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CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
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CELLULAR, TISSUE AND GENE THERAPIES ADVISORY COMMITTEE
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44th MEETING
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TELECONFERENCE
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OPEN SESSION
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THURSDAY,
JULY 26, 2007
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This
transcript has not been edited or corrected, but appears as received from the
commercial transcribing service. Accordingly the Food and Drug Administration
makes no representation as to its accuracy
The
open session convened at 11:00 a.m. at the National Institutes of Health,
Building 29B, Conference Rooms A/B,
COMMITTEE MEMBERS PRESENT:
WALTER J. URBA, M.D., Ph.D., Chair
MATTHEW J. ALLEN, D.V.M., Ph.D., Member
MICHÉLE P. CALOS, Ph.D., Member
JEFFREY S. CHAMBERLAIN, Ph.D., Member
RICHARD J. CHAPPELL, Ph.D., Member
COMMITTEE MEMBERS PRESENT (Continued):
FARSHID GUILAK, Ph.D., Member
KURT C. GUNTER, M.D., Industry Representative
LARRY W. KWAK, M.D., Ph.D., Member
DORIS A. TAYLOR, Ph.D., Member
SAVIO LAU-CHING WOO, Ph.D., Member
GAIL DAPOLITO, Executive Secretary
FDA PARTICIPANTS PRESENT:
TAKELE ARGAW, D.V.M., Staff Fellow, GTIB
SERGE BEAUCAGE, Ph.D., Senior Investigator,
Laboratory ofChemistry, DTP
RALPH BERNSTEIN, Ph.D., Regulatory Scientist,
Laboratory of Immunology, DTP
EDA BLOOM, Ph.D., Chief, GTIB
ANDREW BYRNES, Ph.D., Senior Staff Fellow, GTIB
KATHRYN CARBONE, M.D., Associate Director for
Research,
CBER
KATHLEEN CLOUSE, Ph.D., Director, DMA
SUZANNE EPSTEIN, Ph.D., Associate Director for
Research,
OCTGT
DAVID FRUCHT, M.D., Senior Staff Fellow,
Laboratory of Cell Biology, DMA
STEVEN KOZLOWSKI, M.D., Director, OBP
NANCY MARKOVITZ, Ph.D., Senior Staff Fellow, GTIB
FDA PARTICIPANTS PRESENT (Continued):
EDWARD MAX, M.D., Ph.D., Senior Investigator,
Laboratory of Immunology, DTP
MICHAEL NORCROSS, M.D., Senior Investigator,
Laboratory of Immunology, DTP
RAJ PURI, M.D., Ph.D., Director, Division of
Cellular
and
Gene Therapies
AMY ROSENBERG, M.D., Director, DTP
JINHAI WANG, M.D., Staff Scientist, Laboratory of
Immunology,
DTP
CAROLYN WILSON, Ph.D., Senior Investigator, GTIB
CELIA
TABLE OF
CONTENTS
PAGE
Conflict of Interest Statement ................. 5
Introduction, Site Visit Process, Kathryn
Carbone,
M.D. ........................... 11
Overview Research, OCTGT, Celia Witten, M.D.,
Ph.D. ................................... 24
Overview Research, GTIB, Eda Bloom, Ph.D. ..... 31
Overview Research, OBP,
Overview Research, DMA, OBP, Kathleen Clouse,
Ph.D. ................................... 51
Overview Research, DTP, OBP, Amy Rosenberg, M.D. 58
Open Public Hearing Adjourned.................. 70
P R O C E E D I
N G S
(11:06
a.m.)
MS.
DAPOLITO: Okay. Then let's go ahead and get started. Did you have any welcoming remarks?
CHAIRPERSON
URBA: Yes, I guess I would just like to
thank everyone for taking time out in their schedules to be together with us
this morning to go over these site visits, and if you want to go right into the
roll call and conflicts of interest, that would be great.
MS.
DAPOLITO: Okay. That's what I'll do then.
I'm
going to read the conflict of interest statement with the hopes that we'll get
another couple of members on board by then.
If
you are not talking and could put it on mute, that would be great.
The
Food and Drug Administration convenes today's meeting of this Cellular Tissue
and Gene Therapies Advisory Committee under the authority of the Federal
Advisory Committee Act of 1972. With the
exception of the industry representative, all members of the committee are
special government employees and are subject to the federal conflict of
interest laws and regulations.
The
following information on the status of this Advisory Committee's compliance
with federal conflict of interest laws, including, but not limited to, 18 USC
Subsection 208 and 21 USC Subsection 355(n)(4), is provided to participants of
today's meeting and to the public. FDA
determined that members of this Advisory Committee are in compliance with
federal ethics and conflict of interest laws, including, but not limited to, 18
USC Section 208 and 21 USC Section 355(n)(4).
Under
18 USC 208, applicable to all government agencies and 21 USC 355(n)(4)
applicable to certain FDA committees, Congress has authorized FDA to grant
waivers to special government employees who have financial conflicts when it is
determined that the agency's need for a particular individual's services
outweighs his or her financial conflict of interest -- that's Section 208 --
and where participation is necessary to afford essential expertise, Section
355.
Today's
agenda includes a review and discussion of the intramural research programs in
the Gene Transfer and Immunogenicity Branch, Office of Cellular Tissue and Gene
Therapies, Center for Biologics Evaluation and Research, and in the
laboratories of immunology and chemistry and the laboratory of cell biology in
the Divisions of Therapeutic Proteins and Monoclonal Antibodies, Office of
Biotechnology Products, Center for Drug Evaluation and Research.
Based
on the agenda, it was determined that the committee discussion presents on
actual or appearance of a conflict of interest for today's meeting.
Dr.
Gunter serves as the industry representative acting on behalf of all related
industry and is employed by Hospira, Incorporated.
Industry
representatives are not special government employees and do not vote. This conflict of interest statement will be
available for review at the registration table.
We
would like to remind members that if the discussions involve any other products
or firms not already on the agenda for which an FDA participant has a personal
or imputed financial interest, the participants need to exclude themselves from
such involvement, and their exclusion will be noted for the record.
FDA
encourages all other participants to advise the Committee of any financial
relationships that you may have with the firms that could be affected by the
committee discussions.
Thank
you.
So
what I'll do is I'll call the roll for the record of the Committee and then
we'll introduce the FDA participants, and we will go on to the
presentations. I think the members have
their slides. They can follow along, and
I would remind the presenters to please indicate when you're changing slides
for those on the phone.
I'll
start by calling roll. Dr. Urba.
CHAIRPERSON
URBA: Here.
MS.
DAPOLITO: Dr. Calos. Dr. Calos.
PARTICIPANT: She may have her mute on.
MS.
DAPOLITO: I know she was here.
DR.
CALOS: Oh, wait. Can you hear me?
MS.
DAPOLITO: Yes.
DR.
CALOS: Okay.
MS.
DAPOLITO: Okay. Dr. Chamberlain.
DR.
CHAMBERLAIN: Present.
MS.
DAPOLITO: All right. Dr. Tomford.
(No
response.)
MS.
DAPOLITO: Not yet. Dr. Gerson, have you joined us yet? Not yet.
Dr.
Guilak.
DR.
GUILAK: Here.
MS.
DAPOLITO: All right. Dr. Allen.
DR.
ALLEN: Present.
MS.
DAPOLITO: Dr. Taylor.
DR.
TAYLOR: Here.
MS.
DAPOLITO: Dr. Kwak.
DR.
KWAK: Present.
MS.
DAPOLITO: Dr. Chappell. Dr. Chappell, are you there still?
DR.
CHAPPELL: Yes.
MS.
DAPOLITO: Okay, and Dr. Woo.
DR.
WOO: I'm here.
MS.
DAPOLITO: All right. Thank you very much.
We'd
like to go around the table here on site.
On site we do have FDA speakers.
We have some audience, and we have a transcriber and a video. We are being videotaped, too, for those on
the phone to let you know who we have here.
And
we'd like to go around the table now and introduce the FDA participants, and
I'll start with Dr. Witten.
DR.
WITTEN: Celia Witten, Officer Director
of OCTGT.
DR.
BLOOM: Eda Bloom, Branch Chief, General
Transfer and Immunogenicity Branch, DCGT, OCTGT.
DR.
ROSENBERG: Amy Rosenberg, Director,
Division of Therapeutic Proteins.
MS.
DAPOLITO: Do you want to introduce your
lab staff, Amy?
DR.
ROSENBERG: They can go ahead.
DR.
MAX: Ed Max, DTP.
DR.
BERNSTEIN: Ralph Bernstein, DTP.
DR.
BEAUCAGE: Serge Beaucage, DPT.
DR.
NORCROSS: Mike Norcross, DTP.
DR.
WANG: Jinhai Wang, DTP.
DR.
CLOUSE: Kathleen Clouse, Director,
Division of Monoclonal Antibodies, and Dr. David Frucht will be calling in
about 12:10. He was called out of town
on an urgent family matter.
DR.
SHORES:
DR.
KOZLOWSKI: Steve Kozlowski, Director of
OBP.
DR.
EPSTEIN: Suzanne Epstein, OC Director of
Research at OCTGT.
DR.
PURI: Raj Puri, Division Director of
Division of Gene Therapy, and I have staff here, GTIB. They can introduce themselves.
Carolyn.
DR.
WILSON: Carolyn Wilson, GTIB and DCGT.
DR.
ARGAW. Takele Argaw, GTIB.
DR.
BYRNES: Andrew Byrnes, GTIB.
DR.
MARKOVITZ: Nancy Markovitz, GTIB.
MS.
DAPOLITO: Okay, all right. Thank you.
Okay. Did someone just join us?
DR.
GERSON: Hello.
MS.
DAPOLITO: Dr. Gerson?
DR.
GERSON: I'm here.
MS.
DAPOLITO: Thank you. We just did a roll call and introduced the
FDA.
DR.
PURI: And Dr. Carbone is on the phone.
MS.
DAPOLITO: Yes, and Dr. Carbone is on the
phone.
Dr.
Carbone, are you ready for your slide presentation?
DR.
CARBONE: Certainly am.
MS.
DAPOLITO: Okay. We're going to start with Dr. Carbone then.
DR.
CARBONE: I'll start with Slide l. We can
skip that because that's just my name.
What I'd like to talk about is just the Division of CBER today and a
little bit about the site visit process, a little bit about critical path, and
I'll be brief.
I'm
with some people who weren't here for my presentation to the site visit
community. I'll just review the
highlights with the Committee.
Basically,
if you look at the second slide which has the division, the real important
points there are two. One is the fact
that we actually facilitate development and approval and for all products for
the American public, and that we consider international and global health and
the public health a real primary goal for this center.
Next
slide.
And
when I say "biologics," I mean the complex biologics. Of course the OP people have a biologics
portfolio as well.
The
next slide is a small, brief chart showing the orientation, and the only thing
I want to point out here is that there are four offices that participated in
the research enterprise, which is a major part of the facilitation effort, and
that's the Office of Biostatistics and Epidemiology, Office of Blood Research
and Review, Office of Vaccines Research and Review, and this office, the Office
of Cellular Tissue and Gene Therapy.
They
also have a wonderful engagement in our research management process from the
Office of Compliance and Biological Qualities, although they currently do not
do research.
The
next slide which is Slide 4, just gives you a brief overview of the concept of
scientific research in the evaluation process.
We all know scientific research from the point of view of product
development, both the early discovery phases in the development through
clinical trial research.
However,
there is an evaluation science which is important, and one of the areas of
focus for the FDA and which overall has been somewhat neglected in the massive
investment in biotechnology and other kinds of biologics discovery for
products.
And
so part of our goal is to develop the scientific pools and information we need
to regulate on a scientific basis because once we're outside the scientific
basis, it becomes the philosophical discussion, and that's where a lot of the
problems arise both in the inabilities to predict outcomes in a scientific
manner and also disputes regard certain safety issues, et cetera.
The
more we know about how to evaluate our products appropriately, the better.
The
next slide, Slide 5, just shows that the critical path, which is a portion of
the FDA research that applies directly in facilitating the biologics product
development, really happens early in the process and involvement in design and
discovery is actually quite important. We
would like to have particularly the tools to predict clinical efficacy and
safety issues actually in the preclinical phase. So that kind of evaluation process in science
is extremely important.
Obviously
clinical development and improvement in clinical trial development phase is
important, but we would prefer products not fail in that stage, in late Phase 3
clinical development. It is a very
expensive way to fail. We would like to
have better predictors early in the process, and biologics both in OPD and in
CBER have led the way in terms of early and frequent interactions with sponsors
which are often academia, small biotech, et cetera, because the early
interventions often have a huge impact in key products being successful
products going downstream.
Next
slide, six.
Bottom
line is people ask. The first thing I'm
ever asked is, "Oh, does FDA do research?"
The
second thing that comes out is, "Oh, why does FDA do research?"
And
one of the things we'd like to explain is that there are reasons that FDA
science is so definitely value added to the process, and that includes the fact
that innovators who are people who typically understand product development
well; they understand science and have areas of scientific expertise, but
they're working for specific products typically in a proprietary setting, and
they're discovering their assays, their standards, their methods are not shared
with others.
CBER
scientists are also one of the few groups that are expert not only in
scientific disciplines but in the biological product development. They also have the opportunity to see success
and failures and missed opportunities across the board, and therefore, their
scientific input and scientific assessments and scientific activities in terms
of research and have broad impact in the field and help all products in a
particular category to move ahead.
The
science, of course, needs to be communicated to be valuable, and CBER guidance
documents, other public communications, publications and peer review of the
science so that it can be either repeated and others in the scientific
community agree with the findings or it can be disputed. It's very important, and so guidance and
other documents based on good science makes for better predictive critical
path.
And
finally, CBER can actually play a convening and coordinating role a
disinterested, if you will, from a financial point of view or a non-conflicting
party that helps coordinate sponsors and gets scientific questions answered
that are going to help cross product category.
Next
slide, Slide 7.
I
wanted to point out that the CBER researchers that were reviewed here are
fairly unique, and OBP and CBER are the two groups that routinely have
researchers doing a standard regulatory review.
And I've looked at them on this slide, but it's really too much, and
this includes both actual being on site in sections, being there as part of
experts when our experts go on section, as well as writing guidances, reviewing
R&D, et cetera.
So
they are fully integrated in the part of the process. In fact, it has always been my belief that
CBER researchers, research regulators, in general, identify clear issues that
need resolving better because they're actually involved in the regulatory
process and see the challenges at the table, if you will.
The
next slide is a culture issue that I have tried to promote, which is the
discussion that often follows the FDA dose research discussion with "oh,
well, I see. NIH does the basic research
and you do the applied research."
The
bottom line at CBER is one that's mission relevant. It's the research output and how it is
applicable to support the complex biological products. It is not whether it is basic. It is not whether it's applied. That really doesn't matter. It's whether it's applicable, and sometimes
some of the most major improvements and assistance that CBER scientists have
given have been in the basic biochemical arenas.
So
we really approach and utilize all kinds of science. The key is how it relates to the product
development and approval.
The
next slide is basically one slide that summarizes years of work with a variety
of research and regulatory science and the quality office, and that includes a
curricular pattern where every year the pattern is to review the regulatory and
public health portfolio and analyze the regulatory portfolio based on
scientific issues and challenges.
We,
of course, track very carefully INDs, BLAs based on titles, base on sponsors,
but what's done here is to identify the key scientific issues and challenges
within those regulatory processes and to formulate a report from in the office.
And
that was submitted this year. Research
priorities are then developed because once you identify the key scientific
challenges, you have to identify those that can be resolved without resources
that need urgent resolution, and if you will, maybe then focus on either low
hanging fruit where we can have an impact or major public health issues that
are so significant that we must work on them.
The
offices sends them and provides the center with their research plan and budget
which is formulated, and we're currently in that process now for '07 because
we're just initiating this formal initiative, and this year we're, if you will,
beta testing the process.
But
in '06 they submitted research plans and budget. We developed a form that we liked, and it was
very informative, and now the process is being repeated. Next year we have the process more on target
with timing because it will be the final product in research management.
And
then we have, of course, the scientific program review both for performance as
well as prioritization and future scientific quality and their plans, and then
an annual report is required, and that also is currently in the works.
And
then with the Advisory Committee, the first presentation will be involving the
response to the office site visit and a discussion of this process for that
office, and that will be coming up for OCTGT.
The goal here is to have public input responses and to make the planning
process and the prioritization process back-and-forth and allow, of course,
public input for interested parties.
Next
slide is Slide 10.
Basically
there are two kinds of things we do here.
We either create regulatory pathways where there are few or none, and
that's particularly applicable to this office, or in some cases where there is,
quote, historical regulatory pathways, such as in vaccines, which oddly enough
are really some of our oldest and most established products. We have to improve and update with 21st
century science those regulatory pathways.
As
you can see, our portfolio tends to and always has tended to focus on safety,
and we do product quality as an issue and product efficacy, but safety is key,
particularly because our products are either fairly novel or they're products
like vaccines that are administered to healthy people, and therefore, the
safety bar is quite high.
Next
slide.
Slide
11, I will let you read to yourself, but we also developed this as part of the
research management initiative, Guide Principles for Science at CBER, and you
will note words like "collaborative," "crosscutting,"
"multi-disciplinary." Our
staff really lead the chase in terms of having that total scientist, the renaissance
scientist who really is quite broad in their expertise and quite forward
thinking, and yet collaboration is key because science in this world these days
is an international and certainly multi-institutional effort, and I'll leave
you to read those yourself.
Today,
just for a little bit of site visit definitions, I want to sort of give you
some CBERese, if you will. Today we have
senior investigators, staff scientists that may be already converted staff
presenting under review. A converted
staff is tenured and, therefore, they're evaluated either for promotion to a
higher GS level, for example, or for simple progress.
We
have asked the Committee to comment both on their previous performance and on
their future plans.
Then
we have another category which is being reviewed, which is service fellows,
which are considered non-permanent. If
you're a non-tenured STEs we have two versions of those. One is the staff fellow or visiting
associate, who is evaluated from conversion to staff scientist or support
scientist, and let me just say as an aside not necessarily because that
individual could not be an independent investigator, but because of financial
or budgetary reasons, administrative needs it has been determined that there is
not a need for a second independent program in this area.
And
so these scientists form part of a team working under a principal investigator
and contribute tremendously to the effort, but sometimes the staff scientist
designation is clearly an administrative designation because we have very
talented staff.
Senior
science staff fellows and visiting scientists are also temporary, not permanent
MPEs, and those when they come in are considered senior investigator track, and
so they're evaluated for conversion to senior investigator and all the things
that go with that, including independence, ability to run an independent
program, et cetera.
The
next slide, 13.
Basically
the site visit team is now viewed as the Roman Coliseum, and appropriately what
they help us out with is to identify staff that are on track and help as
experts in their field given suggestions for improvement. They identify staff that are not on the right
track. They help us with prescriptive
advice to get the staff on track, which we appreciate.
And
so with the non-permanent staff, the fellows, if you will, service fellows, we
like to get them reviewed mid-cycle and then once at the end of their
seven-year track so that in the mid-cycle review they have a chance to change
direction, change course and take the advice of the site visit in order to
improve their programs if it's needed.
Next
slide is 14.
The
site visit report is what we're talking about today. Basically at the end of the review of the
team, the oral summaries presented to the research management, and there's an
opportunity for discussion and clarification.
A
draft report has been written. It has
been distributed to the Advisory Committee.
The final report is here today to be discussed, and the final approval
by the Advisory Committee, and then that report becomes a major document that
is used for the promotion or conversion of staff.
And
on the next slide you'll see, Slide 15, that that report which is in red, the
Advisory Committee approved report at Slide 15 is part of a package that goes
forward to the promotions or conversions committee, and that includes other
elements, such as curriculum vitae, bibliography, the nominating memorandum
from the advisors of that individual.
Locations are submitted, words of recommendation. Again, other outside scientific reviews are
sought, and that entire package is reviewed by the promotions and evaluation
committee, which contains both research and regulatory scientific staff because
an entire scientific and regulatory performance review is performed in
parallel. Then that committee makes a
recommendation. The center director will
ultimately decide on the outcome.
The
final slide.
I
just want to say thank you very much for all of your time and energy and help
in this and every site visit that is performed by the Advisory Committee and
the site visits because we greatly appreciate it. We would like to recognize the FDA, along
with OBPs who participate in this process as having one of the most rigorous
and high quality scientific evaluation processes in the FDA.
I
just want to thank you and take any questions if you have any.
CHAIRPERSON
URBA: Well, thank you, Dr. Carbone.
We
left some time after Dr. Witten and Dr. Bloom's presentation for
questions. So unless there's some
burning question from a Committee member, I would suggest we go on to Dr.
Witten's presentation.
DR.
CARBONE: Super.
DR.
WITTEN: Okay. Thank you.
This
is Dr. Witten. Do you have the
slides? I'm assuming everyone has the
slides in front of them. That's true?
CHAIRPERSON
URBA: Yes.
MS.
DAPOLITO: That is why you say
"change slide."
DR.
WITTEN: All right, good. All right.
So the topics I'm going to cover -- this is on Slide 2 -- are the
mission and organizational structure of research in our office, the Office of
Cell Tissue and Gene Therapy; the regulatory scope of our work; and then some
highlights of what our research actually covers.
Next
slide.
So
the mission in OCTGT is to facilitate development of approval and access to
safe and effective medical products. Our
products are quite innovative. So some
of the research that we do is a very cutting edge, not necessarily on the
products, but on research on test methods of other tools that might be needed
in product evaluation and development.
Next
slide.
This
slide gives the structure of the office, our office, and as you can see,
there's three divisions that actually do regulatory work, and one of those
divisions that does lab and other research, that is the Division of Cellular
and Gene Therapies. Dr. Puri is the
Division Director of that division.
Next
slide.
And
here on this slide is a scheme describing the organization of that
division. So we are today talking about
the Gene Transfer and Immunogenicity Branch, which is depicted in this slide.
Next
slide.
Okay. So I mentioned that products regulated by our
office are quite cutting edge and also diverse.
Here is a general overview of the types of products we regulate: cell therapy, gene therapy, tumor vaccines,
and immunotherapy, tissue based product, xenotransplantation products, and
these aren't mutually exclusive categories.
That is, some of the vaccines might also be considered cell and gene
therapy, and certainly some of the cell therapies would be considered
xenotransplantation products. So it's
more of an overview of the technology of our products rather than specific
product categories.
Next
slide.
On
this slide I've listed the regulatory portfolio and activities, and as you can
see, we're a very active office in terms of the research that's here. There's over 1,100 active INDs, IDEs, and
master files. These are active, meaning
there's a number of amendments for these that we have to look at because
they're ongoing studies.
There's
one licensed product, but there's a number of products that are in Phase 3 or
in discussion about Phase 3, and these are some of the regulatory activities
that we participate in.
Next
slide.
We're
relatively small, but our reach is large as I've indicated in the previous
slides about the scope of our work. So
much of our both regulatory and really our research work, too, is done with
partnerships.
And
I've listed here some of the types of groups that we partner with, the National
Toxicology Program and other organizations, NIH and CDC. We have some specific initiatives with these
different agencies, in particularly with NCI.
We have a lot of interactions.
We've
listed the IOTF Program, but there's others.
We had a workshop this year on cancer vaccines that was conducted within
NCI. We have a lot of interactions with
NIH. The Stem Cell Task Force is only
one example.
We
have an MOU with MINDS. There are not
all of these listed, but it just gives you a flavor of some of the kinds of
outreach and interactions we do, and certainly there are international
partnerships, ICH and WHO, but as you can imagine, there's a lot of interest in
the field, and we do have a fair amount of discussion with our regulatory
counterparts and other areas.
Next
slide.
Here
I've just listed specifically. I have on
an earlier slide that we participated in guidance document development. I have in this slide an update and from
when. It is the significant guidance
documents from this calendar year. You
can see that they're fairly significant: a knee cartilage tissue engineering
guidance document and one that we worked on together with cancer drugs; the
finalization on clinical trial endpoints for cancer drugs and biologics. We also regulate human tissue and finalize
the eligibility determination guidance document, which is certainly very
important in enhancing tissue safety, and also the core blood guidance document
that was discussed at a meeting that was conducted earlier this calendar year
was issued indirect this year.
Next
slide.
I'm
not going to cover the roles and work of the researcher reviewers again sine
Kathy Carbone has already gone through it, but I will just echo what she said
in that there's a unique role of the researcher reviewers, and both components
of their work here are important and are recognized both in terms of the
research and the regulatory component, and I think they are very intimately
tied together.
Next
slide.
So
this list of contributions in the research area and the regulatory area,
specifically for the branch that we're going to be discussing today since the
2003 site visit, and I know that Dr. Bloom, following me, is going to go into
more detail about what her branch does, but you can get the idea from this that
not only does the office overall participate in IND review guidance document,
regulatory work and active research, but in particular, this branch has been
extremely active in all of these areas that I have mentioned.
Next
slide. Okay.
So
I think also Dr. Carbone did discuss what is the goal of research at FDA or at
CBER, and the goal is to stay ahead of the curve as these products and
technologies evolve.
So,
in particular, in our field we look at the research that's going to address the
regulatory needs of tomorrow. We have a
good idea of what the anticipated products are based on our regulatory work,
and we use that knowledge to feed into some of the objectives of our research
program.
Next
slide.
So
that we do systematically look periodically internally, as Dr. Carbone did
mention. There is a system across, you
know, CBER to look at what are the critical path issues in these products, and
our research is different from what sponsors do. The sponsors will study individual products
and have proprietary results, whereas we look at studies relevant to product
classes.
So,
for example, if a sponsor wants to do toxicology testing of his or her
particular product in an area where test methods don't really exist, they have
a double challenge where they're developing the test methodology and of
developing their product, and then that test methodology is done by them and
relevant to what they do. So we try to
encourage development of cross-cutting tools, such as test methods, for
example, that can be used by anybody and where there could be a greater
understanding of these tools, you know, as they are used across the field. People have a greater understanding of what
the results mean.
Next
slide.
I've
listed on this slide our current research areas. This is across the office, and Dr. Bloom will
be focusing specifically on the research in that branch.
Next
slide.
I
just want to mention reference materials are certainly an important part of our
research. It's not basic science research in a way developing reference
materials, but it's along the lines that I mentioned of assisting the evolution
of standardized test methodologies.
Last
slide.
And
so lastly, I just want to thank everyone for participating in our review
program. It's very important to us to
make sure that we, you know, are reviewed and that we make sure that we're
evolving in both a relevant way regulatorily and that our science continues to
be of high quality and we get input from outside as is needed in all scientific
endeavors.
And
now I'll turn it over to Dr. Bloom.
DR. BLOOM:
Thank you.
I'm
going to speak with you this morning about the Gene Transfer and Immunogenicity
Branch site visit that happened on March 2nd and summarize for you some of the
information that was presented at that site visit.
The
investigators at the site visit include myself, Dr. Andrew Byrnes, Dr. Suzanne
Epstein, Dr. Nancy Markovitz, Dr. Carolyn Wilson, and Dr. Takele Argaw.
I
would like to say that while my presentation will focus on the research of this
group, I may refer to one of Dr. Witten's slides on the regulatory activities,
and you can see that we have a quite substantial role in regulating INDs and
the licensed supplements.
Our
particular branch regulates samples of all of the types of products that are
received in the Division of Cellular and Gene Therapies, including gene
therapies, cellular therapies, xenotransplantation products, tumor vaccines and
basically the whole nine yards.
So,
in general, problems in development of cell and gene therapy products include
-- I'm sorry. I'm on the second slide
now -- include that there are a lack of preclinical models to predict
performance of gene and cellular therapy products in vivo.
There
is a potential for transmission of infectious agents to the patient and even
beyond, especially for certain xenotransplantation products and certain gene
therapy factors. So not all of the
products pose this kind of risk, but many of them do.
And,
in fact, some of these products were often intended for lengthy or even
permanent residents in the recipient, which raises the risk level.
The
complications of the product or --excuse me -- manufacture of the products are
quite complicated, and the structure of these products are, as you can well
appreciate, very, very difficult to describe and quantitate.
So
the challenges for the Gene Transfer and Immunogenicity Branch, in particular,
include on the next slide now product safety, which is affected by virus
containing products. For example,
unintended replicating viruses in viral vectors and in xenotransplantation
products and other products pose risks not only to the immediate patient
receiving these products, but also beyond the patient, and that's an issue of
safety.
Some
of our products contain intentionally replicating viruses. Generally these are intended to be attenuated
or selected in their replication properties, for example, Herpes simplex
viruses.
Viral
vectors themselves also carry inherent risks, such as toxicity, tumorigenicity
and off-target effects. Immunogenicity
of these products impacts both safety and efficacy. Immune responses to viruses and transgene
products, xenotransplantation and cell therapy products can severely compromise
the efficacy, as well as harming, potentially, the recipient.
In
addition, many of the products that we regulate rely on immunologic activity
for their mode of action, such as tumor vaccines or immunotherapy, documented
immunotherapy products.
The
Gene Transfer and Immunogenicity Branch now in the next slide addresses these
challenges through critical path research.
We use multiple viral systems, and we use a flexible system to address
immunogenicity in the function of many OCTGT products.
We
believe that the predictability in the clinic of these products comes from
understanding the fate and effect in vivo from the role of structure and
function in product safety and from interaction of these products with the
immune system.
Slide
5 is just to tell you that I am about to discuss with you the individual
products that were presented at the site visit on March 2nd.
(Pause
in proceedings to respond to cell phone interruption.)
DR.
BLOOM: So I'm going to do these in
alphabetical order by the investigator.
The first one is my own, and it is the immunobiology of cellular therapy
and xenotransplantation products, especially immunogenicity issues. What this slide shows is that in
xenotransplantation, which is obviously transplantation between species, we've
shown that immunity includes natural killer cells and T cells, antibody is also
known to play a role.
We've
also evaluated the role of regulatory T cells and shown that they inhibit CD4
positive T cell responses.
Autologous
cellular therapies include primarily those that are expanded, though they don't
necessarily have to be, expanded in vitro, and these include as I've said
before tumor vaccines and adopting immunotherapies, and they need to be
immunologically active, and these include, for example NK cells, T cells, also
dendritic cells, among others.
Our
transplantation, the immunologic response to these is primarily T cell
dependent, and sometimes we have shown that NK cells can play an important
role, for example, in the latter case with human embryonic stem cells or their
differentiated progeny.
Slide
7 provides one tidbit of data from this program and shows that we have been
working with collaborators at NIH to develop a preclinical model in
xenotransplantation and we have been using this model to evaluate the potential
for regulatory T cell activity in vivo.
The
two figures shown show that when baboon CD4 positive, CD25 positive regulatory
T cells are expanded, they strongly supplant both the proliferative and
cytokine production of the baboon responder effector cells, which are CD4
positive, CD25 negative.
The
impact of this program on cell therapy and xenotransplantation products is show
in Slide 8 and includes our showing the NK cells must be considered as immune
mediators for the rejection of both xenogeneic transplants and certain
allogeneic cell therapy products.
We
believe that efficacy may be affected by the types of responses of the
recipient and the micro environment. We
also believe that safety is important because it's important to have an intact
immune system in addition.
So
while you want to reduce the immune response of these products, you also need
an intact immune system to deal with infectious agents.
We
hope that these studies of the patient immune responses in vitro may eventually
allow us to predict immunity in vivo and can serve as biomarkers of clinical
benefit.
The
next project on Slide 9 is that of Dr. Andrew Byrnes, and it is the safety and
biodistribution of adenoviral vectors.
Adenoviral vectors comprise a very large segment of the INDs reviewed in
OCTGT, more than 80 active INDs in the
Adenoviral
vectors have four pharmacokinetics after systemic injection in that they are
rapidly cleared by the liver actually, and in efficient therapy may be due also
to that as well as to toxicities. Ad.
vectors are taken up by Kupffer cells as shown in the bottom of this slide, and
as you know, Kupffer cells are in the liver, and that appears to be a very
common source of the pharmacokinetics, or Dr. Byrnes has shown this appears to
be a good source of pharmacokinetic compromise.
So
the next slide suggests how Kupffer cells recognize adenovirus. He has developed a new assay for quantitating
the Kupffer cell uptake of adenovirus and has shown its scavenger receptors are
important for their uptake of adenovirus, and again, these would impact on the
biodistribution and on the efficacy and safety of these products.
So
on Slide 11 we summarize the critical path issues in adenoviral gene
therapy. Kupffer cells prevent ad. gene
therapies from reach its full potential, and its future goals are to understand
how Kupffer cells recognize adenovirus and to develop rational strategies to
block Kupffer cells in order to enhance the gene delivery and decrease vector
toxicity.
The
third project beginning with Slide 12 is that of Dr. Suzanne Epstein and
involves influenza, which is a serious public health problem. Influenza as we all know can cause very high
mortality from seasonal outbreaks, and we're all acutely aware now of the
potential for pandemic outbreak in the not unforeseeable future, and vaccine
supply may be delayed or inadequate in these cases.
The
work in Dr. Epstein's program involves new vaccine technologies that can
cross-protect broadly against different, divergent Influenza A subtypes, and
part of the impetus from this is that historical data suggests possible
cross-protection in the pandemic flu of 1957.
The
data shown in Slide 13 show that vaccines may differ in their ability to
cross-protect against mismatched influenza subtypes.
So
live attenuated virus similar to an available vaccine was not as effective in
cross-protection against H5N1, which was used for challenge, as an experimental
vaccine which she tested which was based on conserved antigens and uses a DNA
prime recombinant ad. boost mechanism.
The
implications for the public health and product regulation of this project is
shown in Slide 14, and the project addresses DHHS and center-wide priorities on
the control of epidemic and pandemic influenza, but also on
counter-bioterrorism because influenza is now actually considered a
counter-terrorism agent, but it represents a control of emerging infectious
disease without having to know which strain is coming. So that's the purpose of the
cross-protection.
Finally,
safety and efficacy impact in gene therapy is because antibody and T cell
responses to viral vectors can block efficacy and cause immunopathology, and
flu serves as a model of that.
The
next project on Slide 15 is that of Dr. Nancy Markovitz, and it's the identity
and safety studies of herpes simplex viruses and vectors.
Replicating
viruses used in cancer therapy can contain unrecorded mutations, and this is
something that has been very well shown by Dr. Markovitz.
As
far as safety is concerned, in contrast to what is frequently reported, Herpes
simplex viruses similar to those that are actually used in clinical trials do,
indeed, appear to replicate in normal brain cells in mice.
So
the next slide shows that what we've already referred to, is that unexpected
mutations in herpes simplex virus for clinical use can -- she has detected
them. They can be detected. So our 3617 is a parent strain of virus G207,
which is used clinically, and R3617 is what Dr. Markovitz has used in her
experiments.
Now,
sequence analysis has proven that the mobility shift which she sees of the UL3
protein was due to a single based substitution, and that single based
substitution resulted in the truncation of the UL protein, demonstrating that
unrecorded, unreported mutations can actually have very marked effects on the
viral products.
In
the third slide of this project, number 17, are figures that show the herpes
based virus similar to those. Again,
this is the R3617 virus, that it can replicate in cells of normal mouse brains,
as you can see by the electromicroscopic picture on the right.
The
next set of projects are those of Dr. Carolyn Wilson, and Slide 18 shows a
brief introduction to E. bola virus, which is a little different than what
you've heard about so far. E. bola virus
has a very high fatality rate with rapid disease progress, and there is no
proven cure and there is no vaccine available for these viruses.
Infection
by the viruses suppress both the innate and adaptive immune responses and,
thus, it exacerbates pathogenic outcome.
It also prevents the development of protective immune response.
DHHS
has designated E. bola virus as a high priority bioterrorist agent.
Dr.
Wilson's group has collaborated to produce monoclonal antibodies against
specific epitopes of three E. bola virus species and the epitope are conserved
between the species. The anti-F88
monoclonal antibodies, as you can see in
Slide 19, can neutralize several different strains -- excuse me -- several different
viruses. Back up once. I apologize.
Several
different monoclonal antibodies against the F88 determinant can neutralize
several different strains of E. bola virus.
In fact, these monoclonal
antibodies that she has produced neutralize better than the 133 3.16 monoclonal antibody, which is
typically used in these types of studies.
So
the impact of these studies on counter-bioterrorism is that there may be a
possibility; it is possible to develop antibodies for passive transfer, and
this is done by targeting conserved epitopes.
These epitopes, the antibodies against these epitopes can block entry
and, therefore, reduce virus burden, and because the epitopes selected are
critical for viral entry, one can avoid potential for immune escape mutants.
The
broad protection to various filovirus species is an important plus in these
studies and in the potential outcome of these studies, and it compliments
vaccine strategy in that the development of monoclonal antibodies against E.
bola virus may provide immediate protection in the event of an outbreak, where
vaccine strategies would be needed prior to an outbreak.
In
addition, Dr. Wilson has been working with the National Toxicology Program or
NTP in a study for safety assessment of retroviral vectors for the risk of tumorigenicity. You may remember that there were a number of
leukemias that developed in children receiving retroviral gene therapy for
absence of the Gamma C chain, and so it is important to determine how these
types of leukemias could develop, and so the study is to determine the
sensitivity of a preclinical model for detecting vector mediated insertional
immunogenesis, tumorigenesis, and to examine the impact of the vector backbone,
the dose, and enhancer deletion on tumor frequency.
The
study will assess retroviral vectors representing three different retroviral
genera, including gamma retroviruses, lentiviruses, and spumaviruses or
fomivirus.
Now,
Dr. Takele Argaw in Dr. Wilson's group has been looking at the porcine
endogenous retrovirus, and the reason for that is because porcine endogenous
retrovirus occurs, which is present in all porcine cells, is considered to be a
risk of xenotransplantation in that it can affect human cells in vitro.
And
so what these data show is that Dr. Argaw has been able to identify particular
residues that when mutated actually reduce the ability of perv. to infect human
cells.
So
the regulatory impact of the retrovirus program is that it addresses risk
associated with retroviral vectors, including identifying a model to assess
insertional mutagenesis from a retroviral vector, and using models to assess
the relative risks based on different vector types, dose and structure.
In
porcine xenotransplantation, again, a retroviral agent is considered a very
serious potential safety risk and Dr. Argaw has identified residues that are
required for the transmission of this virus that may allow development of a
means to block the infection by the virus and to reduce the risk of
transmission.
In
summary, the Gene Transfer and Immunogenicity Branch is addressing regulatory
challenges using critical path research.
We look at gene therapy vector safety, xenotransplantation safety,
cellular therapy and xenotransplantation product efficacy and address
center-wide and departmental priorities, including pandemic flu and
counter-bioterrorism.
Thank
you very much.
CHAIRPERSON
URBA: Thank you, all the speakers.
And
now we have a few moments for questions from any of the Committee members or
any of the previous speakers.
(No
response.)
CHAIRPERSON
URBA: No questions? Okay.
Gail, shall we move on to the next part?
MS.
DAPOLITO: Yes, we should. We lost Dr. Shores for a second. We're trying to round her up. Give us two seconds.
CHAIRPERSON
URBA: Okay.
MS.
DAPOLITO: Here she is. Are you ready, Dr. Shores?
DR.
SHORES: Got you.
MS.
DAPOLITO: Okay.
DR.
SHORES: So hello. My name is
And
I want to thank you all for participating in this particular meeting and our
site visit committee, headed by Dr. Gerson, that was so important for the peer
review process that is essential to maintaining our integrity as a research
group.
Although
I said I'm a sherbert between groups, many of the things are similar between
our two groups, and many of the things that Dr. Carbone mentioned are also true
for us. So I won't dwell on those, but I
think where we are particularly the same is in the way our research interacts
with and critically supports our regulatory mission to provide safe and
effective drugs to the public.
So
by way of quickly introducing OBP, if you turn to the next page OBP, the Office
of Biotechnology Products, is part of a super office called the Office of
Pharmaceutical Sciences in the Center for Drug Evaluation and Research. The OBP is headed by Steve Kozlowski, and I'm
the Deputy, and it's composed of two sister divisions. We're going to be hearing from both those
divisions today.
There
is the Division of Monoclonal Antibodies, headed by Kathleen Clouse, and this
is a group that regulates a variety of different monoclonal antibodies as well
as related products, such as Fc fusion proteins.
The
sister division is the Division of Therapeutic Proteins headed by Amy
Rosenberg, and that group reviews a large number of different therapeutic
proteins, enzymes, cytokine growth factors, and toxins.
So
we can move to the next page.
So
what does OBP do? And we do a great deal
of regulatory work, and I won't perseverate on that too much, but we scrutinize
a large number of submissions from industry, from pre-INDs, to INDs, to
510(k)s. These eventually hopefully will
lead to license applications, such as BLAs, NDAs, PMAs, and we actually have
coverage of up to 90 different license applications in OBP right now, which
represents about a one-third increase in the last year or year and a half.
And
none of these applications are static.
Sponsors are constantly tweaking them, and just as science moves
forward, so will sponsors move to meet these challenges and tweak their
products.
We
engage in inspections, and we write guidance documents. We participate in many different meetings
both with industry, as well as scientific meetings, and we consult a lot on our
areas of immunogenicity.
But
what we want to focus on today is a site visit report, and the site visit took
place on February 23rd, and it included David Frucht, Michael
Norcross, Serge Beaucage, and Ed Max, and very much appreciate the input on the
quality of the research programs that you heard and their mission relevance.
And
regarding mission relevance, I'll just quickly say, and this is on Slide 4,
there are a number of very important issues that arise in the review of
biotechnology products, and I've listed some of these here, and I won't go
through them individually really, but to mention that they're made in many
different cell substrates. So
microbiology is a huge issue. Immunology
is a huge issue for these therapeutic proteins both regarding safety, as well
as efficacy, and sometimes the mechanism of action isn't even clearly
understood, and this is a big issue for us.
And
all of these issues are things that we recognize as we review these
applications, and these are things that industry doesn't really want to pursue
at least in the detail that's needed or they can't pursue.
And
so those are the factors that really drive our research, and as we go to the
next page, it's why we use this researcher reviewer model, and as does
CBER. We have perhaps successfully
employed this model, I think, and it means that the very same people that are
reviewing documents from industry may have active research programs that are applicable
to the products that they're reviewing.
And
so our regulatory reviews and identification of problems ends up impacting on
our bench research and the types of programs that we follow, and then it sweeps
back so that we learn from our research, then feeds into our regulatory review
in many different ways, in our interactions with sponsors and in the
publication of the guidance documents, and in many ways.
So
with the constant challenges posed by biotechnology products, how can you be
prepared to deal with the problems that you know exist, as well as to be
prepared for the unknown? And to
paraphrase something from Louis Pasteur, a prepared mind may be the best way to
approach these unknown factors that arise in the future.
So
on page 6, you can get an idea of the type of research, broad research programs
that OBP supports, and you're going to be hearing from four individual
laboratories that are engaged in research in these areas.
In
the area of immunity, you're going to be reading and evaluating a report from
Ed Max's lab and his colleague Ralph Bernstein that looks at the generation and
control of antibody responses and isotype switching. Very important in considering anaphylactic
reactions to therapeutic proteins.
On
the next page is our programs in microbiology and infection, and you'll be
hearing from two investigators in that area.
David Frucht, who does critical research on characterization of the
anthrax lethal toxin and its role in disease, and it's very important for our
ongoing bioterrorism efforts. And you
have reviewed the report from Mike Norcross and his colleague Jinhai Wang
regarding HIV and the cytokines and chemokines that are involved in its
activity.
And
then finally, work from Serge Beaucage who has been a mover and shaker in DNA
and ODN synthesis for years and his research has recently taken him into the
area of looking at interaction with the toll-like receptors, as well as in the
last slide, how to make these ODNs better for both the in vivo and in vitro
applications.
So
I'll stop now and had over to Kathleen Clouse who will discuss David Frucht's
work and the Division of Monoclonal Antibodies.
(Pause
in proceedings for teleconference interruption.)
DR.
CLOUSE: Okay. We were trying to reach Dr. Frucht since
we're running a little bit early. So he may
call in in the middle of my presentation.
So our apologies. We tried to
coordinate timing.
MR.
FRUCHT: This is David Frucht.
DR.
CLOUSE: Hi, David.
Okay. The Division of Monoclonal antibodies, if you
look on the second slide, has as its mission to insure that safe and
efficacious and high quality monoclonal antibody and related products are
available to the American public, and in order to do this, we have to make sure
that we maintain and retain a diverse, knowledgeable, and scientifically based
and dedicated staff that's actively involved in research and regulatory review
and that the research programs are applicable to the regulatory review process.
In
the next slide, you can see that as was published in Nature Biotechnology
in September 2005, there was a statement made that monoclonal antibodies now
comprise the majority of recombinant proteins that are currently in the clinic,
with more than 150 products in studies worldwide.
The
reality is at present more than 300 novel products are currently under review
in our division alone.
The
next slide shows you the organization of the Division of Monoclonal
Antibodies. As mentioned, I serve as the
Director. Dr. Patrick Swann is the
Deputy Director. Dr. Swann also serves
as the Chief of the Regulatory Science and Policy Branch, where we have at
least eight full-time reviewers who have come up through the research
laboratories, and we have three major research laboratory groups: the lab of cell biology, for which I'm Chief;
the laboratory of immunobiology; and the laboratory of molecular and
development immunology.
Being
site visited in February was Dr. David Frucht.
He is one of the principal investigators in the laboratory of cell
biology, and his research emphasis is on
counter-bioterrorism with the program dealing directly with anthrax research.
And
in the next two slides summarizing some of David's credentials and
accomplishments, he's established an independent research program to
characterize the activity of anthrax legal toxin both in vitro and in vivo.
From
a regulatory standpoint, he reviews products for infectious diseases, and these
include antibodies targeting anthrax toxin, which are under consideration for
inclusion in the strategic national stockpile under emergency use authorization. So these products have a more rapid
development pathway than some of our other products.
He
also reviews monoclonal antibodies and related molecules that function as
agonists or antagonists for hematologic indications. He participates in pre-approval
inspections. He serves on working groups
for guidance document development, most notably anthrax therapeutics
development and drug-drug interactions.
He
serves as a co-chair for the CDER/CBER inter-center biotechnology
counter-terrorism working group, and he has served as chair for the CMC session
of an FDA sponsored workshop on immune therapies for anthrax infection.
And
in the next slide, continuing on, he is Board certified in internal medicine
and infectious diseases, hence the nature of his regulatory assignments. He performs weekly clinical rounds at the
National Institutes of Health, and he serves on editorial boards for the Journal
of Immunology and the Journal of Biological Chemistry.
He's
been awarded competitive HHS grants and CBER/FDA grants for
counter-bioterrorism research efforts, and his duties as a commissioned officer
in the U.S. Public Health Service include being a member of the Incident
Response Coordination Team where he's on call every five months for deployment,
and he has had six deployments in the past three years.
And
he was also selected for the Physicians Professional Advisory Committee to the
Surgeon General.
And
in the next slide summarizing his research program objectives, first of all,
it's to identify the biological markers for the activity of anthrax lethal
toxin in humans and in animal models; to assess the biological significance of
these markers in the pathology of toxemia and/or anthrax infection; and to
establish the scientific basis for the development of more relevant bioassays
in order to assess product potency.
And
these objectives are important for addressing issues relevant to seeking
approval for these products under the animal rule, in other words, where
efficacy testing is done in animal models and not in humans.
And
in the next slide, the final slide, his research program milestones are best
conveyed in the summary of his publications, and you can see they're broken
down into categories where he has assessed the effects of anthrax legal toxins
on multiple cell populations, including macrophages, human T lymphocytes,
B-lymphocytes, and now most recently neutrophils.
So
in the first one, he showed that anthrax lethal toxin activates murine
macrophages, leading to the release of IL-1 beta and IL-18, and this study was
basically performed in order to identify new biomarkers and determine strain
susceptibility factors in the models that were used.
The
second publication, "Anthrax Lethal Toxin Targets Human T Cells Leading to
a Blockade and Proliferation in Cytokine Production," and this was to form
the basis for determining the pathogenic mechanism and the basis for new
bioassays.
Third,
"Anthrax Lethal Toxin Blocks B Cell Proliferation in Immunoglobulin
Production." Before B cells were
not thought to be that intricately involved or affected by the anthrax lethal
toxin, and this provided insight into a pathogenic mechanism and the basis for
a new bioassay.
And
finally, "Anthrax Lethal Toxin Promotes Super Oxide and Elastase
Production in Neutrophils." This is
for the identification of potentially more biologically relevant biomarkers for
lethal toxin activity.
And
with that I think we're due to take any questions you may have for me or for
Dr. Shores or for Dr. Frucht on the phone.
CHAIRPERSON
URBA: Thank you, Dr. Clouse, and thank
you, Dr. Frucht, for being available.
The
presentations are now open for any questions from any Committee members.
DR.
TAYLOR: I'd like to get a sense of how
much time Dr. Frucht actually spends on research.
DR.
CARBONE: David.
(No
response.)
DR.
CARBONE: David spends -- he may have
trouble unmuting his phone. We were
dealing with that previously.
David
spends probably about 40 to 50 percent of his time on research due to
regulatory work loads at present.
DR.
FRUCHT: Can you hear me?
DR.
CARBONE: David, are you there?
DR.
FRUCHT: Can you hear me?
DR.
CARBONE: Yes.
DR.
FRUCHT: Fifty percent, either
supervising or performing necessary work.
Sorry about that.
MS.
DAPOLITO: Dr. Taylor, does that help
answer your question?
DR.
TAYLOR: Yes. Yes, it does.
And
is the goal to maintain a 50-50 divide or do you anticipate as this research
takes off you will still have the capacity to do that?
DR.
FRUCHT: I anticipate that I'll have the
capacity to do the research that I've set out to do spending 50 percent of my
time on research and 50 percent of my time doing regulatory work, yes.
DR.
TAYLOR: Okay.
DR.
FRUCHT: I think the goals that I've set
out are reasonable to accomplish in three years. I supervise the lab. Right now I have two other folks. There's another position that will be filled
this year probably, and with that support, I think I'll be able to accomplish
these goals.
DR.
TAYLOR: Thank you.
CHAIRPERSON
URBA: Other questions.
DR.
CARBONE: This is Kathy Carbone.
I'd
just like to make a statement for people within CBER. We do target a goal of about 50-50, 50
percent regulation, 50 percent research.
Sometimes it goes up; sometimes it goes down, depending on crises, but
we hope the staff can average that.
CHAIRPERSON
URBA: Thank you.
Other
questions?
If
not, Gail, go on to Dr. Rosenberg.
MS.
DAPOLITO: Okay.
DR.
ROSENBERG: Hi. I'm going to give you an update of the groups
reviewed sine the site visit who are in the Division of Therapeutic Protein.
The
Division of Therapeutic Proteins, as you can see on Slide 2, is divided into
three different laboratories. The
Laboratory of Immunology and the Laboratory of Chemistry each have members who
were site visited in February and on whom I will give you updates today.
In
the Laboratory of Immunology headed by
As
well, the laboratory of Dr. Ed Max was being evaluated for progress and within
his group, Dr. Ralph Bernstein was being evaluated for conversion to staff
scientist.
In
the Laboratory of Chemistry, headed by Gibbes Johnson, Dr. Serge Beaucage's
group was being evaluated for progress.
And
so let us go into these individual laboratories. So the regulatory responsibilities of the
Laboratory of Immunology concerns expert regulation of numerous products whose
activity or origin is immune system based.
This group expertly regulates products also regulated in other
laboratories. We simply don't have the
largess of personnel to be able to devote everyone's attention to their
particular area of research interest. So
people have to be versatile and have to be very quick in learning about other
kinds of products and to perceive the risks and potential efficacy in other
products.
This
laboratory performs immunogenicity assessments not only on all licensed
products and
This
group is writing immunogenicity guidance documents. We have two draft guidance documents in the
works on clinical concerns and assay guidance, and anticipate drafting an
immunocomparability guidance for follow-on proteins in the near future. Very busy.
So
the persons being site visited are involved in regulation of differing products
within this lab: immunomodulators for
autoimmune disease; CTLA4Ig, the insulin beta chain; HLADR peptides. Drs. Bernstein, Norcross and Wang are very
involved in this, as well as Dr. Mills who is also in Dr. Max's lab. Entities to block immune responses, IL-1
receptor antagonists is also in this group.
Importantly,
the innate immune system modulators have become very prominent, and Drs. Wang
and Norcross are prominent in regulation of these products.
Cytokines
and chemokines, these are licensed interferon products of which there are many.
The most recent iterations have been pegylated, and Dr. Beaucage in the
Laboratory of Chemistry has been vital in helping us with pegylation chemistry
and stability. Drs. Bernstein, Wang, and
Norcross each have a hand in regulating these interferon products.
Numerous
interleukin products, some licensed, most not, are being investigated, and Dr.
Norcross has a hand in regulating these as well as in the chemokines, which are
a relatively new and important growing class of protein therapeutic.
Again,
all DTP products, as well as products throughout FDA, get immunogenicity
assessments, and Drs. Wang, Bernstein, Mills, and Norcross have been prominent
in assessing these products with respect to immunogenicity.
So
let's get into the individual research programs. Dr. Norcross' program is being evaluated for
progress. His research programs consist
of chemokine biology, and of course, the regulatory program to which is
research applies is regulation of chemokine products, and there are important
difficult issues concerning potency assays with regard to these chemokine
products, as well as mechanism of action.
His
research program in HIV-1 immunopathogenesis is applied toward regulation of
protein therapeutics for HIV-1 treatment and prevention, cytokines and
interferons, vaccine adjuvants, as well as chemokine receptor inhibitors.
His
research program that covers aspects of cancer biology applies to the regulation
of protein therapeutics for treatment of malignant states, and again, broad
areas of immunology and autoimmunity.
Research background in that contribute to evaluation of immunogenicity
of therapeutic protein products.
So
let's discuss -- you had Mike's presentation at the site visit. You have read the draft report. I'd like to update you on his accomplishments
since the site visit.
So
in two areas, chemokines and chemokine receptors in HIV-1 infection and
immunology. The laboratory has examined the
heterodimeric interactions between different types of chemokines and
receptors. Expression vectors are
currently being generated to dissect the interactions between CCR5, CXCR4, CD4
and CD26 using FRET techniques.
The
physical interactions between these cell surface proteins may well control
susceptibility to infection and sensitivity to receptor log-ins and
antagonists, and Drs. Wang, Gwan and Norcross have a manuscript in preparation
on this topic, new since the site visit.
In
the area of immune modulation and HIV-1 pathogenesis, studies are ongoing to
examine the effects of HIV-1 infection and HIV proteins on macrophage and
dendritic cell function.
Since
the site visit, HIV infection was found to induce partial dendritic cell
activation, but may contribute to chronic immune activation seen in HIV
infected patients.
And
with regard to this specific inhibitors of TLR, toll-like receptors, and
scavenger receptors are now being evaluated for effects on HIV mediated
activation of monocytes and dendritic cells.
Dr.
Wang, a staff scientist within Dr. Norcross' lab is being evaluated for a
promotion action. His research focus is
on chemokine receptors as host factors in HIV-1 infection in cancer biology. He has had six first author publications since
2001. A patent was filed in this area.
He
has had a special interest in non-CPG immune modulators. He has had one publication in this area and
one patent filed, and Dr. Wang does a lot of CMC review work, INDs and BLAs for
HIV-1, HCV in cancer, and especially lately he's done considerable work on
immunogenicity reviews for therapeutic enzymes in which there are quite a few
thorny issues.
So
Dr. Wang's scientific accomplishments since the site visit consist of the
following. He has had an internal
presentation to FDA. He's had a patent
application. The international
application is to be filed, I presume was filed, should be filed within the
next few days.
In
terms of publication, he's had a publication in the Journal of Immunology
this month on immune responses by regulatory oligodioxy nucleotides.
In
addition, he is first author on a review of immunogenicity of therapeutic
enzymes that was submitted to Nature Biotech, and he has a review that's
currently under internal review on dimerization of chemokine receptors in
living cells. He's got, again, his
ongoing projects in the immune regulatory ODNs really focusing on receptor
trafficking and regulation of monocyte function by plasma site dendritic cells,
as well as this program in chemokine receptors in Cancer Biology. CXCR4 in particular is a focus here.
We
move now on to the research program of Dr. Max, whose laboratory is being
evaluated for progress.
Dr.
Max has an intense focus in class switch recombination, which applies directly to
the regulatory agenda of the immunogenicity approach in therapeutics and
immunomodulatory product review, including products that activate B cells in
the setting of immune deficiency and product qualities associated with T
independent and T dependent B cell activation, such as protein aggregates.
As
well, the focus in the lab is on IgH insulators, the prediction, prevention and
control, their control of immune responses and the ability to predict and to
prevent such responses, and this
directly applies to evaluation of biotech applications that use insulators to
stabilize and enhance transgene expression and replacement of defective genes
and prevention of oncogene activation.
So
an updated on Dr. Max's group since the site visit regard class switch recombination. Additional experiments have been performed
and completed to compare double and single stranded DNA breaks in Ig switch
regions. Only double stranded breaks
were found to be AID dependent, and a manuscript regarding this has been
submitted to J.Exp.Med.
In
addition, chip experiments have been performed to assess the APOBEC3 binding to
Ig switch regions.
Regarding
the insulator project, the program has evaluated in vitro binding of candidate
regulatory proteins, UCSF1 and DB1 to insulator DNA, and these have been
characterized. Barrier activity of the
flanking insulator has been further mapped, and a draft manuscript has been
written regarding a chromatin boundary element downstream of the humanois-G
heavy chain locus.
Dr.
Ralph Bernstein within his group is being evaluated for conversion to staff
scientist. His research focus is on the
insulator elements, three-prime of the murine three-prime IgH locus control
region. He's had three papers since
2001, three manuscripts in preparation.
Dr.
Bernstein has had a very heavy regulatory load with CMC work, workshop
presentations, multiple presentations of scientific and important regulatory
topics for FDA staff.
In
addition, Dr. Bernstein is the inspection coordinator for DTP products, and he
coordinates all of the biennial inspections, helps in identification of issues
for inspection and briefing of inspectors, advice for field inspectors on
scientific issues. Very often this
happens during the inspection and requires work at all hours because inspectors
inspect around the world.
And
Dr. Bernstein has performed multiple inspections particularly of products in
which we are experiencing manufacturing difficulties.
As
well, he's the IT coordinator for DPT, and this also requires a significant
amount of work.
So
since the site visit on his project, Dr. Bernstein has evaluated long lasting
barrier activity and localized it to a .5 kilobase DNA segment upstream of the
insulator. He has studied the DNA Swan
hypersensitivity site upstream of the murine insulator.
He
has made identification of insulator DNA fragments binding to DB1 and MAR. The DB and MA are binding proteins
SATB2. He has prepared a library of DNA
fragments for enhancer blocking trap screen.
He has characterized DNA methylation status of CPG sites in the murine
insulator, and he has made critical contributions to two manuscripts.
Finally,
of the Laboratory of Chemistry in which Dr. Beaucage is located, the regulatory
responsibilities include regulating therapeutic enzymes for oncology
indications, and you see Dr. Beaucage is prominent in regulation of those
products.
Enzyme
replacement therapies are a burgeoning area for regulation because for each
inborn error of metabolism there is an enzyme that can ameliorate the build-up
of substrate, and so you can see here Dr. Beaucage has been the CMC Chair on
two of these therapeutic enzymes.
Drs.
Mills, Wang, and Max have also participated in licensing of these enzymes for
infectious disease indications. Dr.
Norcross is a primary reviewer on the sialidase product, as well as on an
enzyme for counter-terrorism.
So
Dr. Beaucage's progress update. His
research program focuses on optimization of methods for production of
diagnostic and therapeutic oligonucleotides.
The scientific expertise has importantly contributed to regulation of
these products. He's a co-author on the
oligonucleotide guidance document, as well as being an important reviewer of
therapeutic oligonucleotides siRNA and siRNA INDs.
He
has reviewed BLA for PCR based diagnostics.
This was in consultation. Again,
his expertise in chemistry has been vital to us because we're seeing a lot of
pegylated products. Pegylation is very
important for prolonging product half life and for preventing immunogenicity,
as well as regulation of the therapeutic enzymes that I mentioned to you.
So
since the site visit, Dr. Beaucage's group has four manuscripts that are going
to be submitted for publication, and you can see the publications that they're
going to be submitted to.
Moreover,
he has given presentations, invited presentations, at prominent meetings for
oligonucleotides and oligonucleotide products and has two upcoming ones in the
near future.
So
with that I'll close. Thank you very
much for your evaluation of our groups, and we'll take any questions that you
may have at this point.
CHAIRPERSON
URBA: Thank you for that great summary,
Dr. Rosenberg.
Any
questions from the Committee?
DR.
GERSON: Stan Gerson.
I'd
just like to thank Dr. Rosenberg for putting together the particularly useful
information on progress since this site visit, and just comment on how
important it is addressing this that came up during the site visit. And so I'm speaking for the review group, if
I could. Very appreciative.
DR.
ROSENBERG: Thanks very much.
CHAIRPERSON
URBA: Okay, Gail. Hearing no further questions.
MS.
DAPOLITO: Okay. We can go to -- we're a little bit ahead of
schedule -- we can go to the closed hearing.
There has been no prior request to comment to the Committee.
I
should ask if there's anyone in the audience here on site who would like to
address the Committee at this time on the topic at hand.
And
I don't see anyone. So, Dr. Urba, if
you'll give us a couple of minutes to clear the room so that we can go into
closed session.
CHAIRPERSON
URBA: Okay
MS.
DAPOLITO: And if all of the members
would just hang with us for just a moment, please.
(Whereupon,
at 12:34 p.m., the open meeting session was adjourned, to reconvene in closed
session.)