1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

ANTIVIRAL DRUGS ADVISORY COMMITTEE

Friday, March 11, 2005

8:00 a.m.

Salons A and B

Hilton Washington DC North/Gaithersberg

620 Perry Parkway

Gaithersburg, Maryland

P A R T I C I P A N T S

Janet A. Englund, M.D., Chair

Anuja M. Patel, M.P.H., Executive Secretary

Committee Members:

John A. Bartlett, M.D.

Victor G. DeGruttola, Sc.D.

Douglas G. Fish, M.D.

John G. Gerber, M.D.

Richard H. Haubrich, M.D.

Victoria A. Johnson, M.D.

Robert J. Munk, Ph.D. (Consumer Representative)

Lynn A. Paxton, M.D., M.P.H.

Kenneth E. Sherman, M.D., Ph.D.

Eugene Sun, M.D. (Industry Representative)

Maribel Rodriguez-Torres, M.D.

Lauren V. Wood, M.D.

Ronald G. Washburn, M.D.

Special Government Employee Consultants (Voting):

Samuel K. So, M.D., B.S.

Kathleen Schwarz, M.D.

Government Employee Consultants (Voting):

Beth P. Bell, M.D., M.P.H.

Ronald Herbert, D.V.M., Ph.D.

Leonard B. Seeff, M.D.

SGE Patient Representative (Voting)

Brett Grodeck

FDA Participants:

Mark J. Goldberger, M.D., M.P.H., CDER

Debra B. Birnkrant, M.D., CDER

Linda L. Lewis, M.D., CDER

James G. Farrelly, Ph.D., CDER

C O N T E N T S

Call to Order and Opening Remarks,

Janet Englund, M.D., Chair 4

Conflict of Interest Statement, Anuja Patel, M.P.H.

Executive Secretary, FDA 7

Overview of Issues, Debra B. Birnkrant, M.D.,

Director, DAVDP 10

Sponsor Presentation:

Introduction, Elliott Sigal, M.D., Ph.D. 16

Background, Richard Colonno, Ph.D. 20

Nonclinical Safety, Lois Lehman-McKeeman, Ph.D. 28

Clinical Efficacy and Safety, Evren Atillasoy, M.D. 37

Resistance, Richard Colonno, Ph.D. 58

Pharmacovigilance and Summary, Donna Morgan Murray,

Ph.D. 70

Questions from the Committee 77

FDA Presentation:

Carcinogenicity Issues, James G. Farrelly, Ph.D.. 108

Clinical Issues, Linda L. Lewis, M.D. 119

Discussion 151

Advisory Committee Discussion of Questions

Question 1: 185

Question 2: 202

Question 3: 204

Question 4: 221

Question 5: 235

Question 6: 267

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

2 Call to Order and Opening Remarks

3 DR. ENGLUND: Good morning. Welcome,

4 everyone. My name is Janet Englund. I am the

5 acting chairperson today and I would like to

6 welcome you to the Antiviral Drugs Advisory

7 Committee.

8 Today we are going to discuss the new drug

9 application 21-797 and 21-798 for entecavir tablets

10 and entecavir oral solution, respectively, by

11 Bristol-Myers Squibb Company. These drugs are

12 proposed for the treatment of patients with chronic

13 hepatitis B infection.

14 With that, I would like to call the

15 meeting to order and introduce the committee

16 members. In fact, I will have you introduce

17 yourselves because that would be better. I would

18 like to just remind everyone on this committee that

19 this is being transcribed and so, before you speak,

20 you are going to need to identify yourself but, for

21 now, if we could just start maybe with Dr. Sun and

22 just introduce yourself and your affiliation.

23 DR. SUN: Eugene Sun, Abbott Laboratories.

24 DR. GERBER: John Gerber, University of

25 Colorado Health Sciences Center.

1 DR. WASHBURN: Ron Washburn, Shreveport VA

2 and LSU.

3 DR. FISH: Douglas Fish, Albany Medical

4 College, Albany, New York.

5 DR. HERBERT: Ron Herbert, National

6 Institutes of Environmental Health Sciences and the

7 National Toxicology Program.

8 DR. SHERMAN: Ken Sherman, University of

9 Cincinnati.

10 DR. JOHNSON: Victoria Johnson, University

11 of Alabama at Birmingham.

12 DR. PAXTON: Lynn Paxton, Centers for

13 Disease Control and Prevention.

14 DR. WOOD: Lauren Wood, National Cancer

15 Institute.

16 MR. GRODECK: Brett Grodeck, patient

17 representative.

18 MS. PATEL: Anuja Patel, Executive

19 secretary for the Antiviral Drugs Advisory

1 Committee, the Food and Drug Administration.

2 DR. ENGLUND: I am Janet Englund, from

3 Children's Hospital and University of Washington,

4 in Seattle.

5 DR. DEGRUTTOLA: Victor DeGruttola,

6 Harvard School of Public Health.

7 DR. BARTLETT: I am John A. Bartlett, from

8 Duke University.

9 DR. HAUBRICH: Richard Haubrich,

10 University of California in San Diego.

11 DR. MUNK: Bob Munk, consumer

12 representative.

13 DR. SEEFF: Leonard Seeff, Liver Disease

14 Branch, NIDDK, National Institutes of Health.

15 DR. BELL: Beth Bell, Centers for Disease

16 Control and Prevention.

17 DR. SCHWARZ: Kathy Schwarz, Johns Hopkins

18 University.

19 DR. FARRELLY: Jim Farrelly, Division of

20 Antiviral Drugs, FDA.

21 DR. LEWIS: Linda Lewis, Division of

22 Antiviral Drugs, FDA.

23 DR. BIRNKRANT: Debbie Birnkrant, Division

24 Director, Division of Antiviral Drugs, Food and

25 Drug Administration.

1 DR. ENGLUND: And Dr. Mark Goldberger,

2 from the FDA, will be joining us momentarily. At

3 this point I would like to have Anuja Patel read

4 for us the conflict of interest statement.

5 Conflict of Interest Statement

6 MS. PATEL: Thank you. The following

7 announcement addresses the issue of conflict of

8 interest and is made part of the record to preclude

9 even the appearance of such at this meeting. Based

10 on the submitted agenda and all financial interests

11 reported by the committee participants, it has been

12 determined that all interests in firms regulated by

13 the Center for Drug Evaluation and Research present

14 no potential for an appearance of a conflict of

15 interest, with the following exceptions:

16 In accordance with 18 USC Section

17 208(b)(3), full waivers have been granted to the

18 following participants, Dr. Johnson for her

19 employer's contract with a federal agency to

1 provide virology laboratory support for the adult

2 AIDS clinical trials group. The contract is funded

3 for greater than $300,000 per year. Dr. Gerber for

4 consulting on unrelated matters for the sponsor and

5 a competitor. He receives less than $10,001 per

6 year per firm. Dr. Bartlett for serving on

7 speakers bureaus for two competitors. He receives

8 greater than $10,000 from one firm and between

9 $5,001 to $10,000 per year from the other. Dr.

10 Sherman for serving on speakers bureaus for two

11 competitors. He receives from $5,001 to $10,000 a

12 year from each firm. Dr. Munk for consulting on

13 unrelated matters for a competitor. He receives

14 less than $10,001 a year.

15 Dr. Schwarz has been granted waivers under

16 (b)(3) and 21 USC 355(n)(4) for her employer's

17 grant to study competing products. Each grant is

18 funded for less than $100,000 per firm per year.

19 Dr. Haubrich has been granted a (b)(3) waiver for

20 consulting on unrelated matters for a competitor

21 and the sponsor. He receives less than $10,001 per

22 year per firm. Brett Grodeck has been granted a

1 355(n)(4) waiver for owning stock in a competitor,

2 valued at less than $5,001. Because the stock in a

3 competitor does not exceed $25,000, 5 CFR

4 2640.202(a)(2) exception applies and a (b)(3)

5 wavier is not required. Dr. DeGruttola has been

6 granted a (b)(3) waiver for consulting on unrelated

7 matters for two competitors. He receives less than

8 $10,001 a year from each firm.

9 A copy of the waiver statements may be

10 obtained by submitting a written request to the

11 agency's Freedom of Information Office, Room 12A-30

12 of the Parklawn Building.

13 In the event that the discussions involve

14 any other products or firms not already on the

15 agenda for which an FDA participant has a financial

16 interest, the participants are aware of the need to

17 exclude themselves from such involvement and their

18 exclusion will be noted for the record.

19 We would also like to note that Dr. Sun

20 has been invited to participate as an industry

21 representative, acting on behalf of the regulated

22 industry. Dr. Sun is employed by Abbott

1 Laboratories.

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 farm whose products they may wish to comment

6 upon. Thank you.

7 DR. ENGLUND: Thank you, everyone. With

8 that done, I would like to introduce Dr. Debra

9 Birnkrant who will now proceed to give us an

10 overview of the issues and our plan for today.

11 Overview of Issues

12 DR. BIRNKRANT: Good morning. I would

13 also like to welcome our advisory committee members

14 and consultants to this meeting.

15 Today, as was mentioned, we will be

16 discussing the new drug application for the tablet

17 and solution formulations for entecavir for the

18 treatment of chronic hepatitis B infection.

19 The last time this committee met to

20 discuss a similar topic was back in 2002 when we

21 presented the new drug application for adefovir,

22 and on the second day of that meeting we discussed

1 general drug development for hepatitis B. Today's

2 meeting gives us another opportunity to discuss

3 this serious problem.

4 The next two slides were downloaded from

5 cdc.gov. This slide shows the geographic

6 distribution of chronic hepatitis B infection.

7 What you can see in red are high andemic areas in

8 Africa and Asia with hepatitis B prevalence at a

9 rate more than 8 percent, and this is considered

10 high. In gold we have medium prevalence areas, and

11 in green we have low prevalence areas, such as the

12 United States, excluding Alaska. In the high

13 prevalence areas the lifetime risk of acquiring

14 hepatitis B infection approaches 60 percent and is

15 acquired mainly during childhood, whereas in the

16 low prevalence areas the lifetime risk is much

17 lower and occurs in adolescents, adults and

18 well-defined risk groups.

19 This slide shows hepatitis B incidence by

20 year through the years 1966 through 2000 in the

21 United States. What this is dramatic for is the

22 decline in hepatitis B occurring soon after

1 licensure of hepatitis B vaccine. You can see that

2 the incidence drops dramatically over the years in

3 the late '80s and beyond after public health

4 programs adopted hepatitis B vaccination.

5 Although we see this dramatic decrease in

6 the United States of acute hepatitis B it still

7 remains a major problem. It has been estimated

8 that chronic hepatitis B infection affects 350-400

9 million subjects worldwide and approximately 1.25

10 million subjects in the United States. It accounts

11 for, it is estimated, approximately one million

12 deaths per year due to complications of the

13 disease, namely cirrhosis and hepatocellular

14 carcinoma. The treatment options are quite

15 limited. As you can see, there are only three at

16 this point, interferon, lamivudine and adefovir

17 dipivoxil.

18 I will briefly touch on the pros and cons

19 of these therapies. Interferon is used in a

20 limited patient population, however, it is used for

21 a definite period of time and in the limited

22 population the effect is durable. However, the

1 side effect profile is somewhat limiting. With

2 interferon we see flu-like syndrome, depression,

3 alopecia and exacerbation of autoimmune disorders.

4 Lamivudine, a nucleoside analog, is much

5 better tolerated, however, subjects taking

6 lamivudine develop resistance at a rate approaching

7 20 percent per year.

8 Adefovir dipivoxil, a prodrug of adefovir,

9 a nucleotide analog, was approved in 2002. It is

10 active against lamivudine-resistant virus, and is

11 tolerated well except for nephrotoxicity that

12 appears in decompensated patients, more so, and

13 other advanced patients such as those undergoing

14 transplant.

15 Let's turn now to today's subject, that

16 is, entecavir. Entecavir is also a nucleoside

17 analog. It has activity against HBV polymerase,

18 and in vitro it inhibits lamivudine-resistant virus

19 at concentrations 8-32-fold greater than that

20 required for wild type virus.

21 Its antiviral activity has been

22 demonstrated in established animal models. In

1 woodchuck, hepatitis virus infected woodchucks with

2 that disease, 67 percent treated with entecavir

3 survived 3 years compared to a 4 percent survival

4 rate in infected historic controls. So, it appears

5 quite active in this established animal model.

6 Now I will describe pertinent nonclinical

7 pharm/tox findings briefly. There was an increased

8 incidence of tumors in rodent carcinogenicity

9 studies. Lung tumors were observed at low

10 multiples of entecavir exposure relative to humans

11 and it is thought that these tumors may be species

12 specific. Other tumors occurred at much higher

13 multiples of entecavir exposure relative to humans.

14 This topic will be discussed extensively by

15 Bristol-Myers Squibb and Dr. Farrelly of the Food

16 and Drug Administration. What we have to keep in

17 mind here is that the animal data needs to be

18 interpreted in the context of the clinical data,

19 the severity of the disease and the available

20 treatment options. Turning to the clinical

21 studies, I would like to commend Bristol-Myers

22 Squibb for their drug development program for

1 entecavir. They studied a wide population in

2 e-antigen positive, e-antigen negative and

3 lamivudine-resistant subjects. Their trials were

4 multicenter and multinational, using an active

5 control, lamivudine. The endpoints used were

6 similar to other approved therapies.

7 At today's advisory committee meeting we

8 will be asking you to discuss the clinical trial

9 data in the context of these animal carcinogenicity

10 findings and the implications for human use. In

11 addition, we will be asking you to discuss the

12 adequacy of the proposed pharmacovigilance study.

13 We will also pose a question related to pediatric

14 usage.

15 If in the afternoon session when questions

16 are posed you vote that this drug should be

17 approved, we will then proceed to discuss labeling

18 implications and further post-marketing studies.

19 With that, I would like to just briefly

20 review the agenda. Following my comments,

21 Bristol-Myers Squibb will present. This will be

22 followed by a break. Then FDA will present and the