanding and a better understanding of IBS

14 severity and impact, and I am sure that you will

15 hear that very eloquently from the patient

16 testimonies today.


17 We have clear evidence of sustainability

18 of beneficial effects over nearly a year of dosing,

19 48-week data which you will see in the

20 presentations.

21 We have shown beneficial effect across a


22 spectrum of severity of IBS symptoms, and we have

23 also shown positive effects on quality of life and

24 productivity.

25 On the risk side, we have also seen that







1 the relative incidence and nature of ischemic


2 colitis from clinical trials has remained

3 consistent since the initial product approval, and

4 this runs at about the rate of 1 in 700.

5 I think there is increasing clarity that

6 ischemic colitis and constipation are two separate


7 entities in the overall risk profile of Lotronex.

8 [Slide.]

9 Secondly, we have a proposed risk

10 management framework which has been developed based

11 on a comprehensive evaluation of all the data, and


12 the platform of this is really on four points.

13 Firstly, the restriction of the drug to

14 women with diarrhea-predominant IBS who fail to

15 respond to conventional therapy.

16 Secondly, patient and physician agreement


17 processes about both the knowledge of the drug and

18 the agreement to prescribe the drug.

19 Thirdly, mandatory prescription sticker

20 and refill provisions, which you will hear details

21 of.


22 Lastly, a patient/physician education and

23 ongoing evaluation program.

24 I think all of these will give us a better

25 appreciation of the benefit-to-risk ratio for







1 Lotronex if the drug is reintroduced.


2 That is a brief overview of the history of

3 Lotronex. I would like now just to outline the

4 formal presentations for GlaxoSmithKline for the

5 morning.

6 [Slide.]


7 All our speakers are from GlaxoSmithKline

8 with the exception of Dr. Robert Sandler, who we

9 are pleased to welcome from the University of North

10 Carolina.

11 So, without further ado, I would like to


12 ask Dr. Traber to come to the podium to speak

13 about the burden of illness and efficacy of

14 alosetron.

15 Thank you.

16 Burden of Illness and Efficacy of Alosetron


17 Peter G. Traber, M.D.

18 DR. TRABER: Thank you, James, and good

19 morning.

20 [Slide.]

21 My name is Peter Traber. I am the Senior


22 Vice President for Clinical Development and Medical

23 Affairs and the Chief Medical Officer at

24 GlaxoSmithKline. I am also a gastroenterologist.

25 [Slide.]







1 Irritable bowel syndrome is one of over 20


2 functional bowel disorders. The ROME II

3 classification represents a multinational consensus

4 on the definition of these disorders. This

5 important consensus document defines IBS as, "A

6 functional bowel disorder in which abdominal pain


7 is associated with defecation or a change in bowel

8 habits, with features of disordered defecation and

9 distension."

10 [Slide.]

11 The hallmark symptoms of IBS are chronic


12 or recurrent lower abdominal pain or discomfort

13 associated with features of altered bowel function

14 and bloating.

15 Although structural or biochemical

16 abnormalities are not found, it is likely that


17 these disorders relate to abnormalities in motility

18 and/or afferent neurosensitivity as modulated by

19 the central nervous system.

20 [Slide.]

21 The diagnosis of IBS is made by clinical


22 criteria that were developed by an expert panel and

23 published as practice guidelines by the American

24 Gastroenterological Association. Well-defined and

25 easily applied symptom-based criteria in the







1 absence of structural or gastrointestinal disease


2 is required for diagnosis.

3 Following a careful examination, clinical

4 experience indicates that a diagnosis of IBS is

5 rarely missed and the disorder is usually

6 persistent in those who carry the diagnosis.


7 [Slide.]

8 IBS is a common disorder affecting up to

9 20 percent of the U.S. population in

10 epidemiological surveys. The diarrhea-predominant

11 form affects 5 to 10 percent of the U.S.


12 population, representing 25 to 50 percent of IBS

13 patients.

14 Women are more commonly affected and 30

15 percent of individuals report moderate to severe

16 symptoms as self-reported in the surveys. These


17 data provide an insight into why IBS is the most

18 common diagnosis in U.S. gastroenterology practices

19 and one of the top 10 reasons for primary care

20 physician visits.

21 [Slide.]


22 Despite the benign reputation of IBS, it

23 is increasingly recognized that patients with this

24 disorder have worse health-related quality of life

25 than national norms.







1 As shown in this one study, health-related


2 quality of life in patients with IBS was worse for

3 most domains when compared to normal and when

4 compared to patients with Type II diabetes.

5 Moreover, IBS patients have a health-related

6 quality of life that is generally comparable to


7 patients with clinical depression., a

8 well-recognized and very serious functional

9 disorder. In fact, vitality and social functioning

10 are equally impaired in both.

11 [Slide.]


12 Symptoms of IBS and the resultant

13 diminished quality of life have an impact on

14 productivity. Data from the U.S. Householder

15 Survey, shown here, demonstrated that patients with

16 IBS missed three times as many days from work or


17 school because of illness compared to those with no

18 evidence of a functional GI disorder.

19 In data not shown on this slide, there is

20 also an impact on health care system and

21 productivity. This same study found that persons


22 with IBS were more likely to see physicians for

23 both GI and non-GI complaints than were persons

24 with no evidence of functional GI disorders.

25 [Slide.]







1 These impacts of IBS on the quality of


2 life and productivity result annually in 4 million

3 physician visits, 2 million prescriptions, and

4 countless over-the-counter drug purchases. The

5 financial burden on the health care system and U.S.

6 business in 1998 was estimated to total over $22


7 billion.

8 Taken together, this information indicates

9 that IBS is a well-defined condition affecting a

10 large number of individuals and represents a

11 significant burden for both patients and society.


12 The information I have discussed thus far

13 is well accepted in the medical and scientific

14 community. I will now present some recently

15 obtained data that has the potential to expand our

16 view of IBS.


17 [Slide.]

18 As part of our post-approval commitment to

19 FDA, we undertook an epidemiological program to

20 obtain population-based data on background rates

21 for serious events in IBS patients. This was done


22 because of observed adverse events including

23 complications of constipation and ischemic colitis,

24 but also because there is very little knowledge

25 about associated risks and outcomes in IBS







1 patients.


2 Dr. Alec Walker, who is Senior Vice

3 President at Engenics, Epidemiology, and Professor

4 of Epidemiology at Harvard, designed and performed

5 these studies and is here today to answer any

6 questions you may have. I will report only a brief


7 summary of the one completed study.

8 [Slide.]

9 A retrospective cohort study was performed

10 using medical and pharmacy claims data in the

11 United Healthcare Research Database. Cases were


12 identified through a multistage process including

13 validation by individual chart review.

14 Because of the number of patients in the

15 database, this approach allows the study of rare or

16 infrequent events at a population level. Cases


17 were identified in individuals with IBS,

18 complications of constipation requiring

19 hospitalization, and those diagnosed with ischemic

20 colitis.

21 Incidence rates and risk estimate


22 calculations were obtained for patients with IBS

23 and compared to patients without IBS. It is

24 important to note that this study period was before

25 alosetron was introduced to the market.







1 [Slide.]


2 This figure shows the relative risk of

3 developing complications of constipation in IBS

4 patients as compared to non-IBS patients. In this

5 graph, we show three different time segments

6 following the first in-plan record of IBS in order


7 to provide a view of how the relative risk changes

8 over time.

9 The intervals shows are between 3 and 6

10 months, 6 months to 12 months, and greater than 12

11 months. The confidence intervals for relative risk


12 are shown above the bars and indicate that the

13 lower confidence boundary is greater than 1 in all

14 situations.

15 For both men and women, the IBS patients

16 had a marked increase in the relative rate of


17 complications of constipation when compared to

18 patients without IBS, and this relative risk

19 extended out to over 12 months after the in-plan

20 record of IBS.

21 [Slide.]


22 This figure shows that the relative risk

23 of developing colon ischemia in IBS patients is

24 also increased as compared to non-IBS patients.

25 The increased risk was not gender specific and







1 persists 12 months following the in-plan record of


2 IBS.

3 These results suggest that the risks of

4 ischemic colitis among patients carrying a

5 diagnosis of IBS are substantially higher than the

6 general population. Therefore, ischemic colitis,


7 although unusual in IBS patients, may constitute a

8 distinct part of the natural IBS history or be a

9 result of therapy or a manifestation of other bowel

10 pathology that was misdiagnosed as IBS.

11 Taken together, these epidemiological data


12 suggest that contrary to the general belief, IBS

13 patients may be at substantially higher risk than

14 the general population for serious medical

15 disorders.

16 Let me take one more moment to be clear


17 about GlaxoSmithKline's position on the relevance

18 of these emerging epidemiological data to today's

19 discussion. While we believe the data shed

20 important new light on the natural history of IBS,

21 we do not mean to suggest that they reduce the


22 level of concern about risks associated with

23 alosetron and the need for an appropriate risk

24 management plan. Drs. Carter and Wheadon will

25 address those subjects in turn.







1 [Slide.]


2 Current conventional therapy for IBS

3 utilizes a stepped approach starting with education

4 and reassurance, followed by dietary modification

5 that may include fiber supplementation. The use of

6 pharmacological agents, most of which are not


7 approved for this indication, is directed at

8 symptoms and has variable results.

9 Pain and bloating is treated with

10 antispasmodics, and diarrhea and urgency is treated

11 with loperamide or other antidiarrheals.


12 For individuals who failed this

13 traditional therapy, tricyclic antidepressants or a

14 number of alternative approaches including

15 psychotherapy may be used.

16 [Slide.]


17 We were able to catalog what physicians

18 used as traditional or conventional therapy in an

19 open label trial. Two-thirds of patients were

20 treated with antispasmodics, one-third with

21 antidiarrheals, and a quarter with bulking agents.


22 Note that some patients were taking more than one

23 of these classes of therapy. Only 6 percent of

24 patients were placed on antidepressants by their

25 physicians.







1 [Slide.]


2 The success of current treatment options

3 in addressing multiple symptoms of IBS has been

4 quite limited. For this reason, there is a large

5 unmet medical need for new and more effective

6 therapies.


7 Alosetron is a serotonin type 3 or 5-HT3

8 receptor antagonist. 5-HT3 receptors are on

9 sensory neurons of the gut and mediate

10 gastrointestinal reflexes that control motility,

11 secretion, and the perception of pain.


12 In patients with IBS, 5-HT3 receptor

13 antagonists increase colonic compliance, slow

14 colonic transit and improve stool consistency. An

15 extensive preclinical and clinical research program

16 of alosetron has established its utility in IBS.


17 [Slide.]

18 In contrast to currently available agents

19 for IBS, the efficacy of alosetron has been

20 confirmed in multiple large randomized, controlled

21 trials. Ninety-three clinical trials with


22 alosetron comprise the data in the sNDA. These

23 trial enrolled 11,874 patients, which represents

24 nearly 9,000 additional patients since the original

25 file.







1 Thus, there is a substantial body of new


2 evidence to evaluate the efficacy of alosetron.

3 [Slide.]

4 We found that when IBS patients were asked

5 about their most bothersome symptom, the most

6 frequent answer was abdominal pain, followed by the


7 urgency and the number of bowel movements.

8 Therefore, the primary endpoint of the clinical

9 trials was adequate relief of abdominal pain and

10 discomfort as assessed by the patient.

11 Urgency to defecate and the number and


12 consistency of bowel movements were secondary

13 endpoints in the trials.

14 [Slide.]

15 The efficacy of alosetron, 1 mg twice

16 daily, in women with diarrhea-predominant IBS was


17 established in the original NDA through the results

18 of two, well-controlled Phase III trials. In these

19 pivotal trials, patients with moderate to severe

20 symptoms were enrolled after a two-week screening

21 period.


22 Alosetron was compared to placebo over 12

23 weeks, followed by a 4-week period of monitoring to

24 assess symptoms off therapy. The alosetron-treated

25 groups, represented by the yellow lines on these







1 graphs, has significantly greater improvement in


2 the relief of abdominal pain and discomfort than

3 controls.

4 This effect was significant within 1 to 4

5 weeks of treatment initiation. The beneficial

6 effects persisted through the treatment period with


7 no evidence of tolerance, and symptoms returned

8 rapidly upon stopping therapy.

9 Although not shown on this slide, it is

10 very important to note that there were significant

11 improvements in bowel urgencies, stool frequency,


12 and stool consistency in these patients, and these

13 results have been replicated in five

14 placebo-controlled and two comparator trials.

15 Finally, alosetron was more effective than

16 therapy with two smooth muscle relaxants,


17 mebeverine, an antimuscarinic, and trimabutene, a

18 peripheral opioid agonist. Both of these agents

19 are widely used in Europe for IBS, but are not

20 approved in the U.S.

21 [Slide.]


22 The efficacy of alosetron demonstrated in

23 the original NDA has been significantly bolstered

24 in the sNDA. An important finding is the durability

25 of the alosetron effect. As shown in your briefing







1 materials, when alosetron was continued for 12


2 months, the effect over placebo was maintained and

3 symptoms returned to baseline once the drug was

4 stopped. This is important information for

5 prescribing physicians and patients.

6 On the next slides, I will show additional


7 evidence that there is efficacy in patients with

8 severe and debilitating symptoms and that global

9 IBS symptoms, productivity, and quality of life are

10 improved by alosetron therapy.

11 [Slide.]


12 In our discussions with the FDA, the

13 question arose whether patients across the spectrum

14 of severity had relief with alosetron therapy. In

15 order to investigate this issue, we did

16 retrospective subgroup analyses in the six


17 placebo-controlled studies. The weekly adequate

18 relief data were stratified by increasing

19 severities of baseline pain, urgency, and stool

20 frequency.

21 As shown in this graph, patients with


22 moderate severe pain scores, showed in the first

23 two sets of bars, had greater adequate relief with

24 alosetron than with placebo. Alosetron was also

25 more effective than placebo in patients with







1 moderate and severe urgency and moderate and severe


2 stool frequency.

3 Although these analyses are exploratory,

4 they describe patterns of efficacy in moderate and

5 severe patients that are both similar to each other

6 and similar to those seen in patients from the


7 studies individually.

8 At the same time, patients with harder

9 stools, less urgency, and infrequent stools did not

10 receive benefit and therefore should avoid

11 treatment with alosetron.


12 [Slide.]

13 The benefit of alosetron in patients with

14 severe symptoms was further illustrated in two

15 studies completed after approval. As a surrogate

16 for severity, only patients substantially


17 debilitated by urgency were eligible to enter these

18 studies. Enrolled patients in both studies

19 experienced, on average, lack of satisfactory

20 control of bowel urgency on approximately 80

21 percent of days at baseline.


22 This graph shows that in both studies,

23 alosetron significantly increased from baseline the

24 percentage of days with satisfactory control of

25 urgency compared to placebo. Control of one's







1 bowels is a critical issue for patients with IBS.


2 [Slide.]

3 To understand the integrated effect of

4 alosetron, we evaluated global improvement of IBS

5 symptoms in the same two studies completed after

6 approval. Global improvement was compared to


7 baseline using a 7-point Likert scale that has been

8 shown to reflect both clinical and quality of

9 life-associated dimensions of IBS.

10 Alosetron showed improvement over placebo

11 in both studies over the 12-week period. The


12 magnitude of difference between placebo and

13 alosetron in these two studies demonstrates robust

14 efficacy of alosetron in this patient population.

15 [Slide.]

16 In this study, we examined the improvement


17 of global symptoms on alosetron compared to

18 traditional therapy as chosen by the principal

19 investigator. At week 4, there was a 40 percentage

20 point increase in the number of responders on

21 alosetron versus traditional therapy, representing


22 a 3-fold enhancement.

23 Importantly, this effect was maintained

24 through the end of the 24-week study. This is a

25 critical finding because it indicates the robust







1 effect of alosetron as compared to what is


2 currently used in practice.

3 [Slide.]

4 Important new data in the sNDA pertains to

5 patient outcomes as a result of the improvement in

6 clinical symptomatology. In two placebo-controlled


7 studies shown here, alosetron significantly

8 improved productivity as measured by median hours

9 of lost work time as compared to placebo. These

10 data demonstrate that improved symptomatology

11 translated into an important functional


12 improvement.

13 [Slide.]

14 Further information on outcomes is shown

15 on this slide. A disease-specific quality of life

16 questionnaire has been developed to measure nine


17 domains important for patients with IBS. Using

18 this measurement tool in numerous studies,

19 alosetron has consistently produced positive

20 improvements over baseline.

21 Shown on this graph is data from a


22 12-month study completed since NDA approval

23 demonstrating that patients treated with alosetron

24 were significantly improved in the majority of

25 quality of life domains.







1 [Slide.]


2 This graphs shows the quality of life

3 results of the open label comparison study of

4 alosetron versus traditional IBS therapy.

5 Alosetron produced significantly more improvement

6 than traditional therapy in all nine domains.


7 These data show that improvement in IBS symptoms

8 with alosetron translates into a significant

9 enhancement in the quality of life using a

10 validated IBS-specific instrument.

11 [Slide.]


12 We draw two conclusions from this part of

13 the presentation. Alosetron is needed and it

14 works. It is needed because IBS is a well-defined

15 functional bowel disorder which has a large impact

16 on patients, health care, and society.


17 The fact that alosetron works is supported

18 by a substantial body of new data presented as part

19 of this sNDA. Indeed, it is remarkable that all of

20 the randomized controlled trials met primary

21 endpoints in demonstrating the efficacy of


22 alosetron.

23 Thus, in women with diarrhea-predominant

24 IBS and moderate or severe symptoms, alosetron

25 produces robust and consistent improvement on







1 multiple symptom-based endpoints and important


2 function-based endpoints.

3 I would like now to ask my colleague, Dr.

4 Eric Carter, to come and discuss the safety

5 assessment.

6 Safety Assessment and Benefit-Risk Overview


7 Eric Carter, Ph.D., M.D.

8 DR. CARTER: Good morning, ladies and

9 gentlemen.

10 [Slide.]

11 I am Eric Carter. I am Vice President for


12 Clinical Development and Medical Affairs with

13 responsibility for gastroenterology.

14 I will present a summary of the safety

15 data, as well as an overview of the benefit-risk

16 balance for alosetron. The briefing document, the


17 GSK briefing document provides these data in

18 greater detail, and I will endeavor to refer you to

19 specific sections for guidance.

20 [Slide.]

21 The safety focus is on events of special


22 interest, namely, constipation and complications of

23 constipation, as well as ischemic colitis. Special

24 attention will also be given to related outcomes of

25 hospitalization, surgery, and death.







1 [Slide.]


2 I will follow the general approach

3 proposed by the CIOMS IV working group for

4 evaluating safety signals and benefit-risk balance

5 for marketed drugs. I will therefore review the

6 weight of evidence for the dominant risks -


7 complications of constipation and ischemic colitis,

8 and related outcomes, hospitalization, surgery, and

9 death.

10 Our safety database is extensive. It is

11 comprised of data from clinical trials, which is


12 recognized as the most complete and reliable, and

13 therefore used for calculating risk estimates.

14 We also have a spontaneous safety database

15 obtained from the postmarketing period. Exposure

16 of a large number of patients may enable the


17 identification of infrequent safety events,

18 however, the interpretation of individual cases is

19 often limited by lack of detail.

20 Early results on the background frequency

21 of complications of constipation and ischemic


22 colitis in IBS from the epidemiology studies were

23 presented by Dr. Traber. Conclusions drawn from

24 these studies will be used for context.

25 [Slide.]







1 The approach then has been to review,


2 analyze, and interpret the databases, so as to draw

3 conclusions on risk factors, and from this, on

4 steps that can be taken to mitigate risks, as well

5 as severe outcomes.

6 Taken together with information on the


7 burden of illness, on therapeutic alternatives and

8 on benefits afforded by alosetron, conclusions on

9 the overall benefit-risk balance of alosetron will

10 be presented as we understand it today.

11 [Slide.]


12 This table represents a summary of the

13 events of ischemic colitis and serious

14 constipation, as well as outcomes of

15 hospitalization, surgery, and death related to

16 these events, data from the clinical trials and


17 approval in February 2000, and from the clinical

18 trials and the spontaneous databases for today's

19 Advisory Committee meeting.

20 You will note that as the clinical trial

21 populations increased significantly from the time


22 of approval until alosetron was withdrawn, the

23 frequency of ischemic colitis has remained

24 essentially unchanged. I will describe these

25 cases, as well as the cases of serious







1 complications of constipation, in more detail in a


2 moment.

3 At the time, alosetron was withdrawn in

4 November of 2000, approximately 534,000

5 prescriptions had been written for approximately

6 275,000 patients. This is the population for the


7 spontaneous adverse event report.

8 It is relevant to recognize that the

9 spontaneous safety database has continued to change

10 over time. Indeed, extensive publicity and claims

11 presented by plaintiff attorneys continue to


12 generate new reports or additional information in

13 an ongoing manner. The exact numerator, therefore,

14 will depend on cutoff dates. For our briefing

15 document, we agreed with FDA to a February the

16 18th, 2002, cutoff date.


17 You may have noted that the FDA uses a

18 cutoff date of March the 8th, 2002. This was to

19 allow time to process information. The numerator

20 will also depend on how individual cases are

21 classified. Many of the individual cases of


22 special interest, especially in the spontaneous

23 database, are medically complex or contain very

24 little information.

25 We have discussed these with FDA in order







1 to decide how best to classify them. We agreed


2 with the Agency in a great majority of these cases.

3 In some cases, after medical consultation with our

4 experts, we reached different medical opinions as

5 to the exact nature of the disease process leading

6 to the outcomes of hospitalization, surgery, or


7 death, and the role played by alosetron.

8 This may explain some of the differences

9 in our totals, for instance, most notably in the

10 number of deaths that we associate with the use of

11 the drug.


12 Regardless of the exact numbers, we agree

13 that there are serious risks, and this is what we

14 are here to discuss today.

15 [Slide.]

16 Starting then with the constipation data.


17 [Slide.]

18 An adverse event of constipation in a

19 clinical trial was recorded when a patient reported

20 having constipation or if four consecutive days

21 passed without a bowel movement.


22 Serious adverse events of constipation

23 were defined according to the regulatory criteria,

24 which is described in a footnote to page 60 of the

25 briefing document.







1 Complications of constipation included


2 cases of bowel obstruction, ileus, toxic megacolon,

3 and perforation regardless as to whether these met

4 the serious definition of constipation.

5 Complications of constipation also included cases

6 of impaction when this was a serious adverse event.


7 [Slide.]

8 This is a summary of Table 3, which can be

9 found on page 59 of the briefing document, showing

10 the reports of constipation in clinical trial

11 subjects. Constipation was the most frequently


12 reported adverse event. It was reported in a

13 dose-dependent way, 29 percent of subjects on the 1

14 mg BID dose compared to 11 percent of subjects on

15 the 0.5 mg BID dose.

16 Withdrawal due to constipation also


17 increased with increasing dose. Note, however,

18 that only about 2 percent of all patients treated

19 with alosetron received the 0.5 mg BID dose. Note

20 also that in most trials, laxative use was not

21 allowed.


22 [Slide.]

23 This is a graph of all reports of

24 constipation from Month 1 through to Month 3. As

25 you can see, most of the reports of constipation







1 occurred in the first month, and indeed, patients


2 that remained in the trials on the whole did not

3 report further constipation.

4 Seventy-five percent of patients reporting

5 constipation did so in the first month regardless

6 as to whether or not they withdrew. Again, most


7 patients reported constipation only once.

8 [Slide.]

9 Turning now to reports of serious

10 complications of constipation. Eleven reports came

11 from patients receiving alosetron in the repeat


12 dose clinical trials. The time to onset varied

13 greatly and most subjects were withdrawn from the

14 trials. Ten out of 11 were hospitalized.

15 For 9 out of 11 subjects, constipation

16 resolved with conservative therapy. One patient


17 developed a toxic megacolon and underwent a

18 colectomy. One patient developed a small bowel

19 ileus and Crohn's disease was diagnosed at surgery

20 to correct an ileal stenosis.

21 There were three reports in the placebo


22 group involving obstruction. All resolved, but one

23 underwent lysis of adhesions. One subject in the

24 mebeverine arm of the comparative trial developed

25 severe abdominal pain and constipation and was







1 withdrawn.


2 In contrast to the previous slide, this

3 slide demonstrates that the differential rate in

4 all events of constipation between alosetron and

5 placebo is not translated into a similar

6 differential rate of serious complications. Indeed,


7 only approximately 1 percent of patients

8 withdrawing due to constipation did so because of a

9 complication.

10 Additional details are provided on Tables

11 4 to 7 in Attachment 2 of your briefing document.


12 [Slide.]

13 The cumulative risk calculations, shown on

14 this table, as well as the incidence rates at Month

15 1 and Month 12. As we saw, most of the adverse

16 events of constipation occurred in the first month


17 of therapy. Cases of serious complications tended

18 to occur more sporadically.

19 Based on the way serious complications of

20 constipation were defined for the clinical trials,

21 the risk estimates were not treatment related.


22 Also, the incidence rate did not appear to increase

23 over time.

24 [Slide.]

25 So, interrogation of the clinical trial







1 safety database reveals that constipation was the


2 most frequent adverse event reported. It occurred

3 in a dose-dependent manner, mostly in the first

4 month, and mostly once. It was typically managed

5 by withdrawing therapy and instituting routine care

6 including laxatives.


7 There were reports of serious

8 complications of constipation primarily

9 obstructions and impactions, but also one colectomy

10 and one laparotomy in a patient diagnosed with

11 Crohn's disease.


12 The events of serious complications of

13 constipation appeared to occur somewhat

14 intermittently.

15 [Slide.]

16 Turning now to the marketing experience.


17 Serious constipation and complications of

18 constipation were defined slightly differently for

19 the spontaneous safety database. Firstly,

20 constipation was defined by the reporter.

21 Cases assessed as having a serious event


22 according to the regulation were then identified.

23 Cases with an event of constipation or related term

24 were then individually evaluated to identify those

25 in which constipation was the event leading to the







1 assessment of "serious."


2 Serious constipation associated with

3 complications of constipation were then identified,

4 i.e., perforation, toxic megacolon, obstruction,

5 ileus, and impaction.

6 [Slide.]


7 From about 275,000 patients treated with

8 alosetron, we have 100 spontaneous reports of a

9 serious adverse event of constipation with the

10 characteristics that are shown on the table. As

11 was seen in the clinical trials, the time to onset


12 varied, but occurred in the first month in 67

13 percent of cases.

14 In 58 of these 100 cases, the serious

15 adverse event of constipation was associated with

16 complications ranging from fecal impaction to


17 perforation. These cases are described in Tables 8

18 and 9 on pages 69 and 70 of the briefing document.

19 [Slide.]

20 Outcomes of special interest associated

21 with the serious constipation are shown in this


22 table. These are listed in order of severity and

23 not duplicated.

24 There were two deaths. One was an

25 82-year-old patient prescribed alosetron for







1 diarrhea-predominant IBS, who was hospitalized for


2 constipation, and died following surgery for a

3 ruptured diverticulum. The patient was

4 concurrently receiving hydrocordone and belladonna,

5 and reported a five-day history of constipation.

6 The second patient was a 62-year-old woman


7 in a nursing home with Alzheimer's disease and

8 receiving alosetron for the treatment of chronic

9 diarrhea. She underwent surgery to correct Ogilvie

10 syndrome, and was not resuscitated when she

11 developed ARDS.


12 Intestinal surgeries included partial and

13 total colectomy. Anorectal surgeries involved

14 hemorrhoidectomies and rectal fissure repairs.

15 Other patients were treated conservatively with

16 withdrawal of therapy and the institution of


17 routine care.

18 Dr. Mark Koruda, Professor of

19 Gastrointestinal Surgery, is with us. He has

20 reviewed these cases and is ready to answer any

21 questions you may have.


22 [Slide.]

23 In summary, the clinical presentation of

24 spontaneous constipation reports is similar to that

25 seen for clinical trials. The great majority of







1 reports were not serious, and managed


2 conservatively. However, there were cases of

3 complications of constipation with serious sequelae

4 and two deaths.

5 [Slide.]

6 Risk factors for constipation have been


7 derived from interrogation of the databases and, in

8 particular, by careful analysis of the integrated

9 safety data from the clinical trials.

10 The United Healthcare Epidemiology Study

11 proposes that patients may be at risk of developing


12 complications of constipation and bowel surgery in

13 association with IBS. Whether or not this applies

14 equally to all subtypes of IBS is not known.

15 Constipation resulting from alosetron

16 exposure is not unexpected. 5HT3 receptor


17 antagonists slow GI transit and increase saltwater

18 reabsorption from the gut as a class effect.

19 Constipation appears to occur in a

20 dose-dependent manner with most cases occurring in

21 the first month following initiation of therapy and


22 occurring only once. It also increases with age.

23 Serious complications of constipation may

24 occur more intermittently. Review of the serious

25 constipation spontaneous cases suggests that







1 patients with preexisting constipation or


2 co-morbidities that may aggravate the effects of

3 constipation have worse outcomes.

4 These include patients who have had prior

5 complications of constipation or intestinal

6 obstruction, perforation, diverticulitis, and so


7 on. Likewise, many patients developing

8 complications of constipation were using

9 constipating drugs in addition to alosetron.

10 [Slide.]

11 Moving now to ischemic colitis, the second


12 dominant risk.

13 [Slide.]

14 Intestinal ischemia represents a broad

15 spectrum of diseases. Ischemic colitis, more

16 properly termed colonic ischemia, acute mesenteric


17 ischemia, and chronic mesenteric ischemia,

18 represent the main types. These are frequently

19 confused.

20 Actually, each differs in terms of

21 pathophysiology, clinical presentation, natural


22 history, and prognosis, as outlined on the slide.

23 Much more is known about acute and chronic

24 mesenteric ischemia than is known about colonic

25 ischemia at present.







1 Having said this, we believe that the


2 spontaneous cases described as ischemic colitis in

3 the safety databases represent ischemic colitis,

4 and not acute or chronic mesenteric ischemia. The

5 spontaneous database does contain a number of

6 reports of acute and chronic mesenteric ischemia,


7 which are distinct from ischemic colitis. These

8 cases will also be discussed later.

9 Dr. Larry Brandt, who is with us, is an

10 expert on intestinal ischemia. He authored the AGA

11 Technical Review and Guidelines on this topic. He


12 is familiar with the data and is available to

13 answer questions as needed.

14 Dr. Kay Washington is also with us. She

15 is an Associate Professor of GI Pathology, and she

16 is also familiar with the cases and prepared to


17 answer any questions you may have.

18 [Slide.]

19 The size of the clinical trial safety

20 database has increased 4-fold since the time of

21 approval in February 2000 until the time of the


22 sNDA, so approximately 12,000 patients. The number

23 of reports of ischemic colitis has also increased

24 from 4 to 17. Thus, the frequency of reports has

25 remained essentially unchanged during this period







1 at approximately 1 in 700, as reflected in the


2 approved label.

3 [Slide.]

4 We have 17 reports of ischemic colitis

5 from the clinical trials, and 12 met the definition

6 of a serious adverse event. Most occurred in


7 subjects less than 50 years of age. There was no

8 apparent dose effect although numbers in doses

9 other than the 1 mg BID are small.

10 The time to onset was varied, but mostly

11 occurred in the first month. Sixteen out of 17


12 patients withdrew from the trials. Details of each

13 of these cases can be found in Table 10 in

14 Attachment 3 of the briefing document.

15 [Slide.]

16 The clinical presentation was similar in


17 all cases with acute onset abdominal pain and

18 hematochezia. Fifty-three percent of patients were

19 hospitalized for a median duration of three days.

20 Treatment consisted in all but one instance of

21 withdrawal of drug and providing supportive care.


22 Constipation was reported in 18 percent of

23 cases and estrogen use in 50 percent of cases.

24 These are proportions corresponding to those of the

25 overall clinical trial population.







1 [Slide.]


2 In this slide are cumulative risk and

3 incidence rate estimates for the totality of

4 treatment exposures in all trials pooled together.

5 You will note that FDA, in their briefing document,

6 provided several complementary estimates also


7 derived from studies.

8 FDA also presents a study-specific

9 approach directed at identifying a representative

10 estimate in female IBS patients and in female IBS

11 patients in the U.S.


12 Our results show that there is a 5-fold

13 increase in the risk of developing ischemic colitis

14 in alosetron-treated subjects compared to

15 placebo-treated control in terms of events per

16 10,000 patients. This is also reflected in the


17 incidence rates at 12 months expressed in terms of

18 events per 1,000 patient years.

19 [Slide.]

20 From the marketing experience, 80

21 spontaneous reports of ischemic colitis have been


22 received. For a clear interpretation, these were

23 further classified as probable, possible, or

24 insufficient evidence based on the extent of

25 supporting clinical, endoscopic, and pathological







1 information.


2 [Slide.]

3 Only 58 cases met the probable, possible

4 criteria, but summary characteristics are presented

5 on this slide based on available data from all 80

6 cases. The clinical presentation was similar to


7 that seen in clinical trials with early onset.

8 Most patients were less than 65 years old and 60

9 percent were hospitalized.

10 Six spontaneous cases included a report of

11 intestinal surgery. These included two right


12 hemicolectomies and a partial colectomy site

13 unspecified. Brief case summaries are described on

14 page 85 and 86 of the briefing document for these

15 three surgeries. The other three reports did not

16 contain sufficient information.


17 [Slide.]

18 In addition to the cases of ischemic

19 colitis, 12 spontaneous serious adverse event

20 reports of mesenteric ischemia, occlusion, or

21 infarction were received. The clinical


22 presentation varied greatly, and interpretation in

23 all cases is confounded by predisposing conditions

24 including intestinal vascular insufficiency,

25 hypercoagulable states, and thrombotic disease.







1 Given these circumstances, no meaningful


2 signal can be derived regarding a role played by

3 alosetron. Case summaries are shown on page 87 to

4 90 of the briefing document.

5 [Slide.]

6 In summary, then, ischemic colitis


7 generally occurred early in therapy, presenting

8 acutely. It occurred in subjects with a spectrum

9 of baseline symptoms. It was typically transient

10 and resolved without sequelae, and was managed by

11 withdrawing therapy and supportive care. Six


12 spontaneous cases did report surgery. There were

13 no deaths.

14 [Slide.]

15 Ischemic colitis appears to be

16 idiosyncratic and so unpredictable. The


17 epidemiological data proposes that having a

18 diagnosis of IBS carries a baseline risk. The risk

19 observed in clinical trials has remained unchanged

20 over the period of the clinical trial program

21 during which the number of exposed subjects has


22 increased approximately 4-fold.

23 Most of the cases occurred in the first

24 month, although it is recognized that a small

25 number of patients were exposed for more than six







1 months, however. Despite a concerted analytical


2 effort, no specific risk factors including

3 constipation or other medications have been

4 identified. In other words, there is no evidence

5 that constipation predisposes IBS patients to

6 ischemic colitis.


7 [Slide.]

8 What do we conclude then with respect to

9 the benefit-risk balance? Patients with their

10 physician must balance the benefits against the

11 risks when making an informed decision to initiate


12 any new therapy. This will depend on the burden of

13 illness for the patient and what alternative

14 therapies have to offer also in terms of balance

15 between benefits and risks.

16 As presented by Dr. Traber, IBS is


17 associated with a significant burden of illness

18 that requires treatment for many patients. He also

19 indicated that today, therapeutic options remain

20 limited. IBS, therefore, continues to represent a

21 significant unmet medical need.


22 [Slide.]

23 As was also summarized by Dr. Traber,

24 alosetron provides substantial benefits for women

25 with diarrhea-predominant IBS with a spectrum of







1 chronic and debilitating symptoms.


2 [Slide.]

3 The most favorable benefit-risk balance

4 would be achieved by restricting alosetron to women

5 who have failed conventional therapy, and so have

6 no therapeutic alternatives. Conversely, women


7 with episodic or non-debilitating symptoms may not

8 benefit from alosetron and may have an unfavorable

9 benefit-risk balance. These patients would

10 typically be managed with conventional therapy.

11 [Slide.]


12 In conclusion, then, the benefit-risk

13 balance for alosetron is positive for

14 diarrhea-predominant women with IBS who have failed

15 conventional therapy. Implementation of the Risk

16 Management Plan including changes to the label will


17 focus on the population most in need, and will

18 mitigate risks. This will provide the most

19 favorable risk-balance for alosetron.

20 Dr. Wheadon will now take us through the

21 Risk Management Plan. Thank you.


22 Risk Management Plan

23 David Wheadon, M.D.

24 DR. WHEADON: Thank you, Eric.

25 [Slide.]







1 I am David Wheadon, Senior Vice President


2 of U.S. Regulatory Affairs at GlaxoSmithKline. I

3 would like to thank the committee for the

4 opportunity to present the risk management

5 framework for the proposed reintroduction of

6 Lotronex.


7 [Slide.]

8 Before going specifically into the Risk

9 Management Plan, I would to very briefly revisit

10 the issues of benefit-risk calculations and

11 particularly the benefits and associated risk of


12 Lotronex use.

13 As you see here, at the beginning of the

14 determination of benefit-risk by the sponsor and

15 the FDA, the sponsor and the FDA, as a joint team,

16 evaluate the assess the benefits and the potential


17 risk for the pharmaceutical treatment under

18 discussion, and communicate such via labeling and

19 other mechanisms to the prescribing community.

20 The prescribers then are key in

21 determining the benefits and managing the risk for


22 the individual patient for whom the drug is

23 intended. Last, but not least, the patient once

24 informed is the ultimate decisionmaker concerning

25 the balance.







1 [Slide.]


2 As we have heard this morning, IBS carries

3 a significant burden of illness, has a significant

4 quality of life impact. It has reduced

5 productivity particularly in the domains of work

6 and school, and perhaps underlying the reason why


7 we are here today, there continues to be limited

8 treatment options.

9 [Slide.]

10 As Dr. Traber has outlined this morning,

11 Lotronex has been shown to evidence improvement in


12 moderate and severe IBS symptoms, particularly

13 concerning urgency, frequency, and pain. It has

14 also been shown to have global improvement in IBS

15 symptoms, to have an effect on quality of life

16 particularly around such things as sleep and


17 physical and social functioning, and also has been

18 shown to have a beneficial effect on productivity.

19 [Slide.]

20 As Dr. Carter has outlined, there are

21 dominant risks associated with the use of Lotronex


22 particularly constipation, which is an expected

23 outcome given the mechanism of action of Lotronex.

24 The complications of constipation is an

25 event that is potentially avoidable. Severe







1 outcomes can be mitigated by early recognition of


2 signs and symptoms and timely intervention.

3 In terms of ischemic colitis, as best as

4 we know today, this event is idiosyncratic,

5 however, we believe careful monitoring of signs and

6 symptoms is warranted with the overarching goal of


7 mitigating severe outcomes.

8 [Slide.]

9 In terms of the Risk Management Plan that

10 we have put before the committee, the overarching

11 goals are as follow:


12 To restrict use to patients with the most

13 favorable benefit-risk balance. As Dr. Carter has

14 outlined, that continues to be women with

15 diarrhea-predominant IBS who have failed to respond

16 to conventional therapy. Beyond that, as is always


17 true with the use of drugs in treating serious

18 illness, informed patient use is key.

19 Additionally, with the appropriate

20 adherence to the tenets of the Risk Management

21 Plan, we hope to mitigate serious outcomes of


22 constipation and to mitigate the serious outcomes

23 of ischemic colitis.

24 [Slide.]

25 In general, there are certain common core







1 activities associated with risk management plans.


2 The evaluation of the benefits and assessment of

3 risk, which we have all heard this morning, but

4 additionally, balancing the benefits versus the

5 risks particularly in identifying the appropriate

6 target population.


7 Beyond that, the risk must be communicated

8 both in terms of labeling, as well as other

9 mechanisms of communication. The risks should be

10 managed with informed patient use and appropriate

11 prescribing.


12 Ongoing safety evaluation is key, as is

13 true for the safe use of all pharmaceutical

14 products, and ongoing program evaluation to assess

15 the effectiveness of the plan that has been put in

16 place.


17 [Slide.]

18 This schematic is intended to give you in

19 one sort of fell swoop, the overarching goals and

20 tenets of the Risk Management Plan of Lotronex.

21 The physician will serve as the key in determine,


22 first, the appropriate patient for use, that being

23 women with diarrhea-predominant IBS that have

24 failed to respond to conventional therapy, but

25 beyond that, the physician will then sign a form







1 indicating, one, his or her knowledge and


2 experience in treating IBS and in managing the

3 potential complications of treating IBS, but also

4 sign the form indicating that the patient has been

5 appropriately counseled concerning risk and

6 benefits.


7 Additionally, an initial titration period

8 is being proposed based on prudent clinical care,

9 that is, a half dose, 1 mg a day, initiation

10 treatment for 30 days. A prescription will be

11 written by their physician with a sticker affixed


12 to the prescription indicating that the appropriate

13 discussions and counseling has occurred.

14 The patient, once informed, will sign the

15 agreement, as well, indicating that they have been

16 counseled around the benefits and the risks, and


17 the signs the symptoms to be perfect cognizant of.

18 The patient will then take a copy of the

19 signed agreement form along with the prescription

20 with the affixed sticker to the pharmacy. The

21 pharmacist will serve as a real-time check,


22 checking for the sticker, dispensing the

23 prescription with a Medication Guide.

24 Following the initial 30-day treatment

25 period, the patient will return to report any







1 adverse effects and to receive a new prescription,


2 and this is a correction I want you to pay

3 particular attention to - each new prescription

4 will require a new sticker affixed to the

5 prescription. There will be no refills.

6 Underlying this ongoing process will be


7 the FDA and the company evaluating both the

8 efficiency and effectiveness of the program, but

9 also modifying the program as indicated depending

10 on the outcome of the evaluations.

11 [Slide.]


12 Now, to go more specifically into the

13 various responsibilities of the core components of

14 this Risk Management Plan. There is a joint

15 responsibility between ourselves and the FDA

16 particularly around revised labeling.


17 The labeling has been revised, at least

18 proposed to be revised, with a concise box warning

19 that carries the key safety information

20 particularly that serious gastrointestinal events,

21 some fatal, have been reported in association with


22 Lotronex use, these events including ischemic

23 colitis and serious complications of constipation

24 have resulted in hospitalization, blood

25 transfusion, and/or surgery.







1 Physicians who are knowledgeable and


2 experienced in treating IBS and in managing the

3 complications should only prescribe the drug.

4 The indication is limited to women with

5 diarrhea-predominant IBS who have not responded to

6 conventional therapy. Patients will be instructed


7 to discontinue use immediately if symptoms of

8 constipation or ischemic colitis should occur and

9 these occurrences should be reported to the

10 treating physician.

11 As I mentioned, there is also a


12 modification in terms of the initial titration

13 period starting off at a half dose, 1 mg a day for

14 30 days to assess patient tolerance to the

15 treatment.

16 A Medication Guide will be given to the


17 patient both by the treating physician and the

18 pharmacist that will include this key safety

19 information.

20 Beyond this, we propose to meet jointly

21 with the FDA on a regular basis, for example,


22 quarterly to review the evolving safety

23 information.

24 [Slide.]

25 In terms of specific GSK responsibilities,







1 we are proposing to establish an external expert


2 medical review board to review events of special

3 interest. We will also voluntarily expedite

4 reports of events of special interest regardless of

5 the seriousness or the expectedness.

6 We will, as well, provide a Dear Physician


7 and Dear Pharmacist letter conveying the key

8 elements of the Risk Management Plan and the

9 labeling changes.

10 The physician-patient agreement kit will

11 also be provided either via a 1-800 number,


12 described in the Dear Physician letter, or provided

13 via our sales representatives during the

14 introductory period.

15 [Slide.]

16 Additional responsibilities that the


17 Company will carry include providing Lotronex and

18 IBS disease information to physicians via sales

19 representatives, and an Internet web site will also

20 be maintained where all the important information

21 will be collated, as well as the ability for


22 physicians to download the patient agreement forms.

23 [Slide.]

24 In terms of program evaluation, three

25 studies will be proposed or have been proposed to







1 look at the safe use of Lotronex. One will target


2 the utilization of Lotronex in a large managed

3 health care research database, the United

4 Healthcare Research database.

5 This database encompasses 5 million

6 covered lives, and we will look at the


7 appropriateness for therapy for patients that are

8 prescribed Lotronex within this database,

9 specifically focusing on demographic

10 characteristics, IBS history and other GI history,

11 and drugs dispensed in six months prior to Lotronex


12 use or during Lotronex use, specifically to assess

13 whether or not the intended indication and the

14 contraindications have been adhered to.

15 [Slide.]

16 A second study will look at the compliance


17 with the Risk Management Plan. This will be a

18 pharmacy-based postmarketing study in association

19 with the Slone Epidemiology Unit of the Boston

20 University School of Medicine.

21 This study will be conducted in


22 association with a large national retail pharmacy

23 chain. Roughly 2,600 retail pharmacies will

24 participate. Patients that are dispensed Lotronex

25 will be contacted within one week of dispensation







1 of the drug, and questionnaire will be carried out,


2 again focusing on IBS history, receipt of

3 appropriate counseling regarding benefit and risk

4 of Lotronex use, as well as the receipt of a copy

5 of the agreement form and the Medication Guide.

6 A follow-up contact will occur 30 to 45


7 days after the prescription has been filled to

8 assess further patient experience on the drug.

9 [Slide.]

10 A third study will focus specifically on

11 Lotronex safety. The occurrence of events of


12 special interest in relation to Lotronex use will

13 be assessed, again using the United Healthcare

14 Research Database.

15 The incidence of these events in patients

16 receiving Lotronex will be ascertained, as well as


17 the incidence of these events in IBS patients who

18 do not receive Lotronex, in an attempt to further

19 elucidate the possibility of risk factors for these

20 events will be carried out. The target number of

21 Lotronex users will be 10,000 patients.


22 [Slide.]

23 Focusing now on prescriber

24 responsibilities. First and foremost, the

25 prescriber will be responsible for appropriate







1 patient selection based on the modified revised


2 label.

3 Specifically, in addition to the

4 indicating treatment population, that being women

5 with IBS of diarrhea predominance that have failed

6 to respond to conventional therapy,


7 contraindications will be key, as well.

8 So, patients with a history of chronic or

9 severe constipation, that with a history of

10 intestinal obstruction, stricture, toxic megacolon,

11 GI perforation, and/or adhesions, a history of


12 ischemic colitis current or a history of Crohn's

13 disease or ulcerative colitis, active

14 diverticulitis or a history of diverticulitis,

15 those patients that are unable or unwilling to

16 comply or understand the patient-physician


17 agreement, and, as always, those patients with a

18 know hypersensitivity to a component of the drug

19 are clearly contraindicated.

20 [Slide.]

21 The prescriber will sign the agreement


22 form confirming several things: one, that he or

23 she is appropriate in terms of experience in

24 treating IBS and in managing the potential

25 complications of IBS. The physician will also







1 counsel the patient on the benefit-risk associated


2 with the use of Lotronex.

3 [Slide.]

4 The prescriber will also educate the

5 patients on signs and symptoms that require prompt

6 action, obtain patient's signature on the agreement


7 form, and provide a copy of the agreement form to

8 the patient and place a copy in the patient's

9 medical record.

10 [Slide.]

11 Again, these requirements of the


12 prescriber are clearly outlined in the proposed

13 modified label.

14 [Slide.]

15 Once this is carried out, the special

16 sticker will be affixed to the prescription. No


17 verbal orders or prescription orders by facsimile

18 will be allowed. No refills will be allowed.

19 Every prescription, both the initiating

20 prescription, as well as follow-on prescriptions,

21 will require the special sticker. As always, the


22 prescriber will be responsible for active patient

23 follow-up to assess patient response to the drug.

24 [Slide.]

25 In terms of the pharmacist, the pharmacist







1 will only accept written prescriptions with an


2 affixed sticker. The pharmacist will, as well,

3 dispense the Medication Guide, which is reflective

4 of the key information associated with safe

5 Lotronex use, and the pharmacist will, as well,

6 serve as an additional resource for product


7 information.

8 [Slide.]

9 Moving now to patient responsibilities,

10 perhaps the most important. It is incumbent upon

11 the patient to understand the benefits and the


12 risks associated with Lotronex use. Once informed,

13 the patient will make an informed decision

14 regarding treatment and sign the agreement form.

15 The patient will be responsible for

16 following the physician and Medication Guide


17 instructions, and perhaps most importantly, the

18 patient will need to be very able to recognize

19 important signs and symptoms requiring prompt

20 action including discontinuing treatment and

21 seeking medical attention.


22 [Slide.]

23 Again, the modified label and the

24 Medication Guide will clearly elucidate the

25 responsibilities of the patient in terms of reading







1 the Medication Guide, not starting Lotronex if they


2 are constipated, discontinuing the drug and

3 contacting physician if certain key symptoms occur

4 during the course of treatment, particularly

5 constipation, worsening abdominal pain, bloody

6 diarrhea, or blood in the stool, and perhaps also,


7 importantly, to stop taking Lotronex and contact

8 their physician if the drug does not adequately

9 control IBS symptoms after four weeks of taking one

10 tablet twice a day, which is the indicated dosage

11 for treatment.


12 [Slide.]

13 So, as I have described for you this

14 morning, the Lotronex Risk Management Plan is a

15 thorough plan calling for the active engagement of

16 key participants, namely, the physician, who must


17 attest to their experience in treating IBS and

18 managing its complications, the patient, who must

19 be counseled and clearly sign that they understand

20 the incumbent benefits and risks of Lotronex use,

21 the pharmacist, who will serve as a real-time check


22 in terms of the prescriptions and appropriate

23 stickers applied to it, and counseling the patient

24 and providing Medication Guides, and the Agency and

25 the Company, who will be responsible for evaluating







1 the effectiveness of the program and modifying the


2 program as might be indicated with experience.

3 [Slide.]

4 So, we believe the Risk Management Program

5 put before you is designed to address the benefit

6 and mitigate the risk associated with Lotronex use.


7 The modified conditions of use favorably enhance

8 the benefit-risk by restricting access to women

9 with diarrhea-predominant IBS that have not

10 responded to other conventional therapies.

11 The communication plan includes messages


12 to prescribers, pharmacists, and patients, the

13 modified package insert and Medication Guide will

14 carry key safety information that is important for

15 the prescriber and the patient to be fully aware

16 of.


17 The patient-physician agreement process

18 ensures that the appropriate discussion and

19 counseling occurs prior to dispensation of the

20 prescription.

21 The real-time double check at the pharmacy


22 level provides an additional safety measure to

23 ensure that only the appropriate patients are

24 receiving the drug, and the ongoing program

25 evaluation allows for assessment of effectiveness







1 of the program.


2 [Slide.]

3 This plan, we believe allows for informed

4 patient use, should reduce the occurrence of

5 complications of constipation, should mitigate the

6 serious outcomes associated with complications of


7 constipation and ischemic colitis, and perhaps most

8 importantly, should strike a balance between

9 mitigating risk without creating extraordinary

10 barriers to patient access.

11 It is pleasure to introduce Dr. Robert


12 Sandler, who will give us a clinician's perspective

13 on Lotronex use.

14 Clinician's Perspective

15 Robert S. Sandler, M.D.

16 DR. SANDLER: Good morning.


17 [Slide.]

18 I am Robert Sandler. I am Professor of

19 Medicine and Epidemiology at the University of

20 North Carolina at Chapel Hill.

21 I am a gastroenterologists and although I


22 don't specialize in IBS, like most

23 gastroenterologists, patients with IBS comprise the

24 largest group of people that I see in my practice.

25 I am also an epidemiologist and I have







1 done some research on the epidemiology of IBS. I


2 have authored the Burden of Disease Report from the

3 American Gastroenterological Association, and I

4 have had a chance to read some of the epidemiology

5 background papers that are pertinent for the

6 discussion today.


7 So, I am here today as a clinician, as a

8 clinical investigator, as an epidemiologist, and

9 what I would like to do in the next 14 minutes or

10 so is to share with you my impressions after

11 reading the briefing documents from the Company and


12 from the FDA.

13 [Slide.]

14 So, the topics I am going to cover are

15 listed here. I am going to talk about the economic

16 and social burden of IBS, our treatment options,


17 the benefits and potential risks of alosetron, and

18 I will give you my impressions of the risk

19 management program that has been proposed.

20 [Slide.]

21 IBS is a common digestive complaint. The


22 information that we obtained in the Burden of GI

23 Disease Report suggests that there are 15.4 million

24 prevalent cases, 3.6 million office visits, 150,000

25 hospital outpatient visits, and 87,000 emergency







1 room visits.


2 [Slide.]

3 As you might anticipate with that many

4 health care encounters, the economic costs of IBS

5 are considerable. On this slide, I have graphed

6 the total direct costs from 1998 in millions of


7 dollars. Somewhat unexpectedly, the largest

8 component of those costs are hospital costs.

9 Patients with IBS aren't usually admitted to the

10 hospital, and this reflects secondary diagnosis

11 codes for patients with IBS who were admitted to


12 the hospital for some other reason.

13 Now, the other costs on here, I think ware

14 more accurate - outpatient hospital costs,

15 emergency room visits, and office visits, and it is

16 somewhat surprising to note that $80 million was


17 spent on drugs. This is surprising because the

18 drugs that we have currently for IBS are not very

19 effective.

20 So, if we total those direct costs, we

21 come up with about $1.7 billion. We also tried to


22 estimate the indirect costs. These are the costs

23 from people missing work as a consequence of their

24 IBS. That is almost $20 million.

25 In addition, there are these unmeasured







1 collateral costs. We know that patients with IBS


2 are more likely to go to physicians for both GI and

3 non-GI conditions.

4 Although you may quibble with the specific

5 dollar figures, I think that the unmistakable

6 conclusion is that IBS is a very expensive


7 condition.

8 [Slide.]

9 The economic analyses ignore social and

10 emotional costs of IBS that are unmeasured and

11 immeasurable. Physicians, policymakers and critics


12 typically pay insufficient attention to conditions

13 that cause symptoms, but aren't fatal.

14 Let's face it, IBS doesn't commonly kill

15 people, but this lack of appreciation for

16 symptomatic conditions in insensitive and insulting


17 to patients who are suffering.

18 People who say that IBS is not a bad

19 disease have never taken care of patients with IBS.

20 So, given the high prevalence and high impact, we

21 need therapeutic agents that are effective.


22 [Slide.]

23 Unfortunately, there are currently no

24 FDA-approved drugs for IBS that have been proven to

25 be effective in randomized, controlled trials. The







1 drugs that we commonly use are fiber, smooth muscle


2 relaxants, antidepressants, and anxiolytics. These

3 medications are incompletely effective in the

4 patients who are most severely affected, and they

5 don't work for diarrhea.

6 [Slide.]


7 The pharmacologic treatment of IBS was the

8 subject of a systematic review of randomized,

9 controlled trials that was published in the Annals

10 of Internal Medicine in the year 2000. The

11 randomized, controlled trials that were part of


12 that review demonstrated that the only drugs that

13 were effective for IBS were smooth muscle

14 relaxants. They are not available in the United

15 States.

16 In addition, these randomized, controlled


17 trials did not look at the impact on disability or

18 patients' satisfaction with care.

19 [Slide.]

20 In contrast, I think you have seen today

21 there is abundant evidence that alosetron works.


22 This is a graphic that I ran across in the

23 Company's briefing document, and I scanned it in,

24 which accounts for the somewhat uneven quality, but

25 what it does is it look at weekly adequate relief







1 for women with diarrhea-predominant IBS.


2 The reason I selected this particular

3 graph is it shows that the duration of effect was

4 48 weeks, and as a clinician, I am impressed with

5 the durability of the effectiveness of the drug.

6 [Slide.]


7 I am also impressed with the wide range of

8 symptoms for which this drug is effective. You

9 have heard this morning about a large number of

10 studies that have looked at a wide range of

11 different symptoms that our patients with IBS bring


12 to the clinic. Again, as a clinician, I am

13 impressed with the wide range of symptoms for which

14 the drug is effective. So, I think there is no

15 doubt that the drug is effective.

16 [Slide.]


17 Well, what about risks? Our information

18 about risks comes from several different sources.

19 First of all, it comes from controlled clinical

20 trials, and this is really the best evidence on

21 risk. It is the best evidence because there is a


22 comparison group.

23 It is also the best evidence because in

24 randomized, controlled trials, patients are

25 monitored very carefully by their physicians, and I







1 think that, if anything, the adverse events in


2 randomized trials are likely to be overestimated

3 rather than underestimated.

4 Now, we can also find out about risks from

5 spontaneous reports. The limitation of spontaneous

6 reports is that they may be factually uncertain,


7 incomplete, or imprecise. Importantly, the

8 spontaneous reports are unable to account for cases

9 that are not related to the drug. These are cases

10 that occur as part of the background.

11 Now, that is not to say that spontaneous


12 reports aren't important. Spontaneous reports can

13 provide a signal for rare events that we could not

14 determine from randomized, controlled trials, even

15 large randomized, controlled trials. So, I don't

16 want to give you the impression that I don't think


17 spontaneous reports are important, but we need to

18 recognize their limitations.

19 Finally, we can find out about risk from

20 the epidemiology studies. The problem with

21 epidemiology studies is that they can be


22 susceptible to problems of misclassification of

23 disease or exposure, however, they have important

24 strengths.

25 The large epidemiology studies can rival







1 the spontaneous reports in their ability to detect


2 rare events. In addition, and very importantly, the

3 population-based epidemiology studies can provide

4 insight into the background rate of disease in the

5 general population that we can use to place the

6 spontaneous reports in context.


7 [Slide.]

8 Let's turn to the complications of

9 alosetron. The first is constipation, and based on

10 reading the evidence, there is little doubt in my

11 mind that the drug cause constipation. This is a


12 predictable side effect based on the pharmacologic

13 action of the drug. It's a 5HT3 antagonist that

14 may result in constipation.

15 However, it appears that the constipation

16 is dose related, it is more common at higher dose,


17 and importantly, in randomized trials with nearly

18 12,000 patients, so-called complications of

19 constipation were not more frequent in alosetron

20 than in placebo-treated groups.

21 In the epidemiology study, none of these


22 people got alosetron. In the epidemiology study,

23 IBS patients were more than twice as likely to be

24 hospitalized with these constipation complications

25 than non-IBS patients, suggesting that these







1 complications may be a part of the disease, and not


2 a consequence of the therapy.

3 [Slide.]

4 Now, ischemic colitis is potentially more

5 serious. The collection of randomized, controlled

6 trials suggests that people that take alosetron are


7 about 5 to 6 times more likely to develop ischemic

8 colitis.

9 All of the cases in clinical trials were

10 self-limited and they did not result in sequelae,

11 and in the epidemiology study, there was about a


12 4-fold increase in colonic ischemia in IBS patients

13 compared to the non-IBS patients, and I would like

14 to illustrate that with a graphic because I think

15 it is important.

16 [Slide.]


17 So, this is the adjusted relative risk, 95

18 percent confidence interval, of colonic ischemia in

19 5 million members of the United Healthcare

20 Database. None of these people took alosetron.

21 The way the slide works, this is relative


22 risk in a log scale. Compared to the non-IBS

23 patients, individuals who had an IBS diagnosis,

24 within three weeks, were almost 50 times more

25 likely to have a diagnosis of ischemic colitis.







1 Now, how do we interpret that? My


2 interpretation is that these people within three

3 weeks probably didn't have IBS in the first place.

4 They probably had ischemic colitis and within three

5 weeks, the diagnosis was apparent.

6 However, it is also interesting to note


7 that as long as one year after diagnosis, the

8 patients with IBS were still about 3 to 4 times

9 more likely to have a diagnosis of ischemic colitis

10 compared to the non-IBS patients.

11 Well, how do we interpret that? I think


12 there is two possible interpretations. The first

13 interpretation would be that patients with IBS are

14 more likely to develop ischemic colitis. A second

15 interpretation is that there is a group of people

16 who have a poorly defined entity that resembles


17 irritable bowel syndrome, but is, in fact, ischemic

18 colitis, and that diagnosis becomes apparent over

19 time.

20 I think the take-home message from this

21 study is, first of all, we don't understand the


22 entity of ischemic colitis very well, and,

23 secondly, I think that this kind of epidemiology

24 study can provide a context for helping us

25 understand the spontaneous reports, particularly







1 when we see such a high relative risk within three


2 weeks of diagnosis, suggesting that some of those

3 spontaneous reports may, in fact, not have been due

4 to the drug.

5 [Slide.]

6 So, what are my conclusions about risk?


7 With respect to constipation, I think that

8 constipation should be straightforward to manage.

9 Primary care physicians, internists, and

10 gastroenterologists can manage constipation.

11 The complications of constipation are not


12 more common than placebo in randomized, controlled

13 trials, and constipation may be less frequent with

14 a lower starting dose.

15 With respect to ischemic colitis, I think

16 that heightened awareness should provide for early


17 detection, and colonic ischemia is almost always

18 self-limited.

19 I would like to make a couple of comments

20 about risk estimates, because there is lots of risk

21 estimates in those FDA briefing documents, and I


22 would make the following points.

23 With respect to the risk of ischemic

24 colitis in people who take alosetron, the estimate

25 from the collection of randomized, controlled







1 trials is 5.4. That means that people that take


2 alosetron are 5.4 times more likely to get ischemic

3 colitis.

4 But I call your attention to the

5 confidence interval, which is incredibly wide. As

6 a consequence of small numbers, it reflects the


7 imprecision of that estimate.

8 Now, in the FDA briefing document, you

9 also saw mention of something that many people call

10 the etiologic fraction. This is the proportion of

11 cases that are caused by the drug.


12 I would simply point out that because of

13 the wide confidence interval around this risk

14 estimate, and because of the questionable

15 assumptions that go into calculating etiologic

16 fraction, I think that that number may be


17 potentially misleading.

18 Now, perhaps the most useful measure would

19 be attributable risk. This is the excess cases as

20 a consequence of the drug, and our calculations are

21 that there are 3.9 cases per 1,000 per year. The


22 reason this is a useful measure is that we can tell

23 our patients that of every thousand patients who

24 take the drug for a year, 3.9 of them will develop

25 this outcome.







1 [Slide.]


2 I would like to end with my impressions of

3 the risk management program. Now, the risk

4 management program is designed to provide the

5 medication to appropriate patients, specifically,

6 women with diarrhea-predominant IBS who have failed


7 traditional therapy.

8 It is also designed to target appropriate

9 providers, that is, physicians who are experienced

10 and knowledgeable in the management of both IBS and

11 ischemic colitis, who have signed an agreement


12 form, who have counseled patients about risks,

13 safety monitoring, and benefits, who have signed an

14 agreement and placed it in the medical record, and,

15 finally, who have placed a sticker on the

16 prescription and sent it to the pharmacy. This is


17 a lot to ask for busy physicians.

18 Finally, I don't think we should

19 underestimate the value of the Phase IV studies,

20 the studies that have been proposed by the Company,

21 will monitor whether appropriate patients are


22 receiving the medication, and some of the studies

23 can provide new insights about the risks of the

24 drug and about ischemic colitis.

25 [Slide.]







1 So, what are my impressions of the


2 potential impact of the risk management program?

3 It is very clear to me that this risk management

4 program will discourage casual use of this drug.

5 This risk management program is not anemic, it is

6 very onerous, and I think that, if anything, the


7 risk management program might prevent some

8 deserving patients from getting the drug.

9 The management program will alert

10 physicians and patients to potential side effects

11 and will lead to early termination and evaluation


12 for adverse events.

13 Now, physicians deal with risk-benefit

14 issues every day. They do that when they prescribe

15 steroids or NSAIDs or immunosuppressors or

16 biologics, and I think in this case of prescribing


17 alosetron is no different.

18 [Slide.]

19 So, in conclusion, I would make the

20 following observations.

21 IBS is a significant economic and social


22 problem. Our therapeutic options are currently

23 limited. Alosetron has demonstrated consistent

24 benefits in rigorous studies and offers advantages

25 to selected patients, specifically, women with







1 diarrhea-predominant IBS.


2 The risk management program would limit

3 use to knowledgeable physicians and appropriate

4 patients, and, finally, physicians and patients

5 want the option to use an effective drug. As a

6 clinician, I would use this drug in my patients


7 with IBS.

8 Thank you.

9 Summary and Conclusions

10 James B.D. Palmer, M.D.

11 DR. PALMER: Let me just make some brief


12 closing remarks.

13 [Slide.]

14 I think we have heard in the presentations

15 to date that the reintroduction of Lotronex to

16 patients without suitable therapeutic alternatives


17 is supported by a substantial body of new data, a

18 lot more spontaneous data, and we have nearly

19 12,000 patients in our clinical trial database.

20 The proposed Risk Management Plan strikes

21 an appropriate balance between the need to mitigate


22 risk without creating extraordinary barriers to

23 product access.

24 The last thing I would like to mention,

25 which I think is important, is GlaxoSmithKline's







1 expectations. If reintroduction is approved, it is


2 our intention to be extremely cautious with this

3 medicine. I think that is a very important point.

4 We hope we can work with the Advisory

5 Committee and the Agency to achieve a positive

6 outcome and, most of all, help patients with IBS


7 for whom this drug may be effective.

8 Thank you.

9 DR. WOLFE: Thank you, Dr. Palmer. I

10 thank you and your colleagues for your

11 presentations.


12 We are scheduled for a break now, but what

13 I would like to do right before we break is offer

14 the panelists the opportunity to ask for

15 clarification only of any of the presentations by

16 GlaxoSmithKline, not to go deep into depth


17 regarding questions, regarding the drug, rather,

18 clarifications of the presentations.

19 Are there any questions from the

20 panelists?

21 [No response.]


22 DR. WOLFE: If not, we will take a break.

23 We will reconvene at 10:05.

24 [Break.]

25 DR. WOLFE: I would like to call on Dr.







1 Victor Raczkowski from the FDA to start the


2 presentation.

3 FDA Presentation

4 Victor Raczkowski, M.D.

5 DR. RACZKOWSKI: Dr. Wolfe, Dr. Gross,

6 members of the Joint Advisory Committee, invited


7 guests, ladies and gentlemen.

8 [Slide.]

9 My name is Dr. Victor Raczkowski. I am

10 the Acting Director of the Division of

11 Gastrointestinal and Coagulation Drug Products in


12 the Center for Drug Evaluation and Research at the

13 Food and Drug Administration.

14 We have consolidated some of our

15 presentations today, so the order will not be

16 exactly as described in the paper copy that was


17 handed to you.

18 Our presentations will focus primarily on

19 those areas not covered by GlaxoSmithKline or where

20 there are differences in interpretation of the

21 data.


22 [Slide.]

23 We will have four FDA presentations. The

24 first presentation will be the clinical trial

25 experience that will be given by Dr. Thomas







1 Permutt.


2 The second presentation will be the

3 postmarketing experience with Lotronex that will be

4 given by Ms. Ann Corken Mackey.

5 Then, Dr. Tony Piazza-Hepp will discuss

6 the Risk Management Program for Lotronex.


7 I will conclude with a discussion of

8 risk-benefits, as well as some conclusions.

9 I will now introduce Dr. Thomas Permutt,

10 who will talk about clinical trial issues.

11 Lotronex, Clinical Trial Experience


12 Thomas Permutt, Ph.D.

13 [Slide.]

14 DR. PERMUTT: I will be talking about some

15 of the safety data from clinical trials of

16 alosetron. Later, you will hear some discussion on


17 the same issues with reference to the postmarketing

18 data. I also have a few words to say about

19 effectiveness, collaborative work with David

20 Hoberman and Zili Li.

21 [Slide.]


22 The most basic question is how we quantify

23 the risk of adverse events, so they can properly be

24 weighed against the benefit. I will have part of

25 the answer to that, and an important question in







1 itself is how the risk varies with the time of


2 exposure.

3 Once we have some estimate of the risk in

4 the overall population, we have to ask how the risk

5 varies within the population, can we distinguish

6 subpopulations at greater or lesser risk, in other


7 words, can we identify risk factors.

8 The question of subpopulations is also

9 important on the benefit side. If there are

10 serious risks to be borne, they may, nevertheless,

11 be tolerable in patients for whom the benefit is


12 big. Similarly, if we find subgroups less likely

13 to benefit, we would want to avoid exposing them to

14 the risk.

15 [Slide.]

16 The risks that we are most concerned about


17 are serious complications of constipation and

18 ischemic colitis. Let's take complications of

19 constipation first.

20 As you have heard, there are 11 cases

21 among roughly 11,000 patients treated with


22 alosetron in controlled trials, accrued rate of 1

23 per thousand. Most required hospitalization, one

24 required surgery. There are also 3 cases in 3,000

25 placebo patients, as you heard, a nearly identical







1 rate, and the times of exposure are also


2 comparable, 3 months in most cases.

3 So, a statistician might stop there except

4 for a feature of the design of the controlled

5 trials. Patients were, of course, monitored

6 closely in the trials, and there were rules


7 requiring discontinuation of certain patients with

8 constipation.

9 For example, in a single trial which

10 accounted for more than half the cases of serious

11 complications of constipation, 37 percent of


12 alosetron patients experienced constipation, and 12

13 percent of alosetron patients withdrew for that

14 reason compared to 4 percent incidence and less

15 than 1 percent withdrawals on placebo.

16 So, the risk of developing complications


17 in a trial was limited by discontinuation in a way

18 that does not necessarily reflect the risk in

19 clinical practice. For this reason, we think the

20 postmarketing experience is particularly relevant

21 for the complications of constipation, as you will


22 hear later.

23 The other potentially life-threatening

24 risk is ischemic colitis.

25 [Slide.]







1 Excluding some studies with fewer than a


2 hundred patients on alosetron, there are 20

3 controlled trials in our database for alosetron.

4 Among them, as you have heard, they account for

5 11,000 patients treated with alosetron mostly for

6 three months. Ischemic colitis occurred on


7 alosetron in 8 of these studies. There was also a

8 single case of ischemic colitis in a placebo

9 patient.

10 What I have plotted here is Kaplan-Meier

11 estimates of cumulative incidents at three months


12 with 95 percent confidence intervals from the 8

13 studies that had cases on alosetron.

14 Considering all 20 studies, including the

15 12 with no cases, the pooled cumulative incidence

16 is 2 per thousand at three months, and I have


17 marked that with this horizontal line.

18 Now, there is some indication of

19 heterogeneity among the studies. I have to call

20 your attention especially to Study 20, this one

21 here. More than half the cases occurred in this


22 study. It was of six months duration, but again

23 for comparison, what I have plotted here is the

24 three-month cumulative incidence.

25 The confidence interval here barely







1 touches the pooled rate. So, there is some reason


2 to think this study is really different. Of

3 course, it comes to our attention after the fact

4 precisely because the rate is different, so the

5 difference may not be as remarkable as it would

6 seem, but if it really is different, one reason to


7 consider is the possibility of better ascertainment

8 of ischemic colitis in this large study that took

9 place relatively late in the course of development,

10 after the investigators were already sensitive and

11 especially looking for ischemic colitis.


12 Anyway, if you look at this study alone,

13 you get an estimated three-month incidence of 5 per

14 thousand compared to the pooled rate of 2 per

15 thousand.

16 [Slide.]


17 What do we know about the risk over time?

18 I have borrowed a figure from the applicant's

19 background package to illustrate this. They have

20 used a slightly larger pool of studies with about

21 12,000 patients, but it makes very little


22 difference here.

23 The first thing I want to say is there is

24 a lot of useful information in this picture, but

25 hardly any of it is in the right half, that is, the







1 time after six months. Only 700 patients were


2 exposed to alosetron for more than six months in

3 these trials compared to 12,000 in the first month.

4 This here is one case of ischemic colitis

5 after six months, which happened to be in a placebo

6 patient. So no, there is no real reason to think


7 what seems to show in the picture. There is no

8 real reason to think the risk with alosetron levels

9 off here, nor is there a real reason I think to

10 think that the placebo rate catches up to it.

11 [Slide.]


12 That is better. This is the left half of

13 the same graph. Over the first six months, and

14 especially the first three months, we do have

15 information. Now, what is plotted here is the

16 cumulative risk, that is, if a patient takes the


17 drug for three months, say, what is her risk of

18 getting ischemic colitis at some time during those

19 three months.

20 Well, it is about two-tenths of 1 percent

21 of 2 in a thousand, as I said before. Now, this


22 risk continues to rise of over six months, well, it

23 can't get down. The longer I observe you, the more

24 likely you are to have had the event, but the point

25 is it doesn't really flatten out either.







1 The slope of this curve, what is called


2 the hazard, does seem to be bigger in the first

3 month than in the second through six months, maybe

4 as much as double, but not statistically

5 significantly bigger because we are still looking

6 at small numbers of events with a lot of


7 uncertainty.

8 In any case, although the cumulative risk

9 may rise less steeply later on than in the first

10 month, there is every reason to think that it

11 continues to rise. How high it might rise after


12 more than six months, I am not in a position to

13 say, and I don't think anyone else is either.

14 Unfortunately, this is what you really want to know

15 if you are a patient contemplating alosetron over a

16 long period.


17 I heard Dr. Carter say that most cases of

18 ischemic colitis were in the first month, and this

19 is true. It is not as impressive as it might sound

20 because most of the studies were three months long,

21 so you would expect to see a third of the cases in


22 the first month. In fact, we saw somewhat more,

23 but not dramatically more than that.

24 So, it is not as if you are out of the

25 woods after a month or three months. Rather, it is







1 partly that most of the cases were where most of


2 the treated patients were. If we watched people

3 for a year or more, many people, or even for six

4 months rather than only for three months, we might

5 not expect most of the cases to be in the first

6 month.


7 [Slide.]

8 What about risk factors? Well, a number

9 of risk factors for ischemic colitis are known in

10 general populations, but here, in the trial data

11 with alosetron, we have been unable to identify


12 subgroups more or less likely to develop ischemic

13 colitis. That doesn't mean there aren't any. What

14 it means is with 18 cases of ischemic colitis, we

15 haven't been able to figure out what distinguishes

16 the cases from the non-cases.


17 What that means is so far as we can tell,

18 everybody who takes alosetron shares the risk of

19 developing ischemic colitis.

20 [Slide.]

21 If the risk is unavoidable, are there


22 patients in whom it is tolerable in relation to a

23 large benefit? In this connection, I would like to

24 discuss some of the data on urgency and also

25 comment briefly on some of the productivity data







1 that Dr. Traber showed you.


2 [Slide.]

3 Four studies focused on an urgent need to

4 go to the bathroom. I have pooled together two

5 relatively early studies and also separately two

6 later studies in which the patients were worse off


7 at baseline. Looked at a subset of patients who

8 began the study, reporting urgency more than five

9 days a week, and counted how many of them finished

10 the three-month study reporting urgency less than

11 two days a week. There are other ways to cut it


12 with similar results.

13 In the first two studies, it was 32

14 percent compared to 19 percent with placebo, and in

15 the two later studies, it was 50 percent compared

16 to 29 percent for placebo. So, in this group of


17 patients with a lot of room to improve, substantial

18 numbers of them did improve a lot.

19 [Slide.]

20 Now, we have heard about the burden of

21 irritable bowel syndrome in terms of time lost from


22 work among other things. This would also be a

23 natural place to look for big benefits. The

24 sponsored show these data in a slightly different

25 form, and again I have cribbed a graph from their







1 background package.


2 There are unquestionably statistically

3 significant differences between alosetron and

4 placebo in the hours of work lost, but I want to

5 call your attention to the scale here, if you can

6 see it.


7 The differences between treatments are on

8 the order of an hour a week or a day every couple

9 of months, and they are less than this spontaneous

10 improvement that you see with placebo.

11 [Slide.]


12 So, we have some evidence of a big benefit

13 in urgency, not so much in productivity. We should

14 also look for groups less likely to benefit, so as

15 to avoid needless risk for those patients. The

16 sponsor has been able to identify a few such risk


17 factors for lack of efficacy, as you heard, in

18 particular patients with hard or very hard stools,

19 or fewer than two stools per day were less likely

20 to be successfully treated than others.

21 You might also suspect that such patients


22 could be at higher risk for complications of

23 constipation although we don't know that.

24 [Slide.]

25 I posed a number of questions at the







1 beginning, and here is what I think we know about


2 the answer. What is the risk? Well, for

3 complications of constipation, we don't see any

4 excess risk compared to placebo in the controlled

5 trials, but this may be partly because many

6 patients with constipation were discontinued from


7 the controlled trials before they might have

8 developed complications.

9 For ischemic colitis, there is an excess

10 risk, as you have heard, of 2, maybe as much as 5

11 per thousand over three months. How does it change


12 over time? Well, the cumulative risk continues to

13 rise over six months although perhaps less steeply

14 after the first month.

15 After six months, we have too little

16 information to know, and it is something a patient


17 should want to know.

18 Risk factors for ischemic colitis in

19 patients treated with alosetron have not been

20 identified. As far as we know, everyone who takes

21 alosetron shares the risk.


22 Some patients with a lot of room for

23 improvement did improve a lot. In contrast,

24 patients with harder, less frequent stools at

25 baseline did not benefit much.







1 Thank you for your attention. You are


2 going to hear next from Ann Mackey of the Office of

3 Drug Safety about the postmarketing experience.

4 Postmarketing Experience with Lotronex

5 Ann Corken Mackey, R.Ph, M.P.H.

6 MS. MACKEY: Hello. I am going to talk


7 about the postmarketing experience with Lotronex.

8 [Slide.]

9 This presentation is a collaboration

10 between Dr. Allen Brinker, Dr. Zili Li, and myself.

11 [Slide.]


12 This is an outline of my presentation.

13 [Slide.]

14 First, I want to talk a little bit about

15 the Adverse Event Reporting System commonly known

16 as AERS. It is a spontaneous, voluntary


17 surveillance system. It is voluntary reporting by

18 health care professionals and consumers, and

19 mandatory reporting by manufacturers. To date, we

20 have over 2 million reports in the database.

21 [Slide.]


22 Some of the strengths of AERS. It

23 provides for early detection of signals, it

24 identifies rarely occurring adverse events, and it

25 captures information that clinical trials are not







1 able to capture, such as off-label use, use in


2 patient populations other than those studied, drug

3 combinations, and use in contraindicated

4 conditions.

5 [Slide.]

6 Some of the limitations of AERS. It


7 cannot reliably estimate true incidence rates of

8 events because the number is underestimated, and

9 the denominator can only be projected. It is

10 subject to under-reporting. We have evidence that

11 only 1 to 10 percent of adverse events get reported


12 to FDA.

13 There is no certainty that the drug caused

14 the event. It may have been due to underlying

15 disease, concomitant medications, or any other

16 number of factors.


17 [Slide.]

18 In our case series, we looked at ischemic

19 colitis, small bowel ischemia, and serious

20 complications of constipation. The ischemic

21 colitis and serious complications of constipation


22 cases are mutually exclusive. If the co-exist,

23 then, the case was linked to ischemic colitis. All

24 small bowel cases were discussed separately.

25 We captured reports received through March







1 8th, 2002. You heard the sponsor say their cutoff


2 date was February 18th, 2002. This would allow for

3 reports to be received and processed by the FDA.

4 [Slide.]

5 Reports received after the market

6 suspension of Lotronex have come primarily from


7 consumers and available clinical data are not

8 comprehensive. More recently, reports have come

9 from class action lawsuits, and again available

10 clinical data are not comprehensive.

11 Reporter follow-up was intensive prior to


12 the market suspension.

13 [Slide.]

14 First, we will talk about ischemic

15 colitis. Our case definition was based on any or a

16 combination of the following: the term "ischemic


17 colitis" is explicitly used in the AERS report as a

18 possible diagnosis; any endoscopic or histologic

19 evidence of ischemic change or necrosis; or any

20 radiologic evidence of ischemic colitis.

21 [Slide.]


22 We identified 84 cases of ischemic colitis

23 associated with Lotronex; 33 cases were confirmed

24 by biopsy, 17 cases were confirmed by colonoscopy

25 without biopsy, and 33 cases were diagnosis only.







1 These were mutually exclusive.


2 [Slide.]

3 Eighty-one of these patients were female,

4 one was male, and two the gender was unknown. The

5 median and mean age of these patients was 55 years.

6 The range was 25 to 80 years. The time to onset,


7 median was 14 days, the mean was 39 days, and the

8 range was 101 to 200 days.

9 We had time-to-onset information in 66.

10 [Slide.]

11 Presenting symptoms, these are not


12 mutually exclusive. Fifty-four patients reported

13 bloody stool diarrhea, 16 patients reported

14 constipation, and 63 patients reported abdominal

15 pain, 22 patients were using estrogen

16 concomitantly.


17 [Slide.]

18 The outcomes of these cases, and these are

19 not mutually exclusive, 54 patients required

20 hospitalization, 11 patients required surgery.

21 That is 10 resections and one unknown surgery. Two


22 patients required transfusions, and there were 2

23 deaths.

24 Now, the sponsor stated that there were no

25 deaths due to ischemic colitis. This is a







1 difference in assigning the cause of death. Per


2 previous communications with the sponsor, we have

3 agreed to disagree on assigning the cause of death

4 in these two cases.

5 I am presenting the next two slides on

6 behalf of Dr. Allen Brinker.


7 [Slide.]

8 This is information described in his

9 review, which can be found in Appendix 4 of the FDA

10 background package.

11 Epidemiologic studies submitted by Glaxo


12 suggest potential for misdiagnosis of selected

13 conditions as IBS. Examples are inflammatory bowel

14 disease, such as ulcerative colitis and Crohn's

15 disease, and ischemic colitis.

16 By "misdiagnosis," we mean that patients


17 originally given a diagnosis of IBS were later

18 found to have other diagnoses, such as IBD or

19 ischemic colitis.

20 [Slide.]

21 Given the risk of ischemic colitis due


22 Lotronex and the potential for a background rate of

23 ischemic colitis in the IBS population, we can

24 calculate attributable risk.

25 Attributable risk permits attribution of







1 the percentage of spontaneous reports of ischemic


2 colitis in association with Lotronex expected to be

3 due to Lotronex.

4 Based on relative risk of 5.9 for ischemic

5 colitis with Lotronex versus placebo--this is from

6 the initial NDA--the attributable risk is 83


7 percent. Thus, we expect 83 percent of reports of

8 ischemic colitis reported in association with

9 Lotronex to be attributable to Lotronex, the

10 remainder as background cases of ischemic colitis

11 misdiagnosed as IBS.


12 [Slide.]

13 Now, we will talk a little bit about small

14 bowel ischemia. Our case definition was any

15 ischemic change of the small bowel documented by

16 endoscopic, surgical, or pathologic evidence.


17 [Slide.]

18 We identified 6 cases associated with

19 Lotronex. These cases reported ischemia,

20 infarction, or necrosis of the small bowel. They

21 were all female and ranged in age from 33 to 81


22 years.

23 Time to onset was a mean of 10 days for 4

24 of the patients, 120 days for 1 patient, and

25 unknown for 1 patient. There were 5 surgeries and 3







1 deaths. The sponsor's case definition was much


2 broader, and this is why they have identified 12

3 cases.

4 While each of these 6 cases may have an

5 alternative explanation for the small bowel

6 ischemia, because of an association between


7 Lotronex and ischemic colitis, we believe that an

8 association between the drug and small bowel

9 ischemia could not be excluded.

10 [Slide.]

11 Now, we will talk about serious


12 complications of constipation. Our case definition

13 was constipation or suspected constipation that was

14 associated with an ER visit, hospitalization, or

15 complications, including but not limited to, fecal

16 impaction, bowel obstruction, necrosis, or rupture.


17 [Slide.]

18 We identified 113 cases associated with

19 Lotronex, 103 were female, and 10 were male. The

20 median age was 57 years, the mean age was 54 years,

21 and the range was 24 to 82 years.


22 The time to onset, a median of 14 days, a

23 mean of 35 days, and a range of 1 to 180 days. We

24 had time-to-onset information in 79 of the cases.

25 The presenting symptoms, these are not







1 mutually exclusive, 84 patients reported


2 constipation, 28 patients reported bloody stool,

3 and 74 patients reported abdominal pain. Nineteen

4 patients were using estrogen concomitantly.

5 Some of the reports may not have mentioned

6 constipation, but their adverse events led us to


7 believe that they had constipation, and that is why

8 these patients were placed in this category.

9 [Slide.]

10 The outcomes, these are not mutually

11 exclusive, 83 patients required hospitalization, 34


12 patients required surgery, that is 25 intestinal

13 surgeries and 9 anorectal surgeries, 2 patients

14 required transfusions, and there were 2 deaths.

15 [Slide.]

16 There are a total of 14 deaths in patients


17 receiving Lotronex. Association with Lotronex

18 cannot be reasonably excluded in 7 cases - 2 cases

19 of ischemic colitis, 3 cases of small bowel

20 ischemia, 2 cases of serious complications of

21 constipation.


22 [Slide.]

23 Once a drug is introduced into the

24 marketplace, unstudied populations are exposed.

25 This leads to detection of additional and more







1 serious adverse events. When looking at these


2 data, keep in mind that the clinical trials have a

3 denominator of approximately 12,000 patients, and

4 the denominator is unknown for postmarketing data.

5 We look at the first event, ischemic

6 colitis. In clinical trials, there were 18 cases


7 with 1 surgery and no deaths. Postmarketing, there

8 were 84 cases, 10 surgeries and 2 deaths.

9 If we look at small bowel ischemia, there

10 were no cases in clinical trials. Postmarketing,

11 we had 6 cases with 5 surgeries and 3 deaths.


12 If we look at serious complications of

13 constipation, in clinical trials, there were 11

14 cases, 1 surgery, and no deaths. Postmarketing, we

15 had 113 cases, 34 surgeries, and 2 deaths. I

16 should say, though, in the clinical trials, if a


17 patient was constipated for 3 to 4 days, they were

18 taken off the drug and restarted and when

19 constipation abated. If they were constipated for

20 7 days, then, the patient was out of the trial.

21 Clinical trials have strict entry


22 criteria. Use in the real world is less stringent.

23 In this subset of Lotronex adverse effects, we see

24 the following: There were no men in pivotal

25 clinical trials. Among the reporters who reported







1 this information in our case series of 203


2 patients, there were 11 men who received Lotronex.

3 There was no off-label use in clinical

4 trials. Of the reporters who provided indication

5 for use information in our case series, there were

6 22 patients who received Lotronex off-label. Some


7 of the uses, as reported, included diarrhea,

8 constipation-predominant IBS, alternating IBS, and

9 abdominal pain.

10 The potential for use in contraindicated

11 conditions is minimized in clinical trials. Of


12 reporters who provided this information, there were

13 18 patients with apparent clinical

14 contraindications, primarily history of

15 constipation. Others included history of ischemic

16 colitis, history of bowel obstruction, history of


17 inflammatory bowel disease.

18 [Slide.]

19 Conclusions. In review of the IBS

20 literature and studies submitted by Glaxo, we

21 believe there is a real potential for misdiagnosis


22 of selected conditions, such as inflammatory bowel

23 disease and ischemic colitis diagnosed as IBS.

24 We expect that most, 80 plus percent of

25 ischemic colitis cases reported in association with







1 Lotronex can be attributed to Lotronex.


2 [Slide.]

3 Presenting symptoms did not necessarily

4 predict the severity of the outcome. These data do

5 not reveal any potential risk factors for these

6 events. We recognized a potential for unknown


7 risk factors as yet identified.

8 Managing risk in the general population

9 differs form managing risk in clinical trials.

10 Now, Toni Piazza-Hepp will present the

11 Risk Management Program.


12 Lotronex Risk Management Program

13 Toni Piazza-Hepp, Pharm D.

14 DR. PIAZZA-HEPP: Before I begin, I would

15 like to thank my colleagues in the Office of Drug

16 Safety who provided me with valuable input for this


17 presentation.

18 [Slide.]

19 I will be presenting the goals of a

20 Lotronex Risk Management Program. I will also be

21 including a discussion of options that can be


22 considered when designing a plan to meet these

23 goals.

24 [Slide.]

25 In 1999, the FDA Task Force on Risk







1 Management issued a Report to the Commissioner.


2 One of the key recommendations was that the FDA

3 needed to apply a systems framework to medical

4 product risk management.

5 This slide displays a proposed risk

6 management model which is designed to encourage the


7 integration of risk management efforts.

8 First, issues need to be identified and

9 put into context. Earlier this morning we learned

10 about the history and the risks related to

11 Lotronex. We have also heard discussions


12 surrounding the assessment of risks and benefits of

13 Lotronex.

14 In my presentation, I will be identifying

15 goals and risk management options for Lotronex.

16 Following today's meeting, the FDA and


17 GlaxoSmithKline will discuss a selection of a

18 strategy for potential management of Lotronex.

19 If a strategy is selected, it will then be

20 implemented. There will be phase in evaluation of

21 results and a cycle to start all over again. We


22 are involving stakeholders in this process, and

23 today's meeting is one such example of that.

24 [Slide.]

25 We are considering the full range of







1 options for drug access. These include, first, no


2 patient access, for example, the drug is not

3 approved by the FDA or marketing is suspended.

4 Investigational New Drug or IND access

5 allows availability only under a study protocol.

6 For example, cisapride is a drug previously


7 marketed that was withdrawn for safety reasons. It

8 is currently available through a limited access

9 program under an IND.

10 The topic of my presentation will be

11 marketing under restricted distribution, which is


12 the plan proposed by GSK.

13 Finally, there are normal marketing

14 conditions where there are no special restrictions

15 to drug access.

16 [Slide.]


17 There are risk management plans currently

18 in effect that involve restricted distribution.

19 This slide list some of the components common to

20 most plans, and I will be addressing each in more

21 detail. These are education, registrations,


22 prescribing and dispensing restrictions, patient

23 monitoring, and assessment of compliance with

24 program elements and/or ability of program to

25 manage drug risks.







1 [Slide.]


2 The purpose of education is to provide a

3 description of the program, communicate risks and

4 benefits of treatment, and can be used for other

5 purposes, such as encouraging participation in plan

6 assessment activities such as surveys, and


7 encouraging reporting of adverse events.

8 Education is really a critical feature of

9 all risk management programs. Considerations are

10 potential burdens, such as expense and time and

11 investments associated with creating and receiving


12 this education.

13 [Slide.]

14 Some plans include registration of

15 prescribers, patients and/or pharmacists. The

16 purpose is to create a target population for


17 education, monitoring, and conduction of follow-up

18 surveys.

19 Registration also provides mechanisms to

20 measure plan success, such as provision of a

21 patient denominator. You would know the actual


22 number of patients receiving the drug, you wouldn't

23 have to guess or estimate, and linking mandatory

24 surveys to these registrations also can occur.

25 Again, there are considerations along with







1 the additional consideration of patient privacy.


2 [Slide.]

3 The purpose of prescribing and dispensing

4 restrictions are: to limit drug access to targeted

5 patients; to allow pharmacists to verify that

6 prescriptions are written only by authorized


7 prescribers; no refills ensures patients return for

8 follow-up; drug distribution in special packaging

9 can limit drug supply. You can use it for others

10 things like inclusion of a Med Guide, inclusion of

11 surveys, you can have reinforcing messages on


12 packaging, and so on.

13 Again, there are considerations, and one

14 may be patient access issues for patients who may

15 not be able to afford drug, patients who are

16 remotely located, and also it is a concern that


17 these programs may encourage alternate sourcing,

18 such as importing drugs from other countries, going

19 through underground drug networks, and trying to

20 get drugs through the Internet.

21 [Slide.]


22 The purpose of patient monitoring at

23 regular intervals is to assure patient follow-up

24 for both benefit and safety. It provides an

25 opportunity for reinforcing safety messages and an







1 opportunity for obtaining and evaluating adverse


2 event information.

3 Again, you are going to hear there are

4 burdens including the possibility of additional

5 office visits, addition lab tests, and so on.

6 [Slide.]


7 The purpose of assessment of compliance

8 with program elements is to provide data to be able

9 to measure the success of the plan. This can

10 include surveys or patients, prescribers, and/or

11 pharmacists.


12 If the plan includes voluntary surveys,

13 the level of participation may not be adequate and

14 there is a question whether respondents will be

15 representative really of all patients receiving the

16 drug.


17 [Slide.]

18 Some, but not all, of the risk management

19 plans currently in effect are approved under the

20 Subpart H Regulation, which provides a requirement

21 for postmarketing restrictions.


22 [Slide.]

23 I have reproduced some of the regulation,

24 and I will just be hitting on a few of the salient

25 points that is relevant to our discussion today.







1 21CFR314 Subpart H is the regulation


2 covering accelerated approval for serious and

3 life-threatening illnesses. Many of you may be

4 more familiar with it in regard to its use for

5 efficacy based on surrogate endpoints, but there is

6 another piece of this regulation which relates to


7 approval with restrictions to assure safe use.

8 If FDA concludes that a drug product can

9 be safely used only if distribution or use is

10 restricted, the FDA will require such postmarketing

11 restrictions, such as distribution restrictions to


12 certain facilities or physicians with special

13 training or experience, or conditioned on the

14 performance of specified medical procedures, and

15 the limitations are consistent with specific

16 concerns presented by the drug product.


17 [Slide.]

18 The FDA may withdraw approval, following a

19 hearing, if the use after marketing demonstrates

20 that these restrictions are inadequate to assure

21 safe use or if there is failure of the applicant to


22 adhere to the postmarketing restrictions, and there

23 is a few other conditions in that regulation.

24 Also, promotional materials must be

25 submitted to the Agency prior to the time of







1 dissemination.


2 [Slide.]

3 There are advantages to approving

4 restriction programs under Subpart H. Subpart H

5 gives the FDA tighter regulatory control and rapid

6 withdrawal is possible if restrictions are not met


7 or the plan fails to accomplish safe use. Auditing

8 is needed to assess this.

9 Also, the review and pre-approval of all

10 promotional material or advertising material is

11 mandatory.


12 [Slide.]

13 Dr. Houn already mentioned that we do have

14 four drugs currently approved under the Subpart H

15 regulation, and I don't plan on going into the

16 details of these plans any further during my talk,


17 but there were plan details included in the

18 background package.

19 [Slide.]

20 What are the potential options for the

21 design of a Lotronex risk management plan?


22 [Slide.]

23 The GlaxoSmithKline proposal is to

24 reintroduce Lotronex to the market and restrict

25 access under the provisions of Subpart H.







1 [Slide.]


2 The program does have strengths. It has

3 an educational component, enhanced labeling, a

4 Medication Guide, special packaging which provides

5 for a limited supply and includes a Med Guide, a

6 dose titration phase that was discussed by the


7 firm.

8 [Slide.]

9 Expedited reporting of the targeted

10 adverse events of ischemic colitis and serious

11 complications of constipation, pre-approval of


12 promotional materials, a program evaluation

13 component which was described by GSK, further

14 continued study, and Dr. Wheadon had mentioned,

15 although not part of this admitted plan, GSK has

16 updated us that they intend to allow no refills


17 without a new prescription.

18 [Slide.]

19 There are some weaknesses in the

20 GSK-proposed plan. For patient selection, "failed

21 conventional therapy" may not be adequate to


22 describe severe forms of IBS, and this is a topic

23 that we have asked the Advisory Committee to

24 consider today.

25 In regard to qualified prescribers,







1 attestation of qualifications only is proposed. In


2 the current plan, prescribers do not receive

3 education, certification, or registration with GSK

4 prior to receiving a kit with stickers.

5 The program does not limit prescribing to

6 gastroenterologists. This is another area where we


7 are seeking the opinion of the Committee.

8 Monitoring of patients by prescribers on a

9 regular basis is not included in the description of

10 the current plan. Instead, it is the patient that

11 agrees to identify problems relating to benefits


12 and risks, and then initiate contact with their

13 doctor.

14 [Slide.]

15 Dr. Wheadon again already mentioned that

16 the submitted program has been now changed. It


17 originally did not include the concept of stickers

18 on every prescription, but they are planning on

19 adding this concept to their plan.

20 The utility of stickers as an authorized

21 prescriber mechanism is really an untested method.


22 We are not sure how well that is going to work.

23 Also, the program assessment is not designed to

24 measure compliance with the use of stickers.

25 [Slide.]







1 The program assessment includes a


2 voluntary survey--and by "voluntary survey," I mean

3 patients are invited to participate in the survey,

4 but they are not required to do so--using a chain

5 pharmacy, Eckerd Pharmacy patients.

6 There is no assurance that the survey will


7 be representative of all Lotronex patients, and the

8 program does not include other means to more widely

9 distribute the survey, such as via the prescriber

10 or in the special packaging, or require a mandatory

11 survey, and by "mandatory survey," I mean that


12 participation in the survey may very well be a

13 condition of receiving the drug. This may be

14 accomplished via registration of all patients.

15 [Slide.]

16 There are various considerations that were


17 taken into account when creating proposed goals for

18 a Lotronex risk management plan. A letter

19 regarding Lotronex from CDER to IBS patients was

20 posed on the FDA web site in the weeks following

21 marketing suspension.


22 Goals stated in this letter included safer

23 use of Lotronex in appropriately informed patients,

24 continued access to Lotronex by severely affected

25 IBS patients under closely monitored conditions,







1 and continued clinical studies of the benefits and


2 risks and safe use of Lotronex.

3 [Slide.]

4 Now, over a year later, we needed to take

5 additional considerations into account. First,

6 even with continued study, the risk factors for


7 ischemic colitis are still not known, and we should

8 expect that these events will still occur

9 regardless of any risk management program.

10 Complications of constipation may be prevented

11 by recognizing constipation, but some patients did


12 not report constipation before complications

13 occurred.

14 In regard to Subpart H, in addition to the

15 requirement for restricted distribution, there is

16 the issue of IBS is a serious disease, and there


17 should be the ability to determine the success of

18 the plan.

19 [Slide.]

20 The proposed FDA goals for a Lotronex risk

21 management plan are:


22 1. To provide access to severely affected

23 IBS patients, in other words, to better reflect

24 serious forms of IBS and to maximize the benefit

25 portion of the benefit-risk ratio.







1 2. To limit prescribers to qualified


2 physicians.

3 3. To identify ischemic colitis and

4 serious complications of constipation symptoms

5 early through close medical monitoring, in other

6 words follow-up. Regular follow-up would also be


7 needed to assess and initial and continued

8 benefits.

9 4. Measure success of the plan, in other

10 words auditing, where the collection of data would

11 be needed.


12 [Slide.]

13 This slide displays some of the components

14 that I presented earlier, along with the goals that

15 I have just described. A red check mark represents

16 a newly added feature, and the firm has decided to


17 add the "no refill" concept, as I mentioned

18 earlier.

19 So, in this plan, we have education, an

20 authorized prescriber check mechanism, no refills,

21 special packaging, and an auditing mechanism.


22 The submitted plan, however, does not

23 achieve our current goals. In regard to Goal 1, it

24 is uncertain if failed conventional therapy will be

25 adequate to describe severe IBS.







1 For Goal 2, the current plan allows wide,


2 uncontrolled availability of kits with stickers,

3 and does not precertify prescribers or limit

4 prescribing to gastroenterologists prior to

5 allowing them to receive these kits.

6 For Goal 3, follow-up by physicians is not


7 specifically addressed in the current plan.

8 For Goal 4, there is an auditing plan, but

9 it does involve a voluntary survey, so there is a

10 question about the ability to measure plan success.

11 [Slide.]


12 Well, if the GSK plan does not appear to

13 meet the FDA goals, then, alternate plan design

14 should be considered to better meet these goals.

15 We considered how components from other risk

16 management programs might be incorporated into a


17 Lotronex plan in order to better meet these FDA

18 goals, and we have also posed questions to the

19 Advisory Committee seeking input on a number of

20 these components.

21 [Slide.]


22 This slide again displays the components I

23 described earlier and lists the FDA goals. The

24 purpose here is not to vote on one plan or another,

25 but rather to illustrate a process that can be used







1 when considering the value of adding each of these


2 components.

3 As we move from right to left, a red check

4 mark will indicate a newly added feature. Plan D

5 is a GSK plan which I have already reviewed. Plan

6 C adds physician registration prior to receiving


7 kits with stickers, also adds limitation to severe

8 IBS and regular patient follow-up.

9 In doing this, we now achieve Goal 1, that

10 means the severe IBS, and Goal 3 for follow-up.

11 Goal 2 may be met, but there is still a question as


12 to what constitutes a qualified physician.

13 In Plan B, patient registration and

14 limitation to gastroenterologists is added. In

15 doing this, we now achieve all four goals.

16 In Plan A, we also considered the impact


17 of limiting distribution to registered pharmacies

18 only, and although this step would add additional

19 checks and balances, it did not appear essential in

20 the case of Lotronex to meet the four FDA goals.

21 However, education of pharmacists should be


22 stressed as essential to the plan's success.

23 [Slide.]

24 In conclusion, the full range of drug

25 access options needs to be considered in regard to







1 Lotronex. If the approach is to market under


2 Subpart H, begin with a more restrictive plan than

3 that proposed by GSK in order to meet the proposed

4 FDA goals, and to re-evaluate the program at a

5 specified time, for example, at one year or some

6 other specified interval for compliance with


7 program elements and the ability of the program to

8 manage risks, and the modify the program at that

9 time if appropriate.

10 I would now like to introduce Victor

11 Raczkowski who will speak on risks and benefit


12 issues and provide a summary and conclusion for the

13 FDA talks.

14 Thank you.

15 Summary and Conclusions

16 Victor F.C. Raczkowski, M.D.


17 DR. RACZKOWSKI: Good morning.

18 [Slide.]

19 This morning I will address risk-benefit

20 issues related to the use of Lotronex. I will also

21 allude to questions that FDA will be posing to the


22 Advisory Committees, so you may wish to keep your

23 hardcopies at hand.

24 At the end of my talk, I will provide a

25 brief summary of some of the main conclusions







1 reached by the FDA speakers.


2 One goal for a risk management plan for

3 Lotronex is to enhance and ideally to optimize the

4 benefit-risk balance for its use.

5 [Slide.]

6 In my presentation this morning, I will


7 describe, in turn, each of three approaches for

8 modifying the benefit-risk balance for Lotronex. I

9 will focus particularly on appropriate patient

10 selection, trying to answer the question who are

11 the right patients to take Lotronex.


12 The first approach is to limit the use of

13 Lotronex to patients with the most disabling

14 symptoms. The second approach is to establish

15 conditions under which the benefits of Lotronex

16 are increased. The third approach is to establish


17 conditions under which the risks of Lotronex are

18 decreased.

19 Note that the use of one approach does not

20 necessarily exclude the use of another approach.

21 In fact, all three approaches overlap to a great


22 extent, and the approaches can be used together in

23 enhancing the risk-benefit balance of Lotronex.

24 [Slide.]

25 Let's consider the first approach,







1 limiting the use of Lotronex to patients with the


2 most disabling symptoms of IBS. The burden of the

3 illness of IBS varies from patient to patient.

4 Some patients have mild symptoms, whereas, others

5 have moderate or severe symptoms.

6 As has been described earlier today by Dr.


7 Traber of GlaxoSmithKline, approximately 70 percent

8 of patients with IBS have mild symptoms, 25 percent

9 have moderate symptoms, and 5 percent have severe

10 symptoms.

11 Stated differently, symptoms of IBS can


12 vary from being relatively mild to disabling. It

13 stands to reason, then, that patients with IBS with

14 the most disabling symptoms stand to benefit the

15 most from drug therapy and may accept greater risks

16 of drug therapy.


17 We commonly see this principle applied in

18 other therapeutic areas. For example, patients

19 with cancer often accept treatment with highly

20 toxic drugs. Why do patients do this? Because the

21 burden of illness of cancer can be quite high and


22 patients are willing to significant drug toxicities

23 in the hope of a remission or a cure.

24 This approach is also consistent with

25 statements in the 1999 Report to the FDA







1 Commissioner from the Task Force on Risk


2 Management, and I quote, "Medical products are

3 required to be safe, but safety does not mean zero

4 risk. A safe product is one that has reasonable

5 risks given the magnitude of the benefit expected

6 and the alternatives available."


7 Indeed, the first question that we will be

8 posing today to the members of the Advisory

9 Committee asks whether a patient population can be

10 described for which the benefits of Lotronex exceed

11 the risks.


12 This first question indirectly asks

13 whether the use of Lotronex should be limited to

14 patients with the most disabling or most severe

15 symptoms.

16 [Slide.]


17 The second approach to modifying the

18 benefit-risk balance of Lotronex is to question

19 whether it might be possible to enhance the

20 benefits of the drug. We know, for example, that

21 Lotronex has beneficial effects on several symptoms


22 in patient with diarrhea-predominant IBS. These

23 include improving the symptoms of diarrhea,

24 urgency, and abdominal pain and discomfort, and has

25 been described earlier by Dr. Permutt of FDA, FDA







1 has performed analyses that demonstrate that some


2 patients with diarrhea-predominant IBS, who have

3 severe urgency, can have large benefits and

4 substantial relief of their urgency.

5 On the other hand, FDA has also performed

6 analyses that demonstrate that patients with harder


7 stools and stool frequency of less than two times

8 per day appear to have less benefit than those with

9 softer stools or more frequent bowel movements.

10 So, another point for the Advisory

11 Committee to consider today in its answer to


12 Question No. 1 is whether Lotronex should be used

13 exclusively or primarily by patients with severe

14 symptoms, such as urgency, and whether its use

15 should be prohibited or avoided by patients with

16 relatively hard stools and a stool frequency of


17 less two per day.

18 [Slide.]

19 GlaxoSmithKline has presented quality of

20 life data today that suggest that Lotronex improves

21 functional performance, however, as has been


22 summarized by Dr. Permutt, the average gain in

23 productivity, as assessed by hours not lost in the

24 workplace in patients taking Lotronex, was about an

25 hour more per week compared to patients taking







1 placebo.


2 However, another way to assess whether

3 patients taking Lotronex have marked improvement in

4 functional performance could be by prospectively

5 conducting a randomized withdrawal study of

6 irritable bowel symptom patients who have disabling


7 symptoms, and the Advisory Committee will have an

8 opportunity to comment on this possible approach

9 when it answers Question No. 8. That question asks

10 the committee for additional comments about a

11 Lotronex risk management plan including suggestions


12 for additional studies.

13 [Slide.]

14 The third approach to modifying the

15 benefit-risk balance of Lotronex is to question

16 whether it might be possible to decrease the risks


17 of the drug. In this approach, the goal is to

18 avoid adverse events, if possible. I say "if

19 possible," because some serious adverse events

20 associated with Lotronex may largely be avoidable,

21 such as complications of constipation.


22 On the other hand, other adverse events

23 associated with Lotronex may not be avoidable, or

24 they may be avoidable, but we don't yet know how to

25 avoid them. Examples of these adverse events







1 include ischemic colitis and mesenteric ischemia.


2 I will be going through these sub-bullets

3 in the following slides, but way of overview, there

4 are several ways to avoid adverse events, and these

5 include the following four strategies.

6 [Slide.]


7 One way to avoid adverse events if through

8 appropriate patient selection and education, for

9 example, advising patients t discontinue Lotronex

10 when they get constipated.

11 A second way to avoid adverse events is


12 through appropriate physician selection and

13 education, for example, advising physicians not to

14 prescribe Lotronex to patients with constipation.

15 A third way to avoid adverse events is

16 through modifying drug exposure, for example,


17 Lotronex should be discontinued in patients who

18 don't appear to be benefiting from the drug after

19 four weeks of therapy at a dose of 1 mg twice a

20 day.

21 A fourth way to avoid adverse events is to


22 consider relevant a IBS factors, for example,

23 Lotronex may be used as a continuous therapy even

24 though the symptoms of IBS have a waxing and waning

25 course. There may be room here to study whether







1 other dosage regimens, such as intermittent dosing


2 during flares, might be a better way to administer

3 Lotronex.

4 Of course, adverse events can't always be

5 avoided, so the goal then is to manage these

6 adverse events, and the goal here is early


7 detection of warning symptoms and rapid

8 intervention when warning symptoms occur. The idea

9 is to mitigate the seriousness of adverse events by

10 catching them early.

11 An example here with Lotronex would be for


12 patients to detect and react to warning symptoms,

13 such as blood in the stool, which might be a

14 harbinger of ischemic colitis. In these

15 circumstances, the patient should stop taking

16 Lotronex immediately and should contact her doctor


17 right away.

18 This is the overview slide. Let's walk

19 through each of the points and some of their other

20 implications.

21 [Slide.]


22 Let's start with patient selection because

23 appropriate patient selection is one of the

24 principal issues to be discussed today, and it is

25 related to the first question that FDA is asking of







1 the Advisory Committee. I will spend a fair amount


2 of time on this point given its importance.

3 Lotronex should be prescribed only to

4 patients in whom the benefits exceed the risks, and

5 this can be accomplished by appropriate inclusion

6 criteria. By that I mean, giving Lotronex only to


7 patients who stand to benefit.

8 This can also accomplished by appropriate

9 exclusion criteria, and that is, not giving

10 Lotronex to patients who are likely to be harmed by

11 it.


12 So, giving thought as to whether, in

13 special populations, such as men, the evidence

14 supports its widespread use.

15 Another goal of patient selection is to

16 prescribe Lotronex to patients who have been


17 adequately informed of its risks and benefits.

18 [Slide.]

19 How do we best describe the patients in

20 whom the benefits of Lotronex exceed the risks? If

21 one look at how the indication for Lotronex has


22 changed over time, one gets an idea of FDA's and

23 GlaxoSmithKline's thinking on the subject. I will

24 summarize three indications.

25 The indication for Lotronex when it was







1 approved in February 2000, the indication as it was


2 revised in August 2000 after some of its serious

3 postmarketing adverse effects had been reported to

4 FDA, and, third, the revised indication proposed

5 here today by GlaxoSmithKline.

6 GlaxoSmithKline had FDA's input in


7 crafting this current indication, but it is not yet

8 approved.

9 [Slide.]

10 When Lotronex was first approved in

11 February 2000, it had the indication for the


12 treatment of irritable bowel syndrome in women

13 whose predominant bowel symptom is diarrhea. It

14 also had a statement that the safety and

15 effectiveness of Lotronex in men have not been

16 established.


17 These statements came largely from an

18 analysis of two randomized, double-blind,

19 placebo-controlled Phase III efficacy studies, as

20 well as some Phase II dose ranging studies

21 submitted with the original New Drug Application.


22 It is worth noting that Glaxo Wellcome

23 only studied women in those two, Phase III efficacy

24 studies, and to be enrolled, women had to meet the

25 ROME criteria for IBS and were excluded from the







1 study if they had hard stools.


2 Women also underwent lower endoscopic

3 procedures within five years in order to be

4 enrolled in the study. For example, women less

5 than 50 years of age underwent flexible

6 sigmoidoscopy, and patients more than 50 years


7 underwent a full colonoscopy.

8 As it turned out, although efficacy was

9 seen overall in the Lotronex group compared to the

10 placebo group, it was limited to the subgroup of

11 women with diarrhea-predominant IBS, not in women


12 with alternating IBS or constipation-predominant

13 IBS.

14 Therefore, the original indication

15 reflected those findings, and the ROME criteria

16 were summarized in the appendix of the original


17 labeling. Endoscopy, however, was not described in

18 the labeling.

19 Moreover, because men were not studied in

20 the Phase III efficacy studies, the statement that

21 safety and effectiveness in men have not been


22 established was included in the indication.

23 [Slide.]

24 After the indication in June 2000, at

25 which concerns over Lotronex's emerging







1 risk-benefit profile were discussed because of


2 postmarketing reports of serious complications of

3 constipation, and additional postmarketing report

4 of ischemic colitis, FDA worked with Glaxo Wellcome

5 to tighten the indication.

6 The indication at that time was that


7 Lotronex is indicated for the treatment of women

8 with diarrhea-predominant irritable bowel syndrome.

9 Diarrhea-predominant irritable bowel syndrome is

10 characterized by at least three months of recurrent

11 or continuous symptoms of abdominal pain or


12 discomfort with either urgency, an increase in

13 frequency of stool or diarrhea not attributable to

14 organic disease, and there was a reference to see

15 the appendix. The use in men had similar language

16 to the original labeling.


17 This tightening of the indication

18 reflected a sense that a woman should be given a

19 firm diagnosis of diarrhea-predominant IBS in order

20 to be prescribed Lotronex. In other words, the

21 indication was intended to limit or decrease


22 prescribing the Lotronex to women who had a casual

23 or an interim diagnosis of diarrhea-predominant

24 IBS.

25 Moreover, in contrast to the previously







1 approved labeling, the indications suggested that


2 organic etiologies of symptoms, such as diarrhea,

3 should be excluded before prescribing Lotronex,

4 such as through endoscopy.

5 [Slide.]

6 In the appendix, the ROME criteria were


7 adapted to diarrhea-predominant IBS and to make

8 them more user friendly for clinicians.

9 [Slide.]

10 Now, here, in April 2002, we are looking

11 at another possibility of an indication. As


12 mentioned previously, this version of the

13 indication proposed by GlaxoSmithKline had FDA

14 input. Lotronex is indicated only for women with

15 diarrhea-predominant irritable bowel syndrome who

16 have failed to respond to conventional therapy and


17 who have signed the patient-physician agreement.

18 The goal here in part is to delegate

19 Lotronex to second-line status as a treatment for

20 diarrhea-predominant IBS because of some of the

21 risks associated with the use of the drug. The


22 goal in part, as before, is to limit the casual

23 prescribing of Lotronex to patients with symptoms

24 suggestive of diarrhea-predominant IBS.

25 It is worth noting that the ROME criteria







1 are not in the label in any form. One of the down


2 sides of this proposed indication is that Lotronex

3 hasn't really been prospectively studied to see if

4 it is effective in patients who have failed

5 conventional therapies. For example, these

6 patients may be resistant, not just to conventional


7 therapies, but also to Lotronex.

8 [Slide.]

9 Another question is whether this

10 adequately describes the population in whom the

11 benefits of Lotronex exceed the risk. Therefore,


12 more recently, questions have arisen about whether

13 other terms besides "failing conventional therapy"

14 would be appropriate to include in the indication

15 either in place of or in addition to this phrase.

16 For example, patients could be described


17 in terms of the degree of their disability or the

18 degree of the severity of their condition. Again,

19 the first question we pose to the Advisory

20 Committee gets to this point indirectly.

21 [Slide.]


22 Does the proposed plan and the labeling

23 adequately describe appropriate patients? Does it

24 describe appropriate inclusion criteria in terms of

25 the severity of irritable bowel syndrome symptoms,







1 degree of disability from IBS, the chronicity of


2 IBS, the failure of conventional IBS therapies and

3 what those therapies might be, or other important

4 characteristics?

5 [Slide.]

6 An additional point for the Advisory


7 Committee to consider is whether the patient should

8 self-attest to whatever criteria are established to

9 define the population. In other words, the plan

10 proposed by GlaxoSmithKline has a physician

11 self-attest to his or her knowledge of IBS,


12 knowledge of Lotronex, and knowledge of

13 complications associated with Lotronex. Should

14 patients be asked to self-attest to the severity of

15 their IBS symptoms, their degree of disability, the

16 length of time they have had irritable bowel


17 syndrome, et cetera?

18 [Slide.]

19 In terms of informing patients,

20 GlaxoSmithKline's proposed risk management plan has

21 several elements in it, and these have already been


22 discussed and I won't discuss them further here. I

23 will simply note that Question 4 to the Advisory

24 Committee members asks about how to assess whether

25 appropriate patients are receiving Lotronex, and







1 the same question asks whether patient's knowledge


2 is being adequately assessed in the sponsor's risk

3 management plan.

4 [Slide.]

5 I have spent a lot of time focusing on

6 patient selection because appropriate patient


7 selection is likely to be at the heart of any

8 successful risk management plan for Lotronex, but

9 let's move on.

10 Physician selection and education is also

11 an important component of a risk management plan


12 because the presence of these elements could

13 improve the benefit-risk profile of Lotronex by

14 helping to ensure competent and knowledgeable

15 prescribing.

16 Our goal would be to have physicians who


17 are knowledgeable and experienced in the diagnosis

18 and treatment of IBS, who are able to diagnose and

19 manage ischemic colitis and complications of

20 constipation and who are knowledgeable about

21 Lotronex.


22 [Slide.]

23 So, if Lotronex is marketed, should the

24 prescribing of Lotronex be limited only to certain

25 types of physicians, such as physicians with







1 certain knowledge, certain experience, of certain


2 specialties or with important characteristics?

3 This is Question 3 that we will be asking to the

4 Advisory Committee members.

5 [Slide.]

6 Toni Piazza-Hepp has already covered the


7 items in this slide, so next slide, please.

8 [Slide.]

9 So, we have talked about the importance of

10 appropriate selection and education of patients and

11 appropriate selection and education of physicians


12 to improve the benefit-risk of Lotronex. Let's now

13 talk about Lotronex-associated adverse events and

14 how they might be decreased by decreasing exposure

15 to Lotronex.

16 These adverse events include constipation,


17 which is dose related we know, ischemic colitis,

18 and small bowel ischemia, which appear to be

19 idiosyncratic, however, it is not known.

20 [Slide.]

21 The risk of these adverse events will


22 likely be decreased by modifying drug exposure, in

23 other words, not treating patients with Lotronex at

24 doses higher than needed, for longer than needed,

25 or if they don't appear to be responding to the







1 drug.


2 For example, one possibility would be to

3 limit dosage to decrease dosage-related side

4 effects. In the sponsor's proposal, therapy is

5 initiated with an upper titration, and when

6 patients achieve the desired therapeutic effect,


7 they remain at that dose and they do not go to a

8 dose of 1 mg twice a day unless they do not achieve

9 a desired effect at 1 mg once daily.

10 However, unanswered questions are whether

11 it is appropriate to adjust the dose during


12 maintenance therapy or whether drug holidays might

13 be appropriate. Another component of

14 GlaxoSmithKline's plan is to discontinue therapy in

15 non-responders.

16 Ideally, we would be able to continue


17 therapy only in true responders not only to

18 continue therapy in apparent responders, in other

19 words, patients who may be spontaneously improving,

20 and not improving because of a consequence of

21 taking Lotronex.


22 [Slide.]

23 So, we have talked about how patient and

24 physician selection and education and drug usage

25 could improve the benefit-risk of profiled







1 Lotronex. Next, the risk management plan could


2 also consider relevant IBS factors to improve the

3 risk-benefit profile of Lotronex.

4 A few facts have already been discussed.

5 Lotronex is indicated only for diarrhea-predominant

6 IBS, and not for alternating IBS, however, other


7 IBS factors could be considered or evaluated.

8 Symptoms of IBS typically wax and wane,

9 and yet Lotronex is given continuously. Studies

10 could be performed to assess whether intermittent

11 dosing, such as during flares of symptoms, is


12 effective, and if so, how best to dose Lotronex

13 under such conditions. Also, there may be greater

14 risks of serious adverse events during particular

15 phases of the condition. It is also clear that

16 Lotronex should not be used in patients with


17 constipation-predominant IBS.

18 [Slide.]

19 Lastly, if adverse events are not

20 prevented, then, perhaps they can be managed to

21 limit the seriousness of their outcomes. Again,


22 these items have all been discussed.

23 [Slide.]

24 So, in conclusion, the burden of illness

25 is variable in patients with IBS, and Lotronex has







1 beneficial effects on several symptoms of IBS.


2 Patients with the most disabling symptoms stand to

3 benefit the most from Lotronex, and the

4 risk-benefit balance is likely most favorable in

5 patients with the most disabling symptoms.

6 [Slide.]


7 Lotronex is associated with serious, or

8 potentially serious, adverse events, such as

9 complications of constipation, ischemic colitis,

10 mesenteric ischemia, and death.

11 Outcomes of ischemic colitis and


12 constipation, however, vary in seriousness. They

13 range from mild and self-limiting and reversible

14 upon discontinuation of therapy to those that

15 require hospitalization, surgery, or sometimes are

16 associated with death. Presenting symptoms do not


17 necessarily predict the severity of some of these

18 clinical outcomes.

19 [Slide.]

20 Risk factors for ischemic colitis or

21 mesenteric ischemia have not been identified, so as


22 has been stated, potentially everyone who takes

23 Lotronex is at risk. The cumulative risk of

24 ischemic colitis increases over time, and is about

25 2 to 5 per 1,000 patients at 3 months. The risk







1 may decrease after 1 month, but there is little


2 information after 6 months. It possibly continues

3 to rise.

4 [Slide.]

5 Constipation is a frequent dose-related

6 side effect associated with Lotronex, and the


7 numbers that I will quote here are already

8 corrected for placebo.

9 Approximately 25 to 30 percent of patients

10 experience constipation with Lotronex at 1 mg twice

11 per day. Ten percent approximately withdrew from


12 clinical trials because of constipation at 1 mg

13 twice a day.

14 This can be viewed as a safety surrogate

15 marker for potentially more serious outcomes, and,

16 as we have heard, some serious outcomes of


17 constipation are serious, requiring surgery, and

18 have been associated with death.

19 [Slide.]

20 The full range of drug access options

21 should be considered at today's Advisory Committee.


22 One possibility is to begin with a more restrictive

23 plan that could be loosened later and program

24 monitoring should occur at the level of the

25 patient, the level of the physician, and the level







1 of the pharmacist.


2 [Slide.]

3 The success of the plan should be

4 evaluated through process controls and evaluation

5 of outcomes.

6 Thank you.


7 DR. WOLFE: Thank you, Dr. Raczkowski, and

8 thank you to the FDA for your presentation.

9 I am trying to keep on schedule here

10 because we have a very busy schedule and we are

11 behind quite a bit. What I would like to do now is


12 to open up the floor to the panelists for questions

13 for both FDA and for GlaxoSmithKline. Keep in mind

14 these are questions regarding the presentations,

15 not questions which will be subsequently discussed

16 in the afternoon after the questions are posed to


17 us that we need to discuss.

18 Questions on Presentations

19 DR. WOLFE: I know this definition is a

20 little bit vague, but I am going to start off with

21 one question and maybe you will get the gist of


22 what I am getting at. The question I have is

23 actually for both Drs. Piazza-Hepp and for Dr.

24 Carter. This is a question actually I posed back

25 in June 2000 about the risk of, and again, I think







1 the correct term is colonic ischemia, not ischemic


2 colitis. I think it is a better term because, by

3 definition, it is ischemia.

4 But the question comes up about estrogens,

5 and there is a discrepancy in the risk factor--it

6 is a risk factor of estrogens--with the FDA saying


7 about 1 in 4 women were taking estrogens, and

8 GlaxoSmithKline saying about one-half are taking

9 estrogens.

10 Obviously, we all know estrogens can be a

11 risk, and along those same lines, how many of those


12 patients were smokers with or without estrogens?

13 DR. CARTER: Perhaps I can start and

14 answer the GSK part of that question. As far as

15 our fairly intensive, extensive investigation into

16 risk factors of ischemic colitis, we obviously


17 considered the possibility of estrogen because of

18 the anecdotal primarily reports in the literature,

19 and so forth.

20 Again, we could not find estrogen to be a

21 specific risk factor. With respect to the apparent


22 discrepancy in terms of our reporting estrogen use

23 with that of the Agency, I don't have an answer for

24 that.

25 With respect to smoking as an additional







1 risk here, I do remember, Dr. Wolfe, you raising


2 this as a potential combined issue, and again at

3 that time, I think the discussions were that there

4 probably was not as we know a specific risk factor

5 for colon ischemia, but let me defer that perhaps

6 to Dr. Brandt with respect to smoking as a risk


7 factor for colon ischemia.

8 Do you want to come and answer that,

9 Larry?

10 DR. BRANDT: I would say a very brief

11 answer. There are no randomized, placebo-controlled


12 trials to evaluate estrogens, nor are there any

13 type 1 data to show that smoking is a specific risk

14 factor for colon ischemia although it is accepted

15 as a general risk factor for atherosclerotic

16 disease.


17 MS. MACKEY: I am just going to say

18 that--I am talking about postmarketing data--for

19 ischemic colitis cases, we had 22 patients using

20 concomitant estrogen, that is 26 percent, and for

21 the serious complications of constipation, we had


22 19 patients using estrogen concomitantly. That was

23 17 percent.

24 We don't have any smoking data. That is

25 not typically information that we get on







1 spontaneous reports.


2 DR. WOLFE: It is an unresolved

3 discrepancy still because for ischemia, you have

4 still a difference in the numbers, but that is

5 okay. Both of you are saying the same thing. You

6 haven't identified it as a significant risk factor.


7 MS. MACKEY: Correct.

8 DR. WOLFE: Dr. Gross.

9 DR. GROSS: I have a few questions, one

10 also on estrogens. Is it known in the UHC

11 population, what percent of women not on this drug


12 were taking estrogens is one question. The other

13 question is there seems to be conflicting data on

14 whether the complication is dose-dependent or not.

15 Can someone resolve that for us?

16 Thirdly, is there any information at all


17 on what the incidence of inflammatory bowel disease

18 is in patients who initially present with a

19 diagnosis of irritable bowel syndrome?

20 DR. WOLFE: For that last question for the

21 afternoon regarding IBD versus IBS.


22 DR. WALKER: I am Alec Walker from

23 Engenics. For the first question on replacement

24 estrogens, we did do a case-controlled comparison

25 of colonic ischemia in randomly selected control







1 women, and found actually no elevation in risk at


2 all associated with replacement estrogen use. I

3 don't have at hand the percentages that were the

4 same in the two groups, but I can easily get them

5 for you.

6 DR. CARTER: With respect to the question


7 regarding IBD, we don't have that information. I

8 am not familiar with that information.

9 The middle question?

10 DR. GROSS: Dose dependence.

11 DR. CARTER: Dose dependence. It seems to


12 be a feature at least from the clinical trial

13 population where the great majority of patients

14 were exposed to the 1 mg BID dose, that, first of

15 all, we can't really make a comment with respect to

16 dose dependence in terms of complications of


17 constipation.

18 We can make a comment perhaps with respect

19 to patients withdrawing from trials as a result of

20 constipation, but one of the features I think that

21 we have seen is that the adverse event of


22 constipation does not necessarily translate into a

23 complication of constipation.

24 Again, we clearly saw a lack of

25 relationship between the proportion of patients who







1 developed adverse events of constipation with


2 respect to placebo and the proportion of patients

3 that developed complications of constipation with

4 respect to placebo.

5 DR. RICHTER: I have got a couple of

6 questions. First, for Larry Brandt, I am struck by


7 the fact that the age on onset for these patients

8 with whatever you want to call it, ischemic colitis

9 or colonic ischemia, it seemed somewhat young at 55

10 to 52. At least in my clinical experience, these

11 tend to be older patients.


12 Also, I am interested in the normal person

13 presenting with colonic ischemia that we see with

14 abdominal pain and bloody diarrhea, the prevalence

15 of men versus women. Maybe Dr. Brandt can answer

16 that question, and then I have got a second


17 question I would like to follow up with.

18 Is the age, Larry, younger than you would

19 normally see, or does this fit into the normal

20 picture of colonic ischemia?

21 DR. BRANDT: Let's stop there. We will do


22 one at a time. I can't keep track of all these

23 questions.

24 The first question in terms of the age, it

25 is true that in large series of colon ischemia







1 patients, the disease seems to be more common after


2 the age of 50 or 55, however, in recent series that

3 are being reported, there is an increasing

4 percentage of patients that varies anywhere from 10

5 to approximately 20 percent of patients that are

6 under the age of 50 at the time of diagnosis, and


7 most of these are under the age of 35.

8 There is a higher percentage of patients

9 in the younger age group in which an etiology is

10 found, and the majority of these patients, not in

11 this experience but in the literature, are found to


12 either be on medications that may cause that

13 problem or to have underlying coagulation defects.

14 That seems to favor a younger age population.

15 In the literature, there tends not to be

16 in the older age population a gender difference.


17 In the younger age population, there tends to be a

18 female predominance.

19 DR. WOLFE: We are locked into a certain

20 time slot for lunch. That is our limiting factor

21 in the way we are locked into reserving spots. As


22 a result, we are not locked into asking questions,

23 and there are a lot of questions here. I am

24 looking around here, there is at least eight people

25 more who have questions, and we are not going to be







1 able to get to the public forum, which is very


2 important.

3 What I am going to do now, as chair at

4 this meeting, I am going to defer the questions to

5 the Company, I am sure you will be here in the

6 afternoon, I know the FDA will be here in the


7 afternoon, so we will defer questions until the

8 afternoon, and we will move on to the public forum.

9 A meeting like this, it is tough to say no

10 break, but there is going to be no break right now,

11 we just don't have the time to take a break.


12 There will be a short stretch break to get

13 everything all ready for the public forum, so you

14 have about three or four minutes to run out or

15 stretch.

16 [Break.]


17 Open Public Hearing

18 DR. WOLFE: In most instances, one hour

19 only is allowed for the public forum, but because

20 of the nature of this discussion, we are allowing a

21 greater period of time, however, all the speakers


22 who have registered prior to the meeting know that

23 they have a time limitation.

24 I am asking that they please keep to the

25 time limit and actually, there will be a timekeeper







1 with a very loud alarm going off at the end of the


2 time that is allotted.

3 I am going to announce the speaker and

4 then who is on deck. We are starting with Dr.

5 Sidney Wolfe, who will be followed by Ms. Nancy

6 Norton.


7 Dr. Wolfe. No relative of mine.

8 DR. S. WOLFE: We are not sure about that.

9 In a review of 27 randomized,

10 placebo-controlled studies, which a chart is on the

11 first page, one dot represents one study, testing


12 various treatments for irritable bowel syndrome,

13 the median placebo response rate was 47 percent,

14 measured as a percent, improved with rates as high

15 as 84 percent, and in 11 studies, the placebo

16 response rate was 60 percent or greater.


17 The study concluded that the placebo

18 response rate was approximately three times larger

19 than the difference between placebo and drug, the

20 median of which was 16 percent. This is part of

21 the difficulty of finding something that is really


22 effective or irritable bowel.

23 This also applies to alosetron as seen in

24 the second figure there, which is a re-analysis we

25 did of Glaxo data, which we published in the







1 Lancet. What you can see is that over a


2 three-month period, the mean pain and discomfort

3 scores were quite similar. The analysis done by

4 the Company showed a statistically significant

5 difference, but really, the lines are very, very

6 close.


7 The dose that was used in this study, 2 mg

8 a day, 1 mg BID, is twice as much as what the

9 Company is proposing as the starting dose in their

10 attempt to get the drug back on the market, which

11 is a total of 1 mg a day.


12 An FDA review of the use of this lower

13 dose, which was done in dose ranging studies, found

14 that there is no adequate evidence that the 1 mg

15 per day dose, 0.5 twice a day, was significantly

16 better than a placebo.


17 However, there was evidence in the same

18 study of an increased risk at the 1 mg dose, a

19 4-fold increase in constipation severe enough to

20 cause patients to withdraw from the study, compared

21 with placebo.


22 Thus, Glaxo's proposal for remarketing

23 Lotronex has a starting dose of 1 mg a day, which

24 lacks proper evidence of efficacy required by the

25 1962 drug efficacy laws, but causes a significantly







1 greater incidence of severe constipation.


2 From our analysis of adverse event data

3 and FDA briefing documents which were made

4 available yesterday, as of the end of 2001--we

5 don't have more recent data--there were 352

6 hospitalizations associated with the use of


7 alosetron, the majority of which were associated

8 with gastrointestinal adverse reactions including

9 ischemic colitis and severe complications of

10 constipation.

11 Eighty-five cases in the whole database


12 were ischemic colitis, and there were 13 deaths, 7

13 of which according to the FDA show a "strong

14 association with alosetron." Twenty-three patients

15 required surgery because of complications from

16 alosetron. That number is larger than what was


17 presented this morning, it was over 30.

18 That these reported cases are about the

19 tip of the iceberg can be seen from an important

20 clinical trial included in an FDA memo by

21 epidemiologist, Dr. Zili Li, who found that in one


22 large trial, 10 out of 1,819 women being treated

23 with alosetron for diarrhea-predominant irritable

24 bowel syndrome developed ischemic colitis over a

25 24-week duration of the trial. In contrast, there







1 were no cases in the 899 patients in that trial


2 treated with traditional therapy.

3 Again, for those who say that there is

4 some underlying incidence of ischemic colitis in

5 irritable bowel syndrome patients who don't have a

6 drug, I think that may be true, but it is a very


7 small incidence, if any.

8 Since there are 275,000 people who have

9 used the drug, the 85 reported cases of ischemic

10 colitis after approval certainly represent the

11 well-known under-reporting of hundreds of cases of


12 ischemic colitis which may actually have occurred.

13 Glaxo has stated that ischemic colitis

14 mainly occurs because the drug was not used

15 properly, but according to FDA, the first 70 cases

16 that were reported, 80 percent of them, the drug


17 was prescribed as labeled. It is interesting that

18 12 percent of those first 70 cases, the patient was

19 using the 1 mg per day dose being proposed for the

20 new marketing plan.

21 On the next page, there is a table just


22 looking at the changing estimates, the incidence

23 estimates for ischemic colitis, and it goes back to

24 the FDA medical officer, Dr. Senior, back before

25 the drug is approved, finding a risk estimate of 1







1 in 300 over 12 weeks, which would translate into a


2 risk of 14.7 cases per 1,000 years, and finally,

3 the study that was felt by Dr. Zili Li of the FDA

4 to be most representative because the patients were

5 really looked at carefully in terms of the

6 occurrence of ischemic colitis, the trial I just


7 mentioned. It was one case of ischemic colitis per

8 182 patients or a risk of 16.9 per 1,000 patient

9 years.

10 The regulatory options, which you have

11 heard about this morning, include, and the


12 discussion hopefully will include, an IND, because

13 I think it is the only reasonable option compared

14 with some of these Subpart H options that have been

15 described.

16 As mentioned earlier, there has been, with


17 cisapride, another GI drug, according to Johnson &

18 Johnson, the spokesperson told me about 1,000

19 patients had that drug available under their INDs.

20 The necessary combination of safeguards

21 that I think we need to protect people adequately


22 just can't be done in any marketed version. In an

23 FDA slide presentation in an internal meeting a

24 couple weeks ago, the very criteria which I have

25 listed there, life-threatening disease, disease not







1 prevalent, which would make an ideal Subpart H


2 drug, are just not met in this case.

3 The FDA has pointed out in the

4 presentation that you just heard this morning by

5 Dr. Piazza-Hepp, that a number of elements for even

6 a stricter marketing version of the drug are


7 missing in what the Company has proposed, and these

8 would include restriction, as you heard, to

9 gastroenterologists, and most importantly, regular

10 monitoring by physicians.

11 We just don't believe that all these


12 restrictions are realistic for a marketed drug, and

13 if the drug is to be made available, it needs to be

14 under an IND.

15 The conclusion is that with the exception

16 of some drugs used to treat cancer, the frequency


17 and severity of a life-threatening adverse reaction

18 in this case, ischemic colitis, in patients using

19 alosetron is among the highest I have seen for any

20 other drug.

21 This risk, coupled with the marginal


22 benefit, beyond that seen with a placebo alone,

23 results in a risk benefit ratio clearly unfavorable

24 to patients. The reintroduction of Lotronex into

25 the market, even with the restrictions proposed by







1 Glaxo, would be a serious public health mistake


2 likely, if not certain, to result in the need to be

3 on the drug again.

4 I would just like to point that at the end

5 of the public section, Dr. Paul Stolley, who was an

6 epidemiologist at FDA, who worked on this drug,


7 will make a statement.

8 Thank you with 12 seconds to spare.

9 DR. WOLFE: Thank you, Dr. Wolfe, for the

10 succinct presentation. Dr. Wolfe, by the way, is

11 Director of the Public Citizen's Health Research


12 Group, and I ask all speakers, in fairness to

13 everyone, that they state their current --

14 DR. S. WOLFE: No conflict of interest.

15 Sorry.

16 DR. WOLFE: Again, that they state their


17 current or previous financial involvement with any

18 firm whose products they may wish to comment upon.

19 Our next speaker is Ms. Norton, and Mr.

20 Roberts should be on deck.

21 MS. NORTON: I would like to indicate that


22 my expenses have been paid by the International

23 Foundation for Functional Gastrointestinal

24 Disorders.

25 Mr. Chairman, I would like to thank the







1 Advisory Committee for the opportunity to appear


2 before you today. I ask you to consider two issues

3 that are key components of determining benefit and

4 risk in IBS, what are the consequences of

5 alternative therapies or no treatment for chronic

6 multiple symptoms of IBS, and what is the level of


7 disability, morbidity, and mortality associated

8 with IBS.

9 Data reveals that for many people, there

10 are severe consequences and a distressing level of

11 disability, morbidity, and mortality that results


12 from the search for effective treatment for

13 unrelieved chronic symptoms of IBS.

14 The newly signed Veteran Education and

15 Benefits Expansion Act of 2001, H.R. 1291,

16 recognizes IBS as a chronic disability with an


17 associated burden of illness that warrants

18 compensation and disability under covered veterans,

19 for Gulf War veterans.

20 The Expansion Act prompted us to look into

21 the possible IBS mortality in the U.S. Vital


22 Statistics data from the CDC. Remarkably, we found

23 that between 1979 and 1999, 1,031 deaths were

24 attributed to IBS. Where did the presumptions come

25 from IBS does not lead to surgery, does not shorten







1 the life span, and does not cause death? The data


2 says otherwise.

3 We asked several epidemiologists what they

4 thought about the mortality coding associated with

5 IBS. Among the responses were it may or may not

6 represent miscoding, there may be under-reporting


7 of deaths related to medical interventions that

8 were never correctly attributed to the diagnosis of

9 IBS, and finally, we don't know what it means. I

10 think it is time we find out.

11 Let me elaborate on some of the things we


12 do know. People die from procedure-related

13 complications including from diagnostic tests and

14 surgical interventions that are unnecessary, and

15 people with unrelieved chronic symptoms of IBS are

16 at risk for these procedures.


17 In January 2002, I was a panel member at

18 the NIH State of the Science Conference on

19 endoscopic retrograde cholangiopancreatography for

20 diagnosis and therapy. The differential diagnosis

21 of abdominal pain or possible pancreatic or biliary


22 origin includes, in part, clinical apparent

23 entities such as IBS.

24 Diagnostic ERCP has no role in the

25 assessment of these patients. Yet, among those at







1 highest risk for diagnostic ERCP and ERCP-induced


2 pancreatitis and even death are young, otherwise

3 healthy females reporting recurrent abdominal pain.

4 There is a risk of cholecystectomy

5 associated with unrelieved symptoms of IBS. A

6 recent article in the British Journal of Surgery


7 reported that cholecystectomy was common in

8 patients with IBS, most often women. Symptoms of

9 IBS may cause diagnostic confusion and lead to

10 inappropriate surgery.

11 Longstress [ph] cites that the incorrect


12 attribution of IBS symptoms to gynecological

13 pathology can lead to unnecessary surgery. As many

14 as 47 percent of women with IBS have undergone

15 hysterectomy and 55 percent ovarian surgery.

16 Both radical and simple hysterectomy have


17 shown to give rise to changes in urinary function

18 including incontinence and to disturbances of bowel

19 function associated with surgical trauma.

20 There is mortality data in relationship to

21 incontinence. Nokenesian [ph] College reported


22 that incontinence in elderly people living at home

23 has appreciable effects on mortality.

24 Consider that IBS patients run the risk of

25 incontinence not only due to surgical intervention,







1 but also as a result of the inability of the anal


2 sphincter muscle to compensate for repeated bouts

3 of loose stool or diarrhea, and many constipated

4 patients experience fecal incontinence due to

5 seepage around impacted stool.

6 In an IFFGD survey, 25 percent of


7 individuals with IBS reported loss of bowel

8 control, a disability that has enormous impact on a

9 person's life and well-being.

10 I will conclude with the results from the

11 IFFGD survey, IBS in the Real World, a quantitative


12 research study conducted from February to March of

13 2002 among adults drawn from our database. While

14 this information may not generalize all IBS, it

15 clearly represents those at IFFGD that we talked

16 to.


17 In the telephone survey, 350 respondents

18 were interviewed who reported having a diagnosis of

19 IBS. Almost half were diagnosed 10 or more years

20 ago. Symptoms were reported as severe by 43

21 percent, moderate by 40 percent, and mild by 17


22 percent. Nearly half reported daily episodes of

23 IBS symptoms and 70 percent more than weekly

24 episodes.

25 Duration of the IBS episodes was reported







1 on an ongoing or continuous occurring every day of


2 the year by nearly one-quarter of these

3 respondents. Thirty-nine percent rated the pain of

4 their IBS symptoms as extreme or very severe.

5 Symptoms in terms of interfering with

6 daily life were described as extremely or very


7 bothersome by two-thirds of sufferers. Five

8 percent of respondents reported being on disability

9 due to IBS. More than two-thirds reported visiting

10 a physician or health care provider during the past

11 six months for their IBS, with 15 percent of the


12 total sample reporting six or more visits.

13 These IBS sufferers, seeking to control

14 their symptoms, reported using 143 prescription

15 drugs, 71 over-the-counter medications plus 67

16 herbal remedies, a total of 281 different


17 preparations. Yet, overall, fewer than one-third

18 of these IBS sufferers reported satisfaction from

19 the drugs and remedies they used to treat their IBS

20 symptoms.

21 Prescription drugs were more often


22 considered to be effective by those with milder

23 cases of IBS, less frequent episodes, or symptoms

24 that do not interfere with daily activity.

25 Over-the-counter medications were rated as







1 either not effective or only somewhat effective by


2 nearly three-quarters of those currently using

3 them.

4 Significantly, 62 percent report side

5 effects from the prescription drugs being taken.

6 Almost half reported the side effects as severe or


7 moderate. Twelve percent visited the ER, 7 percent

8 were hospitalized, 24 percent had to visit their

9 health care provider, 22 percent had to stop

10 driving, and 18 percent reported missing work or

11 school.


12 In summary, these IBS sufferers face the

13 challenge of living with their disease day-in and

14 day-out for years. Most suffer severe and painful

15 symptoms that seriously impact their daily life.

16 They frequently utilize health care


17 providers due to IBS symptoms, they take a plethora

18 of drugs finding little or no relief. They are

19 dissatisfied with existing medications prescribed

20 for IBS symptoms from which they suffer frequent

21 and sometimes severe side effects.


22 Mr. Chairman and members of the Committee,

23 IBS is a serious disease. For the significant

24 number of people whose symptoms are frequent and

25 often debilitating, treatments are needed to







1 provide symptom relief. Unrelieved symptoms of IBS


2 can lead to disability, morbidity, and even

3 mortality.

4 In this context, a safe and effective drug

5 to relieve the multiple symptoms of IBS would be a

6 significant step forward.


7 Thank you.

8 DR. WOLFE: Thank you, Ms. Norton. You

9 took Dr. Wolfe's extra 15 seconds.

10 Next, we have Mr. Jeffrey Roberts of the

11 IBS Self-Help Group, and Mr. Corey Miller will be


12 on deck.

13 MR. ROBERTS: I am here today representing

14 patients and sufferers, and I have paid all of my

15 own expenses to be here.

16 Members of the Committee, thank you for


17 the opportunity to appear before you. I am the

18 President and Founder of the Irritable Bowel

19 Syndrome Self-Help Group.

20 The 11,000-member Irritable Bowel Syndrome

21 Self-Help Group has endeavored since 1987 to


22 educate and provide support for people who have IBS

23 and to encourage both medical and pharmaceutical

24 research to make our lives easier vis successful

25 Internet web site for sufferers.







1 I have been a sufferer of


2 diarrhea-predominant irritable bowel syndrome for

3 over 25 years. There are challenges that I face

4 each and every day in order to cope with the

5 symptoms of irritable bowel syndrome.

6 It affects my family's lives, my career,


7 and I am constantly reminded of my own physical

8 limitations because of this very burdensome

9 illness.

10 Today, I have the support of the members

11 of the Lotronex Action Group, Irritable Bowel


12 Syndrome Self-Help Group, and Irritable Bowel

13 Syndrome Association. I would like to now invite

14 the members of these groups to stand and be

15 acknowledge for their efforts to date and to

16 represent those members who were too ill to travel


17 here today.

18 Thank you.

19 [Slide.]

20 While taking Lotronex, IBS sufferers

21 reported a complete cessation of their symptoms.


22 It dramatically changed their lives for the better.

23 Following the withdrawal of Lotronex from the

24 market in November 2000, the IBS Self-Help Group

25 was flooded by messages from former Lotronex users







1 who were desperate for access to the medication.


2 Within a month, the Lotronex Action Group

3 was established to bring about access to the

4 medication. In the spring of 2001, the Lotronex

5 Action Group submitted a 1,000-name petition to the

6 FDA asking it to immediately work with the


7 manufacturer GlaxoSmithKline to permanently provide

8 the drug to those diagnosed with

9 diarrhea-predominant irritable bowel syndrome.

10 The petition used data from an electronic

11 survey conducted by the Irritable Bowel Syndrome


12 that identified the side effects from taking

13 Lotronex. Fifty-nine percent of those surveyed

14 indicated they had no side effects at all.

15 [Slide.]

16 Through the months of March through April


17 2002, the IBS Self-Help Group surveyed irritable

18 bowel syndrome sufferers about what type of

19 restrictions, if any, they would be willing to

20 accept for access to IBS medications.

21 Fifty-nine percent of those surveyed


22 responded that medicine specific to IBS should be

23 accessible to a sufferer diagnosed by a family

24 physician or gastroenterologist, and not only a

25 gastroenterologist.







1 It is important that family physicians,


2 and not just gastroenterologists, be able to

3 prescribe Lotronex because many sufferers do not

4 have access to a specialist either because they do

5 not live in a community supported by one or because

6 their medical coverage does not provide access to


7 one.

8 If a decision was made to allow only

9 gastroenterologists to prescribe Lotronex, then

10 many IBS sufferers would have difficulty getting

11 access to it.


12 Furthermore, respondents want

13 prescriptions to cover a 90-day supply. The survey

14 also said that 63 percent are willing to agree to

15 participate in a survey about use and side effects

16 while taking Lotronex sponsored by the


17 pharmaceutical and/or FDA agency.

18 Finally, 96 percent or respondents say

19 that they would sign an informed consent form in

20 order to gain access to a medication.

21 [Slide.]


22 Our survey showed that IBS sufferers are

23 prepared to accept risks related to the use of

24 Lotronex and other effective treatments for IBS.

25 They are also prepared to participate in programs







1 to better characterize risks related to the use of


2 Lotronex and other treatments and to work with the

3 FDA to reduce those risks as much as possible.

4 The IBS Self-Help Group and IBS

5 Association are prepared to place specific risk

6 management information about Lotronex on their web


7 sites in order to reach out to the IBS community.

8 With close to 4 million monthly visitor hits, the

9 highly active web sites can be vehicles to educate

10 and provide signs and symptoms about Lotronex.

11 [Slide.]


12 In conclusion, IBS sufferers' quality of

13 life was dramatically improved with access to

14 Lotronex. IBS sufferers are prepared to accept the

15 risks associated with its use and to work with the

16 FDA to reduce those risks.


17 Adverse events should not deter either the

18 pharmaceutical or FDA from maintaining the drug's

19 availability. Lotronex has a place as an effective

20 treatment for both female and male

21 diarrhea-predominant IBS sufferers. Those who


22 would limit access have obviously never walked a

23 day in our shoes.

24 Thank you.

25 DR. WOLFE: Thank you, Mr. Roberts.







1 Next, we have Corey Miller; on deck, Dr.


2 Stein.

3 Mr. Miller is with the Lotronex Action

4 Group.

5 MR. MILLER: Members of the Committee, my

6 name is Corey Miller and I am here today to speak


7 on behalf of the Lotronex Action Group, for which I

8 am co-founder.

9 [Slide.]

10 The Lotronex Action Group was founded in

11 January 2001 with the help of the IBS Self-Help


12 Group shortly after the removal of Lotronex from

13 the market.

14 The LAG represents approximately 350

15 people that used Lotronex while available. I would

16 like to emphasize that we are a patient group, and


17 we receive no funding from any pharmaceutical

18 company whatsoever. Our goal is to regain access

19 to the medicine Lotronex for both women and men,

20 which we feel is a miracle medicine that

21 substantially improved the quality of our lives.


22 Moreover, the LAG believes strongly that

23 the medicine is safe when prescribed and taken

24 appropriately, and that the benefits far outweigh

25 the potential risks for adverse side effects.







1 [Slide.]


2 The LAG, as mentioned by Mr. Roberts,

3 submitted a petition to the former interim

4 Commissioner, Bernard Schwetz, containing over

5 1,100 signatures of those wanting access to the

6 medicine.


7 I am speaking here today as a patient in

8 great need of a medicine that has, in my opinion,

9 been pulled from the market due to lack of

10 understanding of the debilitating nature that

11 diarrhea-predominant irritable bowel syndrome or


12 IBSD can have.

13 [Slide.]

14 For almost all the members of our group,

15 this medicine was the only effective treatment for

16 our illness. As stated in an open letter from the


17 LAG to the FDA in the summer of 2001, the typical

18 sufferer of IBSD is a 40-year-old female with

19 primary symptoms including multiple and daily

20 explosive diarrhea attacks and severe daily

21 abdominal discomfort.


22 The most common secondary side effects

23 include panic attacks, depression, withdrawal from

24 social and family activities, severe disruption of

25 daily activities, and malnutrition. The typical







1 IBSD patient has suffered from the illness since


2 their early teenage years.

3 The adverse impact of IBSD on patient

4 quality of life is dramatic, causing the typical

5 sufferer to forego many aspects of life that others

6 take for granted. For example, some of our members


7 have been forced to relinquish their social lives,

8 others have given up their careers and live as

9 captives in their own homes.

10 People fortunate enough to have met an

11 understanding partner and to have children often


12 are not able to attend functions with their kids or

13 participate in common daily activities. In many

14 cases, the inability to lead a "normal" life causes

15 severe depression and suicidal thoughts.

16 When IBSD patients try to take part in


17 daily activities, they are often subject to panic

18 attacks when confronted by situations in which a

19 restroom is not nearby or suffer embarrassing

20 accidents of defecation.

21 The Lotronex Action Group is comprised of


22 women and men suffering from the most severe and

23 debilitating symptoms of IBS. Many of us have

24 found Lotronex to be the only effective treatment

25 for IBSD, enabling many patients to assume normal







1 adult lives for the first time.


2 Please believe me when I tell you that all

3 the existing treatments for IBS, ranging from fiber

4 therapy to antispasmodals to antidepressants, do

5 little, if nothing, to provide relief from the pain

6 and discomfort of this illness for the most severe


7 cases.

8 I am telling you this from my personal

9 experience and also have a stack of over 50 letters

10 from some of our members that will attest to the

11 same.


12 [Slide.]

13 It is apparent that IBS has been

14 categorized by the FDA as an illness that does not

15 cause death, therefore, a zero tolerance criteria

16 for adverse side effects has been placed on


17 medicines developed to treat IBS. Why else would

18 we be there today? The percentages shown earlier,

19 in my opinion, clearly show that Lotronex is not

20 that dangerous of a medicine, not much more than

21 any other prescription medicine on the market.


22 What that tells me as a patient is that

23 any medicine ever developed to treat my

24 debilitating illness has to be perfect, and you

25 know as well as I do, and it was mentioned earlier,







1 that all medicines have some associated risks.


2 Current unavailability of Lotronex leaves

3 many patients with no satisfactory treatment

4 option. Some turn to other prescription medicines

5 not suited for their illness, while others abuse

6 over-the-counter medicines like Pepto Bismol and


7 Imodium with serious potential adverse

8 consequences.

9 The member of the Lotronex Action Group

10 are prepared to accept risks related to the use of

11 Lotronex and other effective treatments for IBSD.


12 We are also prepared to participate in programs to

13 better characterize risks related to the use of

14 Lotronex and other treatments, and to work with the

15 FDA and the pharmaceutical companies to reduce

16 those risks to the extent possible.


17 We have requested that the FDA reexamine

18 and redefine the severity of IBSD and the level of

19 risk as tolerable for an effective treatment for

20 this debilitating condition. IBSD, while not

21 directly deadly, can be life threatening and causes


22 severe damage to the quality of the lives of the

23 sick and their families.

24 After taking Lotronex for almost two full

25 years, with no side effects whatsoever, I am only







1 able to be here today because I am now taking


2 prescription medicine Zofran. It's another 5HT3

3 receptor antagonist.

4 I am fortunate that my physicians

5 understand my situation and I can afford the 30

6 dollar-plus price tag per pill. Many others are


7 not so fortunate.

8 To my knowledge, no long-term studies have

9 been done to determine if this medicine is safe for

10 long-term treatment, so you see the FDA has merely

11 shifted the problem. With Lotronex, there is a set


12 of parameters established and the risk is known.

13 It was a much more controllable situations.

14 Now, those 300,000 people that were taking

15 Lotronex, or 275,000, which I saw this morning, are

16 taking, like myself, whatever they can to stop or


17 relieve their suffering.

18 If two people commit suicide due to severe

19 IBS-related depression, which was a major factor in

20 GSK's presentation earlier, that would match the

21 number of probable deaths linked to Lotronex.


22 Again, I quote "probable" because it hasn't been

23 identified that those deaths were linked

24 specifically to Lotronex.

25 Also, I want to add one other item. After







1 hearing of the proposed management proposal this


2 morning by Glaxo, I wanted to address one item on

3 that regarding prescription refills. This is just

4 my personal feeling in general.

5 I am on a couple of medicines to treat IBS

6 since Lotronex was pulled off the market. Being in


7 a working profession, it is a burden, it is very

8 much a burden to go see a doctor. If you are

9 traveling during the week and whatnot, it is very

10 difficult every month, if I am going to be on the

11 medicine for the rest of my life, to go in every


12 month and see a physician and have to get a

13 prescription.

14 I would recommend to the Board to consider

15 that maybe initially, for the first three months or

16 six months that could happen, and then gradually,


17 as a person's need for the medicine has been

18 identified, that maybe that gets reduced and

19 relaxed over time, as long as they are responding

20 favorably to the medicine.

21 Thank you for your time.


22 DR. WOLFE: Thank you, Mr. Miller.

23 Dr. Gary Stein is next. He is

24 representing the American Society of Health System

25 Pharmacists, followed by Mr. Brown.







1 DR. STEIN: Thank you. My name is Gary


2 Stein. I am the Director of Federal Regulatory

3 Affairs for the American Society of Health-System

4 Pharmacists.

5 ASHP is a 31,000-member national

6 professional association representing pharmacists


7 who practice in hospitals and other components of

8 organized health care systems.

9 ASHP has a long-standing commitment to

10 helping pharmacists manage the risks inherent in

11 prescription and non-prescription medication use,


12 and we recognize that the FDA has the same

13 commitment, particularly in regard to new or higher

14 risk drugs.

15 Unfortunately, many of the risk management

16 plans that have been implemented in recent years


17 involve restricted drug distribution systems.

18 There has been a substantial increase in the number

19 of new pharmaceuticals that are available only

20 through limited distribution systems.

21 Increased reliance on restricted drug


22 distribution systems is a growing concern among

23 ASHP's members. These systems often exclude

24 individual hospitals, as well as community

25 pharmacies, from distributing medications and use







1 other means of distribution to deliver medications


2 directly to patients.

3 While a number of drugs have been

4 relegated to restricted drug distribution systems,

5 we lack information on how well these systems

6 work.


7 Pharmacists are responsible for ensuring

8 that medications are readily available for patients

9 who need them. Disruptions in non-standardized

10 distribution processes are not trivial matters.

11 They create procedural confusion for pharmacy and


12 other hospital staff, and increase the potential

13 for mistakes.

14 Any restrictive distribution or special

15 handling procedure that disrupts that central

16 oversight role of pharmacists represents in


17 interruption in standard medication use policies

18 and procedures in the health care system.

19 In November of 2000 and again in January

20 of this year, ASHP drew FDA's attention to this

21 issue. We have suggested that when a manufacturer


22 implements a restricted distribution of a drug

23 product, the FDA should obligate the company to

24 ensure that a patient's usual pharmacist

25 relationship is not disrupted.







1 ASHP also recommended that if a restricted


2 distribution system is being considered by the

3 Agency as a condition for marketing approval,

4 practicing pharmacists, professional pharmacist

5 societies, and patients should be consulted before

6 any restricted distribution requirements are


7 imposed on the product.

8 While restricted distribution systems for

9 individual drugs may have a safety intent, they

10 paradoxically also represent corresponding safety

11 threats in complex health system settings. Any


12 distribution process that bypasses pharmacists'

13 control or requires exceptional procedures in such

14 setting would be contrary to the best interests of

15 patients.

16 ASHP members recognize that some


17 exceptions will inevitably have to be made in a

18 patient's best interests. An important point,

19 however, is that these should truly be

20 extraordinary exceptions.

21 The prospect of multiple unique


22 restrictive drug distribution systems is a

23 frightening picture for health system pharmacists.

24 Deviations that are unique and that greatly differ

25 from standard practice create obstacles in







1 delivering and administering medications safely.


2 The patient-pharmacist relationship should

3 not be misinterpreted as merely a product

4 distribution function. The pharmacist's minimum

5 responsibility is to assess the overall

6 appropriateness of all medications with regard to


7 dose, drug interactions, compliance, and patient

8 counseling.

9 Patient and pharmacist relationships in

10 which this level of care is achieved depend on

11 mutual trust, the pharmacist's thorough awareness


12 of the patient's overall medication use, and the

13 pharmacist's actions to ensure the timely supply of

14 drug products.

15 Restricted distribution systems that limit

16 the pharmacist's ability to develop these


17 relationship are disruptive. Restricted drug

18 distribution systems that involve

19 physician-to-patient delivery prevent pharmacists

20 from providing medication appropriateness, dosage,

21 and interaction checks, patient education and


22 counseling, monitoring and follow-up evaluation.

23 Thoughtful consideration needs to be given

24 to the fact that some of these medications may be

25 initiated or continued for hospitalized patients.







1 Hospital pharmacies may not be able to acquire


2 these medications in a timely manner. This has an

3 adverse effect on patient care and cost. The

4 hospital setting is also where a sticker system

5 fails miserably.

6 ASHP believes that rather than unique drug


7 product distribution schemes, the FDA, in

8 consultation with stakeholders including

9 pharmacists, physicians, nurses, other health care

10 professionals and patients, should develop models

11 or managing patients for whom any high-risk drug


12 product might be indicated and prescribed.

13 Manufacturers should be required to design

14 distribution procedures and supporting patient care

15 materials in conformance with these models.

16 Drug-specific requirements for a model


17 should be developed during pre-approval

18 demonstrations and adjusted over time based on

19 postmarketing surveillance. Pre-approval

20 demonstrations, perhaps through the Centers for

21 Education and Research on Therapeutics, the CERTs,


22 should focus on requirements for ensuring

23 appropriate use and monitoring, such as patient

24 work-up and selection, provider and patient

25 education, and patient monitoring.







1 Such demonstration projects could answer a


2 number of our concerns about important issues, such

3 as uniformity of procedures for patient selection,

4 what kind of distribution systems are most

5 supportive of continuity of care, and what kind of

6 approach is served best for provider and patient


7 education.

8 Thank you very much.

9 DR. WOLFE: Thank you, Dr. Stein.

10 Mr. Brown, followed by Ms. Lisa Kenney.

11 MR. BROWN: Good afternoon, Dr. Wolfe, and


12 members of the Committees. My name is Bill Brown.

13 I am a practicing attorney in Columbus, Ohio. I

14 don't sue doctors, I represent many of you. I have

15 practiced for 42 years and had IBSD for over 40.

16 In 1999, after visiting a number of GI


17 doctors in Columbus with no success, I wound up at

18 the Mayo Clinic, and wound up on an open-label

19 study for alosetron. It was truly my miracle pill.

20 I used it for 16 months until it ran out.

21 I have never had any side effects to it. Nobody


22 has paid me to be here, it's a six and a half hour

23 drive from Columbus to speak for four minutes.

24 Previously, I have filed with you a more

25 detailed statement including my personal experience







1 with IBSD, which I hope you will have time to read.


2 It won't take you more than about five or six

3 minutes.

4 But there are three basic issues that I

5 really want to address, that I think are very

6 important. I am a little appalled almost at


7 Glaxo's comments this morning regarding the

8 availability of this for men. As you can see,

9 there are many of us that suffer with IBSD. It is

10 not just women.

11 That issue needs to be addressed by the


12 Committees, and I believe at least indicate that

13 Glaxo have some sort of a continuing open-label

14 study for us to participate in. I was almost

15 totally cured with this.

16 The second thing, of course, other than


17 gender discrimination, is age. There have been

18 some comments that have said that it gets better

19 with age, and I am here to tell you that IBS is 10

20 times worse than it was at 59, 10 years ago.

21 I have read the entire transcript, your


22 247-page transcript from last year's meeting, so I

23 am familiar with what you have covered. Dr.

24 Camilleri, which is a brother to most of you in

25 this thing, addressed the issue of what he calls







1 this "exquisite dilemma" in last year's


2 Gastroenterology Journal, and I quote him.

3 "Unfortunately, withdrawing a drug while saving

4 some individuals from a serious adverse effect, may

5 deprive others of the only agent able to relieve

6 their suffering."


7 There currently has been much thinking

8 about compassionate use, about restricting

9 dispensation, about waivers, warning labels, none

10 of which seem to address the issue that you need to

11 really address.


12 The biggest item I have seen that needs to

13 be addressed is physician education. If you limit

14 this to GI docs, there may not be one in Apple

15 Valley, Montana, within 400 miles of somebody who

16 needs a drug.


17 My family physician, my primary caregiver

18 in Columbus, knows more about Lotronex and IBS than

19 at least half a dozen GI doctors that I personally

20 know in Columbus. Don't restrict it to just GI

21 docs.


22 I have an older son who is a drug rep for

23 Lilly. He doesn't work with Lotronex, of course, he

24 works with diabetes. His biggest problem is

25 getting in to educate the doctors, to detail them







1 on these drugs. Fortunately, it is no longer an


2 entertainment thing for the doctors anymore. Eli

3 Lilly and other companies have restricted the

4 entertainment of the physicians, but that is the

5 biggest problem.

6 You need to establish, like we have in the


7 legal community, continuing legal education,

8 serious medical education of the doctors who are

9 going to prescribe, maybe set up a class having

10 passed an educational requirement, but please do

11 not eliminate Lotronex. People like Solvay, as you


12 are well aware, interrupted their Cilansetron

13 studies for a year because of what has happened to

14 Lotronex.

15 We need the Lotronex. It is the only

16 thing that is available, and if you stop it, there


17 is going to be very little, if any, additional

18 research on IBS, which we need to have. Consider

19 that.

20 Thank you.

21 DR. WOLFE: Thank you. I am impressed.


22 Four minutes for a lawyer is very, very good.

23 Ms. Kenney, followed by Maria Zargo.

24 MS. KENNEY: My name is Lisa Kenney. I am

25 a member of the IBS Support Group, the Lotronex







1 Action Group, and I am also a long-term sufferer of


2 IBS for over 10 years.

3 I made it here today, and the only reason

4 why is because of my emergency ration of Lotronex

5 given to me by my compassionate and supportive

6 gastroenterologist.


7 I appreciate this opportunity to be heard

8 on behalf of hundreds of thousands of IBS

9 sufferers, many of whom are unable to attend today

10 given the debilitating symptoms of severe

11 intestinal pain and diarrhea.


12 Without Lotronex, our lives are once again

13 severely compromised in ways no other person could

14 possibly understand but the IBS patient, our

15 family, our friends, and our doctors.

16 We are imploring the FDA and


17 GlaxoSmithKline to please return our only hope in

18 controlling IBS by restoring the single most

19 effective and safe IBS drug Lotronex. Prior to

20 Lotronex, living with IBS was a nightmare. By the

21 time I was a senior in college, I knew that life


22 would never be normal. Every normal event was met

23 with trepidation and uncertainty, and every simple

24 task was a major challenge.

25 Getting up in the morning, making it to







1 school, going to work, or even eating a simple meal


2 was a victory in itself without being stuck in the

3 bathroom fatigued and writhing in pain.

4 IBS impacts every aspect of my life -

5 career, education, relationships, marriage,

6 parenting, all had to be rearranged. I had given


7 up a great dream to become a doctor due to this

8 illness. While I have accepted my limitations and

9 acquired a computer career for the many years that

10 followed, the excruciating impact of IBS remains.

11 Then, in May of 2000, something magical


12 happened, and I started Lotronex, and a small hope

13 became a dream come true. I remember that joyful

14 brief period very well. I remember all the

15 youthful years I had missed, all the things I

16 couldn't do, and even simpler still, all the things


17 I couldn't eat or drink, all came back with safe

18 invitation.

19 Even my skin and bones frame, I am fat

20 again, and there was time for family and friends,

21 and energy for work or play. After 10 long years


22 of suffering, endless days and nights twisted in

23 agonizing pain, I felt free for the first time,

24 freedom from IBS.

25 Lotronex removes much of that anxiety and







1 the fear and the shame that we all carry, so there


2 is no more hiding in the bathroom, and there will

3 be no more hiding from the world. I thought life

4 was just beginning.

5 Then, on November 28th, 2000, the

6 unthinkable happened, and in one brief moment,


7 Lotronex was gone. It was as if time had reversed

8 and everything positive, painless and powerful, was

9 taken away, and every day since Lotronex has been

10 removed has been a huge step backwards.

11 They say that IBS is not life threatening,


12 that it does not kill. Well, I disagree. IBS

13 threatens my confidence and my will to survive

14 every single day of my life. It had been

15 increasingly difficult for me as it was before

16 Lotronex, until Lotronex literally saved my life


17 and my livelihood, but without Lotronex, I can no

18 longer sustain a demanding work schedule, and I

19 couldn't face life without it. Life without

20 Lotronex was, for me, a life without quality of

21 life.


22 I have come a long way since my crisis and

23 I have dreams yet to fulfill, but I am unable to

24 meet them without Lotronex. So, I am anxious to

25 return to productive life, and I will continue to







1 be proactive in winning Lotronex back for myself


2 and for countless other people, an undeniable need

3 of this small miracle pill.

4 In closing, we have been informed of the

5 serious side effects of Lotronex, and we

6 acknowledge the potential risk in developing


7 ischemic colitis and severe constipation. We

8 understand that the benefits of Lotronex do not

9 come risk-free, no medication on the market does.

10 We are not so overcome with desperation

11 from our suffering that we would fail to consider


12 these risks seriously, and we would certainly yield

13 to close GI supervision under this medication just

14 to ensure its safety.

15 No other drug has been able to treat IBS

16 symptoms with unparalleled efficacy. Lotronex can


17 save, and has saved, so many lives from further

18 pain and suffering. It has helped to reunite

19 patients with their families, friends, and forge an

20 even closer doctor-patient relationship.

21 As educated consumers and IBS patients, we


22 are more than prepared to accept the risks with the

23 tremendous benefits of Lotronex. So, please don't

24 take away the only hope we have for a much better

25 life, a life with the quality of life.







1 Thank you.


2 DR. WOLFE: Thank you, Ms. Kenney. Maria

3 Zargo is next, followed by Julia Alberino.

4 MS. ZARGO: My name is Maria Zargo. I am

5 a LAG coordinator, but I am here representing

6 myself and some who were unable to attend this


7 meeting. No one has paid for me to speak.

8 I am a wife, mother, former career woman,

9 and I suffer from severe IBS. Most recently I was

10 forced to resign my position with a prestigious

11 Fortune 500 company. I was no longer able to make


12 the 45-minute commute to work every day without

13 stopping at a supermarket to use the restroom. My

14 work life, my family life, and my independence had

15 been permanently compromised until Lotronex came

16 along.


17 I had been on a reduced dosage of Lotronex

18 for nearly two years without side effects. I am

19 living proof that this drug is extremely effective

20 and very safe when used correctly and at the proper

21 dosage.


22 As with any other medication on the

23 market, dosage administration should not be

24 considered a "one-size-fits-all" scenario. Your

25 risk management debacle could be solved if you







1 would only adhere to this advice, advice given by


2 those who are the true experts - the users of

3 Lotronex.

4 All drugs have side effects, and knowing

5 what we know about the risk-benefit ratio of

6 Lotronex, we are willing to accept those risks.


7 The majority of us have expressed a willingness to

8 sign a waiver if need be, as is currently being

9 done with other drugs, but that was never even

10 presented to us an option. Nor have we been given

11 the option of a truly viable compassionate use type


12 program that doctors would be willing to endorse.

13 With Zelnorm's rejection and Cilansetron's

14 approval being questioned, one can only presume

15 that this continues to be politics as usual, and

16 not at all about science and patient needs.


17 It would be easier to have ailments like

18 migraine headaches or IBD because there are

19 effective treatments on the market, and public

20 perception is one of understanding and sympathy.

21 Today, IBS sufferers have no viable alternative


22 medication that works. Lotronex continues to be

23 the only drug ever prescribed that has

24 significantly improved or completely eliminated the

25 horrible, debilitating symptoms of







1 diarrhea-predominant IBS.


2 For those who continue to view IBS as

3 nothing more than a "vexing inconvenience," we hope

4 that the information we provide you with today will

5 change that view. Being hospitalized for

6 dehydration caused by IBS is more than an


7 inconvenience. Stories of suicide attempts

8 attributed to IBS suffering cannot be ignored.

9 Missing out on life's simple pleasures

10 like attending your child's sporting events is

11 downright depressing, and it affects everyone in


12 the family. It goes beyond a quality of life

13 issue. Being afraid to leave your home for

14 extended periods of time for fear of embarrassing

15 incontinence is humiliating and not a mere

16 inconvenience.


17 The cramping and pain, the exhausting,

18 numerous trips to the bathroom, the inability to

19 eat healthy, nutritious foods can be intolerable,

20 and not just an inconvenience. Job loss and family

21 stress are undeniable and commonplace. So, I am


22 hoping that you can understand why I take offense

23 when someone refers to my condition as a mere

24 inconvenience.

25 IBS continues to be poorly understood.







1 Even today, there are still some doctors who are


2 truly misinformed, referring to it as "bathroom

3 anxiety." Because of these misconceptions and lack

4 of information, many patients are misdiagnosed with

5 "mental health" problems and are given unfair

6 labeling and treatment.


7 For this reason, the treatments and

8 medications that have been prescribed over the

9 years have fallen far short of success. I have

10 attached a list of prescription drugs and herbal

11 remedies that patients have tried over the years


12 with little benefit, if at all. This list should

13 have been distributed to you.

14 The bottom line is, sure, there are

15 alternate IBS treatments on the market today. What

16 some refuse to understand is they don't work. We


17 are being subjected to experimenting with dangerous

18 addictive drugs like codeine, Vicodin, and

19 Oxycontin that have a much higher risk factor than

20 Lotronex and do not contain the benefits that

21 Lotronex provides.


22 The FDA worries about the risks associated

23 with Lotronex? What about the side effects and

24 toxicity we are exposed to by taking these other

25 drugs? There is one other drug that I have







1 purposely not listed. That is ondansetron, which


2 is Zofran. It has made it possible for me to

3 travel to Bethesda and speak before you today.

4 It has proven significantly superior over

5 the other remedies I have attached, and only

6 because it is chemically related to Lotronex.


7 In this great country of ours, we often

8 hear the words "freedom of choice." On November

9 28, 2000, that freedom of choice was taken away

10 from us. For many on Lotronex, it was the first

11 time in years in living a normal life was possible,


12 a life that so many take for granted.

13 Finally, please return Lotronex to those

14 of us who so desperately need it. We depend on it,

15 our families depend on it. Please keep the

16 patients' needs at the forefront and put money and


17 politics aside. By continually denying us this

18 right to Lotronex, the long-term repercussions will

19 be catastrophic and future IBS drug research will

20 be kept on the back burner. Our fate is in your

21 hands.


22 Thank you.

23 DR. WOLFE: Thank you, Ms. Zargo.

24 Next, we have Julia Alberino, followed by

25 Terry Olifiers.







1 MS. ALBERINO: Hi. I am Julia Alberino.


2 I am a member of both the IBS Self-Help Group and

3 the Lotronex Action Group, but I am not here today

4 to represent either of them, I am here to represent

5 myself and other patients who cannot travel here.

6 No one has paid my expenses to be here, and I have


7 no affiliations with GlaxoSmithKline, the FDA, or

8 any other party to what is being decided here.

9 I have had IBS for more than 30 years, and

10 I have tried in those 30 years not to let IBS

11 control my life, but the fact is that it has and it


12 does. Every time I have had to cancel a business

13 meeting or a trip, every time I have been too sick

14 to attend a social event, every time I have had to

15 give up a job because the commute was too long and

16 I couldn't commute to the job and be away from a


17 bathroom for that long, IBS was controlling my

18 life.

19 I am an intensely private person, so

20 embarrassing accidents in public could send me into

21 hiding for weeks. In the material that I submitted


22 to you, I described some of those incidents that

23 happened. As I have gotten older and my IBS has

24 gotten worse, I have learned a few tricks.

25 I keep a change of clothes near at hand







1 wherever I am. I scope out the bathrooms every


2 time I am in an unfamiliar place. I watch very

3 carefully what I eat. I have learned to wear

4 protection if I am going to be away from a bathroom

5 for any length of time. I only travel by train

6 because they have bathrooms.


7 That has had an impact on my professional

8 life. I am required to travel as a part of my job.

9 I have often had to rearrange schedules or ask

10 someone else to do it for me.

11 But in all these years of suffering, I did


12 have 22 months that were remarkable. These were

13 the months that I was on Lotronex, and I won't go

14 into how I got it past the time it was withdrawn

15 from the market, but I did use it for nearly two

16 years.


17 During that time, I could meet all of my

18 work responsibilities, I took on new ones. I

19 started graduate school, which I had to drop out of

20 when Lotronex was withdrawn, and I ran out. I was

21 able to stay in school until I ran out of Lotronex.


22 I knew there could be problems. My

23 physician was candid with me before I started

24 Lotronex. She explained the risks of colonic

25 ischemia and severe constipation. She explained







1 the signs and symptoms to look for. She told me we


2 had to stay in close touch during the time that I

3 was on Lotronex, and I will admit on the third day

4 of taking Lotronex, I had have an episode of

5 constipation.

6 I called my doctor, she said skip today's


7 dose. I did. The constipation resolved. So, I

8 think risk management that involves

9 physician-patient communication is crucial. I will

10 grant that. I am not out for give it to us with no

11 restrictions.


12 The night that I came home and found out

13 that Lotronex had been withdrawn, I was devastated.

14 However, I quickly got as much as I could lay my

15 hands on, I cut my dosage down. One pill a day

16 worked for me almost as well as true. Half a pill


17 a day did not work as well, but I did stay on that

18 dose for a while to stretch the supply.

19 I guess the point is no one size fits all.

20 I would also like to stress that patients have

21 responsibility. They have got to know their own


22 bodies, they have got to be in contact with their

23 doctors, and be in touch the minute something goes

24 wrong.

25 My experience, my personal experience is







1 that if Lotronex is prescribed and used correctly


2 and conscientiously, it is safe and effective. I

3 believe this committee can come up with a risk

4 management program that will work, and I would urge

5 that that program involve stringent reporting

6 requirements and patient experience, so that


7 additional information on the safety and efficacy

8 and long-term effects of Lotronex can be compiled

9 and used to make it available to more people in the

10 future.

11 Thank you for allowing me to speak.


12 DR. WOLFE: Thank you, Ms. Alberino.

13 Next, we have Terry Olifiers, followed by

14 Diana Hoyt.

15 MS. OLIFIERS: My name is Terry Olifiers.

16 I am a LAG member here at my own expense.


17 I have suffered with IBS since I was in my

18 early 20s. I am now 55, and that is an awfully

19 long time to have to go through painful intestinal

20 attacks that are unbearable and urgency at

21 inconvenient times.


22 I have tried a number of medications to no

23 avail. At the same time, my IBS has become worse,

24 often causing incontinence. I reviewed this with

25 my doctor, and he prescribed Lotronex.







1 I was started on two pills a day. At


2 first, I experienced constipation, so I stopped

3 taking it and called my doctor. He recommended

4 taking Metamucil and when I was ready, to cut the

5 dose in half. I started taking one pill daily and

6 Metamucil twice a day, and that did the trick.


7 I was skeptical that this medication would

8 work because none had ever before, but I was

9 willing to try anything. Well to my surprise, I

10 suddenly was living a normal life. I could now

11 leave my house without fear. I no longer had the


12 embarrassment of having to change my clothes at

13 work or running into restrooms and trying to figure

14 out how I would leave. It was a miracle.

15 In late November, a friend of mine who was

16 also having great success from Lotronex told me it


17 was being removed from the market. I was

18 devastated. I called the FDA, Glaxo Wellcome, and

19 went to my congressman's office, which on my behalf

20 wrote a letter to the FDA.

21 I was hysterical. I received the


22 information that pharmacies could dispense the

23 Lotronex they had. I am a medical assistant in a

24 pediatric office. I was so desperate that on my

25 day off, I sat with the Yellow Pages and started







1 calling every pharmacy. I had to fax the FDA


2 report to a number of pharmacies to prove they

3 could fill the prescriptions.

4 I called the doctors that I worked for to

5 fill them. I spent over $500 and would gladly have

6 spent more. IBS is extremely life altering, and


7 nobody would go to the lengths that I did for an

8 ineffective medication.

9 Every day I see advertisements for

10 medications with risks that are far greater than

11 Lotronex, and yet they are still on the market.


12 Obviously, the dosage was an issue. Some need the

13 two pills a day, while others need less. Well, I

14 did fine with one pill today. To conserve, I broke

15 pills in half. I found that a half a pill a day

16 still worked for me.


17 The withdrawal of Lotronex was premature.

18 There are thousands of people who have been put in

19 a position since the withdrawal to try other, more

20 dangerous drugs that are not as effective including

21 antidepressants, and that is absurd.


22 Nothing works like Lotronex, and the FDA

23 has admitted that. I have hoarded enough Lotronex

24 that I still continue to take a half a pill a day.

25 To stretch out my time with Lotronex, I skip pills







1 if I can stay home, not a great way to live, I am


2 sure you would agree.

3 I would like to emphasize that after two

4 years on Lotronex, I am healthy and living proof

5 that Lotronex can be used safely and effectively.

6 I am hoping that it will be back on the market


7 before I run out and put into a position where I

8 have to try other drugs that might be harmful to

9 me.

10 Please let us not close our eyes to the

11 need for IBSD patients to be able to have access to


12 Lotronex, so they can live normal, productive

13 lives, enjoy their families and friends, and go on

14 vacations, as I am sure all of you do.

15 This is not too much to ask for, and

16 Lotronex is the answer. To anyone who believes


17 this medication should not be reintroduced, let

18 them contend with IBSD for one week, and they

19 surely would change their minds.

20 Thank you.

21 DR. WOLFE: Thank you.


22 Next, we have Diana Hoyt, followed by

23 Kathleen Ghawi.

24 MS. HOYT: Hi. My name is Diana Hoyt. I

25 want to thank you for giving me the opportunity to







1 speak to you today.


2 Let me begin by reassuring all of you that

3 I have no connection to any drug company, I am not

4 being paid to say this, and I have come here at my

5 own time and expense in hopes that you will hear my

6 plea--I will try not to be emotional--and bring


7 Lotronex back.

8 I took Lotronex for 16 months, and they

9 were the best 16 months of my life. I am a

10 successful business woman, I am a wife, and I am a

11 mother.


12 I have been a recruiter for 15 years, and

13 I manage an award-winning sales office. I say this

14 hopefully to give myself some credibility because I

15 think I am going to be pretty emotional here.

16 Standing here right now is so far outside


17 of my comfort zone. Just to be here, I have to

18 take four Imodium in the morning, I have to not eat

19 for 24 hours, and I am wearing a diaper, and that

20 is pretty pathetic.

21 I take about 8 to 10 imodium a day just to


22 get through the day, and I am sure that is wreaking

23 havoc on my system.

24 Before Lotronex, I thought I had the worse

25 IBS imaginable, and since taking Lotronex, and







1 since its removal, I have met many people that are


2 sicker than I am, which I found hard to believe.

3 They have had to quit their jobs, they can't work,

4 they can't leave their homes, so maybe I should

5 consider myself lucky.

6 I have been trying for months to think


7 about what I would say to all of you, what can I

8 possibly say that would make a difference. I have

9 suffered from the debilitating effects of IBSD for

10 almost 30 years. I am 43 now. I have spent most

11 of my life rushing to a bathroom, sweating, in


12 pain, heart pounding, praying that I would make it

13 in time, and most of the times I don't.

14 I have had accidents by the side of the

15 road, on a deserted street, in my car, at my desk

16 at the office. I have thrown my soiled clothes in


17 a dumpster and cried all the way home.

18 If I am asked to do anything, my first

19 question is always is there a bathroom there and

20 can I handle it. Anywhere I go, anything I do, the

21 bathroom is the number one concern.


22 I am not even going to talk about my

23 family because then I am really going to cry, but

24 they have made such sacrifices for me. I have a

25 3-year-old son and I will never be able to give him







1 a normal life without Lotronex. I can't take him


2 to the park, I can't drive a carpool, I can't do

3 anything that a normal person takes for granted.

4 It is funny that I have kept this bottle

5 for seven months, and it's empty, and it sits in my

6 bathroom, and I think I keep it because it


7 represents hope for me that someday I will be able

8 to fill it back up and I can lead a normal life.

9 I guess I could be selfish and ask that

10 you only allow Lotronex to be given to those of us

11 that it has helped in the past. That would be the


12 easy thing for me to do, but I ask that you find a

13 way to get this life-altering medicine to everyone

14 out there that can benefit from it, whether it be

15 male or female.

16 Let's find reasonable ways to monitor the


17 symptoms, put the responsibility where it belongs,

18 with the doctor and the patient. I hate to think

19 what would have happened to me if I had never had

20 the opportunity to try Lotronex and know that it

21 was out there. It is a miracle drug.


22 I know that it cured me, and it should

23 give hope to everybody out there with IBS that

24 there is something that will make a difference and

25 help you to lead a normal life.







1 Although IBSD may not be life threatening,


2 you can see from my story, and those from everybody

3 out here, that a life without Lotronex is a

4 miserable existence.

5 So, I think quality of life is the issue

6 here. I beg you to bring Lotronex back to those of


7 us who so desperately need it.

8 Thank you very much for listening.

9 DR. WOLFE: Thank you, Ms. Hoyt.

10 Ms. Ghawi is next. Could I ask is Terry

11 Romeo here? If not, the next speaker will be Mike


12 Schmidt.

13 Ms. Ghawi.

14 MS. GHAWI: I am Kathy Ghawi. I am from

15 St. Charles, Illinois. I am also out of my comfort

16 zone. I am a suburban homemaker. I was a soccer


17 mom long before it became very popular.

18 I want to say that I think they should

19 make speaking in front of this committee an olympic

20 event, because condensing your entire adult life

21 with IBSD in four minutes has to go for the gold


22 medal. I will do so.

23 As a college history major, I was saddened

24 to see how they would talk about the ravages of war

25 for World War I and World War II and the Vietnam







1 War, and talk about man's inhumanity to man. Let


2 me assure you the removal of Lotronex, the only

3 effective treatment for IBSD, has to rank right up

4 there with man's inhumanity to man.

5 It is enough my mother suffered, my sister

6 suffered, and now my children. Enough is enough.


7 We have to find some respect for this disorder.

8 It is interesting. We have several cases

9 of IBSD, irritable bowel disease, in our family,

10 and it is interesting how they say that a third of

11 IBD sufferers also have IBS. Well, isn't that


12 something that we have all these drugs to control

13 the irritable bowel disease, and yet you could have

14 the IBS going with no remission. It is very, very

15 sad.

16 There are so few IBD sufferers, but they


17 seem to get all the respect and all the attention.

18 Now, I am not in a competition for pain and

19 suffering. I think pain and suffering is terrible

20 wherever it comes from, and it should be addressed

21 equally.


22 I also wonder, since it is reported that

23 mostly women suffer from IBS, is it possible that

24 this is another gender inequity in terms of

25 research and funding and taking it seriously







1 because it's women? I ask that. I don't have the


2 answers, but I throw that out to the powers that

3 be.

4 I have to tell you that I was insulted

5 because early on in my 36 years of dealing with

6 this condition, I was told it was all in my head


7 amongst other things. Yet, when I was on Lotronex,

8 I lived a normal life. I could eat anything, I

9 could go anywhere. Stress, who doesn't have it

10 every day of their life? Fiber, who needs it?

11 When you had Lotronex, it was not an issue. Diet


12 and exercise. I was even told to lose weight.

13 Well, thank you.

14 Lotronex made me live a normal life. I

15 would ask all of you who are members of the medical

16 community, who told us year ago that it was all in


17 our head, to acknowledge you made a mistake, but

18 now we can correct it, because we have the research

19 available to do something about it.

20 I don't want to see another generation of

21 people to have to go through what I have to go


22 through. I also want to say that I am only here

23 today, not because of the medical community, but

24 because of the support of my family and my friends

25 and the Lotronex Action Group.







1 I want to single out my daughter for


2 traveling all the way. I live in Illinois, she

3 lives in North Carolina. We had a parade up here.

4 It is important that you know that when

5 one person in the family has a chronic disorder,

6 the entire family suffers. It is because of them


7 that I am here today, and I will continue to go on,

8 and the members of my group.

9 I have to tell you, you have got to find a

10 way to resolve whatever goes on behind closed

11 doors. It is not a matter of politics when you are


12 in our shoes. You have got to find the answer.

13 You can't look at the bottom line. It is the

14 patient name at the top line that you have got to

15 look at.

16 I am wearing today a floral lapel. It's


17 the forget-me-not flower. When you are deciding

18 what to do with our lives, take a look at the white

19 forget-me-not. It represents the purity of the

20 patient who wants the cure, and the blue stands for

21 the blue pill Lotronex. Please return it and


22 remember the patient.

23 Thank you.

24 DR. WOLFE: Thank you.

25 Mr. Schmidt, followed by Brenda and







1 Franklin Compton.


2 MR. MORRIS: Good morning. My name is Bob

3 Morris. I will be speaking for Mr. Schmidt who

4 could not be here today.

5 I am an attorney with the firm of Smith,

6 Phillips, Mitchell & Scott in Batesville,


7 Mississippi. We currently represent 20 individuals

8 who could not be here, each of whom took the drug

9 Lotronex and were injured as a result.

10 We have filed a class action in the

11 Southern District, Federal Court, in Southern


12 Mississippi seeking class certification of a

13 nationwide class based on the type of injuries that

14 we are seeing from the use of the drug Lotronex.

15 Our firm is also working in association

16 with the Schmidt firm out of Dallas, Texas, who


17 represents numerous individuals from Texas who also

18 took the drug Lotronex and were injured.

19 I am here representing our clients today

20 and the clients from the Schmidt firm to stand in

21 opposition to the reintroduction of the drug


22 Lotronex under the current proposed scenario.

23 It is our position that the risks outweigh

24 the questionable benefits of Lotronex and that

25 during the time Lotronex was on the market, it was







1 being overprescribed to individuals with IBS, which


2 is, in itself, a poorly defined condition.

3 By the end of 2000, Lotronex was

4 associated with at least five fatalities, 63 cases

5 of ischemic colitis, 75 cases of severe

6 constipation, and 3 cases of mesenteric occlusion.


7 Because of the rate of under-reporting adverse

8 advents to the FDA, it is likely that there were

9 many more adverse events than this, some say

10 perhaps 10 times as many cases.

11 It is our position that this is not an


12 efficacious drug and that there was only a 10 to 15

13 percent difference in the response between patients

14 that received Lotronex and the patients that

15 received placebo. In addition, on a discomfort

16 scale of zero to 4, Lotronex only relieved patient


17 symptoms 0.12 to 0.14 points more than placebo.

18 Furthermore, the endpoints in the studies

19 that Glaxo Wellcome submitted to support this drug

20 were based on self-reported subjective criteria.

21 We also have serious reservations about


22 the proposal of Glaxo Wellcome as to the class of

23 potential users of this drug if it is reintroduced.

24 This is based in part on Glaxo's past marketing

25 record, and also on the fact that a person who







1 fails to respond to conventional treatment may then


2 have access to the drug.

3 We heard today from numerous persons that

4 this is a problematic situation because there does

5 not appear to be an effective treatment that is

6 considered conventional to date. This means that


7 the lack of effective treatment could allow every

8 person with IBS to potentially receive this drug

9 upon reapproval.

10 The prior Medication Guide submitted for

11 Lotronex and required by the FDA shifted the


12 responsibility of preventing adverse events from

13 Glaxo Wellcome to the pharmacists and patients. It

14 is obvious that this did not prevent serious

15 gastrointestinal events.

16 Further, the proposal now set forth by


17 Glaxo Wellcome where it is requiring individuals to

18 diagnose themselves with having ischemic colitis is

19 deemed to be inappropriate at this time.

20 Because there is no pattern with respect

21 to predictive factors for what patients may develop


22 ischemic colitis or severe constipation, even the

23 use of Lotronex in a subpopulation of individuals

24 may result in severe adverse events or fatalities.

25 It is very difficult to require physicians







1 to only prescribe a drug to a restricted patient


2 population when dealing with an ill-defined

3 condition such as IBS. There will be an extremely

4 well-defined criteria necessary to evaluate and

5 decide on which patients should receive Lotronex.

6 Gradually, over time, it is likely that


7 the drug will be prescribed to all IBS patients,

8 and there will be even more fatalities and serious

9 adverse events.

10 An active monitoring program is proposed

11 herein today for Lotronex. If it is reapproved, it


12 is of questionable value since only about 10

13 percent of adverse events are ever reported to the

14 FDA.

15 I would go on record on behalf of my

16 clients from the State of Mississippi and the


17 Schmidt firm's clients whom they represent from the

18 State of Texas, and ask that this drug not be

19 reapproved at this time.

20 Thank you.

21 DR. WOLFE: Thank you.


22 Next, we have Brenda Compton, followed by

23 Dennis Larry.

24 MS. COMPTON: First of all, I just want to

25 say I didn't catch your name, but have you ever







1 soiled your pants in public?


2 My name is Brenda Compton and I have

3 diarrhea-predominant IBS. I don't represent

4 anybody except myself. I paid for my own way up

5 here, and the first thing I did as I came in for

6 the meeting this morning was make sure I knew


7 exactly where the bathroom was as I have always had

8 to do for the last 30 years every time I leave my

9 house.

10 Now, I want you to spend the day in life

11 with me. I am not a statistic, I am a person. I


12 went on a field trip with my son, his sixth grade

13 class, to the Georgia State capital. We boarded a

14 bus in Flowery Branch, and began the one-hour ride.

15 Fifteen minutes into the trip, the cramp hits my

16 gut, and the familiar panic begins. I am soiling


17 my pants.

18 Because this is a common occurrence, I

19 have on lined panties. I pray no one notices the

20 odor. Our school bus arrived and pulls up to the

21 capital steps. I have already made my way to the


22 front, so that I can get to the restroom as quickly

23 as possible.

24 I change panties, throw the ruined ones

25 away, and cry. I try to regain my composure for my







1 son's sake. I go back out to join him and his


2 group, and guess what. It all begins again.

3 This is a scene I have lived out virtually

4 all my adult life, and just when I am convinced it

5 can't get any worse, it does. On June 25th, 1998,

6 I had emergency surgery, and in a matter of two


7 hours, I went from no menopausal symptoms to

8 postmenopausal, depression. The bouts of diarrhea

9 came more often, they came every day now. I began

10 to lose weight at an alarming pace. I dropped to

11 88 pounds.


12 My doctor performed every conceivable and

13 invasive test, if you have never had them, to try

14 to find a cause, but everything was fine, no

15 physical reason. Her only conclusion is I have an

16 incurable disease -- incurable disease called


17 irritable bowel syndrome.

18 Meanwhile, over the coming weeks and

19 months, I continued to lose weight. The doctor

20 orders a bone density scan because I have now

21 reached 77 pounds. My life is in jeopardy. She


22 tells me this. I have lost 11 percent of my left

23 hip because my body has lost every bit of its fat

24 and it is now pulling bone density just for me to

25 live. So, it was life threatening to me. I almost







1 died from it.


2 Then, on May 9th, 2000, I got to my doctor

3 for another visit, but this time there is hope.

4 She tells me a new drug called Lotronex has just

5 been released, and she wants me to try it. I begin

6 that afternoon, and in three days, the diarrhea is


7 gone, a true miracle.

8 Over the coming days, I deal with the fear

9 that it will return, but it doesn't. My weight

10 gradually increases, and my life is a new

11 experience, normal.


12 Then, I remember seeing the morning news

13 on November 28th, 2000, but nothing else registered

14 the rest of the day. I cried uncontrollably. The

15 availability of the only medication that had

16 allowed me to live a normal life for seven


17 wonderful months was gone. Today, I take another

18 drug that sometimes works, sometimes doesn't. Most

19 of the time it doesn't.

20 Once again, the humiliation and fear is

21 back. She sent me into psychotherapy because I was


22 suicidal and severely depressed. I am begging you

23 to bring this drug back. I am not asking you, I am

24 begging you. I keep this as a remembrance of the

25 miracle of my life, and only you can bring it back







1 to me. I have copies of my doctor's letters that


2 my life was threatened, almost went to the

3 hospital.

4 Thank you.

5 DR. WOLFE: Thank you, Ms. Compton.

6 Mr. Larry, to be followed by Dr. Stolley.


7 MR. LARRY: I bring to you an interview of

8 my client, Gloria, from North Florida who suffered

9 bowel perforation following severe constipation.

10 She now is quadriplegic, lives on a PEG tube, lives

11 on oxygen. Here is her story. She asked me to


12 bring this to you because she is addressing her

13 comments to you, the FDA Committee.

14 [Videotape shown. Experience of Gloria

15 Lockett.]

16 DR. WOLFE: Dr. Stolley.


17 DR. STOLLEY: My name is Paul Stolley, and

18 I was formerly the Chairman of the Department of

19 Epidemiology and Preventive Medicine at the

20 University of Maryland School of Medicine at

21 Baltimore.


22 I am co-author of a Foundations of

23 Epidemiology Textbook and currently work half-time

24 at the Public Citizen Health Research Group.

25 During the academic year of 2000-2001, I







1 worked 80 percent time at the FDA as a consultant


2 in epidemiology for the group that collects and

3 evaluates adverse drug reactions.

4 I co-authored and signed the FDA Memo of

5 November 16, 2000, that preceded the November 28th

6 decision by Glaxo to withdraw Lotronex from the


7 market. I am also a practicing physician.

8 In that memo, we argued that there were

9 compelling reasons for withdrawal of Lotronex from

10 the market. The main points we made in that memo

11 were that the drug is minimally effective and for


12 only the diarrhea-predominant form and only in

13 women, and that the price paid for this

14 gender-specific diarrhea-predominant efficacy is

15 much too high - ischemic colitis that can result in

16 surgery, colectomy, and death, severe constipation


17 that can require hospitalization and surgery,

18 mesenteric artery thromboses requiring surgery, and

19 rarely causing death.

20 The rate of ischemic colitis associated

21 with the drug is remarkably elevated and beyond


22 dispute as there were 16 cases in the

23 alosetron-treated arms of the clinical trials and

24 only one case in the placebo arm.

25 While the drug is only approved for 12







1 weeks of use, in actual practice, this chronic


2 condition may be treated indefinitely with the

3 drug.

4 The rate of ischemic colitis associated

5 with Lotronex may be as high as 1 per 300 users in

6 just the 12-week period. While many of these


7 colitis episodes have not led to serious damage,

8 there have been perhaps 7 or more reported

9 fatalities and numerous surgical interventions.

10 The questionable argument has been made

11 that ischemic colitis is a feature of irritable


12 bowel syndrome, however, when the FDA searched its

13 own adverse drug reaction files for reports of

14 ischemic colitis, no reports of ischemic colitis

15 were found associated with loperamide or

16 diphenoxylate.


17 I believe this drug should never have been

18 approved and I urge you not to reintroduce it, as

19 you will just create another mini-epidemic of

20 ischemic colitis and other problems.

21 Thank you.


22 DR. WOLFE: Thank you, Dr. Stolley.

23 This concludes the public forum. I want

24 to thank all those who spoke for a couple of

25 reasons. First of all, I commend you all for







1 doing what physicians can't do very commonly, that


2 is, keeping on time. You did a wonderful job.

3 Many of us run meetings with continuing education,

4 by the way, which includes IBS oftentimes, and our

5 speakers tend to run over. You were wonderful in

6 keeping right to the point and keeping on time.


7 I want to editorialize here to some

8 extent. I want to thank those of you who are the

9 patients, who traveled here great distances, on

10 your own money, and on your own time, to make

11 public what should be a private matter between you,


12 your family, and your physicians, and I thank you

13 all for coming here.

14 We will reconvene at exactly 1:45.

15 [Whereupon, at 12:55 p.m., the proceedings

16 were recessed, to be resumed at 1:45 p.m.]









2 [1:45 p.m.]

3 DR. WOLFE: Before we start the questions,

4 I would like to offer the opportunity for members

5 of the panels to ask FDA and GlaxoSmithKline the

6 questions from before. What I am going to do,


7 instead of just going to individuals, I am going to

8 go right in order around, and if you don't have a

9 question, say pass. I will start again with Dr.

10 Richter, if you want to continue your line of

11 questioning to either FDA of GlaxoSmithKline.


12 Let's try to keep the questions succinct

13 and the answers succinct, as well.

14 More Questions on Presentations

15 DR. RICHTER: The question I have is

16 really for Victor and maybe other people at the


17 FDA. Surely, there must be, I am sure there has

18 been other drugs that have come through the FDA for

19 an IBS indication with diarrhea being a major

20 symptom, and have they had the opportunity to go

21 back and look through those studies to see if there


22 is this unusual instance of ischemic colitis,

23 particularly in the background, because I have to

24 say I find that background data in the normal

25 population of IBD a little surprising from my own







1 clinical experience.


2 DR. RACZKOWSKI: I am going to ask Dr.

3 Hugo Gallotorres to answer the question, but just

4 in general terms, many of the drugs that were

5 developed for IBS or that have any sort of

6 indication for IBS are old drugs, and we certainly


7 are looking at some of the newcomers in this field

8 as to whether this might be a class effect or not.

9 DR. GALLOTORRES: Yes, indeed, we have

10 several applications for diarrhea-prone IBS, but

11 these are INDs and we cannot comment on this, but


12 there are several. I hope that answers your

13 question.

14 DR. RACZKOWSKI: Just one more comment.

15 Some of the other drugs that had been developed in

16 this area, some of the older drugs were the


17 anticholinergics, and they basically failed in

18 terms of being able to demonstrate efficacy for

19 IBS.

20 DR. WOLFE: Dr. Cryer.

21 DR. CRYER: This is a question for the


22 sponsor. So, given that IBS is not infrequently an

23 episodic disease, what can the sponsor tell us

24 about the timing or the incidence of ischemic

25 colitis as it relates to the phase of IBS, which







1 the patients in the clinical trials were in?


2 DR. CARTER: Most likely because of the

3 small number of cases that we saw in the clinical

4 trials, we really don't have that data. Most of

5 the patients I believe, at least based on the

6 baseline characteristics, which on the whole were


7 two weeks in duration, were in the same chronic

8 phase. We don't have any evidence of any change in

9 their baseline presentation. So, I can't answer

10 that question.

11 DR. WOLFE: Dr. Anderson, any questions?



13 DR. WOLFE: Dr. Venitz?

14 DR. VENITZ: Yes, I have a question for

15 Glaxo, as well. I am looking at your background

16 material where you justify your dose, which is


17 right now 1 mg BID. I am on page 22, looking at

18 the results of your Phase IIA studies, and I am

19 wondering whether you have really found the optimal

20 dose, because obviously, one of the things that you

21 are proposing as part of a risk management plan is


22 a dose titration strategy, implying that the dose

23 right now may not be the optimal dose for every

24 patient.

25 So, what is the evidence for you to have







1 started in the first place with a 1 mg BID dose?


2 DR. TRABER: Well, you are quite right

3 that a decision to choose a dose is a very

4 important one in the clinical trial setting. There

5 was a lot of discussion around what dose to choose

6 at the end of the Phase IIA studies.


7 The dose of 1 mg BID was chosen, though,

8 and therefore, all of the Phase III clinical trials

9 were done with that dose. So, therefore, the vast

10 majority of evidence we have is with 1 mg BID.

11 The dose titration issue gets at the fact


12 that the physiological effect or the

13 pharmacological effect of the drug is to cause

14 constipation in a reasonable percentage of

15 patients, and often in drugs that have a

16 predictable type of side effect, clinical practice


17 often dictates some titration up of the dose.

18 Furthermore, when used in the market,

19 there is lots of testimony from patient's

20 physicians that a lower dose works, so we feel the

21 titration that we propose is prudent medical care


22 although the vast majority of our data is based on

23 1 mg BID.

24 DR. VENITZ: I am very much in favor of

25 dose titration, don't misunderstand me. It is just







1 I am looking at your dose titration studies, and it


2 appears that the doses higher than 1 mg, you

3 actually have less of a benefit or less of at least

4 short-term benefit.

5 So, I am not sure whether the 1 mg dose is

6 already at the plateau of your dose response curve


7 or you could even go lower than 0.5, which is what

8 you are proposing right now as your starting dose.

9 [Slide.]

10 DR. CARTER: This was the first of the

11 two, Phase II dose ranging programs in female


12 patients where the 2 mg dose was seen to be more

13 efficacious, at least for the female population

14 there than the lower doses.

15 If we go to the next one, E12.

16 [Slide.]


17 This is the second dose-ranging study

18 where if I can just look at the males first, we see

19 the dose is seemingly no benefit with respect to

20 the placebo for the male, whereas, in the female

21 study, the adequate relief endpoint was clearly


22 beneficial, more beneficial at the 1 mg dose.

23 DR. VENITZ: But as you go higher, at

24 least pharmacology would dictate that you would see

25 more of an effect, and you actually have a







1 reduction as you go to higher and higher doses. I


2 guess that is what I am pointing out to you.

3 DR. CARTER: Right. I mean that is a

4 feature of what we saw in this particular trial.

5 DR. VENITZ: Let me rephrase my question

6 then. Do you see any benefit in going actually


7 lower than the 0.5 as a starting dose and starting

8 maybe at 0.25, or do you think that that is going

9 to be completely futile?

10 DR. CARTER: It may be that this is

11 something that we have to consider, but I suspect


12 that we probably are going to reach a point where

13 the efficacy would just not be shown at that point.

14 DR. VENITZ: The second question that I

15 had, did you actually break this down by the

16 severity of the symptoms and baseline conditions?


17 DR. CARTER: I don't believe we did.

18 Dave, do you know whether we broke this

19 down by severity of symptoms at all?

20 DR. VENITZ: It may be worthwhile doing to

21 see whether a different starting dose, depending on


22 the baseline severity, would benefit.

23 DR. McSORLEY: In the Phase II studies

24 that we did, the first study that was done in

25 Europe had all IBS subtypes and both genders, and







1 what we saw was a beneficial effect primarily in


2 females who had the more diarrhea-like bowel

3 habits, looser stools, more frequent stools.

4 In the 8-2001 study that is shown here,

5 also enrolled both genders, that was done in the

6 U.S., and because of the results we saw by the


7 severity of bowel functions in the previous study,

8 this study was limited to look at just the higher

9 stool consistencies.

10 So, we had evidence from earlier on that

11 it was more beneficial in those with more


12 diarrhea-like symptoms and less beneficial for

13 those with firmer and less frequent stools.

14 DR. VENITZ: Is there any way that you can

15 tease out if there is a different starting dose

16 possibly required for the different subpopulations?


17 DR. McSORLEY: Well, at this point, you

18 can see the numbers are getting pretty small, and

19 that n equal 197 is across all five of the dose

20 groups, so it is probably a little bit difficult to

21 tease that out additionally with so few patients.


22 DR. VENITZ: Okay.

23 DR. WOLFE: There is another. Efficacy is

24 one thing. The other reason is to start at a lower

25 dose. For those of us, let's jog our memories a







1 little bit. When we used sulfasalizine, we started


2 with a 5 mg dose knowing full well it didn't really

3 work, but we did it for safety purposes, and you

4 have shown that constipation is dose-dependent.

5 I can tell you know--this is

6 anecdotal--but some of my patients did well on 1 mg


7 every other day, as did other patients in the

8 audience, and some of the records that I did read.

9 So, mostly for safety purposes, sometimes it is

10 prudent to start at a lower dose to see its

11 tolerance, especially in dose-dependent


12 constipation.

13 So, I would actually ask that you would

14 consider if we go forward with this, starting at a

15 lower dose for that reason.

16 DR. LaMONT: For Dr. Raczkowski, your


17 final slide said that the success of the plan could

18 be evaluated through process controls or evaluation

19 of outcomes, and I just wonder what you had in mind

20 for that and what criteria might be used to finally

21 withdraw the drug.


22 Would it be the same toxicity, worse

23 toxicity--I assume worse toxicity would be one

24 reason, but would similar or identical toxicity be

25 reason to finally withdraw?







1 DR. RACZKOWSKI: These are actually


2 questions that we are posing to the Advisory

3 Committee, Questions 4, 5, and 6 are largely

4 focused on process controls, and Question No. 7 is

5 focused on outcome and whether or not the Advisory

6 Committee feels that those are appropriate.


7 DR. LEVINE: A question for Glaxo and a

8 question afterwards for Dr. Krist. I wondered, it

9 is apparent that during the clinical trials, there

10 was much more attention paid to constipation, both

11 the observation of it and the withdrawal, the


12 statistics are higher for those people who, during

13 the clinical trials, were stopped because of

14 constipation.

15 As it opened into the market, there was

16 less available about the complications. Toward the


17 ends of your studies, when you were still having

18 clinical trials, can you pick out any particular

19 trials in which the incidence of constipation was

20 higher as the public and as the physicians were

21 more aware of it toward the end of your trials or


22 trials that are still under progress, and not

23 analyzed well yet from a chronological point of

24 view?

25 DR. CARTER: No, I can answer that in two







1 ways. First of all, the trials where attention was


2 placed on constipation, and there were two, one

3 trial was the open-label trial that we have

4 referred to before where patients knew that they

5 were on a drug that was potentially constipating,

6 we tended to see more constipation there.


7 In two other trials, the urgency trials

8 that Dr. Traber showed this morning, one of the

9 secondary objectives was to look at the impact of

10 an intervention, withdrawing drug or drug holiday,

11 or instituting laxative use, and we instructed the


12 investigators to make sure that the subjects in

13 these trials proactively reported any event of

14 constipation.

15 What we saw there is that we saw a rise in

16 the reports of adverse events of constipation, a


17 rise in the alosetron-treated group, and a rise in

18 the adverse event reports of constipation in the

19 placebo group, so that the delta was about the

20 same.

21 DR. LEVINE: I will pass on the next one


22 to Dr. Krist because we will probably discuss it,

23 unless you want me to go ahead. Actually, what I

24 was going to ask Dr. Krist is, as a family

25 practitioner, it is apparent on one of the possible







1 routes of approval of this product, is to consider


2 the burden that the physician has to do to take

3 care of it, the interaction, the time involved,

4 gastroenterologists versus family practitioners.

5 I wondered, in your experience using some

6 other drugs where you are, in fact, committed to


7 do--

8 DR. WOLFE: Time out. This is questions

9 to the Company.

10 DR. LEVINE: Just to the company?

11 DR. WOLFE: Yes, Company and FDA.


12 DR. LEVINE: That is what I thought, I

13 don't think this is the time.

14 DR. WOLFE: This is clarification now for

15 presentations. We will get that later on.

16 Actually, we will have some time for that.


17 Dr. Fleming.

18 DR. FLEMING: Several questions. Let me

19 try to highlight two related key questions and just

20 see how time allows.

21 Dr. Raczkowski made a very key point in


22 his presentation, noting that patient selection is

23 at the heart of a risk management plan as we go

24 from here and think how can we either treat or

25 evaluate a patient population in the optimal way,







1 identifying as best we can who those people are


2 that seem to have the greatest chance of a

3 favorable benefit to risk.

4 There are two key aspects of that. One is

5 identifying the population at lowest risk and the

6 population at highest benefit. So, taking things


7 one at a time, where ischemic colitis is a key

8 focus here with incidence rates projected at 2 to 5

9 per 1,000 at three months.

10 We heard several discussions today, and

11 they seem to repeatedly make the same point. Dr.


12 Carter, Dr. Permutt, Dr. Mackey all said data do

13 not reveal any potential risk factors for ischemic

14 colitis, and Dr. Mackey went beyond that to say

15 presenting symptoms do not necessarily predict

16 severity of outcome.


17 So, my first question is, is it proper, am

18 I missing anything, is it proper to conclude at

19 this point, as it relates to ischemic colitis, that

20 we really don't have insights as to who we would

21 identify as that cohort that would be at a lower


22 risk?

23 The second aspect of benefit to risk is

24 benefit, is efficacy, and a similar question arises

25 there, what insights do we have? I know Dr.







1 Raczkowski speculated that patients that have the


2 most disabling symptoms stand to benefit the most.

3 Are there direct data that the FDA or the

4 sponsor can put before us that provides insights

5 about potential effect modifiers? The only thing I

6 could find from this morning's presentation was


7 slide A32 by Dr. Traber that basically looks at

8 potential effect modifiers for efficacy based on

9 baseline level of severity for baseline pain,

10 urgency, and frequency, and it doesn't show any

11 effect modification. It shows the same magnitude


12 of effect that either is not greater effect in any

13 specific subcohort.

14 So, two related questions. Are we missing

15 anything that you folks know that we haven't seen,

16 that would assist us in identifying the subgroup


17 that has the greatest likelihood of achieving

18 favorable benefit to risk?

19 DR. TRABER: Let me speak to the efficacy

20 question first. I also mentioned around that

21 trial, looking at the data, separating it out, that


22 indeed individuals with harder stools, fewer bowel

23 movements, fewer than two bowel movements per day

24 did not have an efficacious response to alosetron.

25 So, there is a subpopulation of individuals that







1 identified themselves as diarrhea-predominant, but


2 did not have an effect.

3 However, the data that I did show, by

4 separating out the information, shows that those

5 with moderate or severe symptoms, as defined by

6 both urgency, numbers of stools, and pain, had


7 similar benefit.

8 In looking at the information with more

9 severe patients, and that would be those patients

10 that had urgency more than 80 percent of the time,

11 more than 80 percent of the days, there was a


12 marked efficacy improvement there, so we did look

13 at more severe groups.

14 But in the post-hoc analysis of the

15 studies, both moderate and severe patients had the

16 same, had effect.


17 DR. FLEMING: Could you show us those data

18 that basically separate out the most severe

19 patients from lesser severe patients to give us a

20 direct data presentation of what that effect

21 modification is?


22 While you are getting that, a second

23 question, you have specifically stated that your

24 proposed target population would be

25 diarrhea-predominant IBS who failed to respond to







1 conventional treatment. Do you have any specific


2 evidence, when we target that group who had failed

3 to respond, to show us that we, in fact, have

4 direct evidence of efficacy in that subcohort? Two

5 additional questions, I guess.

6 DR. TRABER: The direct answer to that is


7 no, we don't have a clinical trial taking patients

8 who have failed a defined conventional therapy and

9 placed them alosetron. What we were looking for in

10 the labeling was a straightforward way to identify

11 individuals that would have more severe


12 debilitating disease, those individuals who have

13 been evaluated to have diarrhea-predominant IBS,

14 who had been treated by a physician and failed

15 conventional therapy, which would be education,

16 reassurance, diet, anticholinergics, and


17 antidiarrheals, and that that subpopulation would

18 be an effective way for physicians to identify a

19 subgroup.

20 The other thing is we did evaluate in

21 comparison alosetron to traditional therapy, so a


22 selected group of individual who were selected for

23 all the same characteristics, and although, on an

24 open-label trial, randomized to either traditional

25 therapy or to alosetron, and saw marked







1 differences.


2 DR. FLEMING: But that would be, of

3 course, a different--I mean those who would be

4 people who hadn't failed obviously.

5 DR. TRABER: It answers a different

6 question.


7 DR. FLEMING: So, essentially, what is

8 really critical if we are looking at a proposed

9 indication, is to, at a minimum, have direct

10 evidence that in that proposed indication, i.e.,

11 those that have failed conventional therapy, that


12 we have confidence of efficacy, but I am eve

13 looking for more than that, the evidence that you

14 would have to confirm what we would hope to be the

15 case, but nevertheless, isn't always true, and that

16 is those with more severe baseline disease, in


17 fact, are those who benefit the most.

18 I think you were going to present

19 something on that?

20 DR. CARTER: If you can put up L-35.

21 [Slide.]


22 This was again post-hoc analysis here,

23 looking at the pooled data from five

24 placebo-controlled trials, looking at symptoms on a

25 daily basis with adequate relief of pain and







1 discomfort as stratified for the most severe


2 symptoms at baseline, and then followed over the

3 duration of the trial here. Weekly adequate relief

4 with the pain severity of greater than 2.5, which

5 was in the moderate to severe category.

6 DR. TRABER: You want a comparison of the


7 less severe patients to the more severe patients.

8 DR. FLEMING: Indeed, as you presented in

9 slide A32. This just seems to be more confirming

10 that you have roughly the same magnitude of effect

11 across all subcohorts.


12 DR. TRABER: Could you put up A32 then.

13 [Slide.]

14 Here, the point is you are correct. We

15 did stratify to what we call moderate and severe

16 pain, urgency, frequency, and so forth. What we


17 don't have on this slide, and I wonder if somebody

18 could find this slide, is those individuals that

19 had harder stools or less than two stools per day,

20 and their effect by alosetron, which is the

21 question you are asking.


22 This is 3 to 4, and this is 4, but there

23 is also a subgroup less than that.

24 Maybe what we can do is find the specific

25 slide for you and come back to that. I think the







1 FDA also concluded from their analysis of the data


2 that the individuals with less than two stools per

3 day also had less efficacy than the moderate to

4 severe.

5 Your other question, which I think was

6 your first one, was about ischemic colitis, and,


7 indeed, you are correct. We found no evidence of a

8 predictor for individuals who might develop

9 ischemic colitis.

10 DR. RACZKOWSKI: Some of the analyses that

11 were done independently by the FDA statistician


12 showed that patients with less severe urgency at

13 baseline tended to respond roughly with the same

14 order of magnitude of a treatment effect as those

15 with more severe urgency.

16 I don't know the details of exactly how


17 the data were cut, but that observation was

18 confirmed. In addition, patients who did have the

19 harder stools or stools less than twice per day

20 also tended to have less benefit.

21 DR. FLEMING: So, in summary, for this


22 critical point that you put before us, at least the

23 data that we have right here either doesn't allow

24 us to identify the risk groups that have the

25 greatest risk or lesser risk, or efficacy, those







1 that have the greatest benefit or lesser benefit at


2 least relative to the analyses that have been done

3 to date?

4 DR. RACZKOWSKI: Well, I think we would be

5 interested in any qualitative advice you might have

6 in that regard.


7 DR. WOLFE: I hate to be a drill sergeant,

8 but we allotted 20 minutes initially for this, so

9 let's again keep these questions succinct, try not

10 to repeat the same question, and answers also

11 succinct.


12 DR. METZ: I have a couple of quick

13 questions.

14 First of all, regarding the colonic

15 ischemia question, I found it interesting it was

16 mentioned earlier that some of the effect of this


17 agent may be to reduce pain sensation, and some

18 patients become so constipated and had a lot of

19 pain, got sick because they didn't know that things

20 were happening.

21 On the other hand, I find that all the


22 patients who presented with colonic ischemia,

23 presented with pain, and that was 75 percent of the

24 time. Colonic ischemia, to my understanding,

25 generally does not present with pain.







1 The next point that comes up is that there


2 were these five cases that were discovered by the

3 FDA, perhaps in dispute by Glaxo, of mesenteric

4 ischemia, which does present with pain and which in

5 itself for me is a real life-threatening condition,

6 and I am wondering if we can clear up the dichotomy


7 between those two. That would be Question No. 1.

8 DR. BRANDT: I think that I can answer

9 that for you. You are correct when you say that

10 patients with colonic ischemia have a pain that is

11 different from pain in patients with acute


12 mesenteric ischemia. I am not going to answer a

13 question that hasn't been asked yet, which speaks

14 to the difference between acute mesenteric ischemia

15 and colon ischemia, but I think it is crucial that

16 at some point in this discussion we do that.


17 To answer your question, patients with

18 colon ischemia frequently have abdominal pain in

19 their presentation, but it is usually a mild pain,

20 an inconsequential pain, and one that the patient

21 might even forget that he or she had it unless


22 prompted and reminded of it.

23 The predominant symptom is almost always

24 rectal bleeding and bloody diarrhea. So, if you

25 have a patient who has what you believe to be colon







1 ischemia, and has severe abdominal pain, then, they


2 either have severe colon ischemia with transmural

3 disease and are close to perforating, who have

4 transmural gangrene, or they have colon ischemia

5 and acute mesenteric ischemia, or they have acute

6 mesenteric ischemia with GI bleeding, and maybe


7 they have elements of both, and perhaps you were a

8 little bit confused, or it is their underlying

9 background disease of abdominal pain.

10 But you are right, the presence of

11 significant pain should make one think


12 significantly about the accuracy of the diagnosis.

13 DR. METZ: Thanks. The other point was in

14 terms of this titration issue and the efficacy at

15 the lower doses. I understand very few patients

16 have been treated 0.5 BID. Our of interest, I would


17 like to know if Glaxo has data on the 0.5 BID,

18 number of patients, and how well they responded,

19 female predominant group. It is probably a small

20 number.

21 In practice, I think what will happen is


22 this drug is really going to be used on an

23 as-needed basis. It will be used briefly and then

24 stopped, and depending on how the disease is going.

25 So, do you have any data on using this agent as it







1 may well be used clinically, which is more of a prn


2 use?

3 DR. CARTER: We don't have any data on the

4 prn use at all. As far as the data on the 0.5 mg

5 BID, I think we have shown you, and what you see in

6 your briefing document is the data that we have


7 there. We don't have any additional data in

8 diarrhea-predominant women.

9 DR. TRABER: I just thought I would

10 quickly follow up on the question that I said I

11 would get back to some data on. We have found some


12 of that.

13 If you could just show the first slide

14 there.

15 [Slide.]

16 We have these cuts for a variety of data.


17 This happens to be the baseline consistency of the

18 stool. This is the most mild group in terms of

19 consistency, and there was no statistical

20 difference between the two groups in terms of

21 consistency in this mild group.


22 [Slide.]

23 However, if you get to the baseline

24 consistency where it was rated 4 to 5, there was a

25 highly significant response from week 2, all the







1 way through the 12 weeks.


2 So, we have these cuts of data showing

3 that the lowest level of symptoms didn't have

4 statistically significant responses.

5 DR. WOLFE: Dr. Gross.

6 DR. GROSS: I am getting the sense that


7 there wasn't a significant effort to try to rule

8 out inflammatory bowel disease in these patients

9 with irritable bowel syndrome.

10 Were the patients that had perforation and

11 death, or other complications, screened at all for


12 Crohn's disease or ulcerative colitis?

13 DR. CARTER: Although we did see some very

14 rare number of cases where the patient was

15 subsequently diagnosed with inflammatory bowel

16 disease that originally been on irritable bowel,


17 most of the patients, at least in the clinical

18 trials, on average, carried a diagnosis, a single

19 diagnosis of IBS for at least 10 years, so these

20 were chronic IBS patients, these were not typically

21 new IBS patients.


22 With respect to the postmarketing

23 surveillance data, we see somewhere in the region

24 of 5 to 20 percent of off-label use, if you will,

25 and some of those will possibly be patients with







1 inflammatory bowel disease.


2 Do we have enough cases to be able to make

3 a statement with respect to a differential impact

4 on complications of constipation or ischemic

5 colitis in inflammatory bowel disease, the answer

6 is no.


7 DR. STROM: Three questions. The first is

8 we are seeing a pretty consistent pattern of on the

9 order of a 30 percent placebo response, perhaps a

10 50 percent response on the drug, very consistently

11 statistically significant, but very modest in


12 magnitude, and yet we are hearing very dramatic

13 response from individual patients that is clearly

14 very convincing.

15 Could we be having here a problem of law

16 of averages, that your 30 to 50 percent is mixing


17 together some people who are having very large

18 effects and other people who are having no

19 response, and so the net effect is a modest

20 response only, but if you, instead of dichotomizing

21 of just response, non-response, you looked at


22 degree of response, you might have a bimodal

23 response, and might be able to pull out a small

24 subgroup of people who should use the drug, and, in

25 fact, will benefit dramatically from it?







1 DR. TRABER: I think this is a very good


2 point. I think the one consistent thing that we

3 have seen in all the trials is the fact that

4 multiple symptoms of IBS are affected by that 20

5 percent differential between the placebo response,

6 and therefore, the global effect in some of the


7 other quality of life effects are pretty

8 pronounced.

9 However, I am going to ask if we have

10 information about the spread of the data for the

11 responders. Dave, do you have any comments on


12 that?

13 DR. McSORLEY: I think that we have shown

14 you, we have tried to retrospectively go back and

15 look at response in different severities of

16 subjects.


17 DR. STROM: Let me try to be clear. I am

18 not asking now severity of how the patient started.

19 I am asking, rather than the response or not

20 response, which is what you average together, look

21 at the degree of response.


22 Was this small, average response that we

23 are seeing, in fact, everybody responded a little

24 bit, or a few people responded a lot, and most

25 people didn't respond at all?







1 DR. McSORLEY: Some of the analyses we


2 have done, in the urgency study we have tried to

3 look at that. I mean I think you still are asking

4 a question of separating out who is responding the

5 most. I think you have to be a severe patient, you

6 would have a greater response than those who would


7 not. If we could show slide N165.

8 [Slide.]

9 This was an analysis that we worked on

10 with the Agency at identifying patients who had

11 urgency control on less than 30 percent of days at


12 baseline, and then identifying responders who had

13 been satisfactorily controlled on at least 75

14 percent of days at months 1, 2, 3, and then overall

15 months.

16 So, what this does is it attempts to


17 identify those who would be making the larger

18 changes from an improvement rather than little

19 changes for people who are not that severe. This

20 was replicated pretty much in both of those urgency

21 studies.


22 If we could go to N166.

23 [Slide.]

24 Further restriction. Again, having less

25 than or equal to 30 percent of days with control at







1 baseline, to then having greater than 85 percent,


2 you see again there is a suggestion of a pretty

3 good difference in the proportion of patients who

4 actually moved quite far.

5 In addition, we did some of these analyses

6 at the request of the Agency to look at some of the


7 quality of life endpoints, again trying to identify

8 those who would show dramatic changes. If I could

9 show slide L14.

10 [Slide.]

11 We have a quality of life instrument, the


12 IBS Quality of Life questionnaire was done in five

13 placebo-controlled studies, and here, we looked at

14 some of the individual questions. This happens to

15 be four questions with respect to the social

16 activities score.


17 What we are showing here is the proportion

18 of patients who changed from rating themselves as

19 "severe" at baseline to having none or mild

20 symptoms at the end of 12 weeks. What this shows

21 is a pretty nice improvement from a more severe


22 state to a very much improved state.

23 If we can look at L15.

24 [Slide.]

25 These are activity function questions, and







1 we see a similar thing.


2 L16.

3 [Slide.]

4 These are two energy questions. I don't

5 know if that actually addresses your question

6 fully, but that is the extent at which we have


7 attempted to identify those patients who would be

8 making large improvements.

9 DR. STROM: This certainly begins to get

10 at it. I guess what I am trying to get a sense,

11 and I think I am hearing the answer to be yes,


12 although if I am hearing you right, I am not

13 totally sure, that there is a subgroup of people

14 who are responding a lot. We have heard that in

15 the testimony. We have seen that in these data.

16 Can you differentiate for us those who


17 were responding a lot from the rest of the people

18 who don't respond as much, if that is true?

19 DR. McSORLEY: We haven't actually done

20 that other side of the equation. What we focused

21 on, again in anticipation of some of these


22 questions, was to try to identify those subsets of

23 patients who were severe, who may derive the most

24 benefit.

25 The clinical trials program was halted







1 when the drug was withdrawn, so we couldn't


2 prospectively identify these kinds of subgroups.

3 We had to retrospectively go back, and all of our

4 focus has been on the more severe patients, and we

5 haven't actually done the complementary side

6 looking at the less severe other than to look at


7 the adequate relief endpoint with respect to those

8 patients who again have lower stool consistency,

9 meaning firmer stools, less stools, less urgency.

10 Those patients we know do not derive as much

11 benefit, in fact, there are at higher odds for a


12 lack of efficacious response.

13 DR. STROM: I will try one more time just

14 to be clear. It is among people who start out

15 severe. I am not asking about the people who start

16 out mild. Among people who start out severe, there


17 is a subset of people who have a major response is

18 what you are saying.

19 I assume there is a complementary subset

20 of people therefore who don't respond much.

21 Have you looked at retrospectively, not as


22 a prospective study, within your clinical trial

23 data, can you differentiate for us, of those people

24 who start out with severe disease, those people who

25 are going to have a large improvement versus those







1 people who are not going to respond at all, because


2 they are being mixed together in the efficacy data

3 we are seeing?

4 DR. WOLFE: Dr. Hoberman from the FDA

5 wants to say something about this, too.

6 DR. HOBERMAN: When I originally reviewed


7 the Lotronex NDA, I noticed an interesting pattern.

8 I think this will get to Dr. Strom's question.

9 If you look at the distribution of

10 response, it turns out that it is highly bimodal.

11 You respond to this drug or you don't respond to


12 this drug. If you break it out by the number of

13 months, consecutive months in which you respond,

14 there is a big spike in the beginning where you

15 don't respond at all, and there is a big spike for

16 people who respond for all three months.


17 In the middle, there is random garbage.

18 So, that is one reason why it was clear to me that

19 if you don't respond to this drug in the first

20 month, you are probably not going to respond. The

21 chances of responding for all three months, if you


22 do respond in the first month, it is about 85

23 percent.

24 Also, getting to this question of yes, we

25 have heard these dramatic responses from the people







1 who have come to testify. That doesn't surprise


2 me. I think it is a small percentage. One of the

3 things I think you have in your packet that I did

4 do was I looked at a very tough threshold for

5 response, that a person had to start with at least

6 70 percent of baseline urgency and had to fall to


7 some threshold for every single week of the 12

8 weeks.

9 So, those are the people I think we have

10 heard from. That happens in the order of 10 to 20

11 percent of the time, around 10 percent, so there


12 really is--it is an absolute 10 percent. I am not

13 talking about a treatment difference, but I think

14 that it may be fair to say that since this drug

15 works, that there is a small number of people who

16 are going to get dramatic effects from it.


17 DR. STROM: That is exactly the group I am

18 looking for. Can you compare, did you do analyses

19 that would compare that 10 percent who would have

20 dramatic responses to the other 90 percent, so that

21 we can try to differentiate them, because if this


22 drug can be steered to the people who are going to

23 dramatically benefit from it, then, obviously, the

24 risk-benefit of the drug dramatically improves?

25 DR. HOBERMAN: I am sorry to disappoint







1 you. I didn't get much further than the Company


2 did. My sense is that is going to be hard to tease

3 out. I took this data from the two urgency trials.

4 I am not sure the numbers are going to be there to

5 really make anything definitive, because I think I

6 agree with the Company that there isn't a whole lot


7 of data here to say that somebody is going to

8 respond, and somebody not respond, unless they have

9 formed stools or something like that when they take

10 the drug.

11 The last thing I might point out is--I


12 don't know whether the Company pointed out--but the

13 baseline urgency of the so-called urgency trials,

14 3011 and 30031, actually was quite a bit higher

15 than the original trials.

16 What at least I found, I don't know about


17 the Company, was that the actual responder rate was

18 higher in the so-called urgency trials with the

19 more severe baseline urgency, both in the drug

20 group and the placebo group, and I wasn't expecting

21 that.


22 I don't know what to make of it, but there

23 is certainly an indication that more severe

24 patients in that general sense might get a little

25 more effect.







1 DR. CARTER: Dr. Wolfe, may I make just


2 one comment? We have talked a lot about the

3 therapeutic gains seen vis-a-vis individual

4 symptoms here, and there have been some comments

5 about that this gain is possibly modest in some

6 instances. I think we all need to remember that


7 IBS is a multi-dimensional syndrome, and what

8 really matters to the patients is not necessarily

9 whether any one or other symptom is improving.

10 So, when we asked the patients, using our

11 global improvement score to integrate the sum of


12 their symptoms, we actually saw therapeutic gains

13 in the order of 30-plus percent, and I would say

14 that that is not a modest effect if we benchmark it

15 across the therapeutic gains of other drugs.

16 DR. WOLFE: I want to move the discussion


17 along, however, this is very valuable because the

18 more we clarify here, the less time it will be

19 necessary, then, to answer the questions later on.

20 I want to make one comment about symptoms

21 in general as opposed to structural lesions. This


22 has nothing to do with IBS, but I think the best

23 example here is when we talk about reflux disease.

24 It is very easy to show healing of esophagitis, but

25 it is much more difficult to show an improvement in







1 pain symptoms.


2 So, when we talk about pain, there is a

3 lot of subjectivity involved, and an improvement is

4 an improvement, and I think we have to keep that in

5 mind.

6 DR. STROM: One comment there and then my


7 other two questions. When you study pain, though,

8 you usually have a bimodal population. You usually

9 have responders and non-responders. In order to

10 maximize the risk-benefit of the drug, we need to

11 identify those responders, so instead of being used


12 in the whole population who are at risk, identify

13 the responders.

14 Let me move to the second question. What

15 is clear is we don't have any information on risk

16 factors for ischemic colitis. In the population


17 that was treated with the drug, there are only 18

18 cases, you are not going to have enough power, it

19 is not a surprise.

20 How about risk factors for ischemic

21 colitis in general, because you would expect that


22 the people who are at higher risk for ischemic

23 colitis in the general population would also be at

24 even higher risk of ischemic colitis when placed on

25 this drug. Those would be logical people to







1 contraindicate use in.


2 DR. BRANDT: There are many risk factors

3 that have been identified for colon ischemia

4 although in the vast majority of cases, even in the

5 older people, the classic population, you don't

6 find anything other than general atherosclerosis in


7 the population.

8 Having said that, the minority of people

9 are well accounted for by medications, of which

10 there are more than 80 that have done this, among

11 which are NSAIDs and sumatriptan, and estrogens, et


12 cetera, coagulation disturbances probably the most

13 common being factor V Leiden, parasitic disorders,

14 and a variety of other factors.

15 DR. STROM: Last question. We have heard

16 a lot about the definition, Dr. Traber talked


17 about, formal definitions of irritable bowel

18 syndrome as a difficult thing to initially define,

19 and a lot has been developed out of this research.

20 Dr. Carter talked about formal definitions for the

21 outcomes and the detailed medical record review


22 needed to achieve that.

23 Dr. Walker's data has been referred to a

24 number of times, suggesting a background rate of

25 serious complications in people who had a diagnosis







1 of irritable bowel syndrome.


2 Was that with or without access to medical

3 records, were those claims diagnoses only or was

4 that with medical records, and what level of

5 medical record review comparable to the clinical

6 trial review were you able to do?


7 DR. WALKER: The complications of

8 constipation that we reported was based on claims

9 data that were structured to be similar to those

10 used in the postmarketing definition, so it was

11 obstruction ileus without surgery, impaction, and


12 the like.

13 When we reviewed the medical records, and

14 we have done that for 80 or so cases, what we are

15 finding is that there is actually very good

16 confirmation of that, but the attribution to


17 constipation is infrequent, maybe 30 percent with

18 your constipation attributable.

19 DR. DAY: I have a number of questions for

20 Dr. Wheadon concerning the risk management plan,

21 however, since so many of the questions this


22 afternoon are going to be devoted to that, I will

23 wait until the appropriate time, but I will be

24 interested in particular in comprehension of the

25 materials prepared, the Medication Guide, the







1 labeling, the physician-patient agreement letter,


2 and so forth, and how they are going to assess

3 comprehension by all of the parties involved, the

4 patients, the physicians, and the pharmacists. So,

5 I will wait until then.

6 DR. WOLFE: Dr. Gardner.


7 DR. GARDNER: Dr. Strom has taken care of

8 two of my three questions, so I will ask the third.

9 For Dr. Walker, when you looked at the

10 United Healthcare databases, specifically, the

11 prescription database, out of which you gave us one


12 finding related to the characteristics of the

13 prescribers, did you get a feeling for the

14 continuation rate, the dispensing patterns there.

15 I am specifically interested because we have heard

16 repeatedly that in the months on market,


17 approximately half a million prescriptions were

18 written for approximately 275,000 people, and for

19 chronic medication, we are now somewhere under two

20 scripts a person in a period of time.

21 I wonder if the pattern or prn use is


22 evident in the prescription data at United

23 Healthcare. Can we get any enlightenment about

24 this?

25 DR. WALKER: There were about 2 1/2







1 prescriptions per patient who received Lotronex


2 during the marketing time. The date of first

3 prescription, of course, extended right up until

4 the end, so that there wasn't an opportunity for

5 everybody to even have a repeat prescription.

6 DR. GARDNER: Sorry, I guess I mean for


7 those that started right out, and I assume it took

8 some time to get on the formulary and all those

9 caveats relating to finding a market, were you able

10 to identify whether, in fact, there is a subgroup

11 of people who are actually using this product


12 chronically and filling every 30 days?

13 DR. WALKER: No, I only have the 2 1/2

14 over the average.

15 DR. HOUN: FDA did some analysis on use.

16 Dr. Zili Li?


17 DR. LI: Yes, we did some additional

18 analysis based on the HMO data. At this time, we

19 have not got final approval about source of data,

20 so I just let you know on the nature of the data.

21 Basically, we did analysis based on about 1 percent


22 of all the prescriptions in the United States, on

23 one HMO network.

24 Another one is from HMO network, which I

25 will say has 20,000 patients, women, used Lotronex







1 during nine-month period. So, it roughly covered


2 10 percent of the patients who have used Lotronex

3 in the United States.

4 So, what we did, what we received from HMO

5 is all the detailed prescriptions, prescription for

6 each members during the nine-month period. Then,


7 we applied the lifetime table analysis to try to

8 estimate, for the patient when they started with

9 the drug, how long they remained in the treatment.

10 The result, the bottom line we got is for

11 all the patients start from day one with Lotronex,


12 by the day 30, about 60 percent of patients would

13 drop from the prescription, so they would not

14 continue their prescription, they would not

15 continue their treatment anymore beyond 30 days.

16 Sixty percent dropped just on their own, whether


17 interaction with the physician, we don't know, for

18 whatever reason, but from the pharmacy data, they

19 do not renew this prescription beyond 30 days, 60

20 percent.

21 About 20 percent of patients, they used up


22 to three months, and roughly, about 10 percent used

23 the drug continuously if we just observe the

24 pattern of prescription, for six months, 10 percent

25 for six months.







1 Since the drug only in the nine months on


2 the market, and the patient beginning very small,

3 so roughly by the month 7 or 8, we got down to 6 or

4 8 percent of population remained on the treatment

5 by the seven or eight months, so we are thinking

6 that is the data you wanted.


7 DR. METZ: You say 60 percent of the

8 people stopped. That meant they didn't renew their

9 prescription.

10 DR. LI: They do not renew it.

11 DR. METZ: But that doesn't necessarily


12 mean they didn't like the drug, and they stopped it

13 because it didn't work, because this could just as

14 well mean that the person was using it prn, and

15 didn't get around to the next prescription because

16 they didn't need it anymore, they hadn't run out.


17 DR. LI: I think you ask a very good

18 question. I could not answer to you at this point

19 why, the reason patient stopped the prescription.

20 Maybe they think they are cured, but at the time, I

21 just let you know intention, our analysis of time


22 is we heard a lot of patients think they have great

23 benefit. We assume those people who demonstrate a

24 great benefit will be the patients who stay on the

25 drug for a long time. So, that is our objective at







1 that time, to try to identify those people, what


2 percent of people were likely to stay on the drug

3 for more than six months or longer, who were likely

4 to benefit from this drug.

5 DR. WOLFE: I think it is multifactorial.

6 Some didn't continue because it didn't work. We


7 know it doesn't work in everybody, and also some

8 take it prn, and some people just stop taking

9 medication. We know that.

10 DR. LI: Thank you.

11 DR. STROM: But it is interesting, it is


12 the same 10 percent figure we heard before of the

13 people who get dramatic responses.

14 DR. CARTER: Can I just add one comment

15 here, and that is, that surrounding all of the

16 publicity in June, we started to see a fairly


17 dramatic drop in the prescription of alosetron, so

18 from the time of the publicity around the adcom in

19 June until it was withdrawn at the end of November,

20 we basically have a bell-shaped curve with peak at

21 just before that time.


22 So, I think that the actual time that we

23 have, of length of time of treatment, it becomes

24 very limited as time goes by.

25 DR. WOLFE: As I said, multifactorial.







1 DR. CAMPBELL: Perhaps I could ask for two


2 clarifications on the risk management program. I

3 believe in the background material, in the

4 evaluation of program effect, a comparator group

5 was identified to be used to compare effect of the

6 program with the actual users.


7 In the presentation, I didn't hear, nor

8 did I see in the materials, a comparator group

9 would be part of that evaluation. First, is that

10 group present or are there issues of privacy here

11 that I would like you to respond to?


12 DR. WHEADON: There was mention of a

13 comparator group in terms of the study focusing on

14 occurrence of events of special interest where you

15 look at patients that were prescribed Lotronex.

16 You would also look at patients with IBS who had


17 not been prescribed Lotronex.

18 Now, there will be some issues in terms of

19 trying to have exact similarities in terms of that

20 cohort, but there will be an attempt as best one

21 can to look at issues around the occurrence of the


22 events of special interest.

23 DR. CAMPBELL: And do you believe you will

24 be able to get the information from the IBS

25 patients who are not part of the risk management







1 program, they will not have signed--


2 DR. WHEADON: Well, again, this is a

3 standard research paradigm in the United Healthcare

4 database with the ability to collect information in

5 an appropriate manner in respect to patient

6 privacy, but I will let Dr. Allen Walker add more


7 specifics around that.

8 DR. WALKER: The matching would be done in

9 terms of health care utilization patterns. The use

10 of claims data, which is clearly deeply encrypted

11 when we use it, would fit under expedited review in


12 the usual epidemiologic application, so I don't

13 anticipate a problem.

14 DR. CAMPBELL: Second question. The

15 proposed relabeling carries a statement "not proven

16 effective in men." Is it your intent that that


17 would disqualify men from participation in the risk

18 management program by the sponsor, or does it mean

19 that the prescribing physician could include the

20 physician, but do that by taking increased

21 liability?


22 DR. WHEADON: Recall that the risk

23 management program is intended to assess the use of

24 the drug in the real world. So, as such, while the

25 indication clearly is earmarked for women with







1 diarrhea-predominant IBS that haven't responded to


2 conventional therapy, if an individual physician

3 chooses to prescribe the drug to a male patient

4 with IBS, that would be a component in looking at

5 patient demographics of those patients that

6 received the drug, that would be assessed under the


7 auspices of the risk management plan.

8 DR. CRAWFORD: My questions also deal with

9 the proposed risk management plans if the product

10 were to be reintroduced. I have one for Dr.

11 Piazza-Hepp and three for Dr. Wheadon or any


12 representative of the sponsor.

13 For the FDA, several times during the

14 presentation of the proposed aspects of different

15 programs, you were talking about pharmacist

16 registration or pharmacy registration. I would


17 like to get it clarified which one is the intent

18 for our consideration for today's advice.

19 For the sponsor, I would like

20 clarifications, please, about patient supply. It

21 was clear that in the proposed risk management


22 plan, you propose a 30-day supply for the first

23 month, and also it was clear that there would be a

24 new prescription required after that, but what is

25 to keep the prescriber, if anything, from writing







1 for a 90-day supply or a 6-month supply? Are there


2 any proposed days supplies limitations?

3 The second question, I would like to hear

4 a little bit more about these stickers. It appears

5 that the physician can make an attestation

6 statement about knowledge and experience, and if I


7 am interpreting it correctly, at that point, any

8 willing physician could get the stickers through an

9 800 number of the sales representatives.

10 Is that correct, and if so, what is the

11 purpose of it?


12 DR. WOLFE: We will discuss that question.

13 DR. CRAWFORD: We will discuss that

14 question? Thank you.

15 Lastly, just a few more remarks, please,

16 about explicitly, does the proposed risk management


17 plan have anything to do with hospitalized or

18 institutionalized patients? I did hear the

19 statement that gastroenterologist in the hospital

20 could write it without a sticker, but will the

21 proposed plan have explicit language about the role


22 of the prescriber, the patient, and the pharmacist

23 for institutionalized patients?

24 DR. PIAZZA-HEPP: I believe the first

25 question was addressed to me, and that was, yes,







1 were you saying registered pharmacists, individual


2 pharmacists, or pharmacies? Just based on the

3 plans that are in effect and do that, it is usually

4 the pharmacies, either a retail pharmacy or some

5 plans actually use a central pharmacy that is

6 registered, and it is limited to that central


7 pharmacy, also some institutions, the pharmacies

8 are registered, and they get training and

9 education. Individual pharmacists, that has not

10 happened to my knowledge.

11 DR. WHEADON: To answer the two that I am


12 allowed to answer right now, focusing initially on

13 the issue of subsequent prescriptions beyond the

14 first 30-day initiation period, the intent is that

15 the desire would be for, as I indicated, active

16 physician follow-up. However, after the first 30


17 days, we are not mandating, in terms of the risk

18 management plan, specifically, that prescription

19 can be limited only to 30 days after the initial

20 treatment period.

21 However, the way we are proposing for the


22 drug to be packaged, in terms of unit of dose sort

23 of packaging, the easiest way of dispensing the

24 drug and the easiest way for the patient to receive

25 the drug, would be in a 30-day framework, but there







1 is nothing that would prevent a physician from


2 deciding to prescribe for longer than 30 days after

3 that initiation period.

4 In terms of hospitalized patients, the

5 risk management plan does not specifically address

6 patients that are hospitalized beyond the standard


7 requirements of the appropriate patients, the

8 agreement form which would be extant, as well, for

9 hospitalized patients, but we haven't addressed

10 specifically how a hospital pharmacy beyond a

11 physician indicating appropriately that the right


12 patient was being prescribed the drug, would adhere

13 to the risk management plan. We were focusing more

14 on outpatient use.

15 DR. COHEN: A quick question regarding

16 also the risk management plan. There is a growing


17 trend to use computerized prescribing and recently

18 with that Accutane Smart program, we learned that

19 the military, the Department of Veterans Affairs,

20 and some other sites, as well, use a system for

21 computerized prescribing that actually communicates


22 directly with the pharmacy systems.

23 So, is thought being given to use that as

24 an alternative to the sticker program? I am not

25 sure whether that has been discussed or not.







1 The second thing is with regards to the


2 pharmacy-based postmarketing study that was being

3 done with Eckerd and the Slone Epidemiology Unit,

4 was there a thought given to expanding it beyond

5 that one pharmacy chain? Was there thought, for

6 example, involving independent pharmacists and


7 survey process of some type?

8 DR. WHEADON: Starting with the first

9 question, we had not intended to include the

10 computer-generated prescription for the allowance

11 of dispensing of the drug. The intent was, at least


12 in the initiation of the program, was to do the

13 paper-dependent process with the sticker applied to

14 the prescription. You might want to discuss that

15 further when we go into dealing with the questions.

16 The second question concerning the Slone


17 Epidemiology Unit and the participation of Eckerd's

18 retail pharmacies, my understanding is--and Dr.

19 Louik, who is here from the Slone Unit, can add

20 beyond this--but we wanted to start with a

21 free-standing chain and sort of, if you will, test


22 the process of the evaluation of the program with

23 Eckerd, and this procedure is already set up with

24 Eckerd, however, I don't know that there is any

25 reason it can't be expanded beyond the Eckerd chain







1 if numbers indicate we need to do that.


2 Dr. Louik, would you like to respond

3 beyond that?

4 DR. LOUIK: Yes, I would just like to add

5 one comment with regard to the independent

6 pharmacists. I think it is important to emphasize


7 that this is a pharmacy chain and a centralized

8 database that will be defining the patient

9 population, and it doesn't depend on any action on

10 the part of an individual pharmacist. I think that

11 is an advantage of the program, as well as the fact


12 that we will have information on both respondents

13 and non-respondents to the program because of the

14 way of identifying Lotronex prescriptions rather

15 than using a pharmacist.

16 MR. LEVIN: In your briefing material, you


17 indicate that you have "no plans" for drug sampling

18 or direct consumer advertising, and I was wondering

19 whether you consider that part of a risk management

20 program, that is, you were sort of saying you are

21 not going to do that, and what are your plans as


22 regards IBS infomercial kind of advertising,

23 non-brand specific, but trying to sort of raise

24 awareness of the disease?

25 DR. WHEADON: I think as I think Dr. Houn







1 and Dr. Piazza-Hepp both referred to, the issues of


2 restricted access under Subpart H, as defined in

3 the Code of Federal Regulations, and as such, such

4 direct-to-consumer advertising would be not

5 allowed, if I recall the restrictions of Subpart H,

6 under those restrictions.


7 DR. HOUN: Subpart H just requires

8 pre-approval, and it does not disallow DTC. I

9 think, though, that at this time, nobody is

10 proposing DTC.

11 DR. WHEADON: Absolutely. The Company is


12 not proposing DTC. In terms of infomercials, if

13 your indication or your question is concerning

14 provisions of information around IBS, as we have

15 indicated, there would be a web site that would

16 provide information on irritable bowel syndrome,


17 that would provide information on the appropriate

18 use of Lotronex for physicians, but obviously, in

19 terms of how web sites are maintained, there could

20 potentially be patient access to that, as well.

21 The intention really is to provide the information


22 concerning safe use of the product as contained in

23 the Medication Guide and in the modified proposed

24 labeling.

25 DR. KRIST: I will ask a pretty quick







1 question here, and I apologize for stepping back,


2 but it is dealing with the postmarketing data. One

3 of the first things we are going to be talking

4 about is are there certain patients that might have

5 a greater benefit-to-risk ratio.

6 One of the things we have been talking


7 about was limiting this to more severely affected

8 patients, and that in the randomized, controlled

9 trials, there are not necessarily any subgroups

10 with higher risks.

11 One of the things that I am interested in


12 is that often when medications are extended to the

13 real world setting, the more severely affected

14 patients might be at a higher risk because they

15 might be more likely to have other comorbidities,

16 and they might be on other additional medications,


17 or since IBS is more of a diagnosis of exclusion,

18 there might be the risk of a more severely or a

19 patient with more severe symptoms having some other

20 underlying pathology.

21 So, what I am interested in is in the


22 postmarketing data, is there anything to suggest

23 that there were more complications in patients who

24 had more severe symptoms.

25 DR. CARTER: Obviously, again, we have to







1 qualify the postmarketing data as being incomplete


2 very often and devoid of information at other

3 times, so it is difficult to draw firm conclusions,

4 but we certainly saw, in looking at individual

5 cases, that patients that, indeed, had

6 comorbidities or were on other medications that


7 might impact, for instance, colon motility, were at

8 higher risk of developing complications. I mean

9 this is a qualitative analysis here, not a

10 quantitative analysis.

11 DR. WOLFE: Ms. Mackey.


12 MS. MACKEY: Yes, we had no information to

13 suggest that based on postmarketing reports.

14 DR. GOLDSTEIN: I would like to come at

15 this from a different direction. Earlier today, we

16 heard the FDA state, someone, and I quote, "There


17 is a real possibility of misdiagnosis of IBS when

18 it was really IBD."

19 We know that there are 15 million

20 sufferers of IBS, many of them who reside in rural

21 areas, and at the conclusion of his summary, Dr.


22 Raczkowski said, "We must avoid adverse events by

23 enhancing chances of a correct diagnosis," all of

24 which leads me to ask the sponsor whether, in fact,

25 they have any plans for materials to make the







1 distinction between IBS and IBD, and/or to


2 recommend any diagnostic procedures that would

3 exclude one.

4 In concluding, I would point out Ms.

5 Norton's rather eloquent plea for the importance of

6 an accurate diagnosis.


7 DR. WOLFE: We are going to actually

8 discuss this indirectly, because this deals with

9 one of the questions regarding who should be the

10 principal persons involved with prescribing this

11 drug, and should it be limited. That is going to


12 be the question discussed because among

13 gastroenterologists, we don't generally confuse IBS

14 with IBD.

15 DR. SULLIVAN: I have a couple of quick

16 questions. I noticed in the briefing package that


17 this is a high clearance drug with a lot of

18 metabolites, and it was unclear to me whether these

19 metabolites have been characterized, whether they

20 are active.

21 Specifically, why I ask the question is,


22 has the sponsor looked to see whether there is any

23 inference on coagulation or anything like that with

24 the major metabolites.

25 DR. KOCH: Kevin Koch, GlaxoSmithKline,







1 Clinical Pharmacology.


2 Yes, we have. The major metabolite that

3 we see, that has activity is 6-hydroxy. It is

4 about equipotent with the parent drug in terms of

5 5HT3 binding activity, but we only see about 1

6 percent.


7 DR. SULLIVAN: What is its duration of

8 action?

9 DR. KOCH: I don't know, we haven't

10 measured that. This is in vitro receptor binding

11 activity for potency. In the serum, we see only 1


12 percent relative to parent of that metabolite, so

13 it is probably not contributing very much in terms

14 of actual activity in vivo.

15 Your second question?

16 DR. SULLIVAN: Whether the metabolites--


17 DR. KOCH: Coagulate?

18 DR. SULLIVAN: If it not important, then

19 it probably doesn't matter. I had some follow-up

20 questions, particularly with respect to the

21 drug-response relationship or I think it is


22 probably fair to say that the sponsor hasn't done a

23 stellar job in clearly figuring out what the

24 minimal efficacious dose is.

25 I am interested to know whether the







1 sponsor has ongoing or plans to look more carefully


2 at the PK-PD relationship. Most small molecules,

3 there is a very good relationship between

4 concentration and response. For example, one would

5 wonder whether the sponsor would ask patients with

6 IBS to take the drug one hour before a meal because


7 Tmax is about an hour.

8 You would expect the maximum

9 pharmacodynamic response to possibly coincide with

10 Tmax. Have you looked at AUC? Have you looked at

11 trough levels? Have you characterized this


12 relationship? I would opine that, had this been

13 done early on in the program, possibly we wouldn't

14 be in the pickle we are now with having gone to

15 market with probably too high a dose.

16 I should also, perhaps, ask Dr. Wheadon to


17 clarify. He said, on his risk-management plan,

18 half the dose. I believe it is the same dose but

19 it is half the exposure. It is the same dose but

20 given less frequently. Once a day was the

21 proposal.


22 DR. KOCH: Just to address your first

23 question on pharmacodynamics. We would have loved

24 to have done that kind of analyses, but we are

25 still searching for a good pharmacodynamic







1 surrogate. As you saw, the effect measures are


2 symptomatic. We don't really have a good dynamic

3 measure.

4 DR. SULLIVAN: I think you have published

5 data on visceral pain. There is, at least in the

6 package insert, one study at the dose of 4


7 milligrams looking at salt and water retention.

8 These are not easy studies to do, but I think they

9 are doable.

10 DR. TRABER: Maybe I could just comment

11 and answer. First of all, you asked if there were


12 ongoing studies. All studies were stopped at the

13 time of withdrawal and clinical trials were orderly

14 shut down. So there are no ongoing clinical

15 trials.

16 The other thing is that the physiological


17 measurements, either balloon distention, colonic

18 motility, other pain sensation and those types of

19 things, there is not, as yet, a good correlation

20 between those and the symptoms for patients with

21 IBS.


22 Indeed, should this come back to market in

23 a restricted-access format, and should we continue

24 to do clinical trials with this compound, we would

25 look at those PK/PD relationships.







1 DR. WOLFE: Could I follow up on that


2 question? How is the drug metabolized? I forget.

3 By which route?

4 DR. KOCH: There are several P450 enzymes

5 involved, 2C9, 1A2, 3A4.

6 DR. WOLFE: Not 19? That is not involved?


7 DR. KOCH: Not 19; no. Or 2D6.

8 DR. SULLIVAN: I think I would agree with

9 the sponsor that there are not likely to be any

10 interactions based on the P450.

11 DR. WOLFE: The question I was getting at


12 was 19. There are a lot of differences with

13 different ethnic populations. If we have got a

14 metabolism but it is not 19, we are not going to

15 see much of a difference, at least that we know of

16 yet. But we may see that in the future.


17 Ms. Blackman, do you have any questions?

18 MS. BLACKMAN: I do have one question. It

19 was indicated by GlaxoSmithKline and seemed to be

20 disputed by the FDA that most of the risk involved

21 in taking Lotronex was within the first month and


22 that we don't have data after six months. However,

23 there was a slide shown that, for 48 weeks, there

24 was efficacy. So what happened to those patients?

25 Were there surgeries, hospitalizations, deaths, for







1 those folks who were on for the long-term safety


2 and efficacy studies?

3 DR. CARTER: Yes. Of course, the number

4 of patients that extended beyond six months was

5 relatively small. But we saw, for instance, one of

6 the ischemic colitis in the placebo patient was in


7 the second six-month period. But there was no--we

8 couldn't tell whether or not there was any

9 differential, if you like, between the two time

10 points in terms of the events of special interest.

11 MS. BLACKMAN: What was the sample size


12 for the people who went 48 weeks?

13 DR. CARTER: The sample size, I believe,

14 was 600, thereabouts.

15 MS. BLACKMAN: I also wonder--I mean,

16 there have been several comments about patients who


17 take NSAIDS, who take other drugs that have serious

18 side effects. Has the FDA done any sort of

19 analysis on how they are comparing this drug, this

20 disorder, compared to other non-life-threatening

21 disorders such as sexual dysfunction and things


22 like that that have had deaths and serious side

23 effects associated with medications that have been

24 approved?

25 DR. HOUN: Yes. Every drug that is







1 approved gets adverse events and we look at them


2 the way we have looked at Lotronex. There are

3 medical officers assigned from the Review Division

4 and Drug Safety Division. There are team meetings

5 over these adverse events.

6 More recently, over the last five years,


7 drug adverse events are being discussed publicly.

8 Resolin was discussed publicly. PPA was discussed

9 publicly. Thalidomide was discussed publicly.

10 Every drug, when we ask for a vote on should it be

11 approved or not, we talk about safety data.


12 So, in terms of all drugs, the look at

13 safety is uniform in the sense that this is

14 something we care about. We look at efficacy. We

15 look at that very carefully, too. But, again, a

16 lot of situations we are put in is that we are


17 looking at apples and oranges. Is ischemic colitis

18 and then adequate relief of IBS symptoms--how do

19 you measure them? That is where we need advice

20 from all stakeholders. That is why you are here

21 today.


22 DR. WOLFE: We will now move on to the

23 questions for us. Dr. Raczkowski will now

24 introduce the questions and then we will answer

25 them, as best we can.







1 Introduction to Questions and Charge


2 to the Committee

3 DR. RACZKOWSKI: This afternoon we have

4 eight questions for the advisory committee's

5 discussion. What I will do, then, is read them

6 into the record.


7 [Slide.]

8 No. 1; Can a patient population with

9 diarrhea-predominant irritable bowel syndrome be

10 described for which the benefits of Lotronex

11 outweigh the risks and, if not, why not? If so,


12 describe the population in terms of the following

13 characteristics: severity of symptoms, degree of

14 disability, chronicity of IBS, failure of

15 conventional IBS therapies and any other important

16 characteristics.


17 [Slide.]

18 No, 2; At this time, should Lotronex be a)

19 available to patients with diarrhea-predominant IBS

20 without marketing restrictions, b) available to IBS

21 patients with appropriate marketing restrictions,


22 to be defined, or c) withheld from the market.

23 Explain.

24 [Slide.]

25 No. 3; If Lotronex is marketed, should the







1 ability to prescribe Lotronex be limited to certain


2 types of physicians. If so, describe the

3 physicians in terms of the following

4 qualifications: knowledge, experience, specialty

5 and any other important characteristics.

6 [Slide.]


7 Question 4 regard patients. 4a;

8 GlaxoSmithKline proposes to restrict use of

9 Lotronex to patients who sign a Patient-Physician

10 agreement. This agreement is then filed in the

11 patient's medical record. Is this adequate to


12 insure that only patients with the most favorably

13 benefit-risk balance receive Lotronex? Is auditing

14 of this agreement needed?

15 b; GlaxoSmithKline proposes a utilization

16 study of United Healthcare Research Database as a


17 mechanism to audit whether appropriate patients are

18 being prescribed Lotronex. Is this auditing

19 mechanism adequate to achieve this goal? If not,

20 describe an adequate auditing mechanism.

21 [Slide.]


22 c; GlaxoSmithKline proposes a

23 pharmacy-based study using the Slone epidemiology

24 unit and Eckerd Corporation to audit patients'

25 knowledge and awareness of the risks and benefits







1 of Lotronex. Is this auditing mechanism adequate


2 to achieve this goal? If not, describe an adequate

3 auditing mechanism. Define adequate performance on

4 either GlaxoSmithKline's or another knowledge

5 audit.

6 d; Should patient enrollment, for example,


7 registration, be part of the risk-management plan?

8 [Slide.]

9 5; Regarding physicians. GlaxoSmithKline

10 proposes a plan in which physicians call a 1-800

11 number to receive a self-attestation kit, including


12 stickers. The physicians self-attest to their

13 qualifications by signing the "Section for the

14 Physician on the Patient-Physician Agreement."

15 This agreement is then filed in the patient's

16 medical record. Is the sponsor's proposal adequate


17 to allow for evaluation of physician adherence to

18 the program; for example, the extent of Lotronex

19 prescribing outside of the program. If not,

20 describe an adequate auditing mechanism.

21 [Slide.]


22 b; Define an adequate level of adherence

23 to the program by physicians. c; Should physician

24 enrollment--for example, registration--be part of

25 the risk-management plan?







1 [Slide.]


2 6; Regarding pharmacists. GlaxoSmithKline

3 proposes the pharmacists accept only written

4 prescriptions with an attached sticker. The goal

5 is to verify in real time the patients being

6 dispensed Lotronex are under the care of enrolled


7 physicians. Also, pharmacists will provide

8 medication guides to patients whenever Lotronex

9 prescriptions are filled or refilled. The goal is

10 to provide patients with written information about

11 the safe and effective use of Lotronex.


12 a; Are the sponsor's proposals to meet

13 each of these goals adequate? If not, describe

14 adequate mechanisms.

15 b; Should pharmacists' adherence to the

16 program be audited? If so, how?


17 [Slide.]

18 7; Regarding safety outcomes. a; Should

19 clinical outcomes--for example, ischemic colitis,

20 severe constipation and death--be used to assess

21 the success of the risk-management program? For


22 example, should the rates and/or degree of severity

23 of ischemic colitis and constipation be monitored

24 with the specific goal of evaluating the

25 effectiveness of the program?







1 b; If so, specify the adverse events that


2 should be assessed and when the assessments should

3 be made. Describe acceptable rates for these

4 adverse events and/or acceptable degrees of

5 severity.

6 8; Please provide any additional comments


7 that you may have about a Lotronex risk-management

8 program; for example, suggestions for additional

9 studies.

10 Thank you very much.

11 DR. WOLFE: Thank you, Dr. Raczkowski.


12 Discussion of Questions

13 DR. WOLFE: Before we get started, I want

14 to point out to the panelists that we have a little

15 less than two hours to accomplish what normally

16 takes four hours. So, we are going to do it in the


17 following way. We are going to go around the table

18 for these questions. We are going to start right

19 in order because, clearly, the first two questions

20 are seminal because if we advise not to go on,

21 there is probably very little reason to go on any


22 further.

23 So we need to concentrate on the first two

24 questions initially and then we will move on. I am

25 also going to have an additional question to pose.







1 I can't say this to the public, but I can


2 say it to you. If you make your comment, and it is

3 your turn, and we will go in different orders, and

4 somebody has already made your comment, don't

5 repeat it. Just say, "I agree with Dr. Smith, Dr.

6 Jones," whoever you agree with. And that's good


7 enough.

8 You also have the right later on to

9 realize, "You know something? Maybe I don't agree

10 with what I said initially. Maybe I changed my

11 mind." You will have time to change your mind


12 because we are going to vote after we have the

13 discussion on each question. So is that clear to

14 everybody? So, again, please try to be succinct.

15 We have less than two hours to discuss what takes

16 four hours.


17 So we will start with question No. 1. I

18 will repeat it again to you. Basically, what we

19 are looking for, is there a patient population for

20 which the benefits of Lotronex outweigh the risks.

21 If not, why not? If so, describe the population in


22 terms of the following characteristics; severity,

23 degree of disability, chronicity, failure of

24 conventional therapies and any other important

25 characteristics.







1 We will start this time, since you went


2 last, we will start with Ms. Blackman.

3 MS. BLACKMAN: I think a patient

4 population can be defined. I think from the

5 studies we have seen, it is a little difficult

6 because they weren't stratified necessarily. But


7 there are measures for severity. I think urgency

8 and stool consistency and pain are the more severe

9 characteristics that should be looked at for a

10 patient population.

11 DR. SULLIVAN: I would certainly agree. I


12 think that it is abundantly clear, at least from

13 the patient representatives, that people that have

14 diarrhea-dependent urgency, the pain is,

15 perhaps--if it is associated with that, then,

16 clearly, it is helpful. Pain, I think, is


17 questionable from another point of view.

18 But I think, overall, the benefits far

19 outweigh the risks for this population.

20 DR. GOLDSTEIN: I agree with my two

21 colleagues with no reservations at present.


22 DR. KRIST: I think--you know, one of the

23 things we have been talking about when trying to

24 identify groups that are at greater benefit is that

25 the randomized controlled trials don't show very







1 many specific characteristics. I think the ones we


2 pointed out are diarrhea and at least two episodes

3 of urgency per day, and then trying to think about

4 which groups might have lower risks.

5 Once again looking at the severe adverse

6 events, there are not specific subgroups at greater


7 risk. But I do think you can--certainly

8 restricting it more to patients have failed the

9 conventional therapy will lower exposure to

10 potential risks and that way decrease the gross

11 number of adverse events.


12 DR. LEVIN: I guess I have heard nothing

13 yet that gives me comfort that we can identify that

14 subset of patients clearly enough to make the

15 statement that the benefit would outweigh the risk.

16 But I am willing to be educated as we go around the


17 room.

18 DR. COHEN: I would go along with previous

19 colleagues other than Dr. Levin. I agree.

20 DR. CRAWFORD: I also concur with the

21 previous comments. The only thing I would like to


22 have added to this is to specify is are we talking

23 about females only or males and females?

24 DR. WOLFE: Why don't you tell us?

25 DR. CRAWFORD: Certainly the data that







1 were presented were for females. But I was


2 certainly also swayed by many of the patient

3 representative comments. I defer to those with

4 more clinical expertise.

5 DR. WOLFE: Remember, one of the questions

6 at the end is are there further studies that you


7 would recommend.

8 DR. CRAWFORD: Thank you. Then I would

9 like to recommend more studies. Thank you.

10 DR. CAMPBELL: I, too, agree. It is

11 possible to identify a patient population, if only,


12 we, in fact, have done that--if, in fact, only

13 through an IND mechanism. But there is a way to

14 define that population. The challenge is how and

15 my only comment is a very high threshold needs to

16 be established.


17 DR. GARDNER: I agree with the comments so

18 far. The one thing that we haven't discussed and

19 maybe we need more data about, the comment was made

20 that the people in the clinical trials all have

21 long-term established disease and that helped to


22 distinguish that, perhaps, from people who, in Dr.

23 Walker's studies, had colonic ischemia within three

24 weeks, or three months, of a diagnosis, something

25 like that.







1 So, perhaps, rather than severity, maybe


2 we could look at the possibility of some measure of

3 chronicity or long-term duration of disease to help

4 us understand this because that might also, then,

5 carry with it the likelihood, perhaps, of having

6 failed on other therapies or at least not getting


7 adequate coverage on other therapies as well as

8 having ruled out other things earlier on.

9 DR. WOLFE: By the way, it is called

10 proper diagnosis.

11 DR. GARDNER: Yes; it may be called


12 proper diagnosis which is a topic for later on, I

13 assume.

14 DR. WOLFE: Dr. Day?

15 DR. DAY: I agree that a group of people

16 can be identified who would benefit from this drug.


17 I think very careful explication of what

18 constitutes mild, moderate and severe situations

19 needs to be made, perhaps even in the labeling

20 because, depending upon what we say about who can

21 prescribe such a drug, if it is reintroduced, if


22 there are physicians out there who take patient

23 complaints and so on, how are they going to

24 interpret what is mild and what is severe.

25 We had some cutoffs today that indicated







1 that only 5 percent of people with this complaint


2 are in the severe category. I am not sure that all

3 of our patient representatives would agree that

4 there are only 5 percent of people with this

5 complaint who should be so treated. So I would

6 like to make sure that the communication is


7 adequate and clear and forceful about what

8 constitutes these categories of severity.

9 DR. STROM: I also agree. I would add

10 three substantial restrictions in terms of defining

11 the group I think is at sufficiently high benefit


12 to be worth the risk. I do not think the

13 risk-benefit is warranted for the up to 20 percent

14 of the population that we have heard has IBS. I

15 think one definition would be severity and I would

16 be much more comfortable with a 5 percent


17 severe--the top 5 percent than the large numbers,

18 given the whole population is at risk.

19 Second, I would want excluded from the

20 population people who we know, a priori, are at

21 high risk of ischemic colitis based on other data.


22 So I would want to see formal risk-factor studies

23 of ischemic colitis and a predictive model for who

24 is at high risk of ischemic colitis, and the

25 people who have those risk factors should be







1 contraindicated.


2 The third is I would like to see a formal

3 predictive model to get at this 10 percent that we

4 have now heard twice seem to be responders. Both

5 within the clinical-trial data and within the HMO

6 data, we have heard the same thing and both of


7 those are rich data sources that could be used to

8 get us predictive models to try to say, so instead

9 of saying there is 20 percent of the population

10 using it, or 15 million people, you take the 5

11 percent who are severe, you take the 10 percent of


12 those who are likely to be responders, and we are

13 talking now about 0.5 percent who would be exposed

14 to the risk, and, in the process, making it

15 available to virtually everybody, hopefully, who

16 really would benefit from it.


17 DR. GROSS: I think definitions are the

18 problem we keep bumping up against here. I can't

19 define what is severe. I think I have to leave

20 that up to our gastroenterology colleagues, but I

21 would feel more comfortable if I had a chance to


22 review those definitions once they are determined.

23 I haven't heard the definitions yet.

24 I think we also need to add some criteria

25 for what is irritable bowel syndrome and some







1 determination, if we are going to treat the people


2 with this drug, do we need to do screening

3 procedures such as colonoscopy. Certainly, a

4 flex-sig is clearly not enough. And do we also

5 want to work them up for clotting disorders.

6 DR. HOUN: Could you answer that?


7 DR. WOLFE: Could we answer that?

8 DR. HOUN: As part of severity, Dr. Gross

9 is saying--he is asking about should there be,

10 should there be.

11 DR. WOLFE: I am going to say something.


12 I will get to that.

13 DR. HOUN: I am wondering if he has his

14 opinion.

15 DR. GROSS: I can't define severity. I am

16 not a gastroenterologist. I would like to see what


17 definitions they come up with before I would say

18 yes.

19 DR. WOLFE: I must be getting old because

20 I go back to history sometimes. But, on Day 1 of

21 medical school, we learned, in pharmacology, that


22 all drugs have an LD50 which varies from drug to

23 drug. Actually I forget who mentioned this before,

24 but someone mentioned this before, we use drugs

25 every day that have a significant risk, not only







1 for conditions.


2 I will give you one just striking example.

3 For osteoarthritis, which my rheumatology colleague

4 consider a nondeforming disease, consider it

5 inflammation. They don't consider it arthritis.

6 We use NSAIDs which carry a definable risk which


7 includes death. We use them every day. I doubt if

8 there is one person in this room who hasn't used

9 these drugs.

10 We all know they work. We all know they

11 have a risk. We all know we are rolling the dice


12 sometimes taking them, but we still take them.

13 In this situation, we are entering a new

14 era. I point out that--my specialty is acid

15 secretion. We have been there, we have done that,

16 and we know the answer. We have got the final


17 pathway. It is already taken care of. But this is

18 a new frontier. Neuroscience is a new frontier.

19 The enteric nervous system is even newer.

20 That is really why we are not sure what we

21 are doing is yet complete. And we are not going to


22 know for decades. But this is a first attempt to

23 try to understand what we are doing with regard to

24 treating a very debilitating disease which has a

25 very big impact on quality of life. It isn't







1 necessarily lethal, by itself, but can lead to


2 lethal consequences.

3 So I think we do have a definition. As a

4 gastroenterologist, we know how to diagnose IBS.

5 That is what we do for three years of a fellowship.

6 The diagnosis--I think it is fairly clear here. If


7 a person has to be referred to gastroenterologist,

8 that is severe IBS. That is severe enough to

9 warrant the use because the person referring to the

10 gastroenterologist has tried the other remedies

11 that are standard therapy which really haven't


12 proven to work.

13 So that, by itself, someone who wants--I

14 think we all agree, it has to be diarrhea-dominant

15 IBS. I don't think there is any doubt at all. We

16 can't include anybody with constipation in there.


17 So it has to be someone with IBS who has

18 diarrhea-dominant--I would call it IBS-DD, not

19 IBS-D. Right now, all we have is evidence in

20 randomized controlled trials that it really works

21 for women.


22 Now, having said that, that doesn't mean a

23 physician can't use it for a man by law, as far as

24 I know. But I think it warrants further studies to

25 show that it does, indeed, work for men if it is







1 going to work at all, or it doesn't work for men


2 for the average person.

3 The other thing, I agree completely with

4 Dr. Strom. Anybody with a hypercoagulable state,

5 until proved otherwise, should be excluded. It

6 should be a contraindication using this drug until


7 we know for sure that it is safe. That seems to be

8 a risk factor for any kind of ischemic disease.

9 We don't know for sure here, but it makes

10 sense. Ischemia is caused by hypercoagulation in

11 other instances. So I think we define the


12 population fairly easily for us, for

13 gastroenterologists; it is someone with IBS who is

14 diarrhea-dominant, who has failed other remedies

15 and has a definite--the diagnosis by our definition

16 of the ROME criteria.


17 DR. METZ: Far be it from me to disagree

18 with the chairman after such an eloquent speech,

19 but I would like to just add a couple of points. I

20 think the global assessment on how your patient is

21 doing is probably the most important indication for


22 trying this agent and that, by me, defines a group

23 of patients that have tried other therapies

24 beforehand, who have been referred on to a

25 gastroenterologist. It is not a specific symptom.







1 I think the urgency seems to me to be


2 helpful in that it shows a group of patients who do

3 get benefit. I am particularly concerned about

4 missing diagnoses and whether you do that by

5 forcing every patient to have the appropriate

6 exclusion endoscopic procedure or not is something


7 we need to discuss, whether you look at chronicity

8 before they actually get onto this agent, how long

9 you have had the disease beforehand so we are

10 excluding those who have active IBD or something

11 else as well that might be getting in the way.


12 Patients who don't respond to a first

13 trial or a first month of therapy I think should

14 not be allowed to continue with the drug which is

15 one issue I would add onto what Dr. Wolfe said

16 beforehand.


17 DR. FLEMING: Can we define a patient

18 population in which benefits outweigh the risks.

19 Let me try to answer that first globally in terms

20 of the entire dataset. We actually haven't talked

21 in length today about benefits. With time limited,


22 we have, understandably, really been focusing on

23 risks.

24 If we look at the benefits data that was

25 presented to us, particularly in the pivotal







1 studies of the 3001, 3002, 30013 and 06 trials


2 presented by the sponsor on Pages 24 to 26, we

3 certainly see evidence of benefit relative to

4 urgency. We see about a 10 percent improvement in

5 the fraction who had urgency today. Stool

6 frequency is reduced by about 25 percent.


7 The primary endpoint was adequate relief

8 in the past seven days of pain and discomfort. The

9 percent that are successful on that measure seem to

10 be 12 to 15 percent higher. That seems to be the

11 main signal of effect.


12 Interestingly, and the sponsor put this

13 slide up--it is Slide A112. It is also on Page

14 26--if you look at Study 3006, the overall percent

15 that improve here, as the percent of people who do

16 have adequate relief in the past seven days of pain


17 discomfort, which was the primary, No.1 symptom, it

18 is improved by about 12 percent, from 40 to 45

19 percent, up to 55 percent. That is the treatment

20 signal. When these patients, then, go off the

21 placebo control, the success rate drops from 44


22 percent in half.

23 So, more or less, the placebo effect seems

24 to be as large as the treatment effect. The

25 treatment effect added on to the placebo effect,







1 but the placebo effect is substantial and the


2 waxing and waning of the disease process leads to

3 over and above the placebo effect, about a 20,

4 25 percent overall success rate in the control arm.

5 My overall sense of this, then, is I

6 believe there is real effect but, in the global


7 population, as studied in this trial, it is modest.

8 It is at the level that we have to worry about

9 whether they are offsetting AEs.

10 Obviously, as we have spent a great amount

11 of time today, we have concerns about the ischemic


12 colitis and serious constipation and, in my own

13 sense, it is complicated in the entire dataset to

14 say, does this provide a favorable benefit to

15 risk. So I think the questions of the FDA here,

16 which is to say, all right, if it is really


17 complicated in the global dataset, can we find

18 subgroups in which it is less complicated, in which

19 benefit to risk more clearly emerges in a favorable

20 way.

21 The data that we have seen is very limited


22 here. It might be that there are subgroups that

23 have more favorable benefit to risk but, as Dr.

24 Strom said, with the nineteen people having

25 ischemic colitis, no wonder it is not a surprise we







1 have had difficulty discerning who are those people


2 that are at risk.

3 I worries me that even early symptoms,

4 though, make it difficult to know who are those

5 people that are going to have subsequent

6 significant events. In addition to that, from what


7 we have seen, there is little evidence to say where

8 is the efficacy going to be greatest. I think it

9 is reasonable to speculate that those that have the

10 most disabling symptoms at the beginning have the

11 most room to gain.


12 So at least it is reasonable to speculate

13 that those people might well be those that would

14 have a more favorable benefit to risk and yet it is

15 still somewhat speculation because the data show at

16 least just very modest evidence that those that


17 start with a more severe baseline have a better

18 opportunity for benefit.

19 So, based on the data, I struggle being

20 able to say I can see a subgroup in which there is

21 clear evidence of more favorable benefit to risk


22 although I could speculate that, plausibly, if we

23 had a lot more data, it could be those people that

24 start with more serious conditions at baseline.

25 One of the issues that has been raised is







1 can we make modifications to this dose regimen in


2 order to maximize benefit to risk. The difficulty

3 here is I don't even know for sure what the

4 question is because I don't know for sure what the

5 sponsor is proposing the schedule to be. Is it BID

6 or is it QD? If, in fact, it is 1 milligram QD,


7 then we don't have--we have got limited data on

8 efficacy, is Point 1.

9 Point 2 is if the sponsor is planning to

10 go forward, as is written here, and those that have

11 failed to respond to conventional treatment, we


12 have minimal data there as well. Thirdly, and the

13 final point, is that Dr. Raczkowski has put forward

14 some very logical criteria that we might think

15 about in the ways of refining dosing based not only

16 on possibly having the 1 milligram per day dose


17 schedule but titrations, adjusting for maintenance,

18 drug holidays, discontinuing once you are in

19 response, managing AEs more effectively to

20 discontinue more rapidly.

21 All of those things may help on safety but


22 I don't have a clue how that is going to effect

23 efficacy. So if we make these modifications,

24 including dose changes, and we select patient

25 populations such as those for whom no other therapy







1 is effective, we have got very limited


2 understanding of what actual efficacy is.

3 The bottom line is I can't look at all

4 these data and say, clearly, there are subgroups

5 that could be benefitted here where there is clear

6 evidence they may well be, but the data here, at


7 this point, don't allow me to conclude clearly

8 benefit to risk is especially favorable in any

9 specific subgroup with any specific schedule that

10 we have proposed.

11 DR. LEVINE: I think there is evidence


12 that many of us in gastroenterology see patients

13 who are referred to us with IBS and they really

14 haven't had conventional therapy. They have had

15 short courses of fiber. They have had inadequate

16 courses. And it goes on and on with all the drugs


17 that we see.

18 So the first problem is this is the fact

19 that the definition of chronicity is easy but the

20 definition of conventional therapy, even in a

21 gastroenterologist's office, is not always


22 adequate. I think, given that, there is also, as

23 we have heard today from the public, a very small

24 and dramatic group which probably we can identify.

25 I would doubt it is more than 5 or 10 percent of







1 all patients with IBS. I think that is the group


2 that would be targeted.

3 I think, since originally, when it was

4 available on the market, it was grossly overused

5 and it was not 5 or 10 percent of the market. I

6 would dare say it was almost anybody, occasionally,


7 because of the demands of the patient for

8 diarrhea-producing IBS.

9 So I would say it would be important to

10 look at other drugs. It would be important to be

11 very strict about admission to the type of


12 severity. I don't think that will be too

13 difficult. I think we can talk about the number of

14 bowel movements, accidents, et cetera, and we can

15 identify the group that really would need this.

16 I also think, in deference to the


17 chairman, I am a little hesitant about gender

18 differences. I think they are true. It is true

19 Dr. Camileri is not here but he has alluded to

20 evidence that, even in males and females,

21 neurotransmitters, estrogens--there may be hormonal


22 differences in the normal state which are

23 exaggerated even further in IBS when a balloon in

24 put into the rectum and people measuring tolerance

25 or intolerance.







1 So I think there probably are distinct


2 gender differences that we know very little about

3 so I am a little hesitant to go full-head with

4 males at this point.

5 DR. WOLFE: (Comments off mike)

6 DR. FLEMING: I agree with you. I


7 misspoke. I agree with you.

8 DR. LaMONT: I think we have to be careful

9 to define the features of this first statement as

10 was raised by several previous speakers,

11 particularly what is conventional therapy and


12 primarily who would be patients that would be

13 excluded.

14 What we are coming up with here is

15 actually another clinical trial. We are asking

16 physicians in their offices and pharmacists to


17 actually do another clinical trial and see if we

18 can improve outcomes. It doesn't seem to me that

19 anything that has been said today is going to help

20 us predict who is going to get ischemic colitis but

21 we can probably exclude patients that would get


22 severe complications of constipation by adding

23 exclusion for patients with previous impaction, for

24 example, or patients that have had other problems

25 related to constipation.







1 DR. HOLMBOE: I would just want to agree


2 with some of the things that Dr. Fleming said

3 earlier. What we are really doing by trying to

4 define this population is not necessarily define

5 those characteristics but by characteristics that

6 predict a better benefit to risk ratio. What we


7 are really doing by picking these characteristics

8 is reducing the exposure. We are simply reducing

9 the population that would be exposed to this drug

10 as a risk-management strategy, not that we can

11 necessarily stratify.


12 I think we have heard clearly today, we

13 can't predict who is going to have ischemic

14 colitis, as has been brought up, or colonic

15 ischemia. So I think that, regardless of the

16 population chosen.


17 The second thing is magnitude of benefit

18 actually was fairly similar between those with

19 moderate symptoms and severe. So I think trying to

20 do it on that basis also doesn't make any sense.

21 If you think in numbers of needed to treat, quite


22 frankly, it is not terrible. It is anywhere from

23 eight to twelve patients have to be treated for one

24 patient to benefit. The number needed to harm is

25 around 700 for colonic ischemia.







1 So if you look at it in that terms, not a


2 terrible risk-benefit ratio. It is just that

3 disease under consideration makes it much more

4 difficult because of the severity of the ischemic

5 colitis as a complication. So I agree with the

6 things said by Dr. Fleming and Dr. LaMont


7 previously, if you could be very careful about some

8 of the definitions we come up with regard to

9 conventional therapy, et cetera.

10 DR. VENITZ: I do believe that we have a

11 population that benefits, I am not sure whether we


12 can identify, based on the data. It sounds

13 reasonable to me to assume that people that have a

14 more severe stage of the disease have a better

15 potential for benefit. I would concur with what is

16 said before. Proper diagnosis, to me, is about as


17 important as looking at the severity of the

18 disease.

19 DR. WOLFE: Dr. Anderson?

20 DR. ANDERSON: I take the first question.

21 I believe that a patient population can be


22 identified. For the second part of it, in

23 describing that population, I am going to go with

24 the chair and follow his directions.

25 I do have a concern, however, in the sense







1 that there seem to be a lot of gaps in the data


2 which we have. It may very well be that it would

3 be to our advantage to begin to look at where those

4 gaps are and try to fill them in. Secondly, I

5 think it might be important in the future for the

6 researchers to take a look at those thirteen


7 metabolites that the sponsor said are generated

8 when Lotronex is used.

9 I am a chemist and I am always concerned

10 about the chemicals and what happens in that

11 process. So, even though that is not a part of


12 this question, it was raised earlier and I think

13 that is a good thing to look at.

14 DR. CRYER: With respect to the question

15 of can a patient population potentially be

16 described who might benefit, the answer is yes.


17 But I agree with Dr. Fleming. I don't think that,

18 based on the data that we have seen, that that

19 specific patient population has yet been described.

20 We have guessed, we have assumed, what

21 those characteristics might be. We have assumed


22 that it might be 5 to 10 percent of the population

23 who has diarrhea-predominant IBS, but we don't

24 understand. We don't know who they are. So, in

25 whatever direction we move forward, I would propose







1 that, in that mechanism, we have a very


2 well-defined orderly process, whether it be in a

3 very well-designed registry or if it be in the

4 process of random sampling, as has been proposed by

5 the sponsor, or has not been extensively discussed,

6 whether it be in the form of a clinical trial,


7 continuing clinical trials with access, we need to

8 better define this population in a very orderly

9 fashion.

10 But I don't yet believe that that

11 population which will be has yet been defined.


12 DR. RICHTER: I think we can define this

13 group but it is not going to be as simple as how

14 many bowel movements you have because you tell a

15 patient, "How many bowel movements did you have?"

16 and they know that, to get in the study, you have


17 to have eight a day, they will tell you eight a

18 day.

19 So it tends to be a gestalt. Really, I

20 think the important things that have come out of

21 this discussion that I really support is that there


22 is a group, that this group probably needs to be

23 defined in conjunction with the general physicians

24 and the gastroenterologists working together so

25 that everybody is on the same base, that they have







1 diarrhea-predominant, they have chronicity. Beware


2 of the older person who suddenly presents with

3 irritable bowel symptoms.

4 Each one of these testimonials from the

5 patients are classic histories of that they have

6 had irritable bowel symptoms for twenty or thirty


7 or forty years. I wonder how many of these

8 patients that have gotten these drugs and had bad

9 situations were older and had symptoms that had

10 been going on for four or five or six months. That

11 is not the classical irritable bowel.


12 In light of the testimonials and the fact

13 that this is an averaging of symptoms, I think, if

14 you are going to open this up under some

15 restriction, you ought to allow both genders to

16 have access.


17 DR. WOLFE: Again, the FDA does need some

18 guidance. Actually, what I would like to do here

19 now is be a little simplistic. For Part a) of this

20 question, I want a yes/no. We will go around the

21 room to the voting members. Just a yes/no. We


22 will start with Dr. Richter. Can a patient

23 population be described for which the benefits of

24 Lotronex outweigh the risks?

25 DR. RICHTER: Yes.







1 DR. CRYER: No.



3 DR. VENITZ: Yes.


5 DR. LaMONT: Yes.

6 DR. LEVINE: Yes.


7 DR. FLEMING: No, not with current data

8 DR. METZ: Yes.

9 DR. WOLFE: Yes.

10 DR. GROSS: Yes.

11 DR. STROM: Yes, potentially.


12 DR. WOLFE: Please strike "potentially"

13 from the record.

14 DR. DAY: Yes, carefully.

15 DR. GARDNER: Yes.




18 DR. COHEN: Yes.

19 DR. LEVIN: No.

20 DR. WOLFE: That allows us to move forward

21 to the next question. This will be a little bit


22 more difficult. Actually, there is no vote on this

23 but if you could somehow record what are responses

24 are. Is that good enough for you?

25 DR. HOUN: Tom, could you repeat the







1 numbers?


2 MR. PEREZ: 4 no, 14 yes.

3 DR. RACZKOWSKI: Tom, if you wanted to,

4 you could have people just raise their hands to be

5 sure. Maybe the no's could--

6 MR. PEREZ: I beg your pardon?


7 DR. WOLFE: A recount is demanded.

8 DR. RACZKOWSKI: You might ask people to

9 raise their hands just to be sure.

10 DR. WOLFE: We will do this again real

11 quickly. Those who are voting members, how many


12 vote yes?

13 [Show of hands.]

14 MR. PEREZ: 14.

15 DR. WOLFE: How many vote no?

16 [Show of hands.]


17 MR. PEREZ: 4. Was there a problem?

18 DR. WOLFE: Democracy works. We still

19 have the right number. What I am going to do here

20 is we are going to try, please, just to be very

21 brief. We will go around the room. Just try to


22 get it in one sentence what population you would

23 start with. Identify which population. Two

24 sentences is fine.

25 DR. HOUN: To save time, we did collect







1 the information that people discussed.


2 DR. WOLFE: We will move on, then.

3 DR. HOUN: I would just ask if FDA has any

4 other questions. My question is you did not

5 discuss colonoscopy. There was some concern about

6 misdiagnosis. Is that something that you are


7 recommending?

8 DR. WOLFE: We will discuss this later

9 when it comes to who should be--should this be

10 restricted to gastroenterologists because, again,

11 we spent three years working on how we diagnose


12 IBS. I am not saying we are absolutely perfect in

13 this, but we do a good job.

14 DR. HOUN: The other question is urgency.

15 The descriptions from the testimonial was fecal

16 incontinence. Is that something that you think, in


17 terms of a description in the indications, would be

18 helpful, people who experience this?

19 DR. WOLFE: So you are saying they have to

20 have fecal incontinence before we would prescribe

21 this drug?


22 DR. HOUN: I am asking. Every one of the

23 testimonials described the anguish of that as a

24 marker of their quality-of-life impact and is that

25 something you would recommend, those of you--







1 DR. WOLFE: This is by a show of hands.


2 Do you think it is necessary to have fecal

3 incontinence to be prescribed this drug? How many

4 feel it is necessary to have this, fecal

5 incontinence? Please raise your hand high.

6 DR. LEVINE: Plus other--


7 DR. WOLFE: No, no; she is saying fecal

8 incontinence.

9 DR. LEVINE: Solely?

10 DR. HOUN: As part of--people

11 recommended--


12 DR. LEVINE: It is a part of a spectrum

13 and other symptoms, not alone. Should it be an

14 added indication?

15 DR. WOLFE: I think you are saying it

16 should be so severe, that it is fecal incontinence


17 associated with the symptoms is what you are

18 saying?

19 DR. HOUN: Right.

20 DR. WOLFE: So how many feel there has to

21 be fecal incontinence before you are prescribed the


22 drug?

23 [Show of hands.]

24 DR. HOUN: That gives me an idea. We

25 don't have to vote on that. I just wanted to







1 understand that.


2 DR. WOLFE: I am going to really go for

3 it. How many think, at this point, it has to be

4 diarrhea-dominant IBS?

5 [Show of hands.]

6 DR. WOLFE: So we all--let's attack the


7 gender issues. Do you want the gender issues? Are

8 there data sufficient, at this point, to recommend

9 use of this drug in men? I think we all agreed,

10 those who voted yes, in women there are data to

11 suggest. Let's go to men now. Are the data


12 sufficiently presented by the sponsor to allow

13 recommendation of this drug for use in men? How

14 many would say yes?

15 MS. BLACKMAN: Do you mean allow

16 recommendation of or do you mean allow physicians


17 to prescribe as they see fit because that is two

18 different--

19 DR. WOLFE: No. They have to be

20 recommending to the FDA that they go ahead and say,

21 in the package insert, that it is okay to use it in


22 men, too, based on the data. That is the question

23 I am asking. Does anybody think there is

24 sufficient data at the present time to warrant its

25 approval for use in men?







1 [No response.]


2 DR. WOLFE: How many don't think there is

3 data sufficient to recommend it?

4 [Show of hands.]

5 MR. PEREZ: I need to clarify something

6 here. Are we going to taking votes on this?


7 DR. WOLFE: We just did.

8 MR. PEREZ: No. What I am saying is are

9 we going to record official votes or are we just

10 trying to figure out which direction to go in?

11 DR. WOLFE: I want the FDA to have a sense


12 of what it is looking at.

13 DR. HOUN: No; I want voting just on the

14 official questions. These are additional

15 clarifications and we don't have to have formal

16 votes. We got your overall sense that, in the


17 labeling, men should not be part of the labeling.

18 MR. PEREZ: Thank you for the direction.

19 DR. WOLFE: I think Question 1 is done.

20 What I would like to do is do Question 2 and then

21 take a little bit of a break. How does that sound?


22 So, let's go to Question 2 because this is a key

23 question. At this time, should Lotronex be

24 available to patients with diarrhea-predominant IBS

25 without marketing restrictions, available to IBS







1 patients with appropriate marketing restrictions to


2 be defined or withheld from the market?

3 It is a), b) or c). I think we can answer

4 very quickly. If you want a little explanation,

5 fine, but we have already gone through it to some

6 extent. So, we started in this direction before.


7 Let's start in this direction now. Joel?

8 DR. RICHTER: I could support it in a form

9 of b) but not with this vague program, this risk

10 management program. I am much more enthusiastic

11 for an IND program similar to Cisipride in which


12 gastroenterologists and generalists work together

13 to make sure they have the disease and follow the

14 patient closely and then, with maybe an extended

15 period of time with it as an IND and we have a

16 better issue on the safety thing, then maybe open


17 it up to this restrictive--

18 DR. WOLFE: So you are saying b) with

19 restrictions. Again, our job is to recommend the

20 FDA will work with the sponsor to make--and we will

21 discuss these questions later on as well, what


22 restrictions we recommend.

23 DR. HOUN: Let me just clarify. IND

24 access is the research protocol only. It is not

25 marketing. If you believe that, then it is







1 withheld from the market at this time and you can


2 offer an explanation.

3 DR. RICHTER: Whatever you did with

4 cisipride. You didn't withdraw cisipride from the

5 market.

6 DR. HOUN: No; cisipride is not a marketed


7 drug. It is not a marketed drug. The sponsor has

8 withdrawn it from marketing. It is available under

9 IND only. It is a very onerous process to get

10 cisipride because you have to fill out investigator

11 forms. It is IND only.


12 DR. WOLFE: The other thing is I don't

13 want to discuss other drugs. This is on its own.

14 It stands on its own. Again, the question, is a),

15 without restrictions. First of all, does anybody

16 here feel it should be just without restrictions?


17 [No response.]

18 DR. WOLFE: So we will go to b) and c)

19 now. Do you want this approved with restrictions

20 which will be defined by the FDA or do you want it

21 withheld from the market and make it an IND which


22 the sponsor can then, basically, discuss that

23 option later on?

24 But, right now, do you want it released

25 with restriction or withheld entirely? Joel, do







1 you want to try again?


2 DR. RICHTER: Restrictions.

3 DR. CRYER: Restrictions.


5 DR. VENITZ: b)



7 DR. LaMONT: b)

8 DR. LEVINE: b)

9 DR. FLEMING: c), although I would like a

10 clarification and that is my understanding--what is

11 the understanding of the time line for b) versus c)


12 where c), in my view, and I will clarify in

13 Question 8, will be--there will be a prompt

14 randomized trial done that, hopefully, can get

15 these answers in a very timely way.

16 DR. WOLFE: I want to ask GlaxoSmithKline.


17 If the answer is c), what are you going to do? Are

18 you going to basically--we vote for an IND only,

19 are you going to go ahead and continue studies with

20 this drug?

21 DR. FLEMING: And that question is for,


22 b), what is the time frame to actually get it on

23 the market if that is the strategy?

24 DR. PALMER: Let me answer for b), first

25 of all, which is the approval with restrictions.







1 First of all, the steps to get to market are


2 several. We would have to agree the labeling and

3 agree the risk-management plan with the FDA. That

4 would take some time.

5 I think everyone needs to get on the same

6 page with where we are. We took the drug off the


7 market in November, 2000. We took it off the

8 market. So there is no material. There is no

9 commercial stock available for the drug. There is

10 drug substance that would have to be manufactured

11 into tablets and packaged once the packaging had


12 been agreed with the FDA.

13 So, unfortunately, this would take time.

14 I don't want to be locked in on a time estimate

15 right now, but what we would be looking at is in

16 the order, from this moment, moving forward four


17 to six months before actually drug availability.

18 Does that answer your question?

19 DR. WOLFE: It is very important that

20 everybody in this room understands that. If today,

21 the FDA decides they want it approved, there will


22 be no drug on the market for four to six months.

23 Do you all understand that?

24 That is another question that is going to

25 be asked. Dr. Metz asked me very quietly, but I







1 was going to ask the question also. The drug isn't


2 going to suddenly appear four to six months from

3 now. You are going to have the drug all along.

4 Are you going to have an IND available for those

5 people who would like the drug because they have

6 been on it in the past?


7 DR. PALMER: No. Our position has been

8 constant on this. We withdrew the drug and we have

9 said very consistently that we will not support and

10 IND program moving forward really because we don't

11 think that is the best way to serve the patients


12 who are going to need the drug.

13 We estimate, if you look at women with

14 diarrhea-predominant disease, if you look at

15 consultors and you look at the number of people who

16 might be wanting to access the drug, you are


17 looking probably in excess of 100,000-plus.

18 Frankly, when you get to that level, the logistics

19 of running an IND problem are A, very significant

20 and B, the nature of the IND program would mean, I

21 think, for a lot of the patients that you have


22 heard about speaking today, they would find access

23 to that medicine actually very difficult. It would

24 be very onerous, even more onerous, than the

25 hurdles we have already put in front of the







1 physicians with the restricted access program for


2 physicians who actually do this.

3 DR. WOLFE: Thank you. We are coming back

4 to Dr. Fleming but, in the meantime, anybody who

5 voted previously want to change their vote from b).

6 Everybody has a b) up to Dr. Fleming. Are we all


7 sticking with the b)?

8 Dr. Fleming, we are back to you.

9 DR. FLEMING: Then, just to repeat,

10 recognizing that there is a significant time here

11 to get to implementation under b) and recognizing,


12 in my view, that there are serious unanswered

13 questions about populations in which we have

14 favorably benefit to risk where I believe there

15 should be some prompt conducted randomized trials

16 that, hopefully, could get us answers in a timely


17 way, I vote for c) with the conduct of those trials

18 that would be clarified in the answer to Point No.

19 8

20 DR. METZ: I am an enthusiastic b).

21 DR. WOLFE: b).


22 DR. GROSS: A question first.

23 Thalidomide; is that under a b) type restriction or

24 c)?

25 DR. HOUN: It is under b).







1 DR. GROSS: Okay. I will vote for b).


2 DR. STROM: I vote for b) although with

3 restrictions much more severe than the proposal we

4 heard about before.

5 DR. DAY: b)

6 DR. GARDNER: b), what he said.


7 DR. WOLFE: I like the perfect answer.

8 DR. CAMPBELL: b), what she said. But all

9 of these are researchable questions and we are

10 being asked to make a decision without the data on

11 all of them. All of these should be taken as


12 researchable questions rather than simply yes or

13 no.

14 DR. CRAWFORD: A stricter version of b).

15 DR. COHEN: b), also, with improvements in

16 the risk management program that is being proposed.


17 DR. LEVIN: I concur with Dr. Fleming, c).

18 DR. WOLFE: So we have two c)s and 14 b)s.

19 What is the GPA on that? I think that gives you a

20 sense.

21 Let's take a ten-minute break. It going


22 to be eight-and-a-half minutes. We will start a 4

23 o'clock because we have a lot of questions to

24 answer still.

25 [Break.]







1 DR. WOLFE: Question No. 3; If Lotronex is


2 marketed, should the ability to prescribe Lotronex

3 be limited to certain types of physicians? If so,

4 describe the physicians in terms of the following

5 qualifications; knowledge, experience, specialty

6 and any other important characteristics.


7 We will start with Ms. Blackman. One

8 second, before I go on. The first two questions

9 were clearly very, very important. Not that the

10 other ones aren't, but if you don't want to say

11 anything, don't feel you have to say something.


12 Again, if you feel that someone else has given your

13 response, just say he said or she said.

14 MS. BLACKMAN: I do not think that it

15 should be limited to only gastroenterologists. I

16 feel that there are family practitioners who may


17 have more knowledge about IBS than some of the

18 gastroenterologists. I think that is true. I

19 wonder if there should be some kind of CME program

20 or registration for the physicians who prescribe

21 Lotronex who are trained on diagnosis.


22 But I do want to iterate that misdiagnosis

23 is malpractice. That is not something that the FDA

24 should be regulating. So I would like to see

25 doctors have to go through some kind of program







1 where they enroll, where they register and are able


2 to prescribe.

3 DR. WOLFE: Can I summarize? You are

4 saying anybody who has the proper education in this

5 drug, basically?

6 MS. BLACKMAN: Right.


7 DR. SULLIVAN: I would say that, in an

8 ideal world, it should be a board-certified

9 gastroenterologist. However, we don't live in an

10 ideal world and I think that creates issues for

11 gastroenterologists who claim they are


12 board-eligible, whatever that means.

13 I think that a physician who has some sort

14 of background knowledge should be able to prescribe

15 it and there are various strategies that you could

16 come up with that would deal with that issue. For


17 example, you could have a web-based system where a

18 physician could answer a questionnaire and be

19 registered. There are various strategies which

20 could deal with that issue.

21 So I think that basically any physician


22 who has the training.

23 DR. GOLDSTEIN: I would agree that any

24 physician who has the training but two things. I

25 would remind everyone at the table that this is, in







1 fact, a syndrome not a specific disease. In some


2 iterations, gas and bloating. Other iterations,

3 urgency, et cetera, et cetera. General

4 practitioners, as well as gastroenterologists, see

5 a substantial number of people, and particularly

6 those people who live in the rural, semi-rural,


7 areas without access to care, need it.

8 The second comment is that, as the father

9 of three daughters, I don't want this to be viewed

10 as chauvinistic, but I would urge the sponsor to

11 consider studies in men. We did hear a patient


12 representative, male, today. I think it is

13 something that at least ought to be considered.

14 Finally, I have some sympathy for a

15 suggestion from someone at the head of the table

16 about the desirability in the diagnostic process of


17 considering colonoscopy for a variety of reasons,

18 mostly to get at an accurate diagnosis, exclude IBD

19 and the like. In everyone? No. It would clearly

20 be difficult, if not impossible, to require it.

21 But I think it is something that was said at the


22 head of the table and with which I have

23 considerable sympathy.

24 Finally, the sponsor's program to educate

25 the medical community, I think, is something that







1 needs to be emphasized. They have both the skill


2 and the resources to do this and I think it would

3 make an enormous difference.

4 DR. WOLFE: Dr. Krist, before we go any

5 further, I forgot to say something that needs

6 clarification that I discussed with FDA in the


7 break regarding use in men. The way the label

8 stood before was that it said that effectiveness

9 has not been proven in men yet. So, with that kind

10 of wording, it would allow this drug to be used in

11 men without proven benefit until further studies


12 were done before approval could be obtained. So

13 that leaves the door open for use in men.

14 DR. GOLDSTEIN: I would agree with that

15 and I am sure that the FDA can work out the

16 appropriate language.


17 DR. KRIST: Just as I start to answer this

18 question, clarifying my position here, I am a

19 family physician, so that everyone knows that. I

20 have a pretty strong opinion on No. 3.

21 I do have a lot of concerns, like Dr.


22 Fleming was expressing, about whether the studies

23 have shown the benefits and which groups this is

24 the best for. But clarifying that, if it is

25 decided that this medication--that there are groups







1 of patients who will benefit from this, I do


2 believe that it probably shouldn't be reduced by

3 specialty.

4 I think that the FDA's second goal of

5 trying to ensure that qualified physicians are

6 prescribing this medicine is a good goal and I


7 think that that should be done. But I don't think

8 that saying that only gastroenterologists prescribe

9 it necessarily is going to ensure that that second

10 goal happens. So you won't necessarily ensure the

11 patient safety from that standpoint.


12 I think the other issue is that I think

13 that all physicians will be affected by this even

14 if you restrict it to just one specialty because

15 what is going to happen is patients are going to

16 have complications and they are going to see their


17 primary-care physicians, or the primary-care

18 physician is going to see a patient who is on

19 Lotronex and I will be trying to decide whether to

20 put them on hormone-replacement therapy or using

21 other medications.


22 So it is going to cross specialties even

23 if attempts are made to restrict it to just one

24 specialty. And then, as has been mentioned, there

25 are communities where there are not access to







1 gastroenterologists.


2 I think that one of the other important

3 things to just understand about primary-care

4 physicians, in general, is that--one of the things

5 I teach our students and residents who come through

6 is that primary-care physicians are experts. They


7 are experts in common things. Irritable bowel

8 syndrome is a very common illness.

9 The other thing that they are experts in

10 is recognizing what they know and what they don't

11 know. So there is going to be a lot of room for


12 collaborative work between primary-care physicians

13 and gastroenterologists, particularly with

14 establishing diagnosis and with patients who are

15 more complicated. But I don't think that, just by

16 restricting it to a gastroenterologist, that that


17 would make the difference or ensure a qualified

18 physician for prescribing it.

19 I do like the model that has been

20 mentioned of specific physician CME. A good

21 example would be for institutional review boards or


22 for being a primary investigator with research.

23 There is on-line education through the Department

24 of Health and Human Services to prove that a

25 physician is qualified as opposed to just a







1 physician's statement that they are qualified.


2 The risk of a physician's statement that

3 they are qualified is you have a risk of including

4 physicians who are unconsciously incompetent, who

5 think they are qualified but really aren't,

6 particularly if we are going to ask physicians to


7 go through and, with patients, ensure that an

8 informed or a shared decision is being made.

9 We are asking for a different level of

10 knowledge on this topic. We are asking for doctors

11 to be able to say the risk of ischemic colitis is


12 somewhere between 3 and 17 out of 1000 and specific

13 numbers that many doctors might not normally know,

14 but that a patient will need to know in making a

15 decision on this medicine.

16 DR. LEVIN: The first thing is just a


17 point of information. Is there any precedent for

18 restriction by specialty?

19 DR. HOUN: There have been restrictions

20 for doctors based on ability, like for

21 mifepristone, to diagnose and manage pregnancy,


22 ectopic pregnancy. You don't have to have

23 surgical-intervention skills but we do, in that

24 restricted system, say you have to have a referral

25 system in place to handle surgical intervention.







1 For the other restricted drugs, the


2 physician must register with the program and some

3 of them have specific education that they have to

4 go through to register, but it doesn't preclude

5 multiple specialties from joining the program.

6 DR. LEVIN: I would support the model that


7 was just described, registration but specialty is

8 not enough.

9 DR. COHEN: Today we heard that the drug

10 was clearly overused when it was available and was

11 on the market. We heard that there has been


12 misdiagnosis. To me, as a pharmacist, I would want

13 to make sure, for patient safety reasons, that

14 appropriate individuals were prescribing it. And I

15 would want to restrict it to a gastroenterologist

16 because when I get that prescription with a


17 sticker, that will communicate something to me.

18 But I also, certainly, can see a

19 certification process through CME, et cetera, for

20 family physicians, general-practice physicians.

21 But it would need a certification process of


22 something.

23 DR. CRAWFORD: I concur with what Dr.

24 Cohen just said.

25 DR. CAMPBELL: This is one of those







1 researchable questions. The truth is we don't know


2 how to answer this question. There is no data to

3 drive or inform our decision. As experimentalists

4 in that situation we should say there is no

5 difference until there is a proven difference. So,

6 at this point, I believe it should not be


7 restricted to just gastroenterologists.

8 However, I do believe the criteria for

9 prescribing this medication should be a

10 well-developed credentialing or certification

11 program that would require the prescriber to not


12 only demonstrate appropriate knowledge but to also

13 be able to demonstrate that in practice.

14 DR. GARDNER: I agree with Dr. Campbell

15 and have that documented in some way.

16 DR. DAY: I would like to mention that


17 there is an intermediary plan. The FDA has

18 proposed, in some of the briefing material, that

19 there could be a start with a very conservative

20 plan to be relaxed over time, say, after a period

21 of a year. This would answer Dr. Campbell's


22 concern if it were restricted to specialists for

23 one year and we could look at the incidence and

24 types of AEs, and then relaxed after a year, if

25 that is a satisfactory profile. Then see what is







1 after that. Then we would know better if that has


2 been contributory in the past, that people with

3 insufficient knowledge and experience have been

4 prescribing this drug.

5 I would like to support, in addition, the

6 CME approach and that everyone go through the


7 education and demonstration on line or another

8 means

9 DR. STROM: I should clarify. In

10 answering, I am not only an epidemiologist, I am

11 also a primary-care physician. I think it should


12 be restricted away from primary-care physicians

13 toward gastroenterologists and, in fact,

14 gastroenterologists who have gone through some

15 special registration scheme.

16 I think there are two reasons to restrict


17 it to gastroenterologists. One is the diagnostic

18 certainty, diagnostic correctness thing that we

19 have talked about all day, which I think is a major

20 issue in differentiating inflammatory bowel disease

21 from irritable bowel syndrome.


22 I think even in the group of letters that

23 many of us got lobbying us before this meeting,

24 there were patients who gave their clinical

25 scenarios and it was clear that those patients







1 lobbying for this drug for irritable bowel syndrome


2 really had inflammatory bowel disease and didn't

3 seem to realize that.

4 I think that confusion is a major issue

5 and is a reason why you need gastroenterologists to

6 be the people using it. I think the other reason


7 it should be restricted to gastroenterologists is a

8 question of severity. This is an extraordinarily

9 common condition which is severe in a small subset

10 of people. It is very severe in the subset of

11 people but one way of making sure you are getting


12 it to the most severe people is by restricting the

13 treatment to gastroenterologists.

14 If the irritable bowel syndrome is not

15 sufficiently severe that they have gotten to a

16 gastroenterologist, it is probably not severe


17 enough to need the risk of this drug.

18 DR. GROSS: I am going to propose a middle

19 ground and that is that if the general internist

20 wants to use the drug, it must be done in

21 consultation with a gastroenterologist, although


22 the general internist can prescribe it after

23 approval by the gastroenterologist.

24 The reason for this is a couple-fold. I,

25 personally, know several cases of general







1 internists seeing the patient with IBS that turned


2 out to be inflammatory bowel disease and the

3 diagnosis was delayed not by a matter of a month or

4 two but by a year or two.

5 Secondly, as far as certification is

6 concerned, there is something called book knowledge


7 and something called experience. I think

8 certification would attest to book knowledge but

9 not necessarily to experience.

10 DR. WOLFE: I really have mixed feelings

11 listening to everybody speak but, in an ideal


12 world, I think this would be best restricted,

13 initially, to gastroenterologists. However, if

14 someone is living in the middle of Montana and

15 there is no one around for 400 or 500 miles, that

16 makes it impractical. So you can't put in an


17 insert, "If you live in Montana, you can use it.

18 But, if you don't, you have to go to a

19 gastroenterologist."

20 I think that proficiency--I think that you

21 could word it in such a way that it would say


22 proficiency in digestive diseases and the diagnosis

23 and treatment of irritable bowel syndrome. It does

24 bother me that the question has been raised about

25 confusing this with IBD. Again, experienced







1 gastroenterologists, those who do three years of


2 training, don't have that much difficulty.

3 I am not saying that they are perfect.

4 But they do well. On the other hand, if there is

5 confusion, I think a good primary-care physician

6 will refer the patient on. So some wording can be


7 somehow be put in that allows for consultation or

8 proficiency.

9 The other thing that can be considered,

10 and this comes from doing trials, is sort of five

11 or six questions can be posed. For example, does


12 the patient have blood in their stool. If it is

13 yes, they don't get the drug. It should not be

14 prescribed. Is this disease chronic, defined as

15 more than--we are going to put the ROME criteria in

16 there. Just quick questions, a check list to see


17 if the person really should or should not be taking

18 this drug.

19 So, again, I have mixed feelings but I

20 think, in reality, it would be very difficult to

21 restrict this drug to gastroenterologists only.


22 DR. METZ: I would focus on the fact that

23 IBS is a diagnosis of exclusion and that it is a

24 syndrome and that, in actual fact, to diagnosis

25 this condition, you need to exclude IBD. I think







1 that requires an endoscopic evaluation. We can


2 argue about whether a flex-sig is enough or you

3 need a colonoscopy.

4 But I think one of the issues here is that

5 you would need to go through a check list, as Dr.

6 Wolfe suggested, and if you have had any blood in


7 your stools, you don't count. If you haven't had

8 an endoscopic evaluation to rule out IBD, I think

9 you would be out.

10 That doesn't mean it has to be the

11 gastroenterologist doing the prescribing. But I


12 think they have to be in the loop in the evaluation

13 and the diagnosis of the patient. Once that

14 patient is then put onto a program, I think it

15 would be totally appropriate for a well-trained,

16 primary-care doctor who has gone through CME


17 training, however it is evaluated, to continue

18 prescribing for that patient.

19 But I would like to see a proper diagnosis

20 up front. I think that is where all the issue came

21 for the postmarketing data is I see that sudden


22 jump in the first three months, I am attributing to

23 misdiagnosis and I think you can prevent that.

24 DR. FLEMING: I pass.

25 DR. LEVINE: I would agree with Dr. Wolfe.







1 I do think there is an insurance policy here and I


2 would like it clarified by Dr. Raczkowski. I think

3 anybody who signs off on this in any way is

4 probably liable legally. So if that is true, I

5 think a family practitioner would be, and a

6 gastroenterologist would be, loath to sign anything


7 away if they felt uncomfortable that they didn't

8 know how to manage this. I think that is an

9 insurance policy.

10 Could you clarify that, Dr. Raczkowski?

11 If someone signed off on this, they would be


12 liable?

13 DR. HOUN: I think malpractice is governed

14 by each state and how each state handles those

15 issues. There is not an indemnity form that you

16 would sign saying you accept the risks and will not


17 sue for them. Wherever you practice, the norms, in

18 terms of practice standards, apply to you.

19 DR. LEVINE: But my point is, if a doctor

20 in Montana or in New York writes down and says, I

21 am going to put this person and follow the


22 educational program, et cetera, then he knows that

23 if something happens to that patient, it probably

24 may result in that state in legal problems.

25 So I think that is an issue that should be







1 kept in the back of the mind. In any event, I am


2 with you, Mike. I go along with what you--I would

3 say to everybody, you would have to do it even

4 though I would prefer to see it solely in

5 gastroenterologists.

6 DR. LaMONT: I like the hybrid model where


7 an internist or a primary-care doctor working in

8 conjunction with a specialist can ascertain and

9 establish the diagnosis. So I vote for a hybrid

10 model.

11 DR. HOLMBOE: As a general internist


12 practicing in a city with a very poor population,

13 it is often very difficult, even when there are

14 gastroenterologists in the city, to get them to be

15 seen by gastroenterologists. So I think that, with

16 the model proposed by Dr. Wolfe, that is quite


17 doable.

18 I think that there would have to be some

19 sort of certification. You would have to document

20 you had the knowledge to prescribe the medication.

21 On top of that, I would build in the check list and


22 exclusions into the patient agreement. I would

23 make that part of the form so it becomes part of

24 the records instead of making it separate. That

25 will help remind the physician what to do.







1 Third, although we will get to this later,


2 I think that, particularly for those outside of

3 gastroenterologists who decide to do this, there

4 should be some form of an audit, at least early in

5 the course of their using it, to make sure they are

6 using it properly. I think that would help.


7 DR. VENITZ: I don't think we need any

8 restrictions according to subspecialties but I do

9 think that certification and documentation of

10 competency is required. I am sensitive to Dr.

11 Gross' suggestion that there should be some


12 referral system set up a priori to make sure that

13 the diagnosis is not missed. But, from that point

14 on, I don't see why anybody that understands the

15 drug and the disease but is not an enterologist

16 couldn't follow up and make whatever adjustments.


17 DR. ANDERSON: I agree.

18 DR. CRYER: So what we are trying to

19 accomplish here is to reduce the risk to the

20 patients who are going to be exposed to the drug.

21 I think that is accomplished. I think the case has


22 been well stated that it is accomplished by

23 excluding other diseases which could mimic IBS and

24 its presentation.

25 Also, to the extent that the patient







1 population who is ultimately prescribed this drug


2 mimics or parallels the patient population which

3 was studied in the clinical trial would be

4 desirable. So, to achieve that, if we look back at

5 the exclusion or inclusion criteria for the

6 clinical trials, there were patients who were


7 studied by either flex-sig or colonoscopy within

8 five years of diagnosis.

9 So, to accomplish that in the clinical

10 practice and clinical implementation of this drug,

11 I do not think that prescribing needs to be done by


12 a gastroenterologist. But I do think that this

13 physician-patient agreement needs to reflect the

14 fact that some sort of evaluation for other

15 diseases has been done in a similar way that the

16 clinical trials were actually conducted, possibly,


17 even, to specifically state that evaluations for

18 other processes such as Crohn's disease or

19 ulcerative colitis have been done.

20 I think specifically that needs to be

21 indicated and documented in the section for


22 physicians, that acknowledgment. I also agree that

23 there should be some sort of certification that is

24 done by physicians and, by having that

25 acknowledgment as part of this document, that helps







1 serve as an educational tool for physicians in that


2 every time they go through the prescribing, this

3 prescribing exercise for patients, they go over in

4 their mind that, yes, this patient has been

5 evaluated for Crohn's by someone; yes, he has been

6 evaluated for ulcerative colitis, diverticulitis,


7 and those conditions do not exist.

8 So, to summarize, I don't think it should

9 be done, prescribing restricted to a

10 gastroenterologist but there needs to be some

11 component to document that that evaluation of other


12 disease processes has happened.

13 DR. RICHTER: I see this as a multistep

14 process and there are a lot of unknowns in Question

15 1 and Question 2. For this to be inserted back

16 into the public, this is a place where I do think,


17 in the beginning, we ought to have some

18 restrictions. I think it ought to be restricted to

19 gastroenterologists for the first year, first year

20 and a half, allow the company to do more studies,

21 really get an idea of the safety situation there,


22 not because I think gastroenterologists want this

23 drug restricted to themselves. I think they would

24 prefer this be for everybody.

25 But, until we really have a handle on this







1 ischemic-colitis area, by restricting it to


2 gastroenterologists to start with, with a careful

3 monitoring, see how this restrictive

4 system--everybody wins. The patient gets the drug.

5 Hopefully, we have a better idea of the patients

6 that have to, and then widen it with the goal to be


7 that it will be widened after you have had an

8 experience with the gastroenterologist-only drug.

9 DR. WOLFE: Before we go on, I want to

10 state one thing to the audience. There is no

11 conflict here. Dr. Richter stated this very, very


12 clearly. This is actually a shortage of

13 gastroenterologists. We are not looking, right

14 now, for a horde of patients to come to us. So

15 that is not the reason for restriction here at all.

16 There is a serious shortage in many, many


17 places throughout the country. I actually have a

18 question for the FDA and for the sponsor. I would

19 assume--I see several gastroenterologists here work

20 for GSK. I would assume that there will be people

21 available in case there were questions by


22 physicians, to call the 800 number, a consumer

23 number to call. Would that be correct?

24 DR. TRABER: Yes. I think the company

25 would provide, as was mentioned by Dr. Wheadon, a







1 website and 1-800 numbers and lots of information.


2 I would just put into the mix here a couple of

3 comments. One of the most important things I heard

4 from the patients and from a lot of people is to

5 make sure that the people who have the proper

6 risk-benefit have access to this drug.


7 Many of you know that I ran a GI training

8 program. I will just say that there are

9 gastroenterologists that are trained as

10 gastroenterologists who have, then, never treated

11 patients with IBS and they restrict their practice


12 to hepatobiliary disease or whatever. They are no

13 more qualified to, twenty years down the line,

14 treat irritable bowel syndrome as other people, or

15 they may not see patients.

16 Furthermore, there are lots of physicians


17 who may focus in irritable bowel syndrome and see a

18 lot of patients in that way that are not

19 gastroenterologists. So I would just put that into

20 the mix that I am as much for credentialing of

21 gastroenterologists as anybody, but certifying in


22 this particular area is, I think, important.

23 DR. WOLFE: So, to vote on this question,

24 I think I can simplify to some extent. Is there

25 anybody here who doesn't agree there should be some







1 kind of knowledge of IBS that is mandatory to


2 treat? So we all agree there should be some kind

3 of knowledge of IBS and knowledge regarding the use

4 of this drug. I think everybody agrees with that.

5 I think the question could be basically

6 boiled down to does one have to be a


7 gastroenterologist. I think that is the

8 restriction we are talking about. So I think just

9 a simple yes/no right now would suffice because we

10 have to move on. So, again, the question, right

11 now, that we are going to take a vote on, should


12 this drug be restricted to gastroenterologists from

13 Day 1.

14 The specific model, I think you have

15 seen--the FDA has seen a lot of opinions raised

16 here. We can all agree that, in conjunction with


17 someone with expertise in IBS would be desirable.

18 But, right now, I think the question specifically

19 being asked is should we restrict this drug. Let's

20 first answer that, yes or no. Should it be

21 restricted to gastroenterologists, yes/no.


22 DR. LEVIN: Yes; gastroenterologists.

23 DR. WOLFE: This is by hands. Okay. How

24 many feel it should be restricted by

25 gastroenterologists at this point?







1 [Show of hands.]


2 DR. WOLFE: How many feel that it can be

3 restricted to others. There may be abstentions,

4 too--it can be used by others as well.

5 [Show of hands.]

6 DR. WOLFE: With restrictions. We already


7 talked about restrictions. That is understood

8 DR. METZ: Can I insert something? Is one

9 of those restrictions that you have had a

10 preestablished diagnosis including a look at the

11 mucosa?


12 DR. WOLFE: I don't think that is

13 necessary. ROME criteria are available. If you

14 have a twenty-three-year-old woman who comes in

15 with a ten-year history of diarrhea, I don't

16 think--and it fits all the ROME criteria, I don't


17 think it is necessary to do a colonoscopy or a

18 sigmoid in every case. Sometimes I would. It is

19 clinical judgment.

20 DR. GROSS: How about consult with a

21 gastroenterologist who treats IBS and IBD.


22 DR. WOLFE: That is up to you as a

23 primary-care physician. Primary-care physicians, I

24 think if you are uncomfortable, that is why God

25 created gastroenterologists. That is what we are







1 here for.


2 DR. CRYER: Dr. Wolfe, in the patient that

3 you just described, this twenty-three-year-old

4 woman who fits the criteria, it is still possible

5 that she could have IBD. We have learned, we have

6 heard, that IBD is one of those conditions in which


7 there may be increased risk for ischemic-related

8 problems.

9 I don't think that it should be restricted

10 to a gastroenterologist, but I agree with Dr. Metz,

11 there needs to be some sort of validation that we


12 have excluded the possibility of those diseases.

13 DR. WOLFE: So you are saying that every

14 single patient should have some kind of endoscopy

15 of some sort. Let's vote on the

16 gastroenterologists here.


17 DR. CRYER: I am not saying that. I am

18 just saying that there needs to be some sort of

19 confidence in the prescribing physician that those

20 conditions have been evaluated and that confidence

21 needs to be documented in the physician aspect of


22 this form.

23 DR. WOLFE: I agree. We are just saying

24 it different ways. We should be confident that the

25 diagnosis, as confident as we possibly can be. We







1 are never going to be 100 percent confident of


2 anything

3 DR. METZ: The one point that struck me

4 that distinguished the premarketing data from the

5 postmarketing data is that, in all those

6 premarketing studies, there was a screening visit


7 including a scope.

8 Actually, an issue that wasn't raised, I

9 would be very interested in knowing in how many

10 patients who were screened and failed because they

11 had an abnormal endoscopy. I did ask that of Glaxo


12 during the break and I was told very few. But I

13 didn't get a specific answer.

14 DR. WOLFE: It is going to stay very few

15 because we really have to move on. Unfortunately,

16 as the chair, I have another question that I have


17 added in here because the question has been raised

18 by Dr. Fleming and a few others and that is there

19 is really very little data to suggest a

20 dose-dependent dose-response curve for efficacy.

21 But there are data at present to show a


22 dose-response curve for constipation. So we know,

23 for safety issues, there is a dose-response curve

24 there. I would, personally, like to get some

25 recommendations quickly regarding what dose we







1 would start at and for how long we would recommend


2 that dose titration continue.

3 DR. HOUN: Before you begin that, before

4 we leave the prescribers, the qualified

5 prescribers, I understand there is some

6 recommendation that the prescribers, some of them


7 can be in consultation with GI. There is some

8 consideration that this previous exclusion of

9 organic disease should be considered.

10 What I heard different was about an

11 education program prior to being called qualified.


12 I got pretty much that most people would be in

13 favor of that; is that correct?

14 DR. WOLFE: Yes.

15 DR. HOUN: So not just someone who

16 self-attests, but you are saying an active


17 education program. Some people have mentioned you

18 test to show that--

19 DR. WOLFE: You need a quick list, too,

20 before prescribing the medication. That could

21 actually be a very quick education for the patient


22 and for the physician.

23 Can we move on? Since we started at the

24 ends, I am going to start in the middle here. What

25 I would like to propose, and if we spend a lot of







1 time, we will have to cut it. We will just cancel


2 the question. I would actually rather start

3 with--suggest; we don't vote. We suggest to FDA

4 and to the sponsor that the dose be a half

5 milligram.

6 Again, the data show very clearly,


7 starting at a half to 1 to 2, there was a

8 difference in the incidence of constipation. So I

9 propose starting with a half milligram and then

10 going on from there.

11 DR. CRYER: As a point of clarification,


12 do you mean a half milligram BID for a total 1

13 milligram daily dose?

14 DR. WOLFE: I will go back to the example

15 I used before and that was sulfasalazine. We start

16 at 5 milligrams a day on a drug that we used 1 gram


17 four times a day. So I would start with a half

18 milligram a day, go to a gram a day and then to 2

19 grams a day. Milligrams; excuse me. We are not

20 treating elephants. We are treating humans here;

21 yes.


22 So I would start with a half a milligram a day to a

23 milligram a day to 2 milligrams a day.

24 DR. TRABER: I just wanted to remind the

25 committee that what we have proposed is 1 milligram







1 once a day. That is kind of what was in the sNDA.


2 DR. WOLFE: What I am suggesting is maybe

3 you may consider and start with a half a milligram

4 a day

5 DR. METZ: Is there any data on that? In

6 terms of the PK/PD, we heard there isn't any


7 information in the trials--I think the information

8 that you showed us was in BID dosing. So is it 1

9 milligram once a day or 0.5 milligrams twice a day?

10 DR. WHEADON: First of all, I need to

11 clarify one thing. Remember, that we are


12 discussing a supplemental NDA. The NDA that has

13 been approved and was voluntarily withdrawn does

14 not include a 0.5 milligram tablet. It only

15 involves a 1 milligram tablet. So, if you make a

16 recommendation concerning 0.5, you are adding on to


17 the time frame that Dr. Palmer has referred to

18 earlier.

19 So that is another consideration that

20 needs to be kept very strongly in mind.

21 DR. WOLFE: Again, in consideration of


22 safety, you showed data very clearly--in my view,

23 you showed data very clearly showing that a half a

24 milligram a day, total dose, there was, even in

25 those patients, some constipation. When you went







1 to 1 milligram, there was a little more. Then,


2 with 2 milligrams, it was even more, unless I

3 misread the data.

4 So, again, if no one else feels that way,

5 then we will just go to the 1-milligram dose.

6 DR. VENITZ: I am in agreement with what


7 you are saying in terms of starting at a lower

8 dose. I am not sure whether it should be done as

9 part of the standard of care in terms of actually

10 reapproving the drug. But I would encourage the

11 sponsor to do a prospective study.


12 You have a study proposed right now in

13 your risk-management plan. But you look at doses

14 lower than 1 milligram a day; in other words, half

15 a milligram a day, all the way from 0.5 to 2

16 milligrams per day.


17 And you look at safety and efficacy in a

18 prospective trial because, personally, I am not

19 convinced that, with the dose finding that you have

20 done in phase 2A, that you have found the optimized

21 dose. What you would probably find is that the


22 dose, the optimal dose, is going to be different by

23 patient.

24 But I don't think that I would recommend

25 that as the dose that was used for the patient at







1 large, but it should be used as part of clinical


2 trial where you can actually assess the dose

3 response within a patient.

4 DR. PALMER: Can I just raise the issue

5 here? I mean, I think this is a very important

6 issue in terms of the availability of the drug


7 moving forward. I think we all recognized, when we

8 made the proposal for 1 milligram once a day, that

9 this was a pragmatic solution to a safety issue.

10 If we accept the pragmatic solution, then

11 the track, in terms of where everyone wants to be


12 who is sitting out there, which is to have the drug

13 available, is much shorter than the track which is

14 being discussed which is to have a 0.5 milligram

15 tablet, potentially run dose ranging in parallel.

16 We can go either way on these options, but


17 we have to make some decisions. I would be

18 absolutely clear, the 1 milligram once a day is a

19 pragmatic decision based on data on just intuitive

20 up titration, good medical practice and reducing

21 the risk of constipation. I just wanted to make


22 that clear.

23 DR. WOLFE: Is the pill scored? Is the

24 tablet scored?

25 DR. PALMER: The tablet is not scored, as







1 I remember.


2 DR. VENITZ: That is exactly why I was in

3 favor of what you are proposing right now for the

4 standard of care as far as making it available to

5 the public at large. But I also would encourage

6 you, in your phase IV study commitment that you


7 have in here, to add a lower dose, even if that

8 means you are going to have to develop a new, a

9 lower-strength dosage form.

10 DR. PALMER: Again, just to again set the

11 scene of where we are, all work stopped in


12 November, 2000 when we withdrew. If we are now in

13 a mode where we are moving forward, then clearly we

14 are into a different plan because then phase IV

15 commitments, everything else, can come back on the

16 table and we can look at what we need to do to


17 fully characterize the drug.

18 A lot of the things that have been

19 suggested round the table today were actually on

20 the slate to do. Obviously, if we find a way

21 forward, then those would be reactivated.


22 DR. DAY: Speaking of what is on the slate

23 to do, I notice Dr. Hoberman presented data showing

24 that individuals of lower weight had a higher

25 incidence of adverse events. I was wondering if







1 you had given any consideration to titrating the


2 dose as a function of the weight or height-weight

3 considerations per patient.

4 DR. CARTER: I don't believe that we

5 actually gave that as a consideration. But,

6 perhaps, if I am speaking out of school here, one


7 of my colleagues can then correct me. I don't

8 believe that that was ever the case.

9 DR. PALMER: We were in the process of

10 setting up some studies in the Asia-Pacific region

11 looking at people of lighter body mass, smaller


12 body mass. Obviously, they got put on hold at the

13 time that we withdrew the drug.

14 DR. WOLFE: Dr. Goldstein?

15 DR. GOLDSTEIN: One other consideration.

16 I don't know where, if at all, there are pediatric


17 studies done or contemplated. In point of fact,

18 Kline and Barbero, the late Julio Barbero, had done

19 some studies in small children in St. Louis and

20 there are others. But, in terms of an incentive to

21 consider a 500 milligram dose form, or half the 1


22 milligram dose, let me put it that way, that is

23 something that might add a bit of incentive to

24 considering something like that.

25 DR. HOUN: Mr. Chair, I think we should







1 move on.


2 DR. WOLFE: I want a quick yes/no, a show

3 of hands.

4 MR. CARTER: Mr. Chairman, I'm sorry. We

5 do have one slide that shows the constipation data

6 for the 0.5 milligram BID dose that might be


7 pertinent before--

8 DR. WOLFE: That is 1 milligram a day.

9 DR. CARTER: That is 1 milligram a day but

10 that is all that we have. So we don't have a 0.5

11 milligrams QD.


12 DR. WOLFE: Why don't you show it quickly,

13 then.

14 DR. CARTER: E8, please.

15 [Slide.]

16 So we have seen the 11 percent adverse


17 events. Obviously, the numbers are small, 14

18 percent in women, median time to onset, 8 days, and

19 then the withdrawals due to constipation were as

20 you see here. We did have that one subject

21 reporting ischemic colitis, a male patient.


22 DR. WOLFE: You are reinforcing it is a

23 lower incidence of constipation. It is much lower.

24 Let's move on. Just quickly, I want a

25 show of hands. Is there any sentiment for starting







1 at lower than 1 milligram a day, starting at a half


2 a milligram a day? By show of hands. Would

3 anybody interested in a lower dose at the present

4 time?

5 Right now, 1 milligram a day; correct?

6 And then moving upwards. What I am proposing is a


7 half milligram a day and moving upwards.

8 DR. STROM: As part of the study or as

9 part of the initial marketing?

10 DR. WOLFE: As part of the release of the

11 drug.


12 DR. CRYER: I would just like to make one

13 comment. The data that we just saw here was for

14 0.5 milligrams BID. What is currently on the table

15 is for 1 milligram total daily dose per day. To

16 the extent that we can, I really would like to


17 encourage us to make our decisions that are data

18 driven. The data that we have are for 0.5

19 milligrams BID. So I would propose a compromise

20 between the two; yes, 0.5 milligrams, but twice

21 daily because that is the dosage form for which we


22 have data.

23 DR. HOUN: Mr. Chair, I think we should

24 move on.

25 DR. WOLFE: We are moving on.







1 DR. HOUN: It is clear that the company is


2 not prepared at this point to manufacture 0.5. I

3 think we can discuss with them where they would be

4 with manufacturing 0.5 in the future. And I hear

5 your concern that there might be some safety

6 advantages to that and I also hear the concern


7 there might need to be efficacy studies to

8 elaborate more on that efficacy for that dose.

9 DR. WOLFE: We will move to Question 4.

10 GSK proposes to restrict use of Lotronex to

11 patients who sign a patient-physician agreement.


12 This agreement is then filed in the patient's

13 medical record. Is this adequate to ensure that

14 only patients with the most favorable benefit-risk

15 balance receive Lotronex. Is auditing of this

16 agreement needed?


17 We have actually, in a way, discussed the

18 first part of this question by--did we discuss

19 this, do you think, the first part of the question?

20 Everybody agree?

21 Okay. Is auditing of this agreement


22 needed? Do we all think it needs to be audited?

23 Is there anybody who thinks it shouldn't be

24 audited? Okay.

25 We will go the next part, b. GSK proposes







1 a utilization study of UHC as a mechanism to audit


2 whether appropriate patients are being prescribed

3 Lotronex. Is this auditing mechanism adequate to

4 achieve this goal? If not, describe an adequate

5 auditing mechanism.

6 I would like to start with Dr. Gross.


7 DR. GROSS: I have one additional

8 suggestion and that is most educational efforts, if

9 they are didactic, don't work. If they are

10 interactive, they are more likely to work.

11 Therefore, I think, much as the Advisory Committee


12 on Immunization Practices has done for vaccines,

13 some kind of questionnaire should be developed for

14 patients and a separate one for physicians that

15 they need to answer and get correct in order to be

16 prescribed the drug or to prescribe the drug.


17 DR. WOLFE: So you are saying that that,

18 in itself, what they are proposing is not adequate,

19 that more is needed?

20 DR. GROSS: Yes, along the lines I

21 recommended.


22 DR. DAY: I would like to comment more

23 thoroughly on this proposal. Everyone agrees here

24 today that the patient plays a key role in

25 identifying AEs in reporting and so forth. I think







1 that the sponsors put in place a number of good


2 things that will help, the med guides, the

3 patient-physician agreement form, and so on.

4 However, we can put all the appropriate

5 information in all these documents, but if patients

6 cannot find, understand, remember and use the


7 information appropriately in an accurate and

8 efficient way, then it is functionally absent. I

9 think that the patients who are here today are very

10 knowledgeable and very willing to consider all of

11 these things and sign as appropriate.


12 However, there will be new people entering

13 the pool if this drug is reintroduced. The plan,

14 at least provided in the briefing materials by the

15 sponsor, include some knowledge questions within a

16 larger survey mechanism and that mechanism deals


17 with a lot of other things. The only thing that is

18 said about how the data will be analyzed, with

19 respect to knowledge, is that knowledge will be

20 looked at in terms of the other variables such as

21 the demographic variables.


22 They do mention some of the appropriate

23 things to test; a patient's knowledge of the

24 benefits, of the risks and appropriate actions to

25 take. However, it is a written survey and, as the







1 FDA has pointed out today, it is voluntary. If


2 there were a patient registry, then it could be

3 mandatory, they say.

4 Sure. But, still, a written survey that

5 is taken on one's own in one's own residence or in

6 the car or wherever has some inherent limitations.


7 So, if, for example, someone does not answer one of

8 the questions, does that mean that the person does

9 not know or forgot or was interrupted.

10 So there are other mechanisms for this

11 intention in addition to a written survey. There


12 could be a phone survey. That would ensure whether

13 the patient is looking at the medication guide

14 while answering the survey or not. With just the

15 self-take written one, the person could just be

16 going through and ticking off the answers from the


17 medication guide and, therefore, we would be

18 evaluating the ability to read, not the ability to

19 understand, remember and use the information.

20 So the phone survey would add some

21 additional help on some of these matters. I think


22 it would be useful to consider doing a laboratory

23 study which could go into people's knowledge and

24 understanding and ability to apply this information

25 in more depth. Using various cognitive tasks







1 including free recall, recognition and scenario


2 tests, you can probe the same information more and

3 more deeply.

4 When you do this, you can find that,

5 perhaps, when someone is just asked to recall or

6 find information and say it, and if they can't, it


7 doesn't necessarily mean they know nothing about

8 it. Some of the more sensitive measures can be

9 used to show they know something about it. You can

10 also use this mechanism to find out what types of

11 information are communicated well, no problems,


12 versus one or two that people are misunderstanding.

13 Then we could determine, are those one or two

14 things likely to create safety issues.

15 As for what the level of acceptance on

16 such surveys should be, or laboratory studies or


17 whatever they are going to be, it is hard to set an

18 a priori percent correct. It depends upon the

19 nature of the task and the instrument that is being

20 administered. In some of the work in my

21 laboratory, I can find that there are some


22 questions in some original materials, based on

23 original materials, where people get 20, 30 percent

24 correct.

25 That is clearly unacceptable. But, with







1 that information, we can modify the information in


2 the label, in the medication guide, in the

3 patient-physician agreement form and then see a

4 dramatic increase up to over 90 percent. So I

5 don't think we can set an a priori percent-correct

6 level for some of these items but, clearly,


7 something above 85 or something in the high range,

8 given the possible bad outcomes that can come about

9 from some of these types of information if they are

10 not fully understood.

11 As to when this kind of program should be


12 done, the sponsors propose it will be in

13 post-market days. That is fine. I would suggest

14 that a very quick study with a limited number of

15 participants can be done before the drug would be

16 reintroduced to find out exactly what types of


17 information are well understood and see if any

18 stand out that are not understood so that labeling

19 issues and medication-guide issues could be

20 addressed.

21 In my lab, I have compared just a small


22 group, under 100, with thousands that are done in

23 the usual kinds of label-comprehension studies, say

24 when you go from prescription to OTC. Although the

25 overall levels of percent correct may change, the







1 patterns are identical. What you have trouble with


2 out in the real world is what you have trouble with

3 in the lab. So a lab study can be done very

4 quickly.

5 The final point here is that the sponsor

6 would probably perceive this as a burden difficult


7 to meet in the time plan that they would like to

8 have and also that there would be various costs

9 involve. I can just say that these are really

10 relatively minimal given the usual kinds of

11 comprehension studies that go on. As I say, these


12 more limited ones mimic the outcomes of the big

13 ones.

14 Finally, I would like to just mention that

15 this kind of comprehension study could be

16 considered with the physicians and with the


17 pharmacists as well as the patients for the

18 materials that they receive.

19 DR. WOLFE: To summarize, we have two no's

20 so far. You have a lot of studies so far that have

21 been suggested to you. I think that actually


22 answers Question 8 to some extent as well as

23 looking at lower doses.

24 We really have to go on, but does

25 anybody--







1 DR. DAY: I would just point out, it did


2 say, in this question, if the plan does not meet an

3 acceptable level, what would be a plan that would.

4 DR. WOLFE: Oh, yes. That's great. Fine.

5 You did a wonderful job at it. But we have to move

6 on now. Does anybody here disagree with our two


7 respondents so far saying no, everything is

8 wonderful the way it is and leave it this way, the

9 auditing that has been suggested is adequate?

10 So we all agree so far with our two

11 colleagues that what has been planned so far is


12 inadequate and more needs to be done. That is to

13 say, that the drug is going to be delayed until it

14 is--

15 DR. HOUN: Could I have a show of hands of

16 who feels the plan is adequate?


17 [No response.]

18 DR. HOUN: Who feels that it is

19 inadequate. Voting members only, please.

20 [Show of hands.]

21 DR. HOUN: Some abstentions; is that not


22 correct? Who is abstaining? Raise your hand.

23 [One hand raised.]

24 DR. HOUN: Okay.

25 DR. GARDNER: May I just make a







1 clarification? It isn't that I think necessarily


2 that more needs to be done but maybe some different

3 things need to be done or substitutions need to be

4 made because I don't think that this--I am

5 certainly not voting to take everything they have

6 proposed and say, "In addition, you need to do


7 more."

8 DR. WOLFE: Okay. We are on c. GSK

9 proposes the pharmacy-based study using the Slone

10 epidemiology and Eckerd Corporation to audit

11 patients' knowledge and awareness of the risks and


12 benefits of Lotronex. Is this auditing mechanism

13 adequate to achieve this goal? If not, describe an

14 adequate auditing mechanism. We sort of just did

15 that.

16 That's good. So we are saying that, yes,


17 these things are okay, these are okay, but there

18 are additional things that should be considered.

19 You had suggested some already.

20 DR. STROM: Jackie didn't say that these

21 are necessarily okay and other things should be


22 added. There are a number of other suggestions you

23 could make. Patient registration is one of them.

24 Random audits of registered physicians. You can

25 compare numbers of stickers given to sales in order







1 to look to see if, in fact, the numbers are the


2 same.

3 There are a number of ways around it.

4 Personally, I am more comfortable with UHC, not as

5 sufficient, with other things added to it. I have

6 more concerns about the Slone suggestion because of


7 the issue of cooperation, that the people who will

8 participate in that kind of voluntary survey are

9 going to be biased people. They are going to be

10 more likely to be knowledgeable and it is going to

11 lead to misleading information. It is going to


12 make it look better than it is.

13 So I would substitute some of these other

14 things for that, not just simply add, as Jackie

15 specified.

16 DR. GARDNER: I concur.


17 DR. WOLFE: FDA, are you happy with this

18 answer so far?

19 DR. HOUN: Victor, is there any other

20 further clarification? I think the only thing we

21 would like further clarification is on patient


22 enrollment. That is registering of all patients

23 who will get this drug. Is that something the

24 committee thinks should be done or should not be

25 done?







1 DR. WOLFE: Does anybody have any comments


2 on this?

3 DR. GARDNER: You have more information on

4 how the Accutane registry worked, but I have to

5 assume that, since we have now gone through several

6 interactions of additional patient-protection


7 mechanisms, that the patient registry was not

8 meeting the goals that you had. So I don't know

9 why this one would be any different at all.

10 DR. CRYER: I have some fairly strong

11 thoughts about a registry. The point that came


12 across very clear to me in the postmarketing

13 experience is that the postmarketing dataset is

14 incomplete. We have heard that presented by the

15 sponsor. We have heard that presented by the FDA.

16 We have heard it a number of times today.


17 What I really also feel strongly about is

18 getting more data about the safety of this drug.

19 One of the ways to accomplish that is through a

20 registry in which patients, as a condition of

21 receiving the drug, you register for the drug and


22 all of these characteristics that we are trying to

23 capture are then captured through the registry

24 information.

25 So I, personally, would be very strongly







1 in favor of a registry as a condition of enrollment


2 in this prescribing program.

3 DR. BEITZ: I just wanted to clarify a

4 point on the Accutane program. That involves

5 voluntary participation in the Slone survey. It

6 always was voluntary and it continues to be


7 voluntary even in the new program that we have

8 implemented.

9 DR. HOUN: Under patient registration,

10 there are programs such as clozapine requires

11 patient registration as well as the thalidomide


12 requires patient registration. But other programs

13 do not. Some require physician registration only.

14 DR. WOLFE: I have a question. This

15 registration, obviously, implies not forever and

16 forever; at least for the time being. You are


17 saying that you want it until some adequate data

18 are available.

19 DR. HOUN: It sounds like that is why

20 people would like registration here, is to help

21 answer questions about patients, risk factors and


22 identifying responders, perhaps. It sounds like it

23 is an information-gathering tool at this point.

24 DR. WOLFE: There is no reason to attach a

25 time limit to it. You can decide that later on.







1 So let's just vote. How many here would favor--


2 DR. LOUIK: Excuse me. Can I just clarify

3 some differences between this program and the

4 Accutane program, because I think there are some--

5 DR. WOLFE: If you can do it in fifteen

6 seconds.


7 DR. LOUIK: There are some very important

8 differences. First of all, in the Accutane

9 program, which was a voluntary survey, there was no

10 denominator data available. We never knew how many

11 forms were out there or how many patients were


12 approached. In the methodology that we are

13 describing here, we will have denominator data. We

14 will be able to calculate participation rates and

15 we will be able to compare responders and

16 nonresponders on a variety of demographic


17 variables.

18 DR. WOLFE: Thank you. That was pretty

19 good.

20 Let's try to vote at this time. How many

21 favor patient registration?


22 [Show of hands.]

23 DR. CAMPBELL: It is very conditional,

24 yes, until we have some data to describe the

25 operation of it and so forth.







1 DR. WOLFE: How many do not favor patient


2 registration at the present time?

3 [Show of hands.]

4 MR. PEREZ: So we have two abstaining.

5 DR. WOLFE: How many abstain? Somebody

6 abstained. If you don't want to vote, that means


7 you abstain. So how many are in favor of patient

8 registration?

9 [Show of hands.]

10 DR. SELIGMAN: One member of the committee

11 has left. Dr. Richter left.


12 DR. WOLFE: How many are against patient

13 registration?

14 [Show of hands.]

15 MR. PEREZ: We have thirteen in favor, two

16 abstained and three not in favor.


17 DR. WOLFE: Question No. 5 regarding

18 physicians. GSK proposes a plan in which

19 physicians call and 800 number to receive a

20 self-attestation kit including stickers.

21 Physicians self-attest to their qualifications by


22 signing the section for the physician on the

23 patient-physician agreement. This agreement is

24 then filed in the patient's medical record. Is the

25 sponsor's proposal adequate to allow for evaluation







1 of physician adherence to the program? If not,


2 describe an adequate auditing mechanism; b. define

3 an adequate level of adherence to the program by

4 physicians and c. should physician

5 enrollment--i.e., registration--be part of the

6 risk-management plan?


7 DR. GARDNER: Mr. Chairman, didn't we

8 start to address some of this when we dealt with--

9 DR. WOLFE: We sure did.

10 DR. GARDNER: So self-attestation may be

11 out. Can we ask if whatever certification program


12 goes in could be linked to some of these questions?

13 DR. GARDNER: We really had discussed this

14 regarding restricting it. We discussed it fully.

15 We feel some kind of self-attestation is necessary

16 for prescribing this, some kind of evidence of


17 proficiency in the disease, whether that is a

18 learning process, a CME program, a form to fill

19 out, a questionnaire. I think we all agree to that

20 already.

21 DR. GROSS: So it could be tested and


22 there won't be an attestation, there will be a

23 test.

24 DR. CRAWFORD: Since we are considering

25 the physicians as part of the risk management







1 program, at this point, I would like to ask the


2 committee to address whether we should advise that

3 it only be a 30-day supply which is not part of the

4 sponsor's plan.

5 DR. WOLFE: You mean no refills, no

6 automatic refills.


7 DR. CRAWFORD: I brought up earlier, even

8 with a new prescription, it could be a 90-day

9 supply, which effectively is refills, or six

10 months. So, should we as a committee make advice

11 that is more conservative?


12 DR. WOLFE: You actually brought up a very

13 important point and that is a 90-day supply--my

14 definition of a prescription is 30 days but, with

15 some of the plans now, they are 90-day supplies. I

16 am not sure that is what FDA had in mind was a


17 30-day supply. What did you have in mind?

18 DR. HOUN: The sponsor proposed a 30-day

19 supply.

20 DR. WOLFE: So it is 30 days very

21 specifically, then.


22 DR. HOUN: However, I don't think there is

23 any proposal to ensure that 30 days is only being

24 written for--it would allow other doctors to write

25 as they wish. But I think they are







1 recommending--Dr. Wheadon, say what you are


2 recommending.

3 DR. WHEADON: The recommendation is the

4 initial treatment period would be for 30 days at

5 the 1-milligram-a-day initiation paradigm.

6 Following that, it would be up to the prescriber.


7 The intention would be it would be a standard

8 30-day prescription, but there would be no

9 restriction around that with the exception of the

10 unit-dose packaging that would essentially

11 encourage 30-day prescription but would not require


12 it.

13 DR. WOLFE: This kind of has some issues

14 because there are certain plans now that are 90-day

15 plans. So you have to work with some of these

16 companies like Merck-Medco and really discuss these


17 because they are 90-day plans and you are going to

18 get a 90-day prescription. It doesn't mean a

19 person can't be reevaluated at 30 days and the

20 prescription continue. So I think some wording

21 will be required in that requirement.


22 DR. CRYER: I think there are three points

23 which make Dr. Crawford's suggestion a tenable

24 proposition. They are the three following

25 observations. We were told earlier that patients







1 who did not respond after the first month were


2 unlikely to subsequently respond.

3 Two, we know that the sponsor has

4 suggested a titration phase of 1 milligram for one

5 month and 1 milligram twice daily for the second

6 month. Third, it is suggested that the patient


7 attest to if the symptoms have not improved after

8 four weeks of taking the 1 milligram twice daily

9 that she will stop taking her Lotronex.

10 Because of those three observations, I

11 think--I mean, there is no other suggestion other


12 than to have a 30-day supply so that one can

13 evaluate the initial titration phase and then

14 subsequently one can evaluate the subsequent

15 treatment phase on BID.

16 DR. WOLFE: Being in VA it is very


17 different. We have patients who have 90-day plans.

18 So I think what will have to be done is some kind

19 of wording with the companies will have to be

20 worked out before this can be implemented properly.

21 DR. WHEADON: One correction to your


22 statement concerning the force to 1 milligram twice

23 a day. The intention is to have the 1 milligram

24 once a day for the first 30 days, the initiation

25 treatment. There will then be a decision tree.







1 That decision tree is no adverse effects, no


2 efficacy. You then would go to 1 milligram twice a

3 day, which is the indicated efficacious dose.

4 If you have no adverse effects but, as we

5 have heard in terms of some anecdotal experience,

6 you did evidence efficacy, it would be the


7 recommendation in the labeling that you maintain

8 the 1 milligram once a day strategy.

9 DR. CRYER: That seems reasonable. The

10 point that I was trying to get at is that, after 1

11 milligram twice a day for four weeks, the majority


12 of the evidence that I have heard suggests that

13 there really is not a compelling reason to continue

14 after that and there needs to be some way to make

15 that assessment.

16 DR. CAMPBELL: There is a little confusion


17 around here, I think. But my understanding of what

18 we are saying is, during the titration and dosage

19 adjustment period, it will be a 30-day regimen.

20 Beyond that, it is a more flexible regimen. 30

21 days is an arbitrary point in time to make this a


22 locked-in time. I don't think we want to require

23 all of the IBS patients to be seeing a physician

24 every 30 days to get this new prescription.

25 DR. WOLFE: But it is not uncommon with







1 many drugs to reevaluate the new drug, the patient


2 takes it for a month and you reassess. That is not

3 uncommon at all. There are many drugs like that.

4 Theoretically, when NSAIDs were out, you took it 30

5 days or less, two weeks, you drew LFTs. So that is

6 not uncommon at all to see a patient again after


7 30 days of taking a drug for the first time.

8 DR. BALDWIN: No, but that is what I said,

9 during the titration and dosage and developing--

10 DR. WOLFE: After that, every 30 days is

11 not necessary, for sure.


12 The question is what is considered an

13 adequate level of adherence to the program by

14 physicians. Let's start on this side. What is an

15 adequate level? Do you want 100 percent? 90

16 percent? 80 percent? 0 percent?


17 MS. BLACKMAN: I'm sorry; I couldn't

18 understand the question. What was the full

19 question?

20 DR. WOLFE: There is a program in place

21 that physicians have to have the stickers and


22 self-attestation and there is a regular process by

23 which physicians will be prescribing the

24 medication. So there has to be some kind of level

25 of adherence with an auditing mechanism. Do we







1 want 100 percent? Are we demanding 100 percent


2 level of adherence, which is, in my view, fairly

3 unrealistic or will we accept 90 percent? Or do we

4 want 80 percent? What number will we be looking

5 at?

6 I don't have the expertise to really make


7 that recommendation. I need some advice from

8 people who deal with these kinds of things.

9 DR. LaMONT: Mike, the next question has

10 been answered with stickers. So it sounds like it

11 is going to be 100 percent under 6 regarding


12 pharmacists. If Question 6 demands 100 percent, it

13 sounds like, if you write a prescription without a

14 sticker, it is not going to get filled. So it

15 sounds like it has got to be 100 percent.

16 DR. WOLFE: So, people in the


17 risk-management group, is that realistic, 100

18 percent?

19 DR. GARDNER: No; it isn't. And we

20 haven't discussed the stickers yet.

21 DR. LaMONT: Maybe you should do 6 first.


22 DR. WOLFE: We can do them together

23 because they are together because, generally, I am

24 pretty sure pharmacists will only fill

25 prescriptions from people who are qualified to







1 write prescriptions, generally. So it has to be in


2 writing. It can't be by telephone. It can't be by

3 fax. It has to be in writing with a sticker.

4 So are we saying, then, that physicians

5 and pharmacists must adhere to this and 100 percent

6 adherence is required?


7 DR. GARDNER: Are you opening the floor to

8 the discussion of stickers?

9 DR. WOLFE: Sure.

10 DR. GARDNER: Okay. This is not something

11 that makes pharmacists terribly happy. We have


12 already heard earlier today that it doesn't apply.

13 It is very, very difficult for inpatient pharmacy

14 at all. In the outpatient setting, pharmacists are

15 now looking at yellow stickers for Accutane and we

16 may be looking at, I don't know, blue stickers for


17 Lotronex until the next risk-management committee

18 and then we will have some other kind of stickers.

19 We think that, perhaps, a bigger picture

20 needs to be taken here. I know that pharmacy

21 organizations have worked extensively with FDA risk


22 managers to develop a plan for long-range

23 networking of management for circumstances like

24 this involving pharmacy. My recommendation would

25 be that the agency and the sponsor work with the







1 pharmacy community to find an optimal mechanism for


2 managing and adhering to the needs of the

3 risk-management program without this committee

4 dictating that some color stickers be put on

5 outpatient scripts.

6 DR. WOLFE: Could I ask the FDA a


7 question? Does the sticker program work for

8 Accutane?

9 DR. HOUN: The sticker program just went

10 into effect one month ago.

11 DR. GARDNER: April 10.


12 DR. WOLFE: Is it working? Or is it too

13 early? Do you want a sticker program?

14 DR. HOUN: A sticker program is being

15 proposed by GSK as a way to help with the control

16 process.


17 DR. WOLFE: Do you want a sticker program?

18 DR. SELIGMAN: That is what we are asking

19 you.

20 DR. WOLFE: I want to know what they want.

21 DR. HOUN: I think we want a program that


22 works. So I appreciate the pharmacists' concern

23 that one more program is going to put a level of

24 complexity that maybe it is not going to work.

25 DR. WOLFE: Has any physician here ever







1 dealt with a sticker program? We are really


2 shooting from the hip. We have no idea what this

3 entails.

4 DR. GARDNER: Precisely.

5 DR. WOLFE: The pharmacists do know.

6 DR. GARDNER: Furthermore, the requirement


7 of a hard copy with a sticker on it every time may

8 not be optimal from the standpoint of pharmacy

9 practice. We have already heard that in the VA,

10 you have a different--and, perhaps from Michael

11 Cohen, we have heard that in the VA there is a


12 different system. So, I would rather that we not

13 get prescriptive as a committee about what ought to

14 happen with the prescribing logistics.

15 DR. DAY: I don't think Dr. Gardner is

16 saying that it is too much of a burden on the


17 pharmacist but that the pharmacy community should

18 look and see what would be an appropriate way to

19 meet the same goal.

20 DR. COHEN: I have to agree with Dr.

21 Gardner. I have to agree 100 percent that we are


22 just going to see additional programs in the future

23 with stickers. There is a nonstandard program that

24 we are proposing here. There are different facets

25 for each one. It just doesn't make sense to keep







1 going on these sticker programs.


2 MS. CRAWFORD: Mr. Chair, very briefly, I

3 have to catch a plane, if I might add, one aspect

4 of the proposed risk-management program that I,

5 personally, found quite inadequate, lacking and a

6 bit disappointing was with the written part which


7 limits the pharmacist's participation, at least in

8 writing, to a very technical role that any clerk

9 could do, to look at a sticker and to give out a

10 medication guide.

11 I think I would like to ask, in a revised


12 risk-management program, that the sponsor work with

13 the agency in developing a more comprehensive one

14 that looks at the pharmacist's cognitive and

15 clinical skills as well as a member of the team and

16 pharmaceutical care who would know largely of the


17 prior therapy, concurrent therapy, the drug

18 interactions, could educate and counsel patients,

19 could do follow up and monitoring which I feel is

20 neglected in the current plan.

21 DR. WOLFE: Dr. Cryer and then Dr.


22 Holmboe.

23 DR. CRYER: Very briefly. We heard from

24 the pharmacists, from the people who have the

25 pharmacy perspective, that the stickers are







1 unlikely to work in an implemented program. The


2 question states that the goal is to have a program

3 in which dispensed Lotronex is under the care of an

4 enrolled physician. I would suggest that if there

5 were a registry of physicians who were certified

6 for this program that that registry could be


7 provided to the pharmacist to obtain this goal

8 without a sticker.

9 DR. HOLMBOE: I would also point out that

10 simply putting a sticker on the script is not going

11 to attest to the physician's proper prescribing of


12 Lotronex. So I don't see the sticker really

13 helping in ensuring that physicians are using the

14 drug properly. I would, again, go back to some of

15 the things we were talking about earlier and

16 consider some audit of physician practice. The


17 sticker is not going to do that.

18 DR. WOLFE: Last comment from Dr. Strom.

19 DR. STROM: Let me suggest, as a way of

20 trying to summarize, I think the sense you are

21 getting from all of us, and I agree, is that the


22 concept of the sticker, concept of assuring that

23 you have a certified physician, we are in support

24 of. The question is whether the sticker is the

25 right way to do it or whether there is some better







1 way of registration of physicians that might well


2 be much more efficient--a registry of physicians

3 might well be a more efficient way to do it, but I

4 think I am hearing support for some way of

5 guaranteeing that it is being written by a

6 certified physician by whatever mechanism that is.


7 DR. WOLFE: Do you have enough information

8 for this question?

9 DR. HOUN: Yes. I think the remaining

10 question I would have is then do you feel that

11 physicians should be registered and, if you do feel


12 they should be registered, the proposal is the

13 check of registration be the real-time check,

14 whether it be through stickers or some other,

15 looking up at a database. That would be the two

16 questions I have for you.


17 DR. WOLFE: Can I try to answer this for

18 all of us. We talked about this before, about

19 having some kind of proficiency in the diagnosis

20 and treatment and IBS and if there were some kind

21 of questionnaire, an educational process, and


22 then--I had to use certification because it takes

23 three years to be certified in GI, so

24 certification, a process of some sort for the use

25 of this agent, and then also with a check list for







1 the patients, the proper candidate. Is that


2 adequate for you?

3 DR. HOUN: The certification would mean

4 having gone through a hurdle of some type of

5 educational interaction. If you pass, then you are

6 able to prescribe Lotronex. Is that correct?


7 DR. WOLFE: Could that be, for example,

8 faxed on to send to someone at the FDA? Is that

9 possible--or e-mailed or something like that.

10 DR. HOUN: That is the question. Is the

11 name of physician who has completed that hurdle,


12 should that be centralized to be checked by the

13 pharmacist that they, in fact, have been certified,

14 have been qualified. Is that the trek you would

15 prefer as opposed to stickers? Or are there more

16 problems with that?


17 DR. WOLFE: I think that is what we said.

18 The only thing that I have with it, personally, is

19 that it becomes a registration issue and it is

20 almost a privacy issue in a way. But that is a

21 minor issue. I think we, more or less, said we


22 have to do it that way. Does anybody feel

23 differently that we should not register

24 DR. METZ: This seems to me to becoming an

25 incredibly cumbersome system here where you are







1 just getting so many checks and balances all over


2 the place that no one will be able to keep track of

3 it.

4 Correct me if I am wrong. I get the

5 feeling we want to register the patient so we can

6 learn about the outcomes and make informed


7 decisions for the next step. We want to register,

8 one way or another, the physicians because we want

9 to have some way of working out that they are

10 competent to do what they do and, therefore, by

11 virtue competent, they are going to be able to


12 prescribe.

13 I think the pharmacists do their regular

14 job. They have a look at a prescription when it

15 comes by and they say, you know, you are getting a

16 prescription for a drug that has some kind of bad


17 side effects. Have you been aware of those? Let's

18 look at what other drugs you are on. Maybe you are

19 taking an opiate, et cetera.

20 I don't see why you need to have a

21 sticker. I don't see why you need to register


22 them. And I think the bottom line is when you are

23 going to evaluate the outcome. You are going to

24 look at the outcomes and you are going to look at

25 the physicians and the pharmacists are going to do







1 their regular job.


2 Now, correct me if I am wrong, but that is

3 sort of my assessment of it.

4 DR. WOLFE: If you have a patient

5 registry, aren't you going to have a physician

6 registry automatically?


7 DR. HOUN: We don't need to.

8 DR. STROM: Let me say just I think,

9 again, we are asking operational details that

10 probably we would, as a group, be comfortable with

11 any of the various solutions. One solution would


12 be a centralized physician registry. Another

13 mechanism might be the physician has a document, a

14 diploma, from his certification course and he gives

15 a copy to the patient along with the prescription

16 and the patient just takes that with them along


17 with the prescription.

18 I think there are lots of different--I am

19 not saying that is the best way, at all. All I am

20 saying is the goal here is that the pharmacist

21 needs to know--there needs to be communication with


22 the pharmacist that the physician was certified in

23 some way, by whatever mechanism, working it out

24 jointly especially with the pharmacy community,

25 whatever works best for the pharmacy community, to







1 be able to do that.


2 DR. CRAWFORD: Thank you. I agree with

3 the last statement from Dr. Strom, but, Dr. Metz, I

4 would like to add one thing to what you said. I

5 agree that, as part of the regular pharmacy

6 practice, the pharmacist should do the job. I am


7 not saying it should be an extra program except I

8 do think the risk-management program should also

9 include an educational component for the

10 pharmacists.

11 DR. WHEADON: Three very quick points.


12 Number one, I think what Dr. Houn is sort of

13 alluding to, and it is a question we also have, is

14 ownership of these registries. Certainly, from our

15 perspective, it is not the role of the

16 pharmaceutical company to be a certified or a


17 check, if you will, concerning these registries.

18 So that is a problem that maybe the committee can't

19 wrestle with but at some point we will have to

20 wrestle with that.

21 Second of all, I think the point was very


22 well taken that the number of requirements that are

23 being built into this plan have become, to my mind,

24 considerably onerous and I am really concerned that

25 the barriers will be so high that the patients that







1 we heard from earlier today will probably not be


2 able to get access to this drug. That is really a

3 concern.

4 I think those two things just need to kept

5 in mind.

6 DR. WOLFE: That answers your question,


7 doesn't it?

8 DR. HOUN: Thank you.

9 DR. WOLFE: We knew this was going to be

10 tough to answer all these questions. There is a

11 lot of material we covered here today. I think,


12 for Question 8, we have already discussed a lot of

13 other ideas. That doesn't mean we have to stop

14 today. If you have other ideas, you can

15 communicate them to the FDA. I don't think there

16 is any issue there, so we are not going to discuss


17 this any further, just finish up with Question 7.

18 DR. FLEMING: Could I--

19 DR. WOLFE: Yes.

20 DR. FLEMING: Dissenting opinion. I think

21 I would like to have two minutes, at least, for it.


22 I think it is one of the most important issues to

23 put on the table, but I am willing to wait.

24 DR. WOLFE: So you are not happy with the

25 decision to wait, but you will wait.







1 DR. FLEMING: Oh, no. I'm happy to wait.


2 I just want to skip--

3 DR. WOLFE: Oh, no; not skipping it. I am

4 saying we will be able to send questions in and

5 other ideas.

6 DR. FLEMING: No, no. I want to orally


7 convey something today on 8.

8 DR. WOLFE: Go ahead.


10 DR. WOLFE: Knock yourself out. Go ahead.

11 DR. FLEMING: Okay. Given the answer to


12 1, at least from my perspective, that there

13 certainly is promise here but there certainly are,

14 also, uncertainties about what is the population or

15 subpopulation in which we can feel confident we

16 would have a favorable benefit to risk, what I have


17 been struggling with is what is a strategy that

18 will get us a clean and timely answer and, if, in

19 fact, is successful, would also allow us to reduce

20 some of this onerous implementation we have been

21 discussing about for the last hour.


22 We don't know, but there is a lot of

23 reason to anticipate that those patients that have

24 the most disabling symptoms could stand to benefit

25 the most, and we have heard a lot from the







1 testimonials to give credence to that suspicion.


2 So how could we, in a very timely way, address

3 whether or not we get substantial efficacy in that

4 cohort?

5 My proposal would be that we could do from as

6 rapidly as possible a randomized comparative trial


7 that would either be dose arm or two dose arms,

8 depending on the choice of the sponsor and the FDA.

9 It could be the 1 milligram QD and/or 1

10 milligram QD and 1 milligram BID against control.

11 It would involve 500 to 750, max a thousand


12 patients. These would be patients that would be

13 enrolled who would be in this very high-risk

14 category.

15 If this group, as Dr. Hoberman was

16 speculating could be the case, does, in fact--and


17 it follows also from Dr. Strom's earlier

18 questions--if this group has a subcohort that

19 experiences profound benefit, at the benefit that

20 we heard testimonials about today, then that level

21 of benefit, if it occurred in 10 percent of the


22 patients, in my view, would allow much more liberty

23 as to the level of risk that we could accept.

24 A cohort that would stand to gain a great

25 deal would have a favorably benefit to risk even if







1 we were less certain about the exact level of the


2 ischemic colitis. So, with 500 to 750 patients

3 randomized as rapidly as possible, enrolled over,

4 let's say, three months followed for an additional

5 three months--i.e., six months from the time that

6 that study was initiated--we would be in a position


7 to be able to assess, as has been speculated

8 here--that there is a subcohort that would

9 experience a very significant level of clinical

10 benefit, a response that could be obtained in a

11 very rapid time frame and it would be, in fact,


12 possible in this, if we chose to do so, to also

13 answer the question about efficacy in those people

14 who failed to respond conventional therapy.

15 If you, in fact, wish to enroll that

16 cohort, we would actually, for the first time, get


17 direct efficacy information in that cohort. It

18 would also be possible, if we chose to refine the

19 dosing, as has been discussed today, if you wish to

20 titrate, if you wish to discontinue for early

21 nonresponders or if you wish to manage effectively


22 on AEs, all of these could be built into this study

23 that could give us an answer in 12 to 18 months.

24 The second phase would be a separate

25 randomized trial in a much broader cohort that







1 would be, in fact, a larger, longer-term study that


2 would answer the much more difficult question in

3 patients that are not as restricted to those that

4 are the most serious in terms of initial baseline

5 characteristics, can a dosing schedule be

6 identified where we would receive, or we can


7 identify, favorable benefit to risk.

8 So it would be a two-trial strategy where

9 the first trial could be done in a very timely way

10 and, if what we are hearing today in the

11 testimonials is true, that subcohort could identify


12 substantial benefit that would give us clear

13 confidence that we would have favorable benefit to

14 risk even though we would have small numbers in the

15 trial.

16 DR. WOLFE: Dr. Traber has a brief


17 response.

18 DR. TRABER: Just a brief response. I

19 completely concur that there are many different

20 ways that we can continue to study the efficacy and

21 identify patient populations. But let me just say


22 that obtaining drug substance, study start-up,

23 patient enrollment, analysis, and so forth, you

24 just described 18 months to two years of work after

25 which it would have to be analyzed and reviewed.







1 We would be talking about three years hence


2 approving the drug.

3 DR. FLEMING: It could definitely be

4 shorter than that. One thing that has already been

5 on the table is there is going to be six months

6 time before even Option B that we discussed earlier


7 could be implemented, that would allow the planning

8 stage for this trial before it is available. So

9 the planning stage of this trial could occur during

10 this time that the drug wouldn't be available

11 anyway.


12 The point is the drug to study would be

13 available at the end of the planning stage so you

14 wouldn't lose the planning-stage time frame that

15 otherwise you would.

16 DR. WOLFE: We have already voted not to


17 really go that route. We have already voted to

18 have the drug made available when the sponsor can

19 make the drug. That is what we are recommending.

20 You don't have to take our recommendations. That

21 is what we are recommending.


22 The study, I think, that GSK is fully

23 committed to doing a lot of the studies that are

24 being recommended. Am I correct?

25 GSK: That's correct.







1 DR. WOLFE: We have already all voted


2 that--well, not all. Most voted that we would

3 favor that scheme. Is everybody happy--unless you

4 all want to sleep here tonight--is everybody happy,

5 again, corresponding with FDA regarding Question 8

6 with further studies?


7 7a. Does anybody here think that we

8 shouldn't worry about ischemic colitis, severe

9 constipation and death as an endpoint? I think

10 that is clear, through our discussions, we want to

11 look at that. So, 7a., we all want to look at that


12 unless I am way off base.

13 The question is, what are acceptable rates

14 for adverse events and/or acceptable degrees of

15 severity. Basically, what you are saying is we

16 don't know at this point. I don't think we have


17 the answer. Would you say that?

18 DR. FLEMING: For severe events?

19 DR. WOLFE: Do we know what the rate is,

20 what is acceptable?

21 DR. FLEMING: Certainly, the problem is


22 any time we are looking at what is an acceptable

23 rate of severe events or safety events it is in the

24 context of what is the magnitude of benefit we are

25 going to achieve. So, indeed, we have some global







1 data on what the risks of ischemic colitis would be


2 and what we see is evidence of benefit that is at a

3 comparable level in a very subjective manner.

4 So the struggle here today is to try to

5 find the subgroups or the refinements of the

6 management program that will improve benefit to


7 risk.

8 DR. WOLFE: Do you want a number from us?

9 15 percent? Dr. Strom.

10 DR. STROM: I think what is clear from the

11 discussion today is the acceptable rate is


12 somewhere very close to where it is now because, if

13 the rate was lower, we wouldn't even have needed

14 today's meeting. If the rate was higher, the vote

15 would have been, no, don't have it on the market.

16 So, in terms of what is the acceptable


17 rate, it is the rates we heard about today. If

18 there is a way to identify subgroups who are more

19 likely to benefit through the kinds of studies Tom

20 is suggesting or long before that, through analysis

21 of the existing clinical-trial data, as I talked


22 about before, or analysis of the HMO data, as I had

23 talked about before, which could be available

24 potentially in weeks instead of in multiple months,

25 then that could increase the likelihood of benefit







1 and would make the acceptable rate a lot better.


2 DR. WOLFE: Dr. Cryer.

3 DR. CRYER: Ten seconds. The only way for

4 us to know exactly what that rate is going to be is

5 if we capture the denominator data. The only way

6 to have the denominator with confidence is to have


7 a patient registry. That will allow us to

8 understand what the actual rate is. It will also

9 allow us to answer the question of does Lotronex

10 benefit patients in whom conventional therapy has

11 failed. We need the denominator for both of those


12 questions.

13 DR. WOLFE: Can I summarize this by saying

14 that we would accept, right now--oh, is there

15 someone else who wants to speak? Go ahead.

16 DR. GARDNER: I just want to say that I am


17 not comfortable with the agency or the company

18 going away thinking that we believe we have

19 designed a risk-management program by committee

20 here today. I want them to understand that--I know

21 that you have specific questions and that we have


22 had votes but, please, from our perspective, if you

23 would take our best advice and the sense of what

24 our concerns are and, to the extent that any of us

25 can help you, call on us individually, but this is







1 not a wholesale package we have voted out of here


2 today.

3 DR. COHEN: Just a quick comment. It

4 would be great to actually have a meeting on

5 risk-management plans so that we could discuss it

6 openly and maybe come up with some standard ways to


7 approach these kinds of issues.

8 DR. WOLFE: I was going to attempt to

9 summarize saying that we want to get as low as

10 possible the complication rate which is what we are

11 all saying, but we don't know what that is going to


12 be at the present time. We don't want it to be any

13 higher than we have seen. We would like it to be

14 lower. But we are willing to accept right now what

15 we have seen to date.

16 Is that fair? If that is the case, if


17 there are no other comments, then--

18 DR. FLEMING: There are some dissenting

19 votes to that.

20 DR. WOLFE: There are some dissention to

21 what I have just said. But, having said that, we


22 all know there is some dissention. We are not in

23 full agreement, but I think, without spending

24 another few hours really going into these

25 questions, we really can't say much more.







1 Anyway, if that is the case and there are


2 no other pressing comments, I would like to adjourn

3 this meeting and thank everybody for their comments

4 and for their participation.

5 [Whereupon, at 5:25, the meeting was

6 adjourned.]


7 - - -