1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

              CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

 

 

 

 

 

 

 

            BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE

 

                              OPEN SESSION

 

                              Meeting #32

 

 

 

 

 

 

 

 

 

                          Friday, May 10, 2002

 

                               8:10 a.m.

 

 

 

 

 

 

 

 

                              Hilton Hotel

                         Gaithersburg, Maryland

                                                                 2

 

                              PARTICIPANTS

 

      Daniel R. Salomon, M.D., Acting Chair

      Gail Dapolito, Executive Secretary

 

      MEMBERS

 

                Katherine A. High, M.D.

                Richard C. Mulligan, Ph.D.

                Mahendra S. Rao, M.D., Ph.D.

                Alice J. Wolfson, J.D. (Consumer

      Representative)

 

      TEMPORARY VOTING MEMBERS

 

                Martin Dym, M.D.

                Jon W. Gordon, M.D., Ph.D.

                Thomas F. Murray, Ph.D.

                Terence Flotte, M.D.

                Eric T. Juengst, Ph.D.

                R. Jude Samulski, Ph.D.

 

      GUESTS/GUEST SPEAKERS

 

                Valder Arruda, M.D., Ph.D.

                Linda Couto, Ph.D.

                Mark Kay, M.D.

                Stephen M. Rose, Ph.D.

 

      FDA PARTICIPANTS

 

                Jay P. Siegel, M.D.

                Philip D. Noguchi, M.D.

                Daniel Takefman, Ph.D.

                Anne Pilaro, Ph.D.

                                                                 3

 

                            C O N T E N T S

                                                              PAGE

      Welcome/Administrative Remarks

        Dr. Daniel Salomon, Acting Chair                         4

 

      Introduction of Committee                                  5

 

      Conflict of Interest Statement

        Gail Dapolito, Executive Secretary                       8

 

      FDA Introduction

        Potential for Inadvertent Germline Transmission

        of Gene Transfer Vectors: FDA Approach for

        Patient Follow Up

        Daniel Takefman, Ph.D.                                  13

 

      Guest Presentations

        AAV Vector Biology, Jude Samulski, Ph.D.                23

 

      Questions and Answers                                     46

 

        Germline Transmission by Gene Transfer

        Vectors: Assessing the Risk

        Jon Gordon, M.D., Ph.D.                                 61

 

      Questions and Answers                                     84

 

        A Phase I Trial of AAV-Mediated Liver-Directed

        Gene Therapy for Hemophilia B

        Mark Kay, M.D., Ph.D.                                   98

 

        Safety Studies to Support Intrahepatic

        Delivery of AAV, Linda Couto, Ph.D.                    116

 

        Assessing the Risk of Germline Transmission of

        AAV in a Rabbit Model

        Valder Arruda, M.D.                                    130

 

      Questions and Answers                                    144

 

      Open Public Hearing

        Mr. Steven Humes                                       177

        National Hemophilia Foundation

 

        Dr James Johnson, Patient                              184

 

        Dr. Kenneth Chahine, Avigen                            190

 

      Committee Discussion of Questions                        197

                                                                 4

 

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

 

  2                         Opening Remarks

 

  3             DR. SALOMON:  Good morning, everybody.

 

  4   Welcome to day two of the Biological Response

 

  5   Modifiers Advisory Committee Meeting No. 32.  I

 

  6   guess we should call it 32B.  We have got a title.

 

  7   I have been complaining and I finally got what I

 

  8   wanted a title for these meetings.  This one, this

 

  9   is good - Vector Pellucida 2002.  Not my title,

 

 10   but, you know, you can't criticize it, I got what I

 

 11   wanted.  Thank you.

 

 12             So, welcome everybody.  Today we have

 

 13   changed the scenery around the table quite a bit.

 

 14   So, to get reoriented, I think we should go back

 

 15   around again this time and introduce ourselves, so

 

 16   that both the audience, as well as each other, has

 

 17   a little sense of who we are and what we are doing.

 

 18             Just if you can introduce yourself, we

 

 19   will just go around the table and give a few

 

 20   sentences on where you are from and what you do,

 

 21   what kind of expertise you bring.

 

 22             In front of you is a button on the thing.

 

 23   It says speaker.  If you push it, it turns red.

 

 24   Talk, and then when you are done, turn it off.

 

 25   Otherwise, there is a funny feedback.  So if I am

                                                                 5

 

  1   ever looking at you, gesturing, it means to turn it

 

  2   off.  It is one of my big duties.

 

  3                    Introduction of Committee

 

  4             DR. DYM:  Martin Dym, Georgetown

 

  5   University.  I worked on the testis and

 

  6   specifically on spermatogonia, which are the male

 

  7   germline stem cells.

 

  8             DR. FLOTTE:  I am Terry Flotte from the

 

  9   University of Florida.  We have been working on AAV

 

 10   biology, AAV vectors and AAV gene therapy.

 

 11             DR. JUENGST:  I am Eric Juengst.  I am in

 

 12   the Department of Bioethics at Case Western Reserve

 

 13   University and recently rotated off the RAC is

 

 14   where my last connection with these issues.

 

 15             DR. MURRAY:  I am Tom Murray.  I am from

 

 16   the Hastings Center, Bioethics, the world's first

 

 17   bioethics research institute, and my work has been

 

 18   in a variety of issues, but quite a lot in

 

 19   genetics, parents, and children.

 

 20             MS. WOLFSON:  I am Alice Wolfson.  I am

 

 21   the Consumer Advocate.  In this incarnation, I am a

 

 22   policyholder's lawyer representing policyholders

 

 23   against their insurance companies when they don't

 

 24   pay what they are supposed to pay.

 

 25             In my previous incarnation, however, I am,

                                                                 6

 

  1   and was, a women's health activist and a founder of

 

  2   the National Women's Health Network.

 

  3             DR. RAO:  My name is Mahendra Rao.  I am

 

  4   in the Intramural Program at the National Institute

 

  5   on Aging.  I am also a member of the BRMAC.  I work

 

  6   on stem cells, most parts of the body, I guess.

 

  7             DR. SALOMON:  Jude, we missed you the

 

  8   first time around.

 

  9             DR. SAMULSKI:  I am Jude Samulski from the

 

 10   University of North Carolina, and work in the area

 

 11   of AAV vectors.

 

 12             DR. SALOMON:  I am Dan Salomon.  I have

 

 13   the pleasure of chairing the committee today.  I am

 

 14   from the Scripps Research Institute in La Jolla,

 

 15   California.  I work on cell transplantation,

 

 16   particularly islet cell transplantation and tissue

 

 17   engineering and therapeutic gene delivery.

 

 18             MS. DAPOLITO:  Gail Dapolito, Center for

 

 19   Biologics.  I am the Executive Secretary of the

 

 20   committee.

 

 21             DR. GORDON:  Jon Gordon from Mount Sinai

 

 22   School of Medicine.  I make a lot of transgenic

 

 23   mouse models of disease and gene therapy for

 

 24   disease.  I was on the RAC.  I am actually the

 

 25   first person to say the word "transgenic," if that

                                                                 7

 

  1   means anything.

 

  2             DR. SALOMON:  It means a lot.

 

  3             DR. PILARO:  I am Anne Pilaro.  I am an

 

  4   expert toxicologist in the Division of Clinical

 

  5   Trials at CBER.  I regulate a lot of the gene

 

  6   therapy protocols, in fact, I think I have 167

 

  7   active right now.

 

  8             DR. TAKEFMAN:  Dan Takefman.  I am a gene

 

  9   therapy product reviewer with the Division of

 

 10   Cellular and Gene Therapies, CBER.

 

 11             DR. NOGUCHI:  Phil Noguchi.  I am director

 

 12   of the Division of Cell and Gene Therapy at CBER.

 

 13             DR. SALOMON:  Welcome.  We will be joined

 

 14   a little bit later by my colleague to the right,

 

 15   Richard Mulligan from Harvard Medical School.

 

 16             This is interesting for two reasons.  One

 

 17   is that this is kind of a revisit to a very

 

 18   important area that the BRMAC dealt with, not the

 

 19   last time, but I guess at least two times ago,

 

 20   where we initially talked about how to address

 

 21   potential regulatory issues specifically with this

 

 22   Avigen trial, and then more generally with how to

 

 23   deal with the potential of infection germline in

 

 24   this case with semen.

 

 25             We got into the whole discussion about

                                                                 8

 

  1   semen versus infecting the motile sperm and what

 

  2   was the evidence, if any, that you could really

 

  3   infect the germline, the spermatogonia, or infect

 

  4   the sperm themselves, and very much tried to deal

 

  5   with some of the practical issues of what you would

 

  6   demand of any company of a sponsor in doing this

 

  7   kind of research, and to do it in such a way that

 

  8   you wouldn't put an unnecessary hold that could

 

  9   therefore interrupt a very important trial unless

 

 10   there was awfully good evidence.

 

 11             It is also very interesting in that it is

 

 12   an interesting theme for the two days.  In some way

 

 13   I am sorry that some of you weren't here yesterday

 

 14   where there we were really talking about another

 

 15   kind of germline transfer issue, the injection of

 

 16   ooplasm into oocytes for infertile women, but it is

 

 17   an interesting thing now to go on to the idea of

 

 18   potentially doing something like this through

 

 19   therapeutic gene delivery.

 

 20             We have to read the conflict of interest.

 

 21   Gail.

 

 22                  Conflict of Interest Statement

 

 23             MS. DAPOLITO:  I would just like to read

 

 24   for the public record, the conflict of interest

 

 25   statement for today's meeting.

                                                                 9

 

  1             Pursuant to the authority granted under

 

  2   the Committee charter, the Director of FDA Center

 

  3   for Biologics Evaluation and Research has appointed

 

  4   Drs. Terence Flotte, Jon Gordon, Eric Juengst,

 

  5   Thomas Murray, Daniel Salomon, and Jude Samulski as

 

  6   temporary voting members for the discussions

 

  7   regarding issues related to germline transmission

 

  8   of gene therapy vectors.

 

  9             Dr. Salomon serves as the Acting Chair for

 

 10   today's session.

 

 11             To determine if any conflicts of interest

 

 12   existed, the Agency reviewed the submitted agenda

 

 13   and all financial interests reported by the meeting

 

 14   participants.  As a result of this review, the

 

 15   following disclosures are being made:

 

 16             In accordance with 18 U.S.C. 208, Drs.

 

 17   Terence Flotte, Jonathan Gordon, Daniel Salomon,

 

 18   and Jude Samulski were granted waivers permitting

 

 19   them to participate fully in the committee

 

 20   discussions.  Dr. Richard Mulligan was granted a

 

 21   limited waiver for this discussion which permits

 

 22   him to participate in the committee discussion

 

 23   without a vote.  Dr. Katherine High recused herself

 

 24   from this committee meeting.

 

 25             In regards to FDA's invited guests, the

                                                                10

 

  1   Agency has determined that services of these guests

 

  2   are essential.  The following interests are being

 

  3   made public to allow meeting participants to

 

  4   objectively evaluate any presentation and/or

 

  5   comments made by the guests related to the

 

  6   discussions of issues of germline transmission of

 

  7   gene therapy vectors.

 

  8             Dr. Valder Arruda is employed by the

 

  9   University of Pennsylvania.  He is involved in the

 

 10   studies of adeno-associated virus vectors.  Dr.

 

 11   Stephen Rose is employed by the Office of

 

 12   Biotechnology Activities, NIH.

 

 13             In the event that the discussions involve

 

 14   other products or firms not already on the agenda,

 

 15   for which FDA's participants have 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 public record.

 

 19             With respect to all other meeting

 

 20   participants, we ask in the interest of fairness

 

 21   that you state your name, affiliation, and address

 

 22   any current or previous financial involvement with

 

 23   any firm whose product you wish to comment upon.

 

 24             Copies of these waivers addressed in this

 

 25   announcement are available by written request under

                                                                11

 

  1   the Freedom of Information Act.

 

  2             As a final note, as a courtesy to the

 

  3   committee discussants and your neighbors in the

 

  4   audience, we ask that cell phones and pagers be put

 

  5   in silent mode.

 

  6             Thanks.

 

  7             DR. SALOMON:  Thank you, Gail.

 

  8             What we will do here is begin with an FDA

 

  9   introduction from Dan Takefman, will kind of walk

 

 10   us through some of the key issues that the FDA

 

 11   wants to answer.  Remember that part of the dynamic

 

 12   here is that we are an FDA Advisory Committee.

 

 13             There will be times when we all, certainly

 

 14   myself as a scientist, get really interested in

 

 15   some scientific question, but at some point you

 

 16   will have to forgive me if we steer away from that

 

 17   since, if we are not really answering the FDA's

 

 18   question, then, we are not doing what we are

 

 19   supposed to be doing here.

 

 20             In the meantime, though, obviously, to the

 

 21   extent that any of these scientific issues are

 

 22   relevant to answering the questions, you know, you

 

 23   obviously are here and your expertise is greatly

 

 24   welcomed.

 

 25             I guess the other thing, as long as I am

                                                                12

 

  1   giving an introduction on that score, I will just

 

  2   say that we are going to try and come to consensus

 

  3   on some of these questions, but in some instances,

 

  4   there is no consensus, and there is no effort here

 

  5   on my part to force this group into consensus, so

 

  6   well-articulated, minority opinions or even just

 

  7   where we go, I am sorry, but there is no way we can

 

  8   agree on it, that's the kind of information that we

 

  9   need to pin down.

 

 10             So it is important for us to make sure

 

 11   that we have represented everything as evenly as

 

 12   possible for the community.  The last thing I will

 

 13   say to the audience is that I feel you also are

 

 14   participants in this meeting.  This is an open

 

 15   public meeting.  That mike in the center is open. I

 

 16   welcome all of you, if you have something to say,

 

 17   to come up during the meeting during discussion and

 

 18   make your points, and we will definitely be here to

 

 19   listen to them and try and make sure that we do an

 

 20   adequate discussion of this.

 

 21             Dan, you are on.

 

 22                         FDA Introduction

 

 23        Potential for Inadvertent Germline Transmission of

 

 24         Gene Transfer Vectors: FDA Approach for Patient

 

 25                            Follow Up

                                                                13

 

  1                      Daniel Takefman, Ph.D.

 

  2             DR. TAKEFMAN:  Thank you.  I would like to

 

  3   welcome the committee and speakers, and thank

 

  4   everyone for participating in today's meeting.

 

  5             [Slide.

 

  6             The topic for today is the discussion of

 

  7   potential for inadvertent germline transmission of

 

  8   gene transfer vectors, and as Dan said, this has

 

  9   been a topic of previous discussions and public

 

 10   meetings.  Today, we will be discussing the finding

 

 11   of vector sequences in patient semen and to discuss

 

 12   FDA's current approach for patient follow up.

 

 13             [Slide.

 

 14             Concerns regarding inadvertent germline

 

 15   transmission, or IGLT, are twofold.

 

 16   Societal/ethical concerns are based on previous

 

 17   public discussions and publications in which

 

 18   deliberate germline alteration has been deemed

 

 19   unacceptable.

 

 20             Additionally, there are potential adverse

 

 21   biological effects, such as genetic disorders,

 

 22   birth defects, and lethality to developing fetus,

 

 23   just to list a few which are also of concern.

 

 24             [Slide.

 

 25             What is the likelihood that IGLT would be

                                                                14

 

  1   deleterious?  Well, retroviruses have been used as

 

  2   tools to investigate the role of certain genes

 

  3   which are important in development.  I refer to, in

 

  4   this slide, data involving retroviral insertion to

 

  5   the germline of mice and as a specific example, a

 

  6   retrovirus was used to infect a murine blastocyst.

 

  7   In this case, this infection resulted in a mouse

 

  8   strain with a lethal embryonic mutation, which was

 

  9   induced by proviral insertion into the alpha-1

 

 10   collagen gene.  This mutation was recessive, so

 

 11   that the phenotypic effect required homozygosity.

 

 12             [Slide.

 

 13             So data exist suggesting that in the case

 

 14   of retroviruses, deliberate insertion into the

 

 15   germline may be deleterious, but what about data

 

 16   from preclinical animal studies regarding the

 

 17   ability of gene transfer vectors to transmit to the

 

 18   germline?

 

 19             Well, the FDA does require biodistribution

 

 20   studies with gene transfer vectors in relevant

 

 21   animal models.  These biodistribution studies,

 

 22   performed in support of clinical trials, have shown

 

 23   evidence of vector dissemination to gonadal tissue.

 

 24             However, in most studies, vector sequences

 

 25   have not been detected in semen samples, and the

                                                                15

 

  1   point I need to make in regards to these

 

  2   preclinical studies is that they are not always

 

  3   predictive of human experience.

 

  4             A case in point is today's topic in which

 

  5   vector sequences were found in semen from clinical

 

  6   trial subjects, however, initial preclinical

 

  7   studies, such as those done in dogs, demonstrated

 

  8   no detectable vector in semen.

 

  9             Again, certainly in today's case, animal

 

 10   studies are not always predictive.

 

 11             [Slide.

 

 12             I would like to give an update on the kind

 

 13   of current active gene transfer INDs we currently

 

 14   have in file just to give you an idea of what is

 

 15   being used in the clinic.

 

 16             You can see here in regards to retroviral

 

 17   vectors, they are predominantly being used in ex

 

 18   vivo types of gene transfer studies, while