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.
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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
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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
7
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