1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

GASTROINTESTINAL DRUGS ADVISORY COMMITTEE

AND

DRUG SAFETY AND RISK MANAGEMENT SUBCOMMITTEE

OF THE ADVISORY COMMITTEE FOR

PHARMACEUTICAL SCIENCE

 

 

 

 

 

 

 

 

 

 

Tuesday, April 23, 2002

8:00 a.m.

 

 

 

 

 

 

 

 

Holiday Inn Bethesda

Versailles I and II

8120 Wisconsin Avenue

Bethesda, Maryland

 

 

 

 

 

2

PARTICIPANTS

M. Michael Wolfe, M.D., Chair

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

MEMBERS OF THE GASTROINTESTINAL DRUGS ADVISORY

COMMITTEE

Byron Cryer, M.D.

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

Representative)

John T. LaMont, M.D.

Robert A. Levine, M.D.

David C. Metz, M.D.

Joel Richter, M.D.

ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

Gloria Anderson, Ph.D. (Consumer

Representative)

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

DRUG SAFETY AND DRUG MANAGEMENT SUBCOMMITTEE

OF THE

ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

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.

PATIENT REPRESENTATIVE (Non-Voting)

Carlar Blackman

CONSULTANTS (Voting)

Thomas Fleming, Ph.D.

Arthur Levin, M.P.H.

GUESTS (Non-Voting)

Alex Krist, M.D.

GUEST INDUSTRY REPRESENTATIVES

George S. Goldstein, M.D.

John T. Sullivan, M.D.

FDA

Julie Beitz, M.D.

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

Victor Raczkowski, M.D.

Paul Seligman, M.D.

 

 

 

 

 

3

C O N T E N T S

PAGE

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

Introduction:

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

Introduction:

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

 

 

 

 

 

4

C O N T E N T S(Continued)

PAGE

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

Committee:

Victor Raczkowski, M.D. 291

Discussion of Questions 295

 

 

 

 

 

5

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

 

 

 

 

 

6

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

 

 

 

 

 

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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

 

 

 

 

 

8

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

 

 

 

 

 

9

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

 

 

 

 

 

10

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

 

 

 

 

 

11

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

 

 

 

 

 

12

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

 

 

 

 

 

13

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

 

 

 

 

 

14

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

 

 

 

 

 

15

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

 

 

 

 

 

16

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

 

 

 

 

 

17

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

 

 

 

 

 

18

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.

 

 

 

 

 

19

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

 

 

 

 

 

20

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.

 

 

 

 

 

21

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

 

 

 

 

 

22

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.

 

 

 

 

 

23

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

 

 

 

 

 

24

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

 

 

 

 

 

25

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.]

 

 

 

 

 

26

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

 

 

 

 

 

27

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,

 

 

 

 

 

28

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

 

 

 

 

 

29

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

 

 

 

 

 

30

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.]

 

 

 

 

 

31

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

 

 

 

 

 

32

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.

 

 

 

 

 

33

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.]

 

 

 

 

 

34

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

 

 

 

 

 

35

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.

 

 

 

 

 

36

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

 

 

 

 

 

37

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.

 

 

 

 

 

38

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.

 

 

 

 

 

39

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.

 

 

 

 

 

40

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

 

 

 

 

 

41

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

 

 

 

 

 

42

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

 

 

 

 

 

43

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

 

 

 

 

 

44

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

 

 

 

 

 

45

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.

 

 

 

 

 

46

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

 

 

 

 

 

47

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.

 

 

 

 

 

48

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.]

 

 

 

 

 

49

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

 

 

 

 

 

50

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

 

 

 

 

 

51

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.

 

 

 

 

 

52

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

 

 

 

 

 

53

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

 

 

 

 

 

54

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

 

 

 

 

 

55

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

 

 

 

 

 

56

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

 

 

 

 

 

57

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

 

 

 

 

 

58

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

 

 

 

 

 

59

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.

 

 

 

 

 

60

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

 

 

 

 

 

61

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.

 

 

 

 

 

62

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

 

 

 

 

 

63

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.

 

 

 

 

 

64

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 baseli