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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
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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.
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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
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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,
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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
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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
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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.
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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
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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
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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
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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