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                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

                                                                 2

 

                        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

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                            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

 

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  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.

 

                                                                 5

 

  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

 

                                                                 6

 

  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.

 

                                                                 7

 

  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

 

                                                                 8

 

  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

 

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  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

 

                                                                10

 

  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

 

                                                                11

 

  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

 

                                                                12

 

  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

 

                                                                13

 

  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

 

                                                                14

 

  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

 

                                                                15

 

  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