FOOD AND DRUG ADMINISTRATION
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BLOOD PRODUCTS ADVISORY
COMMITTEE
OFFICE SITE VISIT REVIEW
OF THE OFFICE OF BLOOD
RESEARCH AND REVIEW
(Open Session)
July 22, 2005
Gaithersburg Holiday Inn
2 Montgomery Village Avenue
Gaithersburg, Maryland
Proceedings By:
CASET Associates, Ltd.
10201 Lee Highway, Suite 180
Fairfax, Virginia 22030
(703) 352-0091
List of Participants:
James Allen, Chair
William Freas
Harvey Klein
Marcos Intaglietta
Donna DiMichele
Michael Busch
Harvey Alter
Suzette Priola
George Schreiber
Michael Strong
Peter Tomasulo
Ching Wang
TABLE OF CONTENTS
Page
Welcome and Opening Remarks: James Allen 5
Introduction and Charge to the Committee: Karen Midthun 6
Overview of CBER Research Programs: Kathryn M. Carbone 11
Overview, Office of Blood Research and Review:
Jay Epstein 42
Overview of the Research Program of the Division of 79
Blood Applications: Alan E. Williams
Overview of the Research Program of the Division of 96
Emerging and Transfusion Transmitted Diseases:
Hira Nakhasi
Overview of the Research Program of the Division of 130
Hematology: Basil Golding
Open Public Hearing 164
P R O C E E D I N
G S (8:03 a.m.)
DR.
FREAS: My name is Bill Freas. I am the acting Executive Secretary for
today's subcommittee meeting on the Blood Products Advisory Committee. At this time, I would like to go around and
introduce the guests seated at the table.
I
guess I started a few seconds too early.
In just a second I'll start my introductions, because if I go out of
order, I will get a little confused.
At
the end of the table we have the court reporter. Sitting next to the court reporter we have Dr. Harvey Alter. He is chief of infectious diseases,
Department of Transfusion Medicine, National Institutes of Health.
In
the next chair, Dr. Busch is here and he will soon be joining us, Dr. Michael
Busch, who is a vice president, research and scientific affairs, Blood Systems,
Incorporated.
Next
we have Dr. Donna DiMichele. She is
associate professor of pediatrics and public health, Weill Medical College and
Graduate School.
Next
we have Dr. Marcos Intaglietta, professor of applied mechanics and
bioengineering, University of California, San Diego.
Around
the corner of the table, we have Dr. Harvey Klein, chief, Department of
Transfusion Medicine, National Institutes of Health.
In
the center of the table, we have our Chair, Dr. James Allen, president and CEO,
American Social Health Association.
Around
the corner of the table we have Dr. Ching Wang, professor of chemistry and
pharmaceutical chemistry, University of California-San Francisco.
Next
we have Dr. Peter Tomasulo, executive vice president, chief medical officer,
Blood Systems Incorporated.
Next
we have Dr. Michael Strong, executive vice president and chief operating
officer, Puget Sound Blood Center.
Next
we have Dr. George Schreiber, vice president, health studies, Westat,
Rockville.
At
the end of the table we have Dr. Suzette Priola, senior investigator,
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories.
FDA
is continually changing and improving its advisory committee COI process. Today we have from the ethics branch of
FDA's office Miss Jenny Slaughter, to read the conflict of interest statement
for the subcommittee meeting. Miss
Slaughter.
MS.
SLAUGHTER: Thank you, Dr. Freas. Good morning. The Food and Drug Administration is convening today's meeting, a
subcommittee to the Blood Products Advisory Committee, under the authority of
the Federal Advisory Committee Act of 1972.
All members of the subcommittee are special government employees or regular
federal employees from other agencies subject to federal conflict of interest
laws and regulations.
FDA
has determined that members of the subcommittee are in compliance with federal
conflict of interest laws, including but not limited to 18 USC 208 and 21 USC
355 and 4. Under 18 USC 208, which is
applicable to all government agencies, and 21 USC 355, which is applicable only
to FDA, 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 the particular individual services outweighs his or her financial
conflict of interest.
Members
who are special government employees at today's meeting, including SGEs
appointed as temporary voting members, have been screened for potential
financial conflicts of their own, as well as those imputed to them, including
those of their employer, spouse or minor child, and they will be related to the
discussion of today's meeting. These
interests may include investments consulting, expert witness testimony,
contracts, grants, cooperative research and development agreements, teaching,
speaking and writing, patents and royalties, and primary employment.
Today's
agenda is devoted to the discussion and review of intramural research programs
in the Office of Blood Research and Review.
In addition to the participation of today's subcommittee members, and
pursuant to the authority granted under the committee charter, the director of
FDA's Center for Biologics Evaluation and Research has appointed the following
SGEs as temporary voting members: Dr.
Harvey Alter, Dr. Michael Busch, Dr. Marcos Intaglietta, Dr. Suzette Priola,
Dr. Michael Strong, Dr. Peter Tomasulo, and Dr. C. C. Wang.
In
accordance with 18 USC Section 208.b.3, general matters have been granted to
the following participants: Dr. James
Allen, Dr. Michael Busch, Dr. Donna DiMichele, Dr. Marcos Intaglietta, Dr.
George Schreiber, Dr. Michael Strong and Dr. Peter Tomasulo.
A
copy of these waivers may be obtained by submitting a request to the agency's
Freedom of Information Office, Room 12A30 of the Parklawn Building.
In
the event that the discussions involve any other products or firms not already
on the agenda for which an FDA participant has a financial interest, the
participants are aware of the need to exclude themselves from such involvement,
and their exclusion will be noted for the record.
Finally,
with respect to all other participants, we ask in the interest of fairness that
they address any current or previous financial involvement with any firm whose
products they may wish to comment upon.
This
statement will be available for review at the registration table. Thank you.
DR.
FREAS: Thank you, Miss Slaughter. Before I turn the microphone over to our Chair
to start the meeting, I would like everybody to take a few seconds to check
your cell phone, and please put it on the silent mode so it will be less
disruptive to the meeting.
Dr.
Allen, I turn the meeting over to you.
Agenda Item: Welcome and Opening Remarks
DR.
ALLEN: Thank you. This is a unique opportunity. This is the first review of this type that
has been conducted, as I understand it, at the Food and Drug
Administration. We will be very helpful
and very important to them as they go through their management review processes
as they work with the Administration and Congress in developing budgets and
setting priorities for future staff development and research opportunities.
I
want to thank each one of the committee members. This is a big obligation.
It is not just a day out of your life.
I'm sure you have spent quite a bit of time reviewing the materials that
FDA staff put together. I possibly will
be getting back in touch with you afterwards as we develop the report asking
for your advice and ideas.
We
have a busy schedule ahead of us today.
We will be listening to reports.
We will be asking questions.
Later in the afternoon we will getting together and putting together our
thoughts and summaries for presentation to the senior FDA staff at the end of
the day.
Currently
scheduled, we run until five p.m. In
actual fact, we are going to need to truncate that. I personally need to be out the door right at four p.m. We will be looking for opportunities as we
go through the day to shave a few minutes off here and there, so that we can
try to wrap up no later than four p.m. this afternoon.
As
I indicated, this is the first of a series of processes that the FDA is going
through. Since it is the first, I want
to invite each one of you, if you are not certain as we move through the day,
and want to ask questions not just of the people who are making presentations,
but of the senior FDA staff, to clarify the intent of what is needed, what do
they need back, please feel free to do so.
I think this is a learning process for them as well as for us, and we
want to give them the most useful set of materials that we can at the
conclusion of this.
So
without taking more time, I would like to invite Dr. Karen Midthun, Deputy
Director, Center for Biologics Evaluation and Research, to introduce our
responsibilities and give the charge to the committee.
Agenda Item: Introduction and Charge to the Committee
DR.
MIDTHUN: Good morning, and
welcome. This activity is very, very
important to us and a new one also, as Dr. Allen has pointed out. Dr. Goodman, the Center director, regrets
that he could not be here today, but again, I want to stress that this is an
extremely important activity to him, and indeed this office level overview and
input on the research program is something that has been initiated at his
request.
I
am going to give some introductory comments about the Center, and then go over
the charge to the committee today. I
want to stress that what we want is your input on the research and the
substance of the research, rather than on management or organization
thereof. So I will move on to my first
slide.
I
just want to go over the vision of CBER.
Essentially we believe that innovative technology advances public
health, and that helps our mission, which is to protect and improve public
health and individual health in the U.S. and where feasible, globally, to
facilitate the development, approval and access to safe and effective products
and promising new technologies, and to strengthen the Center for Biologics as a
preeminent regulatory organization for biologics.
The
organization of the Center is that there are eight offices that report to the
Center Director, Dr. Goodman. A few of
the offices is what we refer to as our product offices, the Office of Blood,
which is the subject of today's meeting, the Office of Vaccines and the Office
of Cell, Tissue and Gene Therapy. Then
we also have the Office of Compliance and Biologics Quality and the Office of
Biostatistics and Epidemiology, which are very much involved in our regulatory
and our review work, as well as research.
Then we have other offices that are also critical to our management, the
Office of Management, the Office of Information Technology, and the Office of
Communications, Training and Manufacturers Assistance.
What
are the products that are regulated at CBER?
They include blood, blood components, blood derivatives, vaccines, both
preventive and therapeutic, allergenics, cell and gene therapies, tissues,
xenotransplantation and related devices.
Let's
move on to the critical path research initiative. Many of you have probably heard of that. That is an agency-wide effort, and it is
intended to identify and focus on regulatory and scientific opportunities to
improve product development and availability, also to provide opportunity to
promote and preserve the science base of the Center for Biologics and the
FDA. To this end, we at the Center for
Biologics are seeking input to identify opportunities, collaborators and
priorities. We initiated a public
workshop to this end this past October.
These site visits are an extension to try to get input at the office
level into our activities, and also have a public process as part of setting
our priorities.
What
is the unique role of FDA in the critical path? FDA scientists are involved in the review during product
development. They see the successes,
the failures, and the missed opportunities.
FDA guidance documents are science based. They are intended to foster innovation and improve chances for
success. We believe strongly that
scientific expertise in certain areas is critical to making informed decisions
about the safety and effectiveness of products, and whether clinical studies of
investigational products should proceed.
The
goal of today's review is -- what we are asking the subcommittee to do is to
access the strengths, the weaknesses, the opportunities and the needs of the
Office of Blood research program. We
want you to make recommendations that further the dynamic and responsive
research programs that are intended to facilitate the development of safe and
effective biological products.
The
objectives are to increase the visibility and transparency of how research
programs are integrated into our regulatory process, to identify the
contributions of the Office of Blood research to product development and
availability, to determine the opportunities for research, expansion, direction
and new collaborations, and to identify needs and strategies for future
research, and also recommendations for attracting qualified science and medical
experts to the Office of Blood research and review.
Again,
we believe that CBER has responsibility for some of our most important products
-- blood, vaccines and tissues -- and we have a critical role in facilitating
the development of innovative medical products that contribute to individual
health, public health and counterterrorism, and as such, expertise, partnership
and wise use of our resources are essential.
So we very much welcome and appreciate your input, and recognize the
very large work that you have signed on to do, and we very much appreciate
that.
In
closing, I would like to say, we are looking forward very much to your input on
the research program. The focus is the
research rather than the management or the organization thereof. We really want your input on the substance,
so that we can use that to improve what we are doing.
Thank
you.
DR.
ALLEN: Thank you, Dr. Midthun. Any questions that any of the committee
members would like to ask?
I
thought your objectives slide was very helpful. We may want to put that up later in the day as we go through our
deliberations.
DR.
MIDTHUN: Sure. Thank you.
DR.
ALLEN: Thank you. Dr. Kathryn Carbone, associate director for
research, is going to give us an overview of the CBER research programs.
Agenda Item: Overview of CBER Research Programs
DR.
CARBONE: In your packet you have a copy
of the slide. You will see a nice
picture of the Washington Monument.
This slide is provided by Dr. Goodman.
He makes the prettiest slides.
But we will move, rather than waste time with that.
I
am going to start today by saying, first of all, thank you. I think we have tasked the members of our
advisory committee with so many important things throughout the course of the
year, and the thought that we added to both our internal committee members and
Dr. Freas' office's hardworking folks, and the advisory committee as well as
our guests yet another task, but we really appreciate the fact that you have
agreed to come today and help us. It is
going to be very valuable and very important.
As we all know, science can't happen in a vacuum, and we welcome your
input.
Today
I am going to start by explaining a little bit about what is the critical path FDA
research initiative, and then follow with a little introduction of the overall
research program at CBER, then start to drill down as we go through the various
talks this morning.
The
critical path research was initiated through the Office of the Commissioner
through the perception that, although biomedical research funding has grown
exponentially, that the actual licensing of products was decreasing. In CBER we have maintained a fairly active
licensing output. However, in certain
areas, some of which are in this office and in other offices, we have still
some gaps and ways to go to getting the science in place to do the
regulation. So the perception that we
are simply throwing money at one side of the equation without preparing the
pathway for licenses to occur was not going to be the solution. We needed to cover both ends of the
spectrum.
What
is a critical path? Of course, we could
not use translational research, which is a phrase that has great meaning and a
different meaning to many people. But
we wanted to try and emphasize that there is this black box to many
people. Industry and FDA are very aware
of the science of making a product, but in many cases, because we do deal in
edge of the wedge and high biotech products, we are dealing with sponsors who
don't necessarily know these pathways well.
In addition, we are dealing with products that don't have pathways, and
ones that have to be created.
So
the basic path in developing a product is of course, the research leads to the
prototype, preclinical testing to see if it is safe and worth going into people
from an efficacy point of view. Then
clinically the product is tested. If
the testing looks good, then an application is provided and the FDA comes in
here and works on the application to help evaluate the product. Then if the product succeeds, it is
approved.
The
critical path is focused on the last half of the pathway. What many times happens is, something that
looks wonderful in preclinical development gets through hundreds of millions of
dollars of phase three trials, and suddenly doesn't look so good, and the
development effort is for naught. So
the ability to earlier predict failures or, better yet, earlier predict the
winners, would be a significant advance.
Sometimes products that can be made in a beaker can't be made in the
hundreds of liters of development that need to be made for a commercial
product, so those products fail.
Sometimes the clinical development is limited because the tests aren't
available to evaluate the safety of these products.
Many
of these things occur in what is to most science a black box. So a part of the effort of transparency is
to talk about these problems, look at them as opportunities for solutions, and
fix them so that products move forward in a more efficient fashion.
There
is a document put out. It is highly
relevant for the drug end of things. Of
course, the Office of Blood deals with a lot of interesting and unique aspects
that aren't traditional for typical drugs.
But nonetheless, as a thought piece this is a very important document.
It
basically talks about identifying and focusing upon and managing the regulatory
and scientific opportunities to improve product development, in other words, to
identify potency and effectiveness standards, safety issues that need to be
resolved early, and consistency in manufacturing quality. This last one is probably the most neglected
when it comes to early product development, particularly in terms of very high
tech novel biological products, but great ideas and really promising products
in a test tube are often still a far way away from knowing how to manufacture
that product consistently, or even test it for consistency. That will be discussed later today.
These
important scientific issues need to feed into policy and guidance. As a result, the science base at the FDA is
quite important to maintain.
As
Dr. Midthun was saying, why the FDA? We
review paperwork. A lot of the science
happens outside, and it will continue always to happen outside. The problem is, in order to review the
paperwork adequately and try and assist in the effective review, we need a
science base here that can participate actively in the process.
So
we view the critical path as a combination of FDA intramural science, FDA collaborating
and externally leveraging, and extramural efforts, making the scientific
community more aware of these issues, so that they get higher on the radar
screen.
To
many people, science is a peripheral byproduct of regulation. It is not part of our core mission. I think the critical path document offered
by Dr. Woodcock goes a long way to try and dispel that notion, but the
scientific part of the review is integral to the process. An application may come in, a problem that
is identified, something that is otherwise holding up this application,
scientific questions are raised. They
can be resolved in academic, government
or other sponsors and the FDA. The
science then feeds back, and is fed back often into advisory committees like
this for public input. Development of a
public standard is put out. Guidances
and standards then communicate this to the outside world, and then the
application moves forward, and future applications have a much clearer pathway.
In
1998, a subcommittee for external review of CBER research -- CBER was the first
center that underwent this review -- produced what was called the Korn report,
which was distributed to the committee.
What we will talk about a little bit today is, although we are not
completely unique in the agency in this regard, our center has probably the
largest group of what we call the research reviewer. I modified that to researcher regulator, since our researchers do
much more than simply review. I will
talk about that in a minute. The bottom
line is that the same person handling the document and making an evaluation is
the same person who can go to the lab and either work on a specific problem, or
at least is familiar with the area.
However,
I don't want to leave anyone with the notion that all people who do very
important regulatory work at CBER are lab scientists. We have an outstanding cadre of regulatory scientists, clinical
review scientists, and you will see some work presented today through Dr.
Williams' division, that doesn't involve necessarily laboratory work, but it is
still high quality science that results in better evaluations of products.
Multi-tasking. Having come from academia myself, the
concept of multi-tasking was not a difficult one, since we all taught students
and saw patients and worked in a lab.
That is what our people do at CBER.
In addition to doing research, and we target about 50 percent average
time of the research regulator, they will be reviewing INDs and DOAs, helping
in the development of policy and guidances, meeting with sponsors and advisory
committees, participating in inspections, evaluating postmarketing and drug
reaction information, risk assessments and the research performed relevant to
this. This view of the FDA's core
mission gives them the opportunity to target research to solving some of the
problems that they run into in the regulatory world.
Part
of our evaluation and review of research at CBER is further strengthening the
bond between the fulltime regulatory scientists and clinical reviewers, and developing
the team approach to the identification of the problems and scientific
solutions we need.
Mission
relevance. When I started, I started
asking the research regulators to note which INDs and DOAs their research was
applied to. We collected hundreds of
licensing applications and investigation of New Drug Applications to which
their research was feeding into.
More
than 50 percent of our research program is applicable to counterterrorism. I say applicable, because we are not always
working directly on an agent, but identified as an important issue in
counterterrorism products. The critical
part of our research is to keep it in the public domain, so that what we do
internally and with our partners is made public so that it benefits across the
field in categories of products.
I
just want to delve down a little in how we manage our research products at
CBER. Basically we consider it
important to evaluate both past achievements and future plans. Those of you who have R0-1 grants understand
the need to talk about both sides of the coin.
As
many of you are very familiar with, we have laboratory and investigator driven
site visits right down at the bottom to make sure our scientists continue to be
talented and interfacing with the external world, and their expertise
recognized. We also have an internal
management review, which you may or may not be aware of, where they are yearly
required to report their achievements and future plans. This incudes publications, regulatory policy
guidances. This research QAQC is web
based. WE fold it into things like IRB
approvals, AC-UC approvals, all sorts of -- the nitty-gritty of managing a
research program.
The
Office of Research site visits. This as
you know is the first one. We will be
proceeding to Office of Cell, Tissue and Gene Therapies and Vaccines, coming
shortly. As part of this effort to team
build, we are working on developing what we call subject expert teams. This would be teams across office of people
doing research to build a greater critical mass and improve communications
across the offices so, for example, our retroviral experts in every different
product office will be communicating as part of a product team. Because the mission of the organization is
regulation, we felt it is important to keep the administrative reporting within
a product office. However, it is also
important to have our scientists with similar expertise communicating across
the offices.
We
provide researchers with limited intramural support. Those of you with R0-1s know what one grant will get you, so we
do what we can do to provide people with a modicum of support in terms of
laboratory staff. The vast majority of
our people must compete for extramural sources of funding in order to support
their research program.
That
said, we have instituted a research management grant review application
process, so that our partners are selected are carefully reviewed for conflict
of interest, et cetera. We simply can't
apply for NIH R0-1s with principal investigators, et cetera, but there are
limited sources of funding that we are able to apply for, and pretty much our
people have to do this in order to continue.
CBER
research. This is going to be talked
about in much greater detail, but today you will be highlighting in each of the
divisions some of their achievements in supporting the regulatory mission, and
some efforts that were instrumental in getting products through and protecting
the public health as well.
I
wanted to come towards the end with a little bit of discussion of the vision
Dr. Goodman and I and the leadership team have talked about, where CBER wants
to go, where it can go. We must of
necessity be very focused in our efforts, and much of our work is delivered to
us rather than something that we a priori decide to go after. But nonetheless, this is just an example of
initiatives that would be important for us to pursue. However, that said, I also want to say that this part of the
process is very important, to listen to our stakeholders as well as our advisors,
to identify other areas that are very important that we should be attending
to.
Developing
and making available well-characterized cell banks for vaccines and biological
productions would be a tremendous asset across the board. Characterization of cell therapies and links
of these cell therapy characterizations to standardized clinical outcomes, very
important. All sorts of new assay
standards, biomarkers, surrogates for efficacy are desperately needed to move
the products forward. Method and validation
of pathogen inactivation for products of interest to this office and others,
and then trying to do multi pathogen detection methodologies. Improving longevity in storage of animal and
tissue for new vaccines, assay standards and reagents, and enhanced clinical
trial design and analysis, this is an important contribution of our Office of
Epidemiology and Statistics.
So
bottom line, our people are here today to seek your input. I think they would welcome it. They are a hardworking, talented group of
people who have a very unique expertise, which is the attention to the
scientific tools and knowledge that are needed to get products moved forward
effectively and to protect the public health.
We
are welcoming your input. We really
appreciate the opportunity to be transparent and to get your help in developing
the areas of scientific expertise that we need to pursue.
Thank
you very much.
DR.
ALLEN: Thank you, Dr. Carbone. Any questions from the committee?
DR.
WANG: I fully agree that people who
engage in regulatory affairs should be active scientists themselves. Also, I am very impressed by the kind of
research that is going on at CBER.
I
am just a little bit unclear how these individual research programs are
initiated and approved, and how the internal resources are being allocated, how
all these decisions were made.
DR.
CARBONE: Currently the product offices
make those decisions. They do this in
consultation with myself. They receive
the funding from Dr. Goodman.
To
the research program reporting, the individual is required to not only say what
they did successfully, but what they plan to do in the next year, and all the
supervisors must go and evaluate this program.
So the people who make the funding go through and evaluate the annual
reports.
In
addition, there is a four-year cycle of site visits, where the person must
present both what they have achieved and what they plan to do. So we get external comment on their
scientific input. As a matter of fact,
in one advisory committee, a question was asked about von Wilbern's factor
research, whether we should pursue this, whether there was any value. The experts on the site visit committee felt
that there was a need for this kind of research, so that kind of input.
So
that is a decision along the managerial chain of the product offices, but we
get a lot of external input as well through the site visits, so it is a
multiple source to decide.
DR.
ALLEN: I think that was a very good
question, Dr. Wang. You may want to
raise it again at the end of our discussions or at the end of the
presentations. It may be an issue that
we would want to talk about and comment on during our review.
Yes,
Dr. Strong.
DR.
STRONG: Along similar lines, these
folks have a lot of responsibility, having to do with their own research,
having to do with the regulatory process, having to balance that along with
sit-in meetings like this all day long.
You mentioned that they have both internal and external support, or they
are required to get external support. I
am wondering about the balance of that.
What is the percentage roughly of what they get supported internally
versus what they have to get outside?
DR.
CARBONE: It varies by office, but it
can go from zero to 70 percent, depending.
For example, there was an issue where a public call came out through NIH
about cell substrate applications. Cell
substrate is in an exact 100,000 percent alignment with what we do, and some of
our people very successfully competed for those funds, which essentially gave
them the opportunity to further their cell substrate work. So this is the kind of application.
All
the applications are reviewed through the command chain, including myself, so
that if the office director, division director or even myself feel that the
work is outside the mission, the application doesn't get submitted. Or we have a lawyer, Mr. Murphy, who starts
the conflict of interest evaluation, and the offices have control of that as
well, if there are any conflicts perceived.
That is even for the application process, before the money gets here
there is another whole process for conflicts of interest.
So
the focus on target is maintained through this sort of application. The application is reviewed before it is
even out of here. But the fact of the
matter is, we want to do cell substrate research, looking at adventitious agent
assays to evaluate cell substrates, making better test result substrates, which
we can't do nearly as much without this external support.
DR.
STRONG: So are you saying then that
each individual investigator is judged on their own particular area as to what
they are required to be supported externally or internally?
DR.
CARBONE: There is no requirement. It is simply a matter of what they can
produce. In other words, they can
produce a little bit with the limited intramural support. If they can get targeted funds to expand
that, then with the approval of the office, they are permitted to. But it has to stay in alignment with what
they want to do. It is a simple fact of
life with the research resources here.
DR.
ALLEN: But the source of external
support is limited much more than it would be for most academic researchers.
DR.
CARBONE: Yes, it is limited, what we
can apply for, yes.
DR.
ALLEN: Do you want to just quickly
review where they can and cannot go for --
DR.
CARBONE: Anything that is directly
involving regulated industry would be difficult to achieve. If it was permitted, it would require
recusal of the person from any regulatory decision making, which we try to
avoid, since we are limited in our personnel resources as well.
They
can participate with academia, for example, if there is an academic
partner. The partner may be a principal
investigator. There is a cooperative
research agreement, which is legislation that permits transfers of money for
involving cooperative research, something like the Gates Foundation, although
we are in discussions with them because of the technical ways of the research
agreement, something that was viewed as non-sponsor focused, but more public
health oriented.
As
I mentioned, select initiatives through NIH intramural programs, often programs
that NIH sends out to their intramural scientists, they will include FDA
scientists as opportunities.
DR.
ALLEN: But not NIH extramural?
DR.
CARBONE: NIH extramurals are R0-1 funds
now. They can't do that.
DR.
ALTER: This is on the same theme. To me there is a little bit of a disconnect,
as I talked over the last years to people working in FDA. They are disheartened by cutbacks in their
staffs, by cutbacks in their programs, that research is being diminished, and
have sounded demoralized. Then I read
what is going on, and I am very impressed by the depth of what is going on, and
by the high signs of it. I am trying to
figure out how that is happening.
I
am wondering, now that you are more transparent, now that the science is very
directed to FDA issues, in a previous review I did, one of the problems was
that the research going on was not totally relevant to the FDA mission. But now it seems to me.
DR.
CARBONE: Thank you.
DR.
ALTER: So is one of the outcomes
possibly that we would support Congress or whoever to give more to your
research program, to recognize it as a legitimate endeavor?
DR.
CARBONE: First of all, I want to
recognize and appreciate the comment that you feel the research is more
directed, because we have worked hard, not just to make it more directed, but
to work with our scientists to better explain why it is connected, because
sometimes this becomes unclear with the scientists in this proprietary black
box. I think they have worked hard to
do that.
We
will take any support from anywhere we can get it, let me just say that,
because things are truly in desperate times in the whole agency. That said, I would really like to focus more
today on the science topics, areas of expertise we need, projects that we are
not doing that we should be, rather than talk about the funding, because in my
opinion, coming from the extramural world, it is much more important to have
something worth paying for first, and then taking that out and saying, this is
valuable and then looking for ways to support it.
Being
an extramural scientist, I think that what I perceived here, coming here about
ten years ago, was that our science is much more extramurally driven type
science, in that we would have a mission.
We have a significant section, being as you know the first part on an
R0-1, this is the way we are driven as well.
We are not here just for the science sake. We want to do good science that is, I would say, applicable -- I
don't like the basic or applied -- applicable to our regulatory mission.
So
I think first, the goal is to have good science worth supporting, that we can
take and feel comfortable that the value is there. Then at that point we will have to deal with how to get the
funding. It is a multi-level problem
issue throughout the government all the way up through the FDA. I think what you can help us with the most
here today is to give us guidance as to make our scientific program really
worth supporting. That is where I would
focus today.
DR.
DIMICHELE: Thank you for that. My question is related, but slightly
different. In academia, the 50-50
split, clinical, medicine research, is often very difficult to accomplish. It is probably the most difficult position
we ever put academicians in.
What
happens is that people who are in that split don't oftentimes have enough time
to search out funding opportunities to see what is going on around them, look
for opportunities for collaboration.
This is going to relate to one of the mandates that we have, that is, to
help you attract scientists and people who are willing to do research in this
kind of environment.
So
I have two questions. The first is,
with respect to funding, how does the Office of Research help its investigators
not only go through all the regulatory stuff about approving funding, but look
for funding opportunities, particularly since there are so many overlays of
acceptability, and identify potentials for outside collaborations based on
helping them understand what is going on out there.
The
second is, how are scientists coming into this environment trained in
regulatory affairs, in terms of doing their mission? That is not one of the things that you come out of med school or
a Ph.D program really understanding how to do.
So how does a person come in here and learn how to do regulatory, and
still do research?
DR.
CARBONE: Those are very good
questions. In terms of the sources of
funding, in the year and a half or two years I have been in this position, we
have worked on many levels, we are beginning to work on trying to do that. We have a very good web-based science -- it
is called CBER research central, if you will; it is web-based.
Recently
it came to light that there had been a discussion about joining Community of
Science, which obviously provides search engines, grants and opportunities,
which provide the big universe, to pare down to what we can apply for.
I
will be frank with you, the cost was prohibitive and we couldn't afford
it. But the good news is, it turns out
that through other avenues, we were able to link up with NIH, and we now can
join Community of Science through that avenue.
So investigators and associates for research in each office were
provided with the information, and it is also on our website. So that is a first step to get the universe.
I
have held little town hall meetings about site visit presentations and how to
go about this. There is a planned town
hall meeting about how to write a grant.
We have little internal grants that, after individuals apply within the
Center, I request that anybody who would like to meet and discuss their grant
applications, say they didn't get funding.
In many cases it is simply one of those, you have 30 people and three
opportunities for funding, but in many cases there are problems with titles,
things from people that aren't trained in writing grants.
Then
we seek larger partners. We are working
with the agency to develop funding.
Sometimes the problem is not the funding agency is inappropriate; there
is no mechanism to receive those funds for research. So we are working with the Office of the Commissioner. We have sent forward a proposal that they
are evaluating for different approaches to opportunities to get specifically
research funding.
One
of the other things is the push-pull, unfortunately, as you noted about the
time spent writing grants and trying to get the funds and do the work of the
grant, the regulatory work. One of the
things is that in some respects, our people are developing an appreciation for
us, again, having come from extramural NIH salary support, and supportive of a
biologist or a technician and a postdoc, is one R0-1. So in essence, we aren't requiring people in any way to go out
and get those funds.
What
we do need help with is the supply money, which is usually smaller pots of
money, smaller grant efforts. I think
as we get -- we are trying to raise institutional partnering. We have a leveraging page, for example. We have just put up where successful
applications have gone, to give our scientists an idea where they can go, that
other people have gone successfully.
But
I think part of the problem that we have to deal with is that often when we
approach even the smaller sources of funding, the foundations, et cetera, they
say, we don't fund federal scientists.
We explain we are not receiving intramural NIH funding, et cetera. But these are bridges that we are working on
to cover. That is an active effort and
that will be continuing. It is a big
part of my job.
The
second thing is training. That is a
very good question. The only place
people really get good regulatory review training is at the FDA. They come here and we train them. We have several courses. I think that highlights one of the -- in my
opinion -- very important aspects of this research program. Because our researchers actually review the
questions that arise, if only I had a surrogate marker, we could drop this
clinical study from 30,000 kids down to 3,000 if we had a surrogate marker of
efficacy; if only we had a way of characterizing this product, I would know
that these three studies were comparable.
Those questions come to the fore.
One
of the things that we have worked on is, there always was a collegial way for a
regulatory scientist or a clinical reviewer to feed into the research
agenda. Pick up the phone, they work
together, we identify problems together.
What we are doing now is making a formal bridge, so that we are going to
bring together the regulatory divisions with the research regulatory divisions,
and develop a yearly process for identification of problems.
Essentially
our regulatory scientists and clinical reviewers will be identifying research
problems as well to feed into our research program. But having us act not just as consultants in theory, but being
faced with the regulatory problems really helps identify the bang for the buck. I think our people, to their great credit,
like academic scientists. When funding
levels get tight, they get very focused, very goal oriented, outcomes oriented,
and have to pare down what they do to become the most essential to what we
need.
Does
that answer your question somewhat?
There will be more time later.
DR.
BUSCH: You answered many of my
questions really well, but the intramural question of intramural funding that
NIH has available, I'm not clear on to what extent your people are qualified to
apply for those funds.
DR.
CARBONE: When I am in intramural, it
would be not the intramural funding that they are based on, but they will put
forward for their Institutes occasionally intramural calls, if you will, for
grants. So these are grant applications
that occur within intramural NIH for intramural NIH scientists. Occasionally we may apply for those as a
federal agency. If we receive funds
from NIH, they have to come from the intramural NIH pot. So this is not the baseline lab budgets
intramural money, this is an occasional call for grants.
They
have them for AIDS. They recently did
this cell substrate call. Very
isolated, small pots.
DR.
ALTER: Just a comment on that. Last week I sat on a bioterrorism review,
which is an extra pot of NIH money, and I would say that about a quarter of the
applications were from FDA.
DR.
KLEIN: One of the research things that
is a little different for the FDA than for other areas is the area of evolving
urgent public health needs, as an example, West Nile virus, the need to do
regulatory work with a real short time line, or VSIG that we heard about
yesterday, needing to find surrogate markers, and do some important research
work in a very short time frame.
How
are funds and resources found and allocated to do those kinds of things, which
come up on a fairly regular basis, clearly are important for our national
public health.
DR.
CARBONE: That is a very good
question. I think one of our strengths,
and one of the reasons for having intramural research is the ability to flex
quickly. You see this as well in extramural
science. As funding goes up for this
and down for that, people flex, but it is on a much longer time frame. So our people just expect that if there is
an emergency, they may have to literally drop what they are doing in one area
and work on a higher priority area.
Sometimes it is simply a matter of transferring the same funds you would
otherwise be spending on area A, your baseline activities to the new area.
When
available, when possible, Dr. Goodman has provided funding for high priority or
urgent issue processes. But the work
gets done if we have to rob from Peter to pay Paul in the intramural
program. We just don't have a great
deal of flexibility. But when there are
funds available, we try and fund -- for example, center-wide resources is our
core facility, which provides a baseline of support for everybody that does DNA
sequencing, peptide sequencing, DNA synthesis, et cetera. We have mass spec available through that
analysis. So when we can support them
in some way to get the job done quicker, our scientists are able to flex.
The
good news of having the scientists in house is, they often see, even if it is a
few weeks' notice, problems coming down the pike that they can prepare
for. But they do a fabulous job of
flexing as they need to. We have had
scientists go from virus A to virus B when virus A regulatory issues become
lesser and virus B is going up. They
will switch their programs, and create a new program. They will do it even on a shorter notice if need be for issues
like West Nile.
We
try and find money, but sometimes it is simply taking money from their current
research and shifting it over.
DR.
TOMASULO: Is there any capacity to
support your needed research programs outside the FDA? So for example, taking from Harvey's question,
something comes up and you just don't have the resources to pursue the issue,
can you go to some other institution and support?
DR.
CARBONE: Well, when you say baseline,
no, it is not an option. In other
words, we have a very dedicated staff, and when there is a public health issue,
we do it, we handle it.
For
example, HHS will come up with additional support for a particular problem that
is high priority. When you talk about
getting money outside, it is a question that is often posed, why don't you just
have NIH do your research. Whenever you
go to somewhere else, it is their priorities that are important. What we try to do is find partners like the
cell substrate, where their priority and our priority are identical, or at
least very close. Going to the outside
necessitates that we must put them ahead of us if you are getting funding,
unless it is for example a special pot that HHS provides for us for a
particular issue.
The
timing is the other issue. If we are
talking truly the urgent, urgent things, we don't have a lot of time to go
carrying a banner around. So we look
for opportunities wherever we can to align.
But we have to always remember when we get money from the outside -- in
some respects this distresses us when we get money from the outside; we are
responding to their priorities, not ours.
We try and find them aligned when we do it.
DR.
ALLEN: Let me just comment on that
also. I think it is also fair to say
that the NIH process is not geared towards identifying urgent emerging problems
and responding to them quickly. The
process for both intramural and especially extramural research is a very long
one, and it is just a different mechanism.
This
has been a good discussion. I have got
just one additional question going back to one of your slides, where you
identified among the total priorities the high percentage of research that has
some relationship to bioterrorism. For
FDA, I think that bothers me. It is not
that it is unimportant; it is just that there is -- most of our lives and most
of our needs and medical issues have little to do with bioterrorism. While we want to be prepared and not
shortchange bioterrorism issues and threats in any way, that should not be the
primary driver of decisions and resource allocations.
DR.
CARBONE: Let me comment on that. When I say bioterrorism, of course, we are
talking about products used to treat or prevent bioterrorism. Interestingly, our role, like the CDC's, is
quite different from NIH. When
preparedness is needed for particular products that may be coming down the
pike, we have to prepare. So in
essence, we are obligated due to our public health mission to deal with things
like -- and I would include bioterrorism/emerging infectious disease. This is perhaps where you get what you are
concerned about a little addressed, because many of the things we are going --
bioterrorism agents are agents which, whether they are released intentionally
or unintentionally, are problematic. So
we have to often deal with them as say improvements in vaccines, improvements
in end points, dealing with the animal efficacy rule. These are all things that would happen for SARS as well as
smallpox. It really doesn't matter
whether it is released intentionally or unintentionally.
Again,
we always try and multi-task so that what we do for a bioterrorism product is
going to feed into our overall improvement for any product in that area. We take our marching orders if you will from
the Department, and that is appropriate.
They are organizing all the agencies.
They have seen fit to provide us with some additional pots of money to
deal with emerging infectious diseases and bioterrorism products, or products
designed to deal with bioterrorism. So
in a sense, by having bioterrorism or bioterrorism relevant activities, we are dealing with the priorities that HHS
has set for us, which are appropriate.
This
is part of the problem with trying to be specific. Sometimes there are proprietary issues, and we can't delve into
the details. But be assured that when we do this, some long term value is
always sought, so that we always align some greater technological advance that
will help a range of products, while we are dealing with a specific
bioterrorism product. For example, our
regular flu program, yearly flu program, has benefitted from having funds for
the pandemic flu program. We were able
to create a BSL-3 plus devoted to influenza because we had those funds.
So
I understand completely what you are saying.
We try and make sure we get a good bang for the buck.
DR.
ALLEN: I know you do.
DR.
ALTER: Good comment. One way you might save some money would be
to turn the air conditioning down.
DR.
CARBONE: I agree. My nose is cold.
DR.
ALLEN: This is the second request for
that. This is a private facility. The downside to that, Harvey, is that we did
that yesterday morning, and by mid-afternoon, the temperature in here was --
Dr. Strong.
DR.
STRONG: I get the feeling that we can
probably keep you up here all day long.
Obviously there is a lot of interest in policy, and we are going to be
getting to the science.
We
got on the subject to bioterrorism. The
sister agency is CDC, and we have mentioned NIH. What is the interface with CDC relative to the kinds of things we
just talked about?
DR.
CARBONE: There is a tremendous amount
of interaction, if you will. CDC is
often oriented more oriented towards surveillance and diagnosis. We would be relied upon to deal with the
products needed when something was identified; we have to be prepared with the
products.
I
think a good example of a collaborative effort was, when SARS was identified as
a problem by public health agencies, we met with the CDC and talked about -- as
the isolates came in and they were interested in distributing an isolate to
various potential sponsors for manufacturing a vaccine, they met with the
FDA. We talked about the kind of GMP,
the kind of history of the virus itself, the tracking of the virus, making the
virus stock, how to do that in such a way that the virus they distribute could
legitimately for our purposes serve as a vaccine seed or at least, a vaccine
reference. That is a tremendous time
saver in the collaboration.
If
for example they had sent out a virus without history or one that had been
through a very dangerous history, then somebody turning around and trying to
use this to manufacture or develop a vaccine would have had to go back to the
drawing board, et cetera. By
collaborating together on that effort, we knew the manufacturer on the product
side. They clearly know how to grow
viruses, and knew about the SARS and the epidemiology. So that would be an example of where we
would collaborate together to serve the public health in flu. There is a tremendous collaboration between
both the laboratory and the public health area. So we work quite closely.
But
they are not product oriented from the point of view of product quality
testing, et cetera. That is the side
that we take care of.
DR.
ALLEN: Just one quick comment, or it is
sort of a question, and then we will move on.
Let me use the fire department analogy.
If you have got a diverse community, volunteer fire departments might
work. You have an urgent need; people
from around the countryside drop whatever they are doing and go.
I
think within an urban environment, it is well recognized that that is not the
most effective way to handle it, so we have developed fire departments, and we
don't expect the firemen to be putting out fires all the time. We expect them to be ready. They train and do other things.
Is
it fair to say that the federal government doesn't view the FDA as needing that
extra capacity, the ability to have people there with sufficient flexibility in
their schedule and resources to absorb the emergency issues and the urgent issues,
in the way that one would expect a fire department to be prepared?
DR.
CARBONE: I would like to back up a
little and just say that I think one of our goals is to prepare for fires, that
is exactly right. In science in
particular, we can't just simply drop dead now and have the science
tomorrow. We have to have a five-year
look.
This
is in part why we are pulling together the office's cross-office, so they can
have discussions about downstream what we need for the baseline. So what people do here is deal with the
baseline applications, the baseline science that we need to do, and then they
insert on that the emerging and urgent issues.
As
far as the view from the outside world, I think that prior to the critical
path, there was simply not much discussion about research and FDA in the same
sentence. I think some people found
that surprising. The first question I
am asked is, is there research? I
didn't know there was research at the FDA.
The second question is, why is there research at the FDA?
So
I won't say there is a government position on it, but I will say that I think
that part of Dr. Goodman's goal in being transparent, part of all our goals, is
to talk about the research, to show the value, to make it more valuable, so
have people understand that having a paid fire department in this case would be
a wise investment.
DR.
ALLEN: Thank you. This has I think been a very good discussion
and an opening for our day.
Our
next presentation is Dr. Jay Epstein, who will be director of the Office of
Blood Research and Review. He will be
giving us an overview of the office, including mission and structure,
regulatory activities and priorities and research program instruction. I think we can truncate then some of the
questions overall. We were to have a
few minutes for discussion among all of the people. We can do that to the extent that there is a need, but I think
what we have just gone through has been a very helpful introduction.
Dr.
Epstein.
Agenda Item:
Overview, Office of Blood Research and Review
DR.
EPSTEIN: Thank you very much, Jim, and
good morning, everyone. My pleasant
task is to provide you with an overview of the research program in the Office
of Blood Research and Review, which I direct.
I hope that I will be able to illuminate you regarding our goals and
objectives, structure and governance, and then to illustrate how our process
works with examples of our historic and current activities.
Dr.
Midthun already reviewed for you the vision for CBER. I won't repeat that, except to say that we believe that the
functions within our office are conforming to the overall vision of CBER. We are the primary FDA component responsible
for facilitating the development, approval and access to safe and effective
blood products. More specifically, we
perform scientific functions related to the regulatory of blood derived and
recombinant analogous products, medical devices that are used to test, collect,
process or store donated blood, and additionally, under an understanding with
our sister Center for Devices and Radiological Health, we are the responsible
component for regulatory of retroviral diagnostic tests.
I
think that is an interesting point, why did that happen. It happened that we had virology
laboratories when the AIDS agent was discovered, and therefore we were in the
unique position to be able to deal with characterization, standardization and
assay validation, because we had these experts in wet labs.
Additionally,
as Dr. Carbone has illuminated, we collaborate in larger CBER programs. Some of these include tissue safety, for
example, validating a diagnostic on a cadaveric blood sample,
xenotransplantation, HIV immunology, vaccine development, et cetera. Some of this will be illustrated in later
talks.
Now,
we are organized in the Office of Blood into the immediate office, myself, Dr.
Goldsmith is my deputy, I have a director for regulatory affairs, and Dr. Tabor
was our director for medical affairs, associate director, but he has just
retired. We have three product divisions,
the Division of Emerging and Transfusion Transmitted Diseases, Dr. Nakhasi will
present to you, Division of Hematology, Dr. Golding will present, and Division
of Blood Applications, and Dr. Williams will present. I also have a small staff that deals with our policy process.
You
have heard already that we have this dual function of science and regulation,
which we believe we harmonize. But just
to give you a feeling of the kind of spectrum of regulatory work, we receive
all the kinds of application that exist in the FDA. We use every regulatory mechanism that exists under the PHS Act
and the FD&C Act. In a typical
year, we have a variety of different kinds of application which have required
review times under either the Prescription Drug User Fee Act or the Medical
Device User Fee Act.
This
was in calendar year 2004, what was received and what was completed. You can see that we essentially completed
about a year's incoming in relation to a year's work, so we just treaded water
with our nose just a little bit above the tide.
I
can't really illustrate for you what this is in terms of a workload demand, but
I can tell you that it represents easily 80 percent of the work output of the
office is the review work.
The
question is always, why do we do research at FDA in general and the Office of
Blood Research and Review in particular.
As has been said already in other words, we believe we are in a unique
position to identify cross-cutting issues by virtue of our regulatory
responsibility and the things that we see confidentially. This also gives us a unique opportunity to
coordinate effort across the spectrum of blood issues and among diverse
industries that are involved with the manufacturing of blood and blood
products. After all, we are in a position
to understand the manufacturing and quality of a device like a screening test
at the same time as to understand what the user's need is before say automation
or data handling or high throughput. So
we occupy that unique role.
This
is in the areas of product characteristic and safety and efficacy
determinations, and also supply impacts, which is not rarely understood, but we
are mindful of trying to make sure that needed products are in fact available
and available timely.
We
are able to resolve scientific questions critical to regulation, as has been
said, standard setting, which can be targets for technology development,
certainly the development of surrogate markers to facilitate clinical
trials. Sometimes it is more basic
understanding of mechanism of action, so that we have a rational approach
toward product validation or clinical study.
We
believe also that having a supported scientific enterprise enhances the quality
of our scientific review, obviously
when we are engaged directly in the kind of problem solving that I described,
but also more generally because this way we have sophisticated regulators who
understand the cutting edge products that come into our office and center.
Then
additionally, having the research program maintains our capacity to investigate
product failures. This is important for
work that we do. A year does not go by
where there are not novel questions raised about products that are not working
as we thought that they would, especially in the blood system. Where we are talking about millions of
component transfusions, it is important to rapidly solve these problems, and
when we can't do it ourselves, at least is makes us effective collaborators.
How
are we organized, and what is the mechanism of oversight? Our research is organized in parallel with
the product review responsibilities down to the branch level. In the next slides I will show you how that
is organized down to the division, and in the divisional presentations you will
get a little bit more of a flavor of this direct linkage.
Of
course, as the office director, I allocate the funds. The power of the purse is the power to direct, and so I do survey
the scene and surface regulatory issues, identify overarching priorities, and
fund the programs accordingly.
However,
I have to tell you that the direct oversight of research in its details, that
is to say, assuring its quality, making sure that the fellows are properly
progressing, that the monies are wisely spent, that kind of oversight is
primarily at the division level under the direction of the division directors
who of course talk to me quite frequently.
Coordination
across CBER is accomplished through our acting liaison for research, who is
presently one of my division directors, Dr. Nakhasi. He cooperates with the other division directors. Dr. Carbone leads this effort, and we do
have a formalized structure which has regular meetings and reviews research
issues across CBER as a whole. It is
our goal to establish an associate director for research, or perhaps combine
that with the associate directorship for medical affairs to further tighten
this linkage to the mission. We are not
quite there yet, but I would say it has been no detriment because Dr. Nakhasi,
wearing a third hat, has done a very highly effective job of insuring
coordination with the larger CBER.
Additionally,
we have a very formal system of publication review, where there have to be two
peer reviewers for every publication.
It has to be signed off by the division director, and then I will review
and sign off on the publication. This
serves the dual function of keeping me well apprised of the output that we are
producing, as well as giving me the opportunity to look at quality and
direction.
Additionally,
as has been said, and I won't belabor it, all the laboratories are on a
periodic external site visit schedule, once every four years. That function is integral to all scientific
tenuring. In other words, if you get a
permanent job as a research scientist, you have to have been peer reviewed, and
additionally, promotions go through that process. The opinion of the site visit is integrated into the promotion
decision.
So
as I promised you a moment ago, I will try to show you some of the correlation
of product responsibilities and areas of research at the division level.
First
and I guess arbitrarily, we have the Division of Emerging and Transfusion
Transmitted Diseases. The product
responsibilities in this division include retroviral donor screening and
diagnostic tests as I have said, so it is not just blood screens, it is all
retroviral diagnostics, HIV, HTLV; hepatitis donor screening tests, emerging
viral agents and tests for bacterial, parasitic and unconventional agents. This roughly also reflects the branch
structure.
So
how do the areas of research correlate?
We are engaged in epidemiology, pathogenesis and diagnostic methodology
for retroviruses and hepatitis agents -- HIV, HTLV, HBV, HCV, HAVE. These are all active programs. In terms of emerging agents, we have
developed a program in West Nile virus detection, looking at assays as well as
metrics of inactivity, and we invested very heavily -- we are fortunate to have
David Asher, who is a world class scientist in this area, who investigates
detection and decontamination of TSE agents, including classic CJD and virion
CJD.
We
have a program which is active in cross-cutting issues of parasitic vaccine
development, which is a scientific gap, and we are, as has been said, firemen,
and we deal ad hoc with emerging issues.
In recent times, these have included vaccinia, whether there is viremia
after vaccination, and whether there are false positive donor screens after
vaccination, transmissibility or detectability of HVA, the blood threat or lack
of threat from SARS, the significance of SENV.
Much of this is also done in collaboration with partners at NIH and
CDC. So I think it is rather self
evident that there is in fact correlation.
In
a similar vein, this is now the Division of Hematology. The product responsibilities include plasma
derived products, immunoglobulin, immunoglobulin intravenous albumin,
coagulation products, et cetera, blood and blood component collection devices,
including aphoresis equipment, hemoglobin based oxygen carrying solutions and
plasma expanders, and bacterial detection devices. Why they live in Hematology instead of Emerging and Transfusion
Transmitted Diseases is because this issue surfaced in conjunction with
platelet safety, and platelets are regulated as a blood component in our
Laboratory of Cellular Hematology.
So
the areas of research, we are engaged in the characterization and
standardization of plasma derivatives.
In fact, we have been engaged in that since the 1950s, and continue to
be world leaders in this area; functional studies of platelets and studies on
platelet safety, chemistry and mechanism of toxicity of hemoglobin based oxygen
carrying solutions, investigation and standardization of bacteria detection
methods, and a cross-cutting activity in HIV vaccine immunology, because we
have a very strong science base in immunology, not surprisingly, in the
Division of Hematology.
Then
in the Division of Blood Applications, the product responsibilities include
blood and plasma licenses, blood establish software, and blood grouping and HLA
reagents. The areas of research here
include donor related epidemiology, validation of donor questionnaires,
monitoring of shortages of products and reagents, quality controls for blood
components, and a little bit of wet laboratory work investigating the
specificity of new blood grouping agents, for example, those based on
monoclonal as opposed to polyclonal antibodies.
Again,
I think it is evident that there is in fact correlation.
By
way of the bird's eye view and historical perspective, I am going to summarize
briefly some of our regulatory and research accomplishments that are highly
pertinent even today.
First
of all, what are some of the things we have done for you lately, in the last
say year and a half? In the area of
product development and approval, we have brought forward approval of rapid
test for HIV-1 and HIV-2, both on blood samples and on oral fluid; the first
barcode scanner for matching the unit with the recipient as a way to reduce
medical errors of mismatch at the bedside; the first approval of a computer
assisted self administered interview system, which is believed based on
behavioral research to be a more accurate way to elicit donor histories,
various new immunohematology and anti-RHD and immunoglobulin IV products. The tests for West Nile are still under
development. Development has been
supported through our laboratory activity, and we issued multiple guidances,
and we have approved initially quality control and most recently, a system
including release testing to control for bacterial contamination of platelets.
On
the area of guidance and rulemaking, the barcode rule was an FDA wide rule
applying to pharmacy products, but it included a section on requiring machine
readable code for blood products. We
have published a draft uniform history questionnaire, which will go a long way
towards standardizing the donor history taking process. That was a collaborative effort including
the FDA, both as a driver and as a collaborator in studies to validate these
questionnaires.
We
have published guidance on the requirement now to screen the blood supply with
nucleic acid tests for HIV and hepatitis-C, and we have done a publication on
the clinical trial standard. We had a
previous one on safety and now one on efficacy of oxygen therapeutics to
facilitate progress in that area, and of course, many guidances on West Nile
screening recently, updated in June.
Additionally,
we have sponsored and cosponsored a large number of public workshops. These of course are oriented toward problem
solving, looking at the conditions of plasma freezing and how that relates to
plasma quality, the issue of novel approaches toward platelet evaluation,
creating a more uniform standard against which to look at novel platelet
products, a workshop closely looking at safety and efficacy considerations for
immune globulin intravenous with the goal of figuring out ways to be more
economical or smaller sized studies with the patients, better use for example
of statistically modeled historical controls, potentially looking at surrogate
markers for efficacy for some indications, et cetera.
We
cosponsored with the Society of Gene Amplification and Technology working group
a symposium looking at NAT standards for a very large number of transmissible
agents. Likewise we were the sponsor or
co-sponsor of the Plasma Fraction Association and Paul Ehrlich Institute annual
workshop on NAT. This is a workshop on
updates in transmissible disease.
We
cosponsored with the Department of Health and Human Services a workshop on rare
plasma protein disorders, to try to foster progress in that area, both at the
clinical level and to streamline regulation, and just two days ago, we had a
workshop on leukocyte reduction, critically examining the issue of whether
there is a general medical benefit for universal leukocyte reduction, the
various issues in terms of standardization and quality control of products
labelled as leukocyte reduced, and some updates on the development of
filtration schemes to remove prions from blood products, including cellular
products.
Additionally
in the area of review management, which will be addressed in a bit more detail
by Dr. Williams, we have been bringing forward what you might call management
innovations. If you will excuse me,
maybe it is really management science.
These are office operating procedures for the review of the various
categories of application, like the device 5-10K, the biologics license
application and so on, and supplement industry meetings, checklists for
aphoresis components, et cetera.
We
have been very busy bringing about a GMP mind set to our review operation, and
correspondingly, we have been bringing forth an initiative working toward
external accreditation of our laboratory activities, including review of risk
assessments and statistical models and other methodological approaches.
You
have already seen this. The overarching
framework is that we have a goal that our research in the blood program should
conform to the needs of critical path to be facilitators of product development.
Here
are some historical examples of how we feel we have done that with our
research. In the 1950s we were
critically involved solving problems of the stability of albumin, what
stabilizers worked, and how many you had to use. In the 1960s we played a major role in developing standardization
of clotting factor potency, both through the development of biologic reference
materials and through the development of reference assays. In the 1970s our laboratories were
critically involved in solving the problem of hypotension from plasma protein
fraction, a preparation similar but less pure than albumin. One of our scientists discovered that it was
due to the presence of a precalicrene activator.
In
the 1980s, we became very concerned with the HIV safety of plasma fractions,
and contributed fundamentally to the literature on HIV clearance and
inactivation in derivative manufacturing.
In
the 1990s, we had this outbreak of hepatitis-C from two immune globulin products subsequent to the introduction of
highly sensitive screening for HCV antibodies.
We were instrumental in bringing forward very quickly assays that could
detect HCV in the products. Then we had
lot release so that only the products with undetectable RNA could be released,
and also validating the pathogen inactivation strategies that are now uniformly
in place for the licensed human derived blood derivatives.
Some
examples of things that are ongoing in the present decade. Refinements to standards for NAT for HIV and
HCV, investigations of the toxicity of hemoglobin solutions, a model called
Transnet for monitoring blood shortages, and as you have already heard,
contributions toward the quality assurance and sensitivity standards for donor
screening for West Nile virus.
Now,
some of our research highlights are enumerated on this slide. I am not going to have time to talk about
them, but some of them you will hear about in greater depth in the divisional
presentations. But this is to give you
the broad brush, what is the sort of work that we are doing in the labs.
Development
of reference reagents, examples, HIV and West Nile. Evaluation of the diagnostic significance of emerging HIV
variants. This is now recognized as a
significant issue worldwide. The point
is, how does it affect the sensitivity of our current diagnostics. Development of an oligonucleotide chip to
detect blood-borne pathogens, including so-called conventional agents and also
candidate bioterror agents, development of a candidate NAT test for detection
of malaria, investigation of possible viremia after smallpox vaccination, the
effect of smallpox vaccination on donor screening tests, mainly specificity,
establishment of standards for thrombin and anti-D immunoglobulin, a murine
model to study the pharmacogenomics of Factor 9 in relation to development of
inhibitors, mechanism of toxicity of various hemoglobin based oxygen carrying
solutions, a modeling of TSE decontamination methods, TSE risk assessment for
plasma derivatives, both the one that came from the U.K. under IND, and then to
examine all the U.S. derivatives, tracking systems to examine fatalities and
look for clues, cognitive evaluation of the donor history questionnaire, and
statistical quality control methods for blood components. I have already touched on some of these, and
you will hear more.
What
I want to do in my remaining slides is attempt to illustrate for you how we
think that the critical path model and mind set works. You will hear about some of these in greater
detail in a minute.
First
of all, we identify a critical path problem or opportunity. Detection of blood-borne pathogens,
obviously an issue. What is the
issue? It is the need for the
development and evaluation of technologies and methods that can screen blood
donors for a large number of pathogens simultaneously. There are only two ways out here, either to
bring forward effective pathogen reduction or clearance or inactivation
strategies, or to have an ever-increasing number of tests. If we are in the paradigm of an ever increasing
number of tests, finding ways to consolidate them becomes critical to
operations in the blood center.
What
we have done? Our humble effort is to
develop and evaluate a prototype multiplex nucleic acid based test and micro
array for blood donor screening, and to develop and provide FDA referenced
panels and materials to spur industry development in this area. The outcome has been to identify critical
parameters for assay development, for example, what kind of primers can you mix
with diverse agents so they work under the same reaction conditions.
We
have developed standardized panels that are being used as a target for industry
to assess different assays, and we have already brought forth proof of concept
for novel assay development. This is
just a graphic illustration which Dr. Nakhasi will review, but it is a gene
chip which can concurrently detect and confirm multiple conventional and
unconventional pathogens.
Another
example, counterterrorism, the safety of the smallpox vaccination. The issue is that smallpox vaccination can
cause life threatening complications in immune deficient individuals, and that
the efficacy of vaccinia immune globulin, a primary prophylactic and
therapeutic, cannot be tested in humans.
You don't give people vaccinia in order to do these studies.
So
what has been the approach? The
approach has been to develop a SKD mouse model to test the efficacy of
immunoglobulin. The outcome was a
transfer of this methodology to industry and the incorporation of this model
helped provide a pathway for the licensure of the first vaccinia immunoglobulin
intravenous product which was the first counterterrorism biologic approved by
CBER. It is a model of how we are
trying to use our labs to solve regulatory problems.
This
is an illustration. If you prophylax
with vaccinia immunoglobulin intravenous, you can convert from 100 percent
fatality to 100 percent survival, based on the timing of administration.
Another
example, hemoglobin based oxygen carriers.
The problem is that blood availability for trauma victims in rural areas
and in disaster situations including war and terrorism attacks is limited. However, the toxicity of the early
generation of hemoglobin based oxygen carrying solutions turns out to be
unacceptable. These products cause
generically vasoconstriction, very high blood pressure and multi organ system
damage. The actions at CBER, at OBRR,
were to attempt to identify the link between the oxidative chemistry of a given
hemoglobin and its toxicity. We
developed an endothelial cell animal based model system to promote the
understanding of blood substitute toxicity.
The outcome is that preclinical testing is now becoming more predictive
of clinical performance, and it has led to the design of a second generation of
hemoglobin based blood substitutes that are now in clinical trials.
Just
to be more specific, one of our investigators, Abdul Aliyash, is credited with
co-discovery of this mechanism of free hemoglobin bonding nitric oxide and
therefore inhibiting the vascular relaxation that nitric oxide otherwise
mediates.
Another
example is monitoring of supply availability during shortages and
emergencies. There is no rapid and
reliable mechanism currently to objectively assess the blood component reagent
or other supply shortages during regional or national emergencies.
What
did we do? In Dr. Williams' group, he
led an effort to develop and pilot a monitoring system called Transnet, which
is a web based system to permit direct reporting of shortages and their medical
impact from all U.S. blood centers and transfusion services. This is as opposed to previous, very
cumbersome, very expensive services that were based on daily funding of
sentinel sites.
The
outcome is that this program was piloted and is planned to be incorporated into
a blood monitoring system at the departmental Secretary's operating center that
is activated in the emergency.
The
future of course is part of your purview -- where are we headed and do we have
the right focus. Some of the potential
critical opportunities that we recognize include the following: Development of nucleic acid based or other
technologies for the detection of bacteria and parasites and blood components,
investigating the potential of nanoparticle based diagnostics for multiple detection
of blood-borne and counterterrorism agents, investigating the diagnostic
implications of variants or so-called mutants of HIV and HPV respectively,
developing diagnostic and donor screening assays for transmissible spongiform
encephalopathies, or at least developing standard materials that can be used to
assess those that come forward. You
will hear a little bit about this in a few minutes from Dr. Golding, the
establishment of cell lines expressing -- receptors, which is a novel approach
to detecting microbial components in blood and plasma derived products.
In
the area of blood product safety, we believe it is important to do animal
inoculation studies to evaluate the infectivity of blood units that have low
titers of West Nile virus with and without antibodies, developing or further
developing animal models to predict the immunogenecity of clotting factors
eight and nine, and the continued development of standards such as the standard
for NAT assays for human -- virus B19.
In
the area of blood product potency, we are about safety, purity, potency. I should have said that. That is our mission under the Public Health
Service Act, so developing an animal model to test functionality of candidate
modified platelet products and developing standards for additional plasma
derived products, for example, alpha-1 proteinase inhibitor.
So
my conclusions from this bird's-eye view are, and I hope I have convinced you,
that research is critical to the mission of my office, that mission related
research facilitates product development on the model of critical path, and
that our research program is focused on regulatory concerns related to product
safety and efficacy, and that these include the prevention and control of
blood-borne infections through testing, inactivation and removal of pathogens,
the characterization and standardization of blood products and methodology
development for product review and product surveillance.
So
please accept my personal thanks for your contribution at this site visit. I look forward to your comments and
report. Thank you.
DR.
ALLEN: Thank you, Jay, that was a
wonderful overview. Questions?
DR.
WANG: I am very impressed by all the
programs you are engaging in, but I got an impression that many of these
programs are out of your own initiatives rather than in response to any claim
in the applications that you tried to validate. How do you separate these two, and how many percent of your
effort is to develop methodology or use your methodology to check on the
application's claim? And how many are
you involved in developing your own diagnostic methods or even the vaccine
development?
DR.
EPSTEIN: It is a fair question. It is hard to give you a hard and fast
number. My back of the envelope
estimate is that about 30 percent of our effort is what you might call
preparation for the future, building infrastructures. So for example, we investigated for a period of years very
heavily in gene based technology for pathogen detection before there were any
product applications. But I think that
really, the bulk of it does derive from regulatory issues that do surface.
Clearly
in the area of West Nile virus, the development of standards so that we had
targets for the sensitivity of the NAT assay development, characterization of variance
to look for virus drift, so that we would know whether NAT assays, which of
course are very, very highly sequence specific, would be robust. That evolved from a product issue.
Similarly,
I think that the vaccinia research all came in the wake of concern over
possible bioterrorism from use of a smallpox agent, and we became aware in
anticipation of the need to have available vaccinia immune globulin intravenous
product. Then we were immediately
confronted with the issue that there was no way to measure the potency.
So
I think there is a balance. It is
certainly true that a lot of what we do is generated from within, but it is
generated on the basis of our perception of where do we need to be in two
years, where do we need to be in five years.
It is because we are sensitive to the public health need, we are
sensitive to what is in the product pipeline in anticipation of an actual
product review.
In
fact, you really don't want to wait for an application to first be asking the
question of what to develop at the laboratory.
You want to be doing that at a much earlier stage. I think that is why that cartoon of the
critical path shows the research engagement starting at a much earlier stage of
the product development pipeline. It is
precisely because we have to recognize problems at an early stage to be in a
position to contribute meaningfully at a later stage.
So
I would say that your observation is correct, but that there is still a long
term linkage which is a very real one.
DR.
DIMICHELE: Jay, I want to give you my
compliments on all the work that you do.
We are very impressed.
One
of the questions I have, and I think maybe you are the proper person to address
this to, when I am reading about everything that is going on, and having read
through the site visit materials, one of the questions I would have is, when
you look at the Laboratory of Plasma Derivatives is doing, because they are in
charge of gamma globulins, they are very interested in serology and therefore
get into a lot of infectious disease issues, and then you look at what the
Department of Emerging and Transmissible Diseases are doing, and a lot of times
they are working on the same organisms, but from a different perspective.
One
of the things that I didn't get a good sense of from reading and looking at
what the collaborations are is, how much collaboration across for instance
these two laboratories or these two divisions would be and how is that fostered
within your oversight.
DR.
EPSTEIN: Yes, thank you, that is a very
insightful question. I appreciate your
kind words.
Well,
things kind of grow organically in science.
What happens is, you are involved in a question or an issue, and you
find yourself also dabbling in somebody else's domain. I think that what we do, because we review
current activities, and we do it collectively, and certainly things are
recorded at my level, we do recognize both the needs and the opportunities for
collaborative effort.
I
think that there are certain things that cause it to happen. For example, Dr. Carbone described the
Center-level interoffice cooperative grant program that is run out of Dr.
Goodman's office. Those tend to be
projects that are cross cutting and where the different groups must collaborate
in order to receive funding.
A
good example of that is in transmissible spongiform encephalopathy. So for instance, our lead group is Dr.
Asher's group, which is in the branch of bacterial, parasitic and
unconventional agents. But the question
of where do prions bind in blood components, and where are they, research along
that line was done by Dr. Vostel, who is in the Division of Hematology. The groups clearly work together.
The
issues related to say HCV in plasma derivatives or parvovirus have been managed
with sharing of technology, bacterial detection. Our review group includes individuals from the Laboratory of
Cellular Hematology and Hematology, but also bacterial, parasitic and
unconventional agents in DTD.
So
we do this. The process however I would
say is not so highly formalized. It
more depends upon the fact that we do talk to each other, we do present our
work to each other, and because I am aware of what is going on in the different
components of the program, I will just say to people, you guys need to
cooperate on this. And the Division
directors do also talk to each other.
It
hasn't been mentioned before, but we have scientific seminars in each of the
divisions. Those are weekly
events. Often they are outside
speakers, but just as often they are the researchers in house. That is another opportunity where people
listen to each other's work and can recognize opportunities and needs for
cooperation.
So
it does happen, but I'm not going to say it happens through a formal process.
DR.
STRONG: Jay, in your fifth or sixth
slide you had the regulatory work output.
You commented that 80 percent of your effort was review. So I am trying to balance these numbers. It is supposed to be 50-50 research and
regulatory. How do you manage that
exercise of distribution of work?
DR.
EPSTEIN: You have to understand that
not everyone is a researcher. When we
say the 50-50 model, we are talking about the subset of people who are using
research resources. Those individuals
are expected to do 50 percent of their laboratory work and 50 percent review,
and they do. But they are not the
larger number of our organization, they are a subset.
I
know we don't want to talk primarily about the resources. I can comment on that, if you wish. So the reason for this is the balance. Most of our staff are in fact not research
reviewers. They are regulatory
scientists and various kinds of support staff.
The 50=50 mix is the researchers.
Everybody else is 110 percent.
DR.
ALLEN: I was adding up, it looked like
it was about 120 percent. You didn't
add in the administrative tasks.
DR.
ALTER: Jay, I see a parallel. You could be the head of the National Cancer
Institute. You would have then two
mechanisms. You would have extramural
R0-1 initiatives, investigator initiatives, and you could have an RFP saying, I
want you to do this, give me your plans.
So
how much of your operation is, an investigator says I would like to study this,
and it sort of fits in our mission? Or
you say, this is what we need to look at, come up with an idea in that realm.
DR.
EPSTEIN: Again, it is a difficult
question to answer. Because our
researchers are regulators, much of what they propose to do is rooted in the
questions they find significant, based on the regulatory work.
So
a fine example of that is HIV variance.
We have to decide whether the assays are sensitive to the variants that
are circulating in our country and worldwide, because they may be brought
in. Dr. Hewlett at her own initiative
recognized the opportunity for a collaboration in Cameroon. Why Cameroon? Because it is the world's hotspot for new HIV strains and
recombinants. So you could say, isn't
that investigator initiated? Well, yes,
it is. But is it mission related? Yes, it is.
I
think that the way this process works is that because we control the laboratory
support, the branches and the sections have to review with the director and
ultimately with me just exactly what they are embarking on, so we do scrutinize
it.
Now,
how much of that is grass roots versus top down? I would say that I will sometimes simply direct the work. I will just say, we need to develop an assay
for X, or we need to develop a standard for Y, or we need to solve this
problem.
Also,
much of that comes organically from what is happening in the field. If we have problems with hemolysis, with
diversion pouches or white particulates in red cells, is it top down or is it
bottom up? There is recognition, and
there is willingness to embark on a project, but I am also going to tell
people, you have to jump on this yesterday.
u have to jump on this yesterday.
So
it does work both ways. But I think the
leavening is that all of the initiatives are scrutinized at the managerial
level. So we know what people are
embarking on and why. So because it is
a dialogue, it is hard to tease out what was a mandate and what was an
initiative. It is because we have the
group process in deciding what we do, so it is very hard to dissect that out.
So
I can't give a number. I would find
that very hard.
DR.
BUSCH: Jay, your group working in
development diagnostic or vaccine development makes a lot o sense in terms of
them understanding what is coming at you.
But is there another motivation?
If you discover some new sequence that is particularly effective at
capturing -- is there any capacity to patent within your organization? Or is that a motivation at all for the
investigators?
DR.
EPSTEIN: I think that it is not the
prime motivation. We have certainly
patented inventions. We have that
right. We don't own the royalties. We own only a small share of royalties if
there ever are royalties. But we can
patent invention.
I
would say that most of the time when that happens, it is a spinoff. So for example, one of our researchers, Dr.
Sebastian Wan, has been very interested in HIV replication. He made the discovery that there is a
significant regulatory role of extracellular TAT, and it therefore became a
potential vaccine or pharmacologic intervention target. I believe he has pursued patenting; he might
have to clarify that for me.
So
I would say that the prime motivation wasn't -- I have to discover something I
can patent. The prime motivation was, I
am trying to solve this problem, but then a discovery gets made and a patent is
possible.
We
encourage that, but I think that the focus of the organization as a whole
really is the public health mission.
That is what motivates people on a daily level, and it is how they
orient their activity. If we make
discoveries, that is great. Similarly,
the discovery about the mechanism of toxicity of hemoglobin based oxygen
carriers. That is marvelous, but why it
happened is that people were trying to solve a mission related problem, and I
would say that it is a sort of a spinoff.
But
yes, we can patent. I'm sure people
don't mind it if they get a patent.
DR.
INTAGLIETTA: Dr. Epstein, thank you
very much for your exhaustive presentation of the extraordinary research
accomplishment of your division.
I
am quite familiar with the work of Abdul Aliyash in identifying the toxicity of
hemoglobin solutions. I should say that
indeed, that has become an international standard, and is widely recognized.
You
made a really interesting comment in saying that you have to identify where you
want to be in the research and in addressing problems that might arise. I got the impression that this to some
extent mostly depends on your own intuition of where this want to be situation
and location is going to be. I was
wondering whether a more structured approach to this might not also help in
identifying where to go.
I
was wondering whether it has ever been considered, for instance, the
establishment of an advisory board or some sort of a mechanism by which to
collect these perceived needs that your institution has to address in the future,
because indeed, in some cases they might be just guesses. Of course there is good science, but you do
have from what I gather a rather directed mission to accomplish.
So
my question is, would it help to establish some sort of a structured mechanism
to identify where you should be in the future.
DR.
EPSTEIN: I think that is a very helpful
comment. Dr. Carbone may want to
comment on this. I think that we are
moving in that direction. In fact,
today's site visit is an effort in that direction, because we have invited you
to comment on the direction.
Outside
input I think would be very helpful to us.
We do have as you know advisory committees. The Department of Health and Human Services advisory committee on
blood safety and availability has at least in the area of emerging infectious
disease taken up the question of the national approach including the agency
approach. I think that we will benefit
from some direction out of that process.
But
I feel that you have made a very construction suggestion. It is in our thinking, but we haven't really
utilized such a process. But Kathy,
would you like to comment, because I know it is part of where we are headed?
DR.
CARBONE: I would, just briefly. I think that is something Dr. Goodman and I
discussed in where we are heading. For
example, the October meeting was a meeting of stakeholders and sponsors broken
down by office to collect needs and ideas for the future, et cetera. So that was the initiation of the
process. I think this is also on the
way, where we are, and then of course the future. So I think that is clearly on the books, discussing approaching
that.
I
will use an example. There is an
element of intuition and guessing, you are absolutely right. But I think part of the issue with what we
can generate -- not that we don't need input, we certainly do -- is the example
of SARS. When SARS came down the pike,
we knew that there would be a vaccine proposed, and we knew the organism. Fortunately, we had somebody who was an
expert in their previous life, and we met as a group across offices, and we
talked about what would be needed to deal with the vaccine, also blood
products. There was immune therapy.
One
of our investigators immediately -- a vaccine specialist, immediately said, if
we are going to make a vaccine, then it is going to be inactivated
vaccine. We know that this organism is
difficult to inactivate. And set about
working on different product procedures for inactivation, documenting
inactivation, all the things we would have to review if a vaccine came in,
identified ways to inactivate the virus.
Just recently this has proven to be valuable to potential sponsors. This information has been published and
transmitted, and we have gotten queries in this area that other groups interested
in the vaccine have had problems inactivating the virus.
So
this is an example where the experience and regulation of a vaccine plus
combined within the expert area and the scientific, identifies and quickly
crystallizes key issues.
So
that said, we agree completely about external process as well, and that is in
the works.
DR.
WANG: My imagination is running a
little wild here. Suppose that out of
your own initiation you successfully develop a diagnostic kit, or even a
vaccine. Will you patent it, license it
to a company, and then eventually an application will come to you for approval?
DR.
EPSTEIN: Well, that is an issue. When we have cooperative research and
development agreements, CRADA's, the individuals involved with the CRADA
obviously cannot be the reviewers. So
there is an issue of recusal in that kind of situation.
We
do participate with the NIH program of technology transfer. Even if we patent something, we can through
the government license it to manufacturers.
But certainly the individuals who were involved in that level would not
be the reviewers.
So
the answer is, we hope to have enough people on board who are knowledgeable
enough to review things that they didn't themselves develop. We recognize that that would be an unacceptable
conflict of interest.
But
on the other hand, there is a lot of more general work with which we can
engage, and we can utilize CRADA's where we feel we have enough staff to deal
with eventual reviews.
DR.
PRIOLA: I want to return for a moment
to Dr. Intaglietta's suggestion and the discussion earlier about flexibility of
the research at FDA, that you can respond rapidly to newly developed
situations.
If
you are going down the path of having an advisory committee or something like
this to help you determine where research should be guided, how would that
affect that flexibility? I think that
is a very important aspect of what you are able to do. DR.
EPSTEIN: I think part of how it would
help is if we can support the basic scientific disciplines critical to our
work, then it enhances our flexibility.
I
think that Dr. Carbone hit the nail on the head when she said that we flex a
lot, and we rob Peter to pay Paul. It
is when we have urgent situations, we do address them. We cannot always address them by continuing
all of our previous work. So sometimes
things get put on the back burner while we address an issue that is more pressing.
I
think though that over the long haul, having better insight into program goals
and targets with the benefit of outside input would only benefit the program,
because we would be better structured to deal with things that are
emerging. It would be rather unusual to
find that their infrastructure was not relevant.
An
example in my own lief, I came here as an I.D. doc, and I started working in
vaccine development, and I was working on herpes viruses. But then AIDS came along. CMV was a big issue in AIDS, especially
early on with gay men, and so it was pertinent to be working on CMV. But meanwhile I was learning the skills that
I was later able to adapt to HIV. That
was done virtually overnight when the agent was discovered.
So
I think that to the extent that having a supported infrastructure, albeit
targeted, would make us more robust as a scientific program, we would end up
being better equipped yet to flex.
I
will say though that as external funding under grants increases, it becomes a
little bit difficult, because you must do what is under your grant. But people do get very creative in finding
mechanisms that are cross cutting. If
you bring in a technology such as the gene chip, it isn't so difficult to
introduce another primer set. You have
already got the infrastructure for the system, and then you are able to
flex. So that is the kind of thing that
goes on.
So
I don't actually see those things as mutually inhibitory. I think the one fosters the other.
We
are at this point about a half an hour behind.
I think it has been a very rich discussion. Dr. Tomasulo, if it is pertinent, go ahead, but we really do need
to move on. But as I said, I think this
has been a very important and rich discussion, and I hesitated to cut it off.
DR.
TOMASULO: Jay, picking up on Marcos'
where you want to be question, can you talk a little bit about monitoring blood
shortages, and what is the ultimate outcome that you expect from that activity,
and what products are included in it? I
believe you monitor plasma derivatives as well as blood products. Can you talk a little bit about that?
DR.
EPSTEIN: Yes, sure. We are not the manufacturers. The government doesn't make anybody make
anything. We can sometimes do it under
contracts; it is rare. So we have a
privatized system. So the ultimate
responsibility to make and distribute products lies with the manufacturers who
we also regulate.
We
see our goals as oversight in order to recognize and characterize problems and
address them from the federal point of view to the extent feasible, which may
be simply providing information. It
might be at times providing regulatory alternatives, for instance, flexibility
in changing licensed laboratories.
Our
ability to monitor shortages is established in regulatory authorities. We have shortage officers, and we do have a
role and responsibility to respond, heavy emphasis on respond, to shortage
reports. We feel that we are
additionally being proactive in monitoring and helping to avert shortages under
the more general mandate that that is part of safety. Lack of adequacy of products is a public health safety issue.
So
we are not generally speaking charged with surveillance of product
distributions. We do that more in a
reactive mode. So for example, with the
issues of immunoglobulin and other derivatives that have gone back over the
recent decades, we do have authority to require periodic reporting of U.S.
distributions of products. We have
exercised that authority to bring about a system where the fractionators give
us a monthly report of their distributions, and we have persuaded them to make
aggregated data public.
We
have as I have already mentioned developed a system for more acute monitoring
of shortage system wide for components, reagents, devices, to monitor the blood
system. The responsibility for that
surveillance has been taken over by the Department, and it doesn't reside with
FDA. In other words, we are not
primarily in the business of supply surveillance -- safety surveillance, yes,
supply surveillance, not exactly.
So
we play a role, and our objective then is to find truth and find ways to
mitigate problems. We have many, many
ways that we can mitigate problems. We
can first of all provide information, so people know what is going on. Secondly, we can provide alerts. For example, we can provide web postings or
letters to physicians indicating that products are in shortage, and you may
want to be mindful of certain things.
For example, where can you go get product, or what are the approved
indications and how might you wish to consider that in your prioritization of
clinical use.
Additionally,
at times we can make product more available by say accelerating a review of a
product, accelerating review of a facility to bring it online. We can at times offer variances for time
limited or temporary granting of alternative procedures. So we do those kinds of things. Or we can permit for example importation of
products under IND, as long as they meet adequate safety and efficacy standards
at the IND level.
So
there are a lot of things that we can do.
I would have to say though, it is more in the reactive mode in the area
of supply.
DR.
ALLEN: Thank you very much, Dr.
Epstein. Let's go ahead and take our
9:30 break at this point. I would ask
that we make it a very short break. I
would like to have Dr. Williams ready to make his presentation in ten minutes.
(Brief
recess.)
DR.
ALLEN: The next presenter from the
divisions will be Dr. Alan Williams, who will give us an overview of the
research programs in the Division of Blood Applications.
Agenda Item: Overview of the Research Program
of the Division of Blood
Applications
DR.
WILLIAMS: Thank you, Jim. What I will start with is an introduction to
the Division of Blood Applications, and then go through some of the initiatives
in the review process itself within the office. In fact, the review process for applications is within the
critical path, and I would argue a very important element within the critical
path. Then we will go through some
other critical path related activities in our division, including standards
development and some of the epidemiologic studies we have been involved with.
I
think two things I want to have you keep in mind throughout the talk. Many of the things I am going to mention,
particularly with respect to the managed review process, is that these are
office wide efforts, and everyone within the office has worked together very
hard to make our review process more efficient. Then secondly, some of the research things that you will
see. A couple of our staff members have
joined FDA within the past five years, and there are some transitional things
that involve collaborations from our previous lives.
So
our principal staff, and those arguably most involved in some of the critical
path work. I direct the Division, ably
assisted by Dr. Sharon Orton. Dr. Orton
also serves as the acting chief of the Blood and Plasma Branch. We have a Devices Review Branch, headed by
Charyl Kochman, a Regulatory Product Management Branch headed by Dr. Sian
Najar, and we have medical officers who work on things like medical evaluations
of reports that come into us, as well as some of the surveillance activities
that I will mention. And I wanted to
specifically mention Judy Saraldi, who just recently has taken up a quality
assurance monitoring role within our office, and helps look at our review
processes as well as several other elements from a quality standpoint.
I
will tell you a little bit more about our branches in this slide. As you saw from Dr. Epstein's slide, we look
at a lot of applications. The bottom
left is the number of license supplements review. That wasn't a typographical error. We actually do look at between 800 and 1,000 license supplements
from blood and plasma establishments, many related to SOP changes from the
establishments. These are done within
our Blood and Plasma Branch in this Division.
It looks at both blood establishment licenses and supplements as well as
source plasma collection licenses and supplements.
Within
our Device Review Branch, we deal with a fairly focused area of devices,
specifically blood establishment computer software, and this includes ancillary
software that interfaces with the primary blood establishment software
component. These are finally called
BECs. They also review in vitro
diagnostics or IVDs related to immunohematology. This can be everything from ABL grouping to HLA typing, and some
of the identification systems related to patients and blood identifiers.
Thirdly,
we have our Regulatory Project Management Branch. This branch is responsible for managing the regulatory applications
from the time they come in the door, getting them logged in, and through the
review divisions, where the scientific reviews related to the disciplines of
hematology and infectious disease are actually done by our laboratory
divisions, which will follow.
We
manage the applications, manage the review process in large part, define the
regulatory paradigm that will define how those applications are reviewed. Then we also serve as the primary interface
with the sponsor of that application.
To
give you a little more detail about some of the review management initiatives
that Dr. Epstein introduced, the goal is an OBRR-wide improvement in our
process, including the time line to review, the efficiency of the process, the
consistency of the reviews and the management, and the documentation related to
the decisions that have been made in the regulatory process.
This
is certainly a good thing to do anyhow, but certainly we are motivated somewhat
by the new MDUFMA and PDUFA 3 regulations, which define some pretty ambitious
time lines for the review process.
I
think some major accomplishments have been made in the initiatives in the area
of documentation of our procedures, making sure that if a telecon or other
sponsor interaction actually contributed through a review division, that that
is well represented in our archival record for that review.
We
improved the sponsor meeting paradigm so that instead of saving some decision
making to a pre-meeting just before the actual sponsor meeting, we try to get a
front-end loading to the review of the questions that have come in from the
sponsors, have our position well established, and wherever possible share that
with the sponsor ahead of time, often in hopes of pre-empting a face to face
meeting and saving everyone's time.
We
have participated in an assertive effort to develop guidance documents faster
and to close out those that have been published in draft, and get those issued
as final. Some of you are aware, it is
a very complicated process from initial scientific development of a document to
actually getting it out the door at the agency, but we have I think worked as a
Center very hard to get these documents developed and published, and many of
them are well along the way.
The
question was raised earlier about training of our staff and particularly our
reviewers and our reviewer researchers.
I think this is one area where there has been a particularly strong
improvement over the past two years.
Center wise, there has been an initiation of a regulatory management
update, coordinated by CBER as a whole.
This is a monthly training session on review processes and some of the
elements that have been changed at the Center level with respect to efficient
management of applications and meeting our legal requirements.
Then
we also within the office have developed a monthly regulatory forum. This is an area that provides us an
opportunity as an office, even though we are in three different geographic
locations, to sit down together and hash over any problems or any regulatory
issues or management issues that we are having. This has been a particularly useful program in terms of
developing our new paradigm for sponsor meetings and training staff as a whole.
Last
in this list, we have developed internal review management metrics to try to
put some definition and teeth into the review process as a whole.
This
next slide on a little cartoon shows a life cycle of a generic application that
comes into our office. This could be a
BLA, a 510K IND, whatever. The application
comes in, we have a document control center that logs it into their database as
being received, and then within a very short time, a process that has also been
improved recently, we receive the application in the office and assign it an
identifier within our regulatory database.
Then copies of this application are distributed to the reviewers. The reviewers take a quick look to see if
the submission qualifies for review, has sufficient elements for review, and we
issue a filing letter to the sponsor saying that we accept this for review, and
you will be hearing from us.
Then
the process of review itself starts, and what we define as a new element is the
mid-cycle of the review process. The idea here is again to front-load the
process, with the target of identifying all major review issues by mid-cycle,
then strategizing interactions with the sponsors that will take place in the
second half of the review with the goal of having those solved and in approval
at the end of that first cycle.
What
we have done is worked toward that goal, but also established a metric, so that
at the mid-cycle review meeting for all of our applications, we maintain a
database with the help of our regulatory project management staff that
documents the date of the mid-cycle meeting, the attendance of the discipline
reviewers at the meeting. The reviewers
are expected to have a written discipline review that has been concurred by
their supervisor available at that meeting.
Again, it is not a completely exhaustive review. It is identifying major elements, major
showstoppers that might be a part of that review.
At
that meeting, as I said, the future actions are strategized on toward a final
action.
In
terms of the final action itself, we are working under very aggressive time
lines with MDUFMA and PDUFA 3. We have
established a metric called T minus ten.
This again is a goal, so that sponsor interactions and final review
memos are complete and documented at ten days before our final action date,
when notification to the sponsor needs to go out the door. We do track that, how successful we are at
doing that, and it gives us a little breathing room if we need a day or two to
finalize a decision, but it serves as a worthy target. The goal here obviously is to maintain an on-time
performance for completing our applications, but also to have the management
signoff at the branch, the division and the office level as necessary done in
sufficient time that the managers have enough time to review everything that
does go out.
I
think these metrics have been very helpful, if not the results of the metrics
themselves, certainly the presence of the metrics has gone a long way towards
helping us review the process.
After
the tragic events of the fall of 2001, we did have an emphasis on emergency
response and our BTCT related responses.
This is one of the areas where I think DBA had a major role, but an
office-wide effort. We developed an
internal SOP for responding to crises, which defines staff responsibilities and
backup. It defines when to initiate and
document a response, when to end a response.
It defined our contacts for both internal and external communications in
time of crisis.
We
have with the Center and really all of HHS developed our continuity of
operations plan, which is under Presidential directive. It is called a COOP. It allows us to continue operations off site
in the event that we need to, and we have staff defined who would be prepared
to continue our functions at a different location.
Then
finally, in anticipation of an event, we have given up-front proactive thought
to agents which could be used as part of a BT or CT related exposure, and
developed our baseline information that we would need, our baseline contacts,
both internal and external, and given preliminary thought to what policy
actions might result from a specific event.
Our
Division like the other two divisions as well has a lot of external liaison
activities. Many of these are with our
colleagues at the AABB, and their standing task forces and committees. These include the -- I'll just mention a
couple, the indoor organizational donor history task force, with which we have
been working closely to get an accepted donor questionnaire that is
standardized and cognitively tested available to the field. We have the primary representatives to the
standards committee and the technical manual committee, and their indoor
organizational task force on disaster response. We have also produced a chapter in Dr. Harmoning's textbook
overviewing the regulatory policies related to blood transfusion.
A
few examples of our critical path activities.
We mentioned the Immunohematology Branch and their reagents and
platforms. This is an area of critical
path related to definition of standards, and I would say, standards related to
products. A lot of our activity within
the Division relates to process and SOP review rather than products, but in
this branch it is products.
Dr.
Epstein mentioned that in many cases, particularly for immunohematologic
reagents, you may face a situation where a reagent is in short supply anyhow,
and a manufacturer is considering ceasing production or in some other way the
reagent may potentially come short.
NTIS would be a good example of this.
We may have to scramble quickly to help look at a potential replacement
reagent, and both through wet laboratory work and review of data determine
whether the specificity is sufficient to cover the territory that that original
reagent would have supplied.
Also,
changes in platforms like infectious disease IDVs, the immunohematology
reagents, some of the procedures are manuals, some are technological, and we
have to facilitate movement between platforms.
Blood
establishment computer software. As Dr.
Epstein mentioned, we have been particularly interested in and supportive of
computer assisted donor screening systems.
The AIDS related behavioral literature does support that computer
assisted screening of subjects does give a better, more precise response to
medical information. Some of these systems
have now been made available to the public and are in use in donor centers
today.
In
addition, radio frequency identification technology is rapidly making its way
known. We have been looking at some of
the consensus standards for interference and compatibility, and reviewing their
relevance to our devices.
In
terms of procedures, we have had a several-year program now to look at the
statistical basis of quality control for biologicals. This has been in close collaboration with our colleagues in the Office
of Biostatistics and Epidemiology. As
you will recall from the regulations both in the U.S. and elsewhere in the
world, quality control is often defined as one percent or N equals four per
month. That is a reachable quality
control system, but it is hard to define just what that says in terms of
defining a product and the extent to which it meets standards. However, if you can define a product as 95
percent of the product meets a standard with 95 percent confidence, that gives
you much more of a definition of what you have.
There
are various statistical approaches to get there. Binomial is one, which is a feasible approach for blood products,
and scan statistics is a recent one that we have been looking at, and are
eventually going to introduce as an FDA accepted way of producing a
standardized quality control paradigm.
In
terms of blood safety and adequacy, there are two elements that I think are
important. We don't carry the
responsibility right now for overseeing the availability of blood in the
country, that is in the Office of Public Health Science under the Assistant
Secretary. We do have the
responsibility for making sure that when we put a policy in place, that we
aren't jeopardizing the adequacy of supply.
So what we need to do is maintain an informed balance between regulatory
intervention and blood supply adequacy.
I
would say every major policy that emerges has had that cost versus donor loss
consideration made very carefully, and often vetted with this committee or a
similar public advisory committee. This
involves risk modeling, and in some cases just scraping whatever data we can to
assess whatever impact a donor deferral policy might have.
This
is an older one, but this is the basic comparison between a donor travel survey
conducted on a multi-center basis among ten blood centers, which was used to
define the theoretical risk reductions for dietary exposure to virion CJD for
travelers to the United Kingdom versus blood supply loss.
This
is the basis of one of the earliest decisions related to virion CJD deferral,
which deferred on the basis of a six-month exposure in the U.K. We knew we would lose 2.2 percent of donors,
and had an 86 percent risk reduction.
This was used subsequently for policies afterwards as well.
The
second area is, improve emergency preparedness through accurate assessment of
blood shortages. This is a Transnet
system that Jay said a few words about, a web-based reporting system, which is
going to be applied to blood and blood components, reagents and supplies
specifically targeted to transfusion services, because they are the best
indicator of when you really have an acute problem.
I
think an important thing that is built into this system is not only where a
product is short, but what is the medical impact of that shortage, anything
from delay of a necessary procedure to use of Rh positive blood in an Rh
negative patient when you wouldn't normally do so.
It
has the capability to be turned on and off as needed. You might turn it on in a holiday period or in the summertime, or
in a time of crisis. It was made
available to DHHS essentially as a turnkey system, and they have announced
their intention to make this one arm of the basis system in the Secretary's operations
command center.
Just
an example of what I meant as far as the medical relevance of a shortage, we
piloted this in the winter of 2002-2003.
It just coincidentally happened at a time when we had a very severe
holiday related blood shortage. So we
were able to not only document the shortage, but get some indicator in our ten
participating sites of what the medical impact of that shortage was.
So
out of the 191 transfusion service reporting days that were part of the pilot
study, there were no delays of emergency or elective surgery. Eleven sites made use of their strategic
reserve, one delay of medically necessary treatment, and 24 transfusion service
days in which Rh negative patients were transfused with Rh positive blood when
they most likely otherwise would not have been. So I think it is important to get the impact of a shortage, as
well as the fact that a shortage exists.
Improvements
to donor screening I won't go into in detail.
Just to say that I think some of us in this room have been founding
members of this effort. It has been a
long haul, six or seven years now. I
think we have approached the point where we have a standardized donor
questionnaire. It has been cognitively
tested for the first time in history, and we are on the verge of having that as
an FDA acceptable questionnaire used potentially throughout the country. We are actively working toward doing the
same sort of a qualification on an abbreviated process for repeat donors.
There
has been some very elegant laboratory work done on West Nile in our office, but
also, I wanted to mention our participation in some targeted epidemiologic
studies. West Nile is one of
those. In collaboration with the
American Red Cross, Dr. Orton in our group conducted a case control study of
West Nile, seropositive donors versus controls for NAT symptoms, and produced
data which helped support a recent decision that we could discontinue the donor
symptom screening question of headache with fever.
This
question originally rose out of some preliminary studies with donors who were
implicated in transmission of the virus in early CDC studies, but it was found
that particularly in the presence of NAT testing that this question was no
longer predictive.
This
is one of the transitional studies I mentioned. We were involved in some survey research with the NHLBI red
study. Donation incentives are common,
but data addressing incentive impact on a motivation of a donor to show up at
the blood center and donate are quite limited.
This
is some survey research. The bottom
line is, we found that heath related incentives are very motivating,
particularly things like availability of a blood credit which many donors think
they have, but in fact may not, cholesterol testing, and other health related
testing, even things like PSA testing, are very encouraging to donors.
On
the other hand, compensatory type incentives, while they are attractive to
younger donors, also appear to turn off about seven to nine percent of the
overall donor population, which is something to keep in mind.
Similar
epidemiologic study of HIV incident infection.
Recent HIV exposure is of interest, because individuals who have
incident HIV exposure have presumably just gone through a blood donor screening
process, and it is interesting to know how that process may have missed a risk
factor. The bottom line is, incident
HCV infection has a high association with injecting drug use, just as prevalent
infection does.
White
particulate matter was an issue of concern a little over a year ago. In early 2003, there was an observation of
abnormal white particles in red cell units.
The bottom line is, our Division collaborated with some blood centers to
look in depth at adverse event reports from transfusion services in some
instances where we know units with particulate matter had been issued and
received, and there was an absence of adverse event reports, which helped us to
a conclusion that this was most likely an event that did not jeopardize blood
safety.
We
have ongoing surveillance using the databases that are available to us. Fatalities both in donors and recipients are
reportable to the FDA. We had a blood
product advisory deliberation in December of 2003 in response to an apparent
blip in donor fatalities, and some intense work between CBER staff and AABB
donor fatality task force. We
recognized that simply defining the period of time after transfusion that would
be allowed as an inclusion criteria clarified this quite a bit. The numbers both from those high years of
2002 and 2003 as well as in 2004 were considerably lowered and more consistent
when more carefully defined.
Similarly,
there is ongoing work looking at recipient fatalities. Transfusion associated lung injury was the
leading fatality cause in 2002 and 2003.
In response to this recognition, FDA issued a dear doctor alert to help
increase the recognition of this as a post transfusion event.
This
is a bar chart showing the contribution of TRALI to total fatalities, and you
can see that after the issuance of that dear doctor letter, one without looking
at it more carefully could perhaps assume that the increased recognition
improved the reporting of TRALI related events.
Just
some closing thoughts. Our staff in the
Division of Blood Applications have worked in concert both with internal and
external collaborators to successfully identify and pursue some unique critical
path opportunities with a multidisciplinary response that has involved
epidemiology, modeling, behavioral science, management science, if you
will. I think we have been able to make
some key measurable advances to public health and to transfusion safety.
Thank
you.
DR.
ALLEN: Thank you, Dr. Williams. I am going to defer questions for Dr.
Williams and the other presenters until we have had a chance to do all of them. If you have got a critical question with
regard to clarification of a point, you may ask it. But otherwise, in terms of general questions and discussion we
are going to defer.
Our
next presenter is Dr. Hira Nakhasi, who is Director of the Division of Emerging
and Transfusion Transmitted Diseases.
He is going to give us an overview of the research program for DETTD.
Agenda Item: Overview of the Research Program
of the Division of Emerging and
Transfusion
Transmitted Diseases
DR.
NAKHASI: Thank you, Dr. Allen. Thank you very much to all the committee
members for coming over here and listening to what we will be presenting to
you, and all the audience who is here to listen to what the research program
is.
First
of all, by way of introduction, my goal here is to present to you the scope,
mission, regulatory relevance and public health impact of the DETTD research
program. I will provide you with
several examples of our accomplishments, and how that goal is met. Both Kathy and Jay did an excellent job and
you did an excellent job of asking the questions clarifying what is the purpose
of today's program. I will try to
provide you with examples of how those fit into what the goals are set in to
begin with.
First
of all, examples which will directly impact our regulatory mission, and how
does it fit into FDA's critical path initiative, which has been described
already, and how we are planning as part of our future needs.
In
the interest of time, I will not give you all the detailed examples from every
principal investigator in our group.
However, the books which we have provided to you will have an extensive
elaboration of that. I will highlight
some of the major examples, and then from there we will go forward.
We
have also in the audience some PIs whose research work I will be
presenting. If there are specific
technical questions, I will be directing those questions to them. Otherwise I will try to answer as much as
possible.
With
that introduction, I would like you to sit back, relax and enjoy the talk.
First
of all, the organization of the Division of Emerging and Transfusion
Transmitted Diseases. The Division is
organized into three research laboratories and one fulltime branch. This was organized recently. The laboratories having organized as Dr.
Epstein pointed out to you earlier on products and what type of research and
product responsibilities these labs have, and what type of research they did
do.
In
addition to that, as I said, we have fulltime reviewers which have interaction
-- the dotted lines show the interaction with each of these branches. The purpose of this is to have a cadre of
people who can interact with all these groups, as well as, they are responsible
for the process as well as the review of science.
In
addition to that, we have a small laboratory which is the product testing
laboratory, and Dr. Bisswas is head of that.
These are the people who test all the lots of any products which are
licensed before they go on to the market.
The
head of the Laboratory of Molecular Biology is Dr. Hewett. The head of the Laboratory of Hepatitis and
Related Emerging Agents is Dr. Kaplan, and Bacterial, Parasitic and
Unconventional Agents is Dr. David Asher, and the Product Review Branch, Dr.
Elliot Cowan. In my immediate office,
myself and Dr. Meade, who many of you know.
The
mission of this Division is to proactively insure the safety of the blood
supply. How do we do that? Through regulation of blood screening and
diagnostic testing to detect infections which contaminate blood and blood
products. In addition to that, we
evaluate new technologies for rapid and flexible screening of blood supply, and
develop policies for the guidance of use of tests and diagnostic products, and
also the implementation.
So
with that responsibility, we plan and conduct research on disease pathogens of
various blood-borne agents. We test the
safety of these tests for these blood-borne pathogens, and in addition to that,
we have an added responsibility, because of the unique expertise, CBER-wide
expertise in the Division, to the development of biomarkers for vaccine safety
and blood-borne agents. I will
elaborate that point further, why we are doing those kind of studies in our
Division.
In
addition to the broad based approach, we also have responsibilities for
testing, for approval of investigational tests, and surveillance of licensed
products. We develop materials for
testing, and which have been already spoken many times. The members of the Division conduct
inspections for these manufacturing facilities. We have done consultations with other agencies and government
components for other issues such as CDC and NIH, HRSA, CMS. We have an outreach, where we discuss the
safety and efficacy of blood donor screening tests, such as forums like this
Blood Products Advisory Committee, tissue, spongiform advisory committee
meeting, and Department of Health and Human Services blood safety and
availability committee.
The
regulatory output for '04 for our Division was approximately 540 applications
we reviewed, which included biological license applications, supplements,
amendments and reports, and PMAs and 5-10Ks and IDEs. In addition to that, our group performed thousands of test kits
and performed several inspections.
From
the research output in '04, in our Division there are nine principal
investigators, and the research publication in the period of '04 were 41.
As
you heard the mantra for the critical path all along this morning. Really our mission is to follow the critical
path challenge for the blood products to insure the blood products safety,
efficacy, availability, while minimizing the destruction to the blood
system. So based on that, I will then
provide you examples, how that mission is achieved.
But
before we do that, I just want to show you a chart illustrating the point, what
impact has this testing of the blood donors with agents such as HIV and HCV
over the year have reduced significantly with this transmission. So therefore, it just speaks volumes by
itself.
So
how did we prioritize research priorities in the Division? We have three broad categories. One is blood safety and availability, which
is related to the retroviral testing of these various agents, both present in
the blood system or emerging such as SARS, vaccinia and others, or West Nile
virus or vaccine safety for blood-borne parasitic agents as well as HIV and
hepatitis agents. I will discuss in
detail why we do that. And other issues
such as manufacturing issues because of the unique expertise of Dr. Asher and
his group in our Division, which goes across the whole CBER regarding the
detection, decontamination and issues for screening assays.
The
first topic of my discussion would be blood safety and availability. I will show you what is the impact on the
U.S. public health, what are the regulatory challenges for us, and then give
you the examples.
The
impact on the U.S. public health is because millions of units are transfused
annually, and there is a risk of transmission of these agents through it. However, since the introduction of tests,
the risk has gone significantly down.
However,
there are new and emerging pathogens which constantly threaten the blood
supply, such as the emergence of the drug resistance as a common variant of HIV
or HBV mutants, and how those mutants impact our ability for testing or
currently existing licensed tests; emerging pathogens such as West Nile virus,
SARS and BT agents, existing parasitic agents which we know, many of them are
transmissible, and we don't have any tests available for those assays; potential
blood donors which are exposed to this, such as TSE agents, or for those for
which we do not have tests available, and which results in a significant loss
in the donor population, and therefore it becomes an issue of blood
availability.
Also,
some of the people who have -- on the basis of certain other tests, and how
those can be re-entered, such as the ones you heard yesterday with the proposal
for -- therefore, the regulatory and scientific challenge based on those public
health impacts is to evaluate sensitivity and specificity of such donor
screening, as well as diagnostic tests for retroviruses, donor screening tests
for hepatitis, West Nile, bacterial, all those agents out there, and to
maintain the safety of the blood supply by assessing the efficacy of thes
existing screening tests or the diagnostic tests, whether they are capable to
identify new and emerging agents, and also gaps in knowledge for critical path
development of protective blood screening tests for parasites. The purpose is not to develop assays, it is
to have a proof of concept or what we would call a gap in knowledge, so that
the information that we have can be useful for evaluating future tests for
these agents.
Some
of the examples in the blood safety and availability category. This is the Hillard group laboratory. The question she asked was, can currently
HIV licensed tests identify retroviral variants. As Dr. Epstein pointed out, this came out by looking at the tests
and based on her research in this area of HIV diagnostics, it became important
for her to evaluate performance of FDA licensed assays with new variants.
So
a study was initiated in Cameroon, because as Dr. Epstein pointed out, it is
the heart of recombinance, it is a country with evolving HIV diversity. What she found out is, one of the
recombinant, which is the major recombinant form, CRF-02AG, were not reliably
detected by some NAT -- so therefore it raises a very important issue, that we
need to have extended national and global surveillance of emerging HIV and
other human retroviral variants, as well as, we need to develop certain
standards of the reference panels which include all these recombinants or the
variants, so that in future tests we may identify them. A very important contribution.
Similarly,
the other contribution in the area of HIV and sensitivity of existing HIV
assays. This is work from Dr. Sabash
Dawin's group. The question he was
asking was, currently existing HIV western blot assays, how can we enhance the
sensitivity of these by modifying the conjugates, poly enzyme conjugates, by
making certain modifications. Again, it
came from his experience as a peptide chemist, and knowing the chemistry of
these things. So if we can modify those
conjugates, you can enhance the same tests, now you can enhance the sensitivity
of these tests.
What
does it do? By modifying the
conjugates, he could increase the sensitivity of the western blot assay, and
such conjugates could then enhance the detection of antibody early on. Let's say the current assays detect as early
as 22 days. With new enhanced
sensitivity, you could detect early on, therefore you can reduce the direct
impact on the public health.
Another
important example is the performance of the West Nile screening assay. As many of you know, the epidemic of West
Nile has been going on for the last four or five years. It became very clear in the very beginning
that this agent is transmitted through blood.
We need to have an assay for screening this agent and for validating
those tests we need to develop reference panels. Dr. Mario Rios in the group developed in collaboration with
industry and other academicians, two isolates of West Nile virus, genetically
characterized them, did the biological characterization such as detecting the
titer viral load, and then subjected it to seven different labs and different
assays, and based on those analyses, they formulated -- when they were
distributed to different laboratories, and based on the FDA's standard of 100
copies per ml, most assays had a satisfactory performance. Again, a direct impact on the validation of
these assays.
The
other important issue in the West Nile virus transmission is the question
whether the blood samples which cannot be detected by current screening assays
and are antibody positive, but sometimes many of them can be such a viral load
that they can only be detected by individual NAT, are they infectious. She asked the question, since she could not
do it in animal studies, to see if first of all in the human primary cell
cultures she developed, and asked the question whether such samples can be
infectious.
Most
of you heard yesterday her presentation.
I don't want to give you the whole data, but the result was that the
presence of antibody reduces in some cases but does not eliminate viral factor
in vitro. Mind you, this is an in vitro
study, and we had a significant discussion about how does it translate in vivo
and whether we need to do those in vitro studies at the moment.
It
raises a concern for potential risk for transmission until we have those
studies. Therefore, she is planning to
do in vitro effective studies to investigate in vivo. So therefore, the question is, what do we see in the field, what
questions we can recognize from looking at these problems post test, and how we
can solve these problems.
The
other good example is the example of comparing the sensitivity of HBV with the
HVG assays for acute HVG infection.
This study was done a couple of years ago by Dr. Bisswas and Dr. Tabor. They tried to compare several HVG assays
licensed or not licensed at that time, and compared the sensitivity of that
assay with the HVG mini-pool NAT or HVG single NAT, and to see that whether NVG
mini-pool NAT will enhance the sensitivity of licensed NVG assays, and
therefore reduce the window period.
The
outcome of that was a small sensitivity increase of pool NAT versus NVG assays
-- results in a marginal increase in safety, but the important observation was,
the implementation of a single donation of NAT will most likely increase the
safety of the blood supply. This issue
was discussed last year in VPAC, and based on that, the recommendation was made
that HVG pooled NAT is not recommended, but it can be used, because it can have
small sensitivity -- but the important thing is to move towards the single unit
NAT.
As
I said, not only the existing or emerging pathogens, but there are other
pathogens. Two years back, as many of
you know, we were hit with an onslaught of new emerging pathogens, West Nile
virus, SARS, monkey pox, name any of those.
So at that time, the issues were becoming very important for us, whether
those agents were having any impact on our blood supply and an impact on the
blood safety. Also, in spite of not having a test available, can currently
available inactivation processes inactivate such agents as for example SARS and
therefore insure the blood safety. Dr. Taylor in the Division has done
the study. She showed that using
solvent detergent, which is the currently available technology, can inactivate
SARS virus, and therefore it insured the safety of blood for transfusion and
blood products.
Another
example is another agent which is emerging which is present all the time,
malaria parasite. We don't have a
malaria parasite assay out there, and this is becoming more and more important
because of immigration from these areas, and people coming from this. In the country there is some transmission
going on, so what kind of tests will be developed? Again, this is a proactive example, if the test comes out tomorrow,
will we be able to evaluate that test?
Dr. Kumar in the Division developed a test using PCR assay, and also a
microarray test which showed a detection limit of one parasite per microliter
of blood, and also, not only can it detect the plasmodium -- the major cause,
but other species which are also contributing to the malaria infection, can
detect other species. So an example of
being proactive to what things can come down the pike.
Another
example is TSE detection. Currently
available detection is immunohistochemical staining of these tissues. It is very subjective because it is just
visual observation. Dr. Asher's group
developed an assay called quantitative marker for metric analysis, i.e.,
computerized digital analysis such as here shown. This is a control slide, this is a histochemical slide which is
stained, and then using QMA analysis, you can enhance the computerized digital
image and therefore it will improve the predictability and the sensitivity of
TSE detection. Again, a very important
contribution.
As
Dr. Epstein pointed out to you, as more and more agents become available,
blood-borne agents that affect the safety of the blood supply, we do not have
the luxury of each individual agent to be screened individually. So there is a way to detect these agents in
a multiplex format, or simultaneously.
The rationale is, increasing the number of agents that threaten the
blood supply, limited blood sample for detection. Therefore, what happens if you do so many tests there is a
problem with error rate, and we need rapid detection sometimes and simultaneous
detection.
So
based on that, in my laboratory we developed a multiplex detection, a
blood-borne pathogen chip, which has oligonucleotides corresponding to many of
these agents such as bacteria, parasite, bioterrorism viruses and agents, and
the regular blood-borne viruses like West Nile and HIV. This whole chip has all of the
oligonucleotides. It has also the
controls at the end. We can show that
simultaneously using three primer pair sets, we can detect three of these
agents, and the sensitivity was 50 cells per ml.
The
purpose here again was that we could detect three agents simultaneously, and
also to understand if there are some more applications which come to us, what
are the problems, then they will try to multiplex three or four or five, since
we have seen that there are some problems, and we cannot keep on doing N number
of multiplexes. So there is a certain
limit with this kind of technology.
In
the same thing, we are now looking at the new technologies like nanotechnology
and multiplexing, and Dr. Hiller's group is looking at that. Also, in collaboration with people in the
industry, we are trying to see how using mass spectrometry we can detect those
agents rapidly and simultaneously.
The
second topic of discussion today is the vaccine safety of these blood-borne
pathogens. The reason why we are
looking in the Office of Blood is because of the CBER wide unique expertise in
some of the blood-borne pathogens. It
profiles the need for all CBER wide.
For example, in parasitic agents, this is the only laboratory in the
CBER which builds with malaria and other things, so therefore it becomes a
CBER-wide unique expertise. Something like hepatitis-A, these are experts only
in the Office of Blood primarily because these are blood related issues, but we
can also ask the question for the safety of the vaccine related issues.
The
unique issues with the vaccine and blood product safety are testing for agents
in vaccines of blood donors, because that becomes also a question. An example which was given previously also,
there was a notion that we will be vaccinating en masse by vaccination. The question came up immediately, what is
the viremia in those donors, can those donors be also used because it became a
blood safety availability issue. The
studies were done by Dr. Hiller's group to show that is no viremia with these
vaccines, and also, those people who got the vaccine, testing their blood did
not impact the sensitivity of other existing tests.
So
therefore, it is very important to know how to respond, not only because of the
blood related issues, but also cross-cutting with the vaccine issues. Also, the role of therapeutic vaccines. I will show you an example of that, and
again, more importantly, the gaps in knowledge for critical path development of
these vaccines.
The
question was asked earlier, are we in the business of developing vaccines. No, we are not developing vaccines. The goal here is to have a proof of concept,
to show that when a vaccine is available, what are the issues, what are the
safety issues, what are the biomarkers which we can look at which will
determine the safety of those issues.
So therefore, the question is not developing the vaccine, but to have a proof
of concept. Also, it is very important
for people in house to know those issues, because when these applications come
to us, we should be able to evaluate when keeping any biological product in
concentration.
What
is the impact on the U.S. public health?
As many of you know, the millions of American travelers and thousands of
U.S. troops are deployed in all these parasitic endemic areas. There is an increased rate of immigration,
which raises the concern for potential for transmission. Known cases of transmission have occurred
through these agents. There are a
significant number of potential donors because we don't have any tests, and
therefore it becomes a blood availability issue. There are no vaccines available at this time. There is a lot of effort going on in
industry to develop various methodologies for these vaccines, especially the
parasitic vaccines. Similarly for the
HIV and HCV vaccines; those efforts have focused on specific areas, because we
know that millions of these HIV and HCV cases are worldwide and there is no
safe and effective vaccine available at this time.
So
the regulatory and scientific challenges for us are the assessment of safety
and development of biomarkers for effective parasite vaccines, cell culture for
some of these hepatitis viruses, because many of these viruses cannot be grown,
and therefore there is a very strong hurdle for developing of these vaccines
for these agents, such as HCV, hepatitis and others. Assessment of the efficacy of viral therapeutic vaccines such as
HIV and West Nile, and selection of markers for donor screening in the
vaccines, as I pointed out when I gave you an example of the vaccine.
This
study was done in my laboratory. We
showed that in looking at the leishmania vaccine as an example here, by
altering one of the essential genes which is important for the growth, this
parasite cannot grow in the form which is infectious. For example, this showed you the parasites in the macro phase,
the wild type, and this is the attenuated wild type, and you can see one or two
parasites. So what it shows us is that
by modifying, attenuating the gene by genetic manipulation, we could reduce the
integrity of in vitro by gene dilution, and therefore it raises the important
issue that such vaccine candidates can be used as vaccines on the outside. There is a lot of effort going on outside
which is looking at various forms of how to develop these parasitic
vaccines. Traditional methodologies
such as subunit vaccines or recombinant proteins have not really been fruitful
so far.
My
point was not in the developing of vaccines, but to show what are the safety
issues. If a person comes up with this kind of a vaccine candidate, and there
are examples out there which they are trying to develop such type of vaccines,
what are the safety issues with that in vaccine development.
Our
group showed that if we took this attenuated parasite and then analyzed the
expression of the genes in this parasite, we could find out there were several
genes which are affected, expressions lower or improved, and expression of
those genes can then be used as a biomarker for the vaccine safety. If you take this vaccine and inject it into
animals or into people, you want to monitor whether that vaccine is still
attenuated or not. By looking at the
expression of these genes, that can be one of the markers.
In
the area of malaria vaccines, a lot of effort has been going on in outside
developing various methodologies, and also the issues of vaccine safety, and
also whether these vaccines are biologically effective or not. Dr. Kumar in the group has been working on
this issue, where he took the approach of developing a multiple antigen peptide
vaccine which has various epitopes which are in both the humeral and the
cellular response, different proteins at various life cycles. It has been shown from the literature and
what is out there that a malaria vaccine which will be only good which will
represent different stages of life cycle.
What
he did was, he developed this multiple antigen peptide and then looked in mice
at different genetic background and found that there was a good humeral as well
as cellular response, from moderate to high.
This is the humeral, this is the cellular response. He compared the two mice with the same genetic
background, except one that is a B6 and HLA-2, which is a human HLA-2 gene,
which could get the protection in the sporicide inhibition assay. So the response could protect the sporicide
inhibition, but could not do in the B6 mice.
So
the issues are very important issues, because one would think when you have got
a good response it will be protective.
However, his analysis showed that it is not uniform. A very important issue for the safety issue.
Another
example is the developing cell lines which can grow these hepatitis
viruses. I can give you an example here
of hepatitis-A virus. Dr. Kaplan's
group has shown that he has developed a cell line where wild type hepatitis-A
virus can be grown. Now this cell
culture system provides us a very effective tool for making modification in the
virus genome and then asking the question how that virus application can be
attenuated, as well as, it also provides us a diagnostic tool to detect blood
products which are infectious and therefore, this will be a very important
contribution.
The
other area of vaccine related issues which are coming out, standing out from
the work done in the laboratory, looking at the blood product, how it can be
impacted in other areas. This is a
slide showing work done by Dr. Darmon, where he showed that PAT protein
enhances the viral replication.
This
is a -- formation assay here, and he showed that there are certain epitopes in
this protein which enhance the replication of the virus, such as the epitope 21
to 40 and 53 to 68. So therefore, using
those epitopes, one can use as a therapeutic vaccine to prevent further
infection, and therefore could be used as a therapeutic vaccine. So therefore, a very important observation
which could be applied in the vaccine area, HIV vaccine area.
The
last issue, not least, is the manufacturing issues, especially focusing in the
TSE issue. Again, the U.S. public
health impact, millions of Americans who have visited or lived in the United
Kingdom and other countries and have got exposed to these TSE agents. We do not know how many people there
are. There is uncertainty about the
incubation period of these things, and the TSE contamination of blood products
has shown to be causing fatal infections.
There are now documented cases of transmitted cases.
The
manufacturing issue. The regulatory and
scientific challenge for us is to establish criteria for accepting TSE
infective -- claims in the biological products, whether it is a blood product
or a vaccine product or any other product, establish the criteria for accepting
TSE infectivity in the contamination claims.
The issue is, when this manufacturing is done, the probability is that
the instruments and other things can be contaminated, so what are the ways we
can validate those decontamination claims.
Most importantly, gaps in the knowledge for the development of the TSE
detection assays that Dr. Epstein had pointed out earlier also.
This
is to give you an example of what the TSE prion diseases look like. This is control prion in infected brain, and
this is early case of CJD, late stage of CJD, and VCJD, which has a different
pattern of format, and this shows you the immunohistochemical staining in the
lymph nodes.
The
issue is, are all the prions infectious.
The discovery made by Dr. Picardos has shown that not all prion proteins
are infectious, because the prion proteins are protein sensitive, and they
generate protease insensitive. So they
become resistant to protease digestion.
You can see both the high molecular and low molecular advance.
What
his data showed is that prion protein infectivity is only associated with the
high molecular advance, not with the low molecular protein resistant forms such
as the example he gives, GSS, which only generates the lower molecular weight
forms. It was shown in animal
experiment in transgenic animals that this does not cause the disease.
Therefore,
what is the significance? This becomes
very important from a diagnostic point of view, because if there was an ELISA
assay which will pick up all the forms, we will know that it may be
infectious. But having this kind of
assay, which is the western blot assay here, we can distinguish that not all
prion proteins are infectious, and therefore it could be important for looking
at the animal derived materials.
The
other example is, I am showing the decontamination of the procedures. Dr. Asher's group, what they did was, they
validated WHO recommended TSE contamination protocols which included treatment
of sodium hydroxide or sodium hypochloride plus autoclaving. They took a scrapie vein from mouse, put it
onto needles on glass plates, and then subjected it to this treatment. What they found was that this treatment
effectively removes, and therefore this is a validated assay.
So
in summary, where are we going? The
future directions for us are to come to validation of new technologies to allow
rapid, sensitive, multiple detection of new and emerging blood-borne
pathogens. Look for how the prevalence
and diagnostic significance of HIV variants, HIV mutants, will impact our
ability to screen those agents.
Focusing on the emerging pathogens such as West Nile virus and other
agents, God knows what, that are coming down the pike, looking at the
infectivity of blood, looking for standard development for validation of those
assays. Then in the area of CJD-VCJD,
the contamination and detection is another area where we are focusing. The development of biomarkers to predict vaccine
safety and the attenuated parasite, similarly focusing on the assays for developing
the cell culture system for hepatitis to evaluate both the blood product and
vaccine safety, and similarly in the area of viral therapeutic vaccines, see
how future vaccines could be developed based on the studies done.
So
in summary, the mission relevant research in ETD, in the areas of viral,
parasitic and TSE diseases, improves not only OBRR's but CBER's as a whole
ability to evaluate the safety and efficacy of blood and blood products and
vaccines. I just want you to take this
message home, that that is the whole purpose of my presentation, and the
purpose of our being in the Division of Emerging Transfusion Transmitted
Diseases.
Last
but not least, I would like to acknowledge the folks, because I am only the
messenger here, so I am just giving you the examples of all the principal
investigators. Some of them I did not
present, some of them I did. I
apologize to those who I did not, but the point was here to show the examples
to see how is our research important for our mission relevance.
The
area of safety and efficacy of human retroviruses, West Nile, smallpox, donor
screening and diagnostic assays, Dr. Hiller, Sawash Darvon, Andrew Dayton and
Mario Rios are the PIs, that is the work presented from their group. The safety and efficacy of donor screening
assays for hepatitis and emerging viruses, the PIs in that group are Dr.
Kaplan, Dr. Taylor, Dr. Tabor and Dr. Bisswas, whose present work I presented
here. Safety of blood from the risk of transmission of parasitic agents and
safety of such vaccines incudes my group, Dr. Kumar and Dr. Alan Debberman, and
the safety of biologics from transmission of TSE en cephalopathies, Dr. David
Asher and Dr. Pickard.
Thank
you very much for your attention.
DR.
ALLEN: Thank you, Dr. Nakhasi. I am convinced. And bonus credit for coming in with the green light still
on.
DR.
DIMICHELE: I know we are trying to save
questions for the end, but I just want one clarification question. Just help me understand the critical path
issues. Let's say we have three
pathogens. We have West Nile, malaria,
leishmania. For West Nile as West Nile
was emerging, the emphasis went into diagnostic testing, not vaccines. Then very rapidly we had a diagnostic test.
Now,
with malaria and leishmania, the approach -- since we don't have diagnostic
tests, right now the approach is into vaccines. I am just trying to understand from a critical path standpoint
how those kind of decisions are made.
And as a corollary to that, for instance, let's say you develop a
malaria vaccine, how are we going to use that vaccine, let's say, license that
out to someone who makes vaccines, how do we use that vaccine to then protect
the American blood supply from malaria?
DR.
NAKHASI: I think that is a very good
question. I think you point in the
right direction. In the area of
parasitic diseases, you said they are not having an immediate impact. As you saw I gave you an example of both
detection as well as vaccine. We also
are focusing our efforts not only just for vaccine safety, but for the
diagnostic areas.
Now,
because there was minimal effort, we had to put a lot of effort in the West
Nile area. The second question is, once
we have a vaccine, how do we go ahead with this technology. Again, here the point I was trying to make
is not really develop a vaccine, it is to have a proof of concept with regard
to the issues which are relevant to the safety of that vaccine. Tomorrow when the vaccine comes on our door,
we as reviewers should be able to ask a specific question, should be able to
review the aspects of the safety issues.
The
example that I gave you for malaria, even though the humeral response was good,
the biological response was not with this approach. So therefore, we know a vaccine comes, we are up to the part of
knowing that there could be. So if we
do develop a vaccine, as Jay and Kathy pointed out to you, there are ways to
transfer technology and things like that, and those people who are involved in
that project will not be able to review that, so therefore, the conflict is not
there.
But
the important point here, the take-home message, is not -- our role is not to
develop a vaccine. It is to insure what
are the issues that the vaccine production -- it is like a safety issue or
biomarker issues.
DR.
DIMICHELE: But if I could just extend
my question for a second, in the meantime you are focusing on vaccine, and
thinking that at some point you might be evaluating vaccines, and now are going
to be in a better position to evaluate vaccines. So how will that translate back into public safety? Do you envision for instance everybody going
overseas being vaccinated against malaria, so when they come back, there is no
chance of having malaria enter the blood supply, and therefore be at risk to
other people? Is that the thinking?
I
am just trying to understand what the public health strategy is, because
obviously you have that in mind, I am assuming.
DR.
NAKHASI: Of course. Before that, I think Kathy Carbone is trying
to --
DR.
CARBONE: I am going to let Hira off the
hook a little bit. Given our incredibly
thin level of expertise, Hira has to with his Division deal with Center
priorities, not just blood priorities.
Since we have no malaria, leishmania, TSEs as far as expertise in the
Office of Vaccines as a Center priority, he group must address both blood and
vaccine issues.
As
far as how a vaccine is used and how we envision, something to keep in mind is,
the FDA regulates what is presented to it.
We also try and be proactive, try and support the public health, but one
could ask the same question, if you have a licensed product A, why bother
dealing with B, C, D, E, F? Because we
have to.
I
agree with some of your thoughts and concerns about how you would utilize the
malaria vaccine, et cetera, but from the point of view of a malaria vaccine
that would be useful for troops going overseas, et cetera, the fact is, if it
is presented to us, we have to deal with it, and we have to know how to deal
with it.
But
I do want to let him off the hook a little bit in terms of prioritizing,
because he is forced to do things for the entire Center that may not be
directly on target for blood.
DR.
DIMICHELE: I just wanted to clarify
that. My line of questioning was not
critical. It was more trying to
understand just how it fit into the processes.
That is all I was trying to do.
DR.
CARBONE: I am trying to help him with
it.
DR.
WANG: I have a similar question on the
same line. Many, many good evaluative
methodologies developed, but I am not clear about the application aspect. Are you applying all these methodologies in
house in checking on all the products, or are you just publishing it, or
actually trying to push for everybody to use it? Are they truly on the cutting edge among all the methodologies
that are available at this point?
DR.
NAKHASI: That is again a good question,
how do we apply. First of all,
obviously we publish these studies. It
just makes us ready for eventualities, when these things come up. There are ways by which one could then see
that the technology modification, for example, the example I gave about the HIV
enhancing the sensitivity of the modification.
So
there are issues by which people have thought about they come to us per
application, and they discuss this at the pre-IND stage. We provide them the information, because we
have seen the failures and successes.
Therefore from that vantage point of view, we go ahead and then provide
advice so that you can avoid those pitfalls, don't go this way, go this
way. That again only comes from our
experience on doing the research.
Jay,
you wanted to say something?
DR.
EPSTEIN: Back on the earlier point
about vaccine work versus blood problem targeted work, when I recruited a new
director in the Division of Emerging
and Transfusion Transmitted Diseases, Hira was our lead candidate. But I knew full well that his background in
CBER was vaccine research, and that that was critical to CBER.
So
the point is, you had asked earlier, what is top down, what is grass
roots. Part of the agreement when Hira
was hired was that work in his group would concurrently look at issues highly
focused on blood such as diagnostics.
So what you would find is that in many of the branches working on
vaccine, there are always concomitant projects looking at issues that are more
directly blood safety related. That is
how we have managed that arrangement with responsibilities for CBER versus
responsibilities of the blood program.
So
I think we shouldn't overstate the immediate relevance to the blood program of
the vaccine research, although there are some very good historical examples
such as the plasma derived hepatitis-B vaccine which was in fact developed in
the forerunner of the blood office; it was then the Division of Blood and Blood
Products. There you had a very direct
relationship between a vaccine made from blood, which also protected the
general population but in particular reduced the hepatitis-B risk from donors,
as you have more vaccinated donors, which has finally come to pass.
But
that link is not always there, to be honest.
However, direction of the work insures that there will always be
relevant projects.
DR.
SCHREIBER: I guess I have the same
uncomfortableness with the pathway as I have been hearing. One of the problems that I have is, I think
there is a lot of very important research done, but I am not quite sure how
useful the research is in terms of FDA.
For
example, we talked about the vaccine, and you talked about using
biomarkers. It would seem to me for the
community who are working on vaccines that the follow-through for the pathway
should be that if you have an application, FDA will accept these markers as a
measure of efficiency. But what I am
hearing is that that gets out into the literature, and it is up to somebody to
pick that up and say, here are some markers and we will use this, as opposed to
a policy. The same thing with Indira's work, where there might be some HIV variance missed.
What
I don't hear is that you take that information and go back to the manufacturers
of the test and try to either push them into the direction to make changes, or
you do something that affects FDA policy.
DR.
NAKHASI: I'm sorry if I didn't make
that point clear. We do that. I think the purpose again, as I pointed out
to Dr. Wang, that the efforts which we do many times develop into
policies. For example, for HBV NAT,
when we did the HBSAG and the comparison with the HBV NAT, that was the policy
-- the results of that research became a policy, that at this point HBV NAT
cannot be recommended. So that was from
that.
Similarly,
for the other issues, we develop the guidance documents. Unfortunately, these guidance documents take
a little longer time to come out, but whatever research efforts are done
internally, they are put into some form or other into guidance form so that it
is available to the people when they are looking at it.
For
example, these biomarkers. Definitely
this is a study that has not been published.
Therefore these issues become much more concrete. It will be important for us to develop a
guidance which we could then use for the purposes of the manufacturers.
DR.
ALLEN: I think your question in
general, George, is of the type that this afternoon we will need to wrestle
with, with the advice certainly of FDA senior staff. But I think those are the issues that we need to deal with.
DR.
ALTER: I agree with the statement that
we can't keep chasing each agent with a separate test. If we don't go the inactivation route, which
would be the most preferable if it became practical, the multiplex idea is a
very relevant and practical issue.
I
was interested to see you already have some data on gene arrays. We have been trying to do that. I have spoken to Rausch, and I was surprised
that Rausch who is pushing it still feels this is much more difficult than they
initially conceived. We are finding it
very difficult to develop.
So
I was wondering, is the data that you seem to already have data, where does
that stand, and how easy is it to do?
And is it relevant?
DR.
NAKHASI: I think that is a good point
again. I think there are limitations to
every -- when you do it in the laboratory versus when you go into large
scale. What we wanted to show, there is
proof of concept, that it is achievable.
The
thing is that multiplexing is already on the way. You have HIV, HCV multiplexing two agents. There are more agents trying to be putting
together some things in detection. So
the question is what are the issues in there, focus on the issues. If we put more than two or three primers in
there, will they affect the sensitivity and specificity of that assay. I think that is where we are putting our
focus; whether the microarray technology
as such can be translated, that needs to be seen.
But
I think the important thing is to understand the basic science and the issues
relevant to that. I think that is where our focus is.
DR.
ALTER: Can you get sensitivity out of
the microarray?
DR.
NAKHASI: I showed you 50 cells, what we
can do at this time. But obviously we
need to get much higher sensitivity, because there are certain issues which we
are still working on.
DR.
KLEIN: At the risk of being accused of
throwing you a softball, I think it may be a little unfair to say you showed
data on leishmania and vaccine, but aren't you also involved in the testing
aspect of that, knowing that you need some expertise there, and there in fact
is a test, but it is not yet ready for prime time in terms of screening?
DR.
NAKHASI: Sure.
DR.
KLEIN: So it is not either-or, really.
DR.
NAKHASI: No, no, it is not either-or,
it is both. I think that is the
thing. It is not either-or. That is why I pointed out that we are doing
both areas. It is not only just the
vaccine issue and not only the blood.
All these issues came out because there are separate other vaccine
issues, but these are much more relevant to blood product issues, and those
came from not only the screening and the diagnostics, but the vaccination.
DR.
KLEIN: Because this is in fact an issue
of importance to blood transfusion today, and one that the Blood Products
Advisory Committee has pointed out in the past.
DR.
NAKHASI: Absolutely, thank you very
much.
DR.
CARBONE: I hear circulating around this
common theme of how does it relate, how does it feed back. I just wanted to do a cycle that we work off
of. One is, we can't tell you often the
specific product or issue that this came from.
We can't tell you, it is proprietary.
So what we do is, if we see this popping up in several different
applications, we pick up the problem, we work on it.
I
believe your data already is published on this multiplexing. We will put this out in the public domain,
not taking any proprietary data, but taking the problem and working on it. It now is out in the public domain in a
publication or a guidance, so that new sponsors circulating through can look at
this information and say, ah-ha, here is a possible avenue, here is something
they showed didn't work.
So
this is a way of communicating across a whole field of products. That is the whole point about critical
path. What we do is unlike a sponsor's
effort to solve a problem that might be between the sponsor and the FDA. We can take a problem you see routinely and
put something in the public domain or in a guidance and help the entire field
move ahead. Unfortunately, the direct
link we simply can't say because it is proprietary information.
DR.
ALLEN: We have got a couple more
requests for questions. Let me just
remind you that we need to get our last presentation in and then come back to
the more general questions.
DR.
WANG: There is one point I am still not
very clear. When you draw the
guideline, are you just drawing it based on your own research results and new
methodology, or are you covering the entire field, all the new development
methodology including proprietary information from individual companies, to
come out with the best testing methodology to recommend to the public? How do you do this, or is it just from your
own view?
DR.
NAKHASI: There are several layers into that. One is what we know out there and where the
areas of improvements, the areas of need, we focus on that. Also, some of it comes from -- because you
can't cover the whole waterfront here, and also it comes from the particular
research area, where the particular individual person is focused on, and sees
how connections can be made to the other needs. So it is a combination of that.
DR.
ALTER: Just a quick observation. It seems to me that the time line for the
critical pathway is identical to the time line to adjusting the air
conditioning. It is still freezing.
DR.
ALLEN: I want you to graph that into a
slide for us.
With that pertinent observation, we will move on
to our third division overview. Dr.
Basil Golding, who is director of the Division of Hematology, will provide us
with an overview of the research program for that division. Dr. Golding.
Agenda Item: Overview of the Research Program
of the Division of Hematology
DR.
GOLDING: Good morning. I would also like to thank the committee and
the audience for this opportunity to present the research that is being
performed in the Division of Hematology.
I am particularly proud to do so, because I think the research is of
high quality. I think my charge here
today is to show you this research in its best light, so you can make your own
decisions about the quality.
The
Division of Hematology has an organization which is shown on the slide. We have a Laboratory of Biochemistry and
Vascular Biology headed by Dr. Aliyash, the Laboratory of Cellular Hematology
headed by Dr. Vastow, a Laboratory of Hemostasis which has an acting lab chief,
Ten Lee. The Laboratory of Plasma
Derivatives is headed by Dr. Dorothy Scott, and the Clinical Review Branch is
headed by Dr. Silverman. So we are four
research review units and a clinical review branch, and we do have weekly
seminars, and a lot of databases with the review branch which provides us their
insight into the gaps in the research that we need to do.
Each
branch has a certain number of PIs that are distributed as follows. I will be inclined to present the work of
these PIs, these principal investigators.
I should point out that you have asked questions about resources. Nearly all these PIs are heavily involved --
all of them, I should say, are heavily involved in review work; at least 50
percent of the time is in review. The
support staffs are one or two people, and the review staff is also heavily
involved in review work, except for the occasions where people are able to
generate outside money and use that money to hire postdocs and other technical
assistants that can then be fulltime workers.
We have been able to generate two other PIs, Dr. Rular and Dr.
Scott. We were able to successfully
apply for biodefense money from the National Institute of Allergies and
Infectious Diseases. Other PIs over the
years including myself have obtained intramural grants from the NIH for AIDS
research and from the Office of Women's Health.
The
money for those grants is hard to come by, it is getting harder to come
by. We have dwindling resources. If we had a graph plotting out budgets over
the last five to ten years, you would see a line going down. There has been a lot of mention of the
critical path. I would like to point
out that the critical pathway has not been funded by Congress or by anybody
else. While it is highly endorsed by
CBER and I think by the FDA, we haven't seen any money to support that
program. So when we identify gaps and
we want to be flexible in dealing with problems, we drop everything else and we
do what needs to be done, but I think it is getting increasingly more difficult
to do that and I'm not sure how long the situation will continue to be feasible
to do that if the resources continue to decrease.
The
scope of regulation in our Division is very broad. We look at similar components of blood such as platelets, red
cells and so on. We look at plasma
derived proteins and analogous recombinant proteins such as Factor VIII. What I would like to point out that if you
think about it from an academic discipline point of view, the scientists in our
Division are very diverse. The reason
for that is that the scheme which is used to make products from plasma can be
used to make products that are regulated by our division. We need that expertise in one Division
because the manufacturing process and the scientific questions arising from
that are all related to this process and the products that can come out as a
result of that process.
The
clinical indications are diverse and include bleeding disorders, shock,
hypovolemia, infectious diseases often associated with immunological deficits,
and replacement therapy in congenital or acquired deficiencies related to
coagulation factors, but also other plasma protein deficiencies that you will see
in a moment.
Our
research priorities are in terms of resolving problems that are critical path
related, and we divide them into these three headings. As was pointed out before, the mission of
the FDA is to assure safety and effectiveness of products, and we now have the
additional change of being involved and engaged in counterterrorism review and
research.
From
a safety point of view I am going to give you a few examples which relate to
product toxicity. The one I am going to
talk about is hemoglobin based oxygen carriers. I am going to talk a little bit about contaminants of plasma
derived products, particularly microbial contaminants, and also mention some
research related to hepatitis-C virus transmission. In terms of efficacy, if I have time I will talk about the
standards that have been developed in our Division and that are critical for
the regulation of these products, assays that have been developed to look at
potency for many of our products, and animal models. The example I have is for platelets. In counterterrorism the two agents that we focus on are anthrax
and smallpox, which I think are highest on the list. We have looked at these in terms of in vitro assays of potency
and animal models.
I
would just concur with what has been said already, that by engaging in a lot of
these areas, we have developed a scientific expertise that allows us to
regulate these products effectively.
Dr.
Epstein mentioned this work, so I can go through these slides quickly and maybe
save a little bit of time in my presentation.
The public impact is clear in situations where red cells are not
available. The regulatory and
scientific challenges relating to that; what we found with our products is that
it is very important to establish what the structure-function relationship
is. Because hemoglobin by itself is
toxic, it has to be modified in order to be used as a product, and we found
that it is very important to look at these chemical modifications in a lot of
detail. The example that I will give
you will show that. We have also been
involved in developing -- in vitro and in vivo assays for looking at efficacy
and safety of these products.
One
of the first generation hemoglobins was made by cross linking with hemoglobin
using oxidized -- these assays were done in the laboratory of Dr. Aliyash. When we looked at normal red cells and
hemoglobin we get a very nice curve.
With this product, we were finding a non-sigmoidal oxygen equilibrium
that was non-saturating and was non-cooperative, and it was not sensitive to pH
changes.
Detailed
investigation of the structure of the hemoglobin revealed the exact nature of
the abnormality of this hemoglobin. The
molecule consists of a heme and a protein part. The heme part was studied by EPR and the normal heme is shown
here. It facilitates the movement of
iron in a vertical plane up and down as oxygen is down in an unrestricted
manner.
When
we looked at this molecule, we found that this molecule was asymmetric, that
the iron instead of moving up and down moved towards one of the nitrogen atoms
and we think as a result of that destabilizes this molecule.
The
protein part of the molecule normally binds oxygen and moves back and forth
into an oxidized and non-oxidized state.
When it is oxidized it is termed a relaxed state and gives up oxygen
quite easily. In contrast, when we
looked at the abnormal protein, when oxidized it moved into a locked state and
was not able to be easily reversed into the tense state, and this also explains
why this hemoglobin did not function normally.
Looking
at it from -- this is a crystal structure of a hemoglobin molecule. What the company thought they would be able
to do is cross with these lysines and stabilize the molecule. What we found by various mass spec -- that
it modified some systems, and that this resulted in the abnormal function of
the molecule. This particular system,
C-93, is in very close proximity to the iron in the heme group, and probably
explains why we noticed that abnormality in the heme.
What
these studies have done is, we have looked at a particular hemoglobin, but we
now have a framework of looking at these modified hemoglobins, and we know how
to approach this. This was published,
and anybody in the field can now benefit from this knowledge in characterizing
and developing their hemoglobin products.
It also gives us a handle on looking at these products before we get
started into clinical trials, and hopefully trying to improve the field so that
the second generation products are more likely to succeed.
This
was work done by Dr. Gula, who is also in Dr. Aliyash's group. What we noticed is that a lot of the first
generation hemoglobins were associated with particularly vascular toxicity. So what Dr. Gula set up was an endothelial
culture system. This is a --
endothelial cells shown as contrast. He
looked to see what happens when he took one of the first generation hemoglobins
and incubated it with oxidation compounds, which will happen in ischemia and
trauma. What we found is some of the
cells were floating on the surface, and when we did a -- for apoptosis, we
found that these cells were undergoing programmed cell death. So clearly this is an assay that could be
used to assess hemoglobins in the future.
We are trying to correlate the assay with in vivo toxicity.
The
next project that I will go through very quickly, one of the products that we
regulate is alpha-1 proteanase inhibitor.
Most patients with hereditary deficiency develop -- in the third and
fourth decade of life, and about 15 percent develop severe liver disease. Such deficient patients can obviously
benefit from augmentation therapy.
The
challenge to us is, we notice that these products do have problems with
polymerization and aggregation, and we think this could be related to -- this
is work done in Dr. Schaeke's lab. The
crystal structure of alpha-1 PI is known by other work. The first theory was proposed based on
indirect evidence is that due to manufacturing, alpha-1 PI does become
partially unfolded due to various treatment.
For example, heat treatment for viral inactivation can unfold this
molecule partially. The theory was that
this flexible loop, as the molecule become unfolded could then insert itself
into the beta sheath of the next alpha-1 PI, so we would get a head to toe polymer
formation. That was work described in
the literature as how polymerization occurs.
In
Dr. Schaeke's lab, what they did is a series of experiments, and I am only
showing one of them, and this is published, where they took one that was
partially unfolded and incubated it in buffer for various periods of time, and
then passed it through a -- HPLC and got the following tracings. For a short incubation, what you see is a
monomer peak, a dimer peak and some polymer formation. When you left alpha-1 PI in buffer for a
longer period of time, the monomer peak remained the same. There was no difference in concentration of
the monomer peak, but the dimer peak started to shrink, and you started to get
very high level of polymer formation.
So based on this and other data, they came forth with the following
proposal, that you first got dimer formation, and the dimers then combined to
form high molecular weight polymers, and this is the more direct explanation of
why polymers occurred.
What
are the implications? We have here a
new understanding of polymer-1 formation.
This knowledge can be used to minimize unfolding of monomers and dimer
formation during manufacturing, for example, by adding appropriate stabilizers
during heat treatment. In the future,
this work will investigate the conformational change in the dimers that result
in spontaneous polymerization.
Immunoglobulin
intravenous. This is work done from my
own lab. We have been aware for a long
time of the issues with patients with this product. A very high percentage have developed a reaction, some of them
severe, but definitely causing the patients to complain about fever, headaches,
chills, indicating or suggesting at least a prior inflammatory reaction. This product when it is made undergoes sterile
filtration, so the product does not have any bacteria, but we know from the
manufacturing that upstream there is some bio burden, and it is very likely
that microbial components are -- in the product, and we do find LPS and
bacterial DNA in the product, and there are strict limits as to how much of
this is allowed.
So
our concern is still about -- we would like to find out how to detect other
bacterial components and maybe devise mechanisms to reduce this contamination
to improve the product safety profile.
What
are the regulatory challenges? The need
for rapid high-throughput assays to detect microbial components in these
products. By the way, this is a
cross-cutting issue, because many of the products made in CBER could end up
with microbial components, so I am only talking about our Division, but I think
this could have CBER wide implications.
So what we are trying to do is to adopt cell lines to express receptors
as a detector system for microbial components.
Our
immune systems have evolved so we know the immune systems have a whole array of
TEL receptors on their surface that can recognize most pathogens that are out
there. What we are trying to do is to
take these TEL receptors and use them as a detection system for microbial
contaminants.
So
for example, it is known that LPS will bind to TEL-4, lipopeptides bind to
TEL-2. This is on the cell
surface. Within the cell there are
other TEL receptors that are sensitive to bacteria components such as
doubled-stranded and single-stranded RNA, and are also sensitive to bacterial
DNA. All these TEL receptors signal NF
kappa-B to the nucleus, and what I am going to show you in the next slide is
that we are going to use this by introducing the reporter gene into the
detection cell line that has NF kappa-B regulation, and -- acting as a
reporter.
So
we double transvect these cells. These
are 293 cells, transvected either with one of the TEL receptors, but
co-transvected with the NF kappa-B reporter gene, so when these cells are
activated, a -- signal can be detected.
If
we now look at different microbial components, -- is a component of the cell
wall of gram positive bacteria, we get a really strong signal when we have
TLR-2 on the surface. When LPS is used
as a ligand, we get a strong signal of TLR-4 containing cell line, and when CPG
oligonucleotide is used, which is highly represented in bacterial DNA, we get a
strong signal in these cells.
The
outcomes we have shown with cell lines expressing TLR, and we are going to try
and develop cell lines with multiple TLR and the reporter gene can detect
microbial components. These cell lines
will be used to develop a record high-throughput system for testing
immunoglobulin products and other CBER products for microbial contaminants.
This
is the Laboratory of Cellular Hematology.
They regulate similar components such as platelets. The public health impact, ten million
platelet units are transfused annually in the United States. Transfusion of sub-optimal products leads to
decreased circulation and the need for more transfusions, increased risk of
infection and allo-immunization.
The
regulatory and scientific challenge I am going to be talking about is to
develop a test for efficacy. In vitro
tests are informative but not predictive, and the in vivo test is an in vivo
survival of radiolabeled platelets in humans, which is burdensome.
The
other project that I am just going to allude to but not show any data is that
we think there is a real problem that platelets and other cell components give
rise to micro particles which can be associated with adverse events to these
products.
So
in terms of platelets, this is using immune deficiency SKD mice that don't have
much of an immune response. If we now
take normal platelets and we infuse them into normal mice, they are very
quickly cleared. In contrast, if we
infuse them into SKD mice, they are cleared over a period of time which we
think can be used to measure survival time of human platelets.
This
is a proof of concept experiment. We
took one day and seven day old human platelets to see if these mice could
detect the difference. This is
percentage of platelets. What you find
is, the one day platelets have a very nice survival time, but then when you
start to look at the seven day platelets it is much reduced in the SKD
mice. So this in vivo assay could be
used to measure human platelet survival and used for product development.
What
I haven't shown you for lack of time is, we have also developed a cytometric
assay to measure micro particle and platelet products. This will enable us to determine whether
micro particles in products are associated with adverse events such as
thrombosis and inflammation. He has
published some of this work.
In
terms of viral detection and antiviral antibodies in immune globulins, this is
one of the areas of close connection between our group and the other division,
Dr. Nakhasi's division, in terms of emerging viral diseases. The public health impact, an estimated two
million Americans suffer from hepatitis-C infection. About 70 percent of them go on to develop chronic hepatitis, and
liver fibrosis, cirrhosis and hepatocellular carcinoma.
The
regulatory challenges relate to screening plasma for hepatitis-C, measuring
hepatitis-C viral neutralizing antibodies in preparations that would have
hepatitis-c immuno globulin. There is
no -- currently in in vitro system there is no animal model available for
looking at HCV infectivity. There are a
few labs that can now grow HCV in vitro, but this is very difficult. I am told recently chimpanzee was the only
model.
This
is a system developed working with Dr. Fizelle at the NIH. They developed a system, and Dr. Yu has been
working with them to neutralize the system to answer some of our research
regulatory questions.
Very
briefly, what they were able to do is make these pseudo particles by using HCV
envelop protein, structured proteins from HIV and green fluorescent protein
into these cells, and the cells will then release these pseudo particles. When you take the pseudo particles and add
them to liver cells, the HA-7 cell line, if these cells can successfully enter
the HA-7 cell, in other words, they have a functional HCV envelope, then you
get this green fluorescence which can be easily detected by flow cytometry. If on the other hand you incubate these
pseudo particles with a neutralizing antibody, you should prevent the entry and
infection of those cells.
So
these are experiments done by Dr. Yu in collaboration with Dr. Fizelle. What they show is that there is a correlation
with what she had previously shown in the chimpanzee and the pseudo particle
assay. She took a control immune
globulin that did not have any anti-HCV, that had been treated with solvent
detergent so it should not have any RNA from the product, but then challenged
the chimps with HCV. This product could
not protect the chimps. It had a low
titer antibody and could not protect.
When she took a high titer antibody which was also inactivated and again
challenged the chimps with viable HCV, this high titer antibody could protect
the chimps. So the pseudo particle assays are being correlated.
If
you take immune globulin preparation that has not been used at this point in
time but was made many years ago, and this preparation was not virally
inactivated, does have RNA, but because it would have a high titer antibody, it
was not infectious. So even though
there was virus here, this antibody was protected.
There
was an interesting story that emerged in the '90s that I am not going to have
time to tell you about, but just to say one fact. Before viral inactivation was instituted, it was thought that the
immune globulin safety could be enhanced by having an ELISA assay to screen out
any positive units by ELISA. So in
other words, if there were antibody positives, you would assume there may be an
infectious risk until those products were removed. But unfortunately what happened, some of the products got by that
had no antibody, but they did have virus.
So as a result there were a large number of transmissions from one
particular product.
So
what Dr. Yu did in this study is to correlate that data in terms of hepatitis
transmission and the pseudo particle assay.
She works now with lots that were made quite a long time but they were
not screened, in other words, they had antibody against hepatitis-C virus. There was no evidence of hepatitis
transmission. In contrast, when the
screening took place, what that effectively did is make sure that there was no
antibody in the product, and then we started to see cases of transmission. So again, a correlation of this pseudo
particle assay showing that when antibody is present in humans, you don't get
transmission, when antibody is absent, you do get transmission.
In
effect, the HCV neutralization in the pseudo particle assay correlates with
infection or lack of infection in chimps, and the pseudo particle assay can be
used in a neutralization assay, which will facilitate development of new
hepatitis-C and immune globulin products.
Future plans include identification and characterization of neutralizing
epitopes.
A
major public health issue is patients who receive Factor VIII and Factor IX
developed inhibitory antibodies. These
neutralizing antibodies to coagulation factors complicate the use of Factor
VIII and Factor IX, and in hemophiliacs, about 20 percent of the patients have
this problem.
What
are some of the research regulatory challenges? Understanding the genetic factors that control whether patients
make antibodies to Factor VIII and Factor IX, and developing preclinical models
to predict product safety and efficacy.
Those two issues are intertwined.
What
Dr. Laser has done is, using genetically well characterized inbred mice, he has
shown that there is a high correlation to certain genes and development of
inhibitory antibodies. These genes are
the MHC genes mainly, but to a lesser extent T-cell receptor genes, the zinc
alpha-2 glucoprotein-1 gene, and that these influenced the antibody response,
and that MHC genes and to a lesser extent cytokine genes such as IL-10 and
interferon gamma control the antibody response to Factor IX. This was to Factor VIII.
He
has also shown, using the hemophiliac dog model, that the Chapel Hill
hemophiliac dogs have a genetic defect identical to that in about 40 percent of
humans. So if you look at a normal dog,
this is a tissue analysis, and you see the color distribution is different,
indicating a DNA rearrangement. In
fact, this is an inversion which very closely mimics the human defect. In addition, the bleeding phenotype is
identical to human hemophilia A, and the dogs making antibodies were treated
with dog Factor VIII.
The
outcomes of mouse genetic studies provide clues for problems of genetic
predisposition to induction of inhibitory antibodies in humans. The Chapel Hill hemophiliac dogs are an
ideal model for preclinical evaluation of products with potential to induce
inhibitory antibody.
In
the field of counterterrorism, one focus is anthrax. This is obviously a major threat to public health and security,
and the same goes for smallpox, which poses a potential bioterrorism
threat. Widespread vaccination is
expected to cause fatalities in susceptible individuals who have progressive --
this occurs in immune compromised people or eczema vaccinatum, which occurs in
people who have eczema or atypic dermatitis.
What
are the regulatory and scientific challenges to developing in vitro and in vivo
models to assist the efficacy of the products that we think will be coming down
the line? These are anthrax immune
globulins, and you have already seen vaccinia immune globulins.
So
in terms of anthrax, in the 2001 outbreak, five out of 11 patients died in
spite of intensive antibiotic treatment.
So combined antibodies from anti-anthrax antibodies may improve survival. The antibody targets the bacillus,
antibodies target the toxin.
Very
quickly we will go through this model because we like the research. Anthrax has three plasmids which call for a
particular antigen which forms a hiptomeric pull, which allows the edema factor
or lethal factor toxin to enter the molecule and to cause cell lysis and also
to induce edema.
For
proof of concept of an animal immune globulin, we did some pilot studies in
sheep. The sheep were immunized with
various anthrax antigens with protective antigen, a lethal factor for the stem
strain, which is a strain which is used for agricultural vaccine purposes. The sheep were immunized, the antibodies
were purified, and the purified antibodies were tested for ability to protect
these mice from a lethal challenge of anthrax.
This
is some of our results which have been published. If you look at the survival of the mice, if you treat them with a
control antibody the mice die; if you treat them with just the antibody by
itself, some of the mice survive after 11 days. If you treat with an antibiotic by itself, some of the mice
survive, but if you use the combination you get almost 100 percent
survival. So this is just the proof of
concept that using this approach could potentially improve survival in
patients.
In
terms of other in vitro assays, Dr. Dabul developed, using the endothelial
assay that I described for the hemoglobin, showed that if you make a monolayer
of endothelial cells and you pass a current through it, it is highly resistant
because it is a confluent layer, but as the layer starts to break down, you get
decreased resistance. So if you treat
with lethal toxin, the resistance decreases, but if you incubate together with
anthrax immune globulin, you decrease the effect of the lethal toxin to a large
extent.
The
other target of lethal toxin is the MEP kinase -- and MEP-1 belongs to this
signal transaction pathway. If you
treat cells with lethal toxin, it cleaves the product, and you cannot protect
this product. On the other hand, if you
add anthrax immune globulin, you block the effects of lethal toxin.
Just
to mention in terms of collaborations, this work was done in collaboration with
the CDC, and they provided us with the anthrax immune globulin.
The
outcomes. Proof of concept that
polyclonal antibodies made in animals can protect against anthrax toxins, and
in the process we have established in house, in vitro and in vivo assays for
testing the efficacy of anthrax immune globulin products.
Vaccinia
immune globulins. This is work done in
Dr. Scott's lab. The complications of
smallpox vaccination as I have already mentioned, you can get progressive
vaccinia in immune compromised people.
Historically the vaccinia immune globulin that was licensed many years
ago reduced fatality from 100 percent to 50 percent, and in cases of eczema
vaccinatum, the VIG reduced fatality from 30 percent to three percent.
What
are the scientific and regulatory challenges?
How can efficacy and potency for VIG products be assessed, and there is
clearly a need for animal models for severe vaccinia and for that case were
eczema vaccinated. What Dr. Scott's lab
has been able to do is develop a mouse model for vaccinia. These are SKD mice that are
immunodeficient. If you scarify one in
the same way that you would scarify a human after shaving off the hair, you
would find that you get these lesions developing over this time period. These are non-healing. Eventually the virus spreads systematically
and these mice die.
This
is some data from her lab showing mouse survival over days. If you challenge the mice with two different
doses of virus, they die. Dr. Itsing
showed pre-exposure prophylaxis, this is post exposure prophylaxis. If you inject the VIG on different days post
exposure, you can improve the survival and the extent of survival depends on
the viral challenge.
The
SKD model can be used to demonstrate that VIG can reduce -- both in pre and
post exposure treatment. This SKD model
was adopted by industry in support of licensure of one of the products.
I
am going to try and save a little bit of time by not going through this in
detail. Just to mention that our
Division has worked over the years with international and national agencies to
develop a whole host of standards which facilitate testing and licensure of
products and assuring the consistency of products that are already licensed.
There
are examples here of Factor VIII, thrombin and immune globulin standards, MET
standards, and you can see again a connection between our division and Dr.
Nakhasi's division. So in terms of
future directions, I am not going to mention future directions for products
that I have already discussed. I
mentioned them earlier.
So
in terms of safety, studying the association of immune globulin products on pro
inflammatory cytokine responses, and we have some preliminary data suggesting
that IL-15 is involved, developing MET and infectivity assays to determine and
quantify hepatitis-C and D-19 viruses, and to look at variance in particular in
plasma derived products, and to look at hemoglobin products, hopefully second
generation products having preclinical models to evaluate oxidative stress and
vaso activity.
In
terms of efficacy, developing an alpha-1 PI standard which hopefully will be
also adopted by the World Health Organization, identifying and characterizing
HCV neutralizing epitopes, and enriching antibodies which have neutralizing
ability; assessing neutralizing antibodies to HAVB-19 and HBV and other viral
pathogens by in vitro culture systems.
We have identified this as a gap, and we are now trying to set up a
program to look at this, and one of the first projects will be to develop
another assay for evaluation of activity of this factor.
In
terms of counterterrorism, anthrax from -- these will be human antibodies from
trans-chromosomal cows will be tested for protective antibodies by in vitro
neutralization of toxin using macrophaged based and endothelial assays, and
also in mouse models which I described earlier, and in terms of vaccinia, already
we have preliminary data that this is going to work, to develop a mouse model
for eczema vaccinatum.
Thank
you very much for your attention. This
has not been exhaustive, but I hope it has also not been exhausting.
DR.
ALLEN: Thank you, Dr. Golding. It is 12:30. Let's take a few questions for Dr. Golding as we did for Dr.
Nakhasi. We will also open it up more
generally for questions to Dr. Williams, since we didn't do that directly at
that point in time. We are having an
open public hearing. I am aware of only
one speaker. We do need to break for
lunch by about one o'clock or at the latest, a few minutes after one. So questions?
DR.
KLEIN: Are there data to suggest to
suggest that the headaches and other adverse effects of VIG are in fact due to
tiny levels of bacterial contaminants that would be picked up with the --
receptor assay?
DR.
GOLDING: Well, there are a lot of
anecdotal reports about immune globulin preparations containing some cytokines
such as tumor necrosis factor. There are
also some reports that some patients who get the product develop these.
I
would say based ont the literature, I would be hard pressed to make a firm
statement. I think the issue is that
many of the products that we regulate in CBER such as for example vaccines that
cannot be sterile filtered or cell gene products that cannot always be sterile
filtered, that there is a high likelihood that many of those do contain. We do know that the IGIVs that are licensed,
we find that it is below the level. We
do find DNA from bacterial DNA by PCR techniques.
Now,
where this directly affects the product in terms of the adverse effects, I
think it is possible. But I don't have
direct proof, and I don't think the literature has direct proof on that matter.
DR.
ALTER: Not a question, but I just feel
I have to comment. I think this
beautiful presentation is a great example of why the FDA should be doing
research. You had eight or nine areas;
every one of them was addressing a specific issue that was relevant, and the
basic research in some of these things is remarkable. The hemoglobin work, the endothelial cell cultures, I think this
is a model. If you have to present to
some funding agency of why the FDA is doing it and what they are doing, this is
a good example.
DR.
GOLDING: Thank you, Dr. Alter. Just to point out that we aren't related.
DR.
WANG: I want to second what Harvey
said. It is a tremendous amount of
accomplishment by 11 researchers. It is
really very impressive.
I
am wondering how many publications on average per year you have generated. Number two, what is the most forefront
research among all these subject matters that you consider really on the
cutting edge at this point?
DR.
GOLDING: We looked at the number of
publications, and we don't want to shame the other divisions by showing the
number. No, that is not true. But each principal investigator has two or
more publications per year. Some years
they have more, some years they have fewer.
But I would point out that the staff is pretty -- some of the
investigators have maybe one or two support staff, and in some of the cases the
support staff are also heavily involved also with review work.
The
quality of the papers is also important.
You were asking about cutting edge.
My answer to that would be, look at the journals we are publishing in --
Blood, PNAS and other high impact journals.
So I am not going to choose which ones are at the forefront. I think they are all at the forefront. I think that all of these PIs should be
supported, fully supported.
DR.
BUSCH: I also agree, it is excellent
work, and a good example of how you can be prescient and get into a field early
and then deliver over the years. The
hemoglobin oxygen carrier work defined the mechanism of the hypertension phenomenon,
et cetera. What you are doing now in
terms of getting into these micro particles, I think that is going to prove to
be a very important area, and very appropriate.
My
question though is with respect to pathogen inactivation of cellular components. That same kind of work, unfortunately what
seems to be evolving is the current first-generation pathogen reduction methods
seem to be facing challenges. I am
curious as to whether in your division or within CBER there is a program, a
basic science or developmental program that would help solve those problems
that were are seeing in pathogen inactivation, and where in CBER those products
are both reviewed and research is being initiated to help that field evolve.
DR.
GOLDING: I absolutely agree with you
that pathogen inactivation is important, from the CBER point of view and from
our point of view. We have seen quite a
few applications in this regard, for cellular therapies and much earlier on for
the others.
What
we are really focused on is for the proteins and for the cells, how has the
pathogen inactivation process altered the product. So our focus has been in looking at the safety and efficacy of
the product once a cell or a protein has been treated. The assay that I described in terms of cell
assays, for example, and looking at platelets, for example, I think if you get
pathogen inactivation and you want to know if your platelets would still
function normally, I think having in vivo and in vitro assays will help develop
that field. That is where I think our
contribution lies.
DR.
TOMASULO: It seems to me that some of
the research you are doing now could lead to requirements that you would impose
on manufacturers that submit products to you, and even that some of the work
could stop at your laboratory and done in theirs. Could you talk about that a little bit?
DR.
GOLDING: I think that is a very
interesting question, and not so easy to answer. I think it is better to deal with a concrete example. Let's take hemoglobins because we discussed
that quite a lot. The first generation
hemoglobins were produced. The
manufacturers from their perspective, they want a product that they can make
and get into clinical trials and market as quickly as possible.
What
we found is that the chemistry is very complicated. I am not faulting the manufacturers for not doing this. I think it is very sophisticated techniques
that are required to unravel what was really going on. But once you started to see the effects in
humans, in the trials that were ongoing, it was necessary for the FDA to say
first of all, some of those trials have to stop and that product cannot go
forward.
But
what are the lessons learned from that?
Then go back to the molecule and find out what is going on. I think what you are asking is, if a new
product is developing -- just say we did this very early on for this particular
product, hypothetical, and we can't know these things early on, but we have
been doing something that is a concern to you or a concern to the
manufacturers.
I
will argue, if we had the foresight to know that these products were going to
have the problems that they had, that it would have been in the public health
interest at least that we did have all of these problems, that they didn't go
into clinical trials, and that we were further along in our second generation.
I
think a lot of times, we investigated these products which weren't that well
characterized, and as a result we don't have a product on the market yet.
DR.
TOMASULO: I guess I was more thinking of
the observations you were making about the immunoglobulin preparations, for
example, the neutralizing antibodies.
This is something that the manufacturers can monitor, can follow, and it
is almost like it has been translated into another area and should be handed
off to them. I don't know if that is
true.
DR.
GOLDING: I think that is also an
important question. I think in this
particular area, a lot of it is due to the specifics. If you want to develop a product, clearly you need to have a
potency assay. The hepatitis-C virus as
you know has been very difficult to -- it has been very difficult for people to
get the potency assay in place. We have
seen this as a stumbling block for the development of that particular product.
I
think ten years ago, many people could have come up with the idea that we need
that product. We don't have the
product. I think what Dr. Yu's group
has done is -- they have been very alert to the situation that we need this
immunoassay, and as soon as the techniques become available, we need to work
with whichever collaborators we can find to develop it. Having knowledge of the technology, as Dr.
Nakhasi said several times, once we are engaged in the research, we understand
what is involved in the assay, what are the pitfalls. So I think for us to develop those assays would be very helpful.
One
other very quick example. When we
started to see transmission of HCV, that was a major public health issue, and
what Dr. Yu's lab was able to do is very quickly, working with others like Dr.
Hewlett, set up PCR assays to measure HCV.
Companies didn't have that assay in place. The companies sent teams of people to make the assay in her lab,
and then went back to the companies, and that allowed us to release the product
so that it was available.
So
if we weren't aware of the problems and we weren't doing these things, I think
we could go on for a long time, but there are many examples where I think there
would be a public health deficiency because we were unable to do the work.
DR.
TOMASULO: I'm not suggesting that it
wasn't very, very important for you to do this, or to continue doing it. I am just questioning how you transfer the
obligation to take advantage of what you have learned on to the manufactures,
and then you plan your future directions to develop another ground-breaking
observation.
DR.
GOLDING: I think in practice what has
happened is that we communicated to the manufacturer as soon as we knew how to
do things that, you could do this, and guided them and transferred the
technology very willingly to the manufacturers, in the case of the HCV PCR, in
the case of the SKD model for approval of an immune globulin. So I think we do it, but I don't think we
have an SOP that tells us, this is how you are supposed to do it.
DR.
ALTER: The people in the, quote, know
in the hepatitis field, myself one of them, say this is a no-brainer. You take anti-HCV positive people out of the
blood supply, why are you allowing them to donate into an immune globulin
product? The FDA said, wait, this
product seems to be safe. Maybe if we
manipulate it, something is going to happen, and sure enough, something
happened. Finally we talked them into
it, and finally something happened.
Then they went ahead and figured out why it happened. It is a beautiful story of them being there
at the beginning and figuring it out at the end. Another reason why you have to have knowledgeable people inside
the agency.
DR.
ALLEN: I think the question you raise,
certainly if you look at the perspective of the people who claim government is
too large, we need to have as much as possible back out at the industry and so
on, they would use the kind of question that you raised as to why it shouldn't
be done here, shouldn't be done at the FDA or a government agency, the
responsibility should be out there. I
think Dr. Golding has answered very well, and we will later this afternoon, I
hope, get further into -- with others on the staff get into discussion about
these, because I think answering that question is part of what the agency needs
in terms of developing its response and moving forward.
DR.
TOMASULO: I don't consider myself in
the camp that you just described. I
have a feeling my question was a little misinterpreted. I'm sorry that I wasn't clear. I was really talking more about planning
future directions for this incredibly productive set of investigators than
criticizing what was done in the past.
DR.
ALLEN: I certainly didn't interpret it
as criticism, nor do I think Dr. Golding did.
It is a very good question, because when you have got very limited
resources, you want to develop things to a certain stage, and then if
appropriate let others pick it up from there, and you take your limited
resources and move on into other directions.
It
is a very important theoretical discussion that we need to enjoin here as part
of the final conclusions of our report, I think.
DR.
DIMICHELE: In listening to both
presentations, which were both outstanding, one of the things that struck me
emerged from one of the recent workshops that was held on rare plasma protein
disorders. Certainly at that workshop
we were focusing on FDA from a regulatory standpoint, and the issue of clinical
trial ad clinical trial design, et cetera.
But
I think we missed a very important point.
In looking at for instance back to the vaccines for malaria and
leishmania, looking at the work that is being done in alpha-1 PI, which was
certainly up there in terms of rare disorders, it struck me that potentially
part of the FDA agenda and part of its priorities could be, if it is not
already, and maybe you are using it as a priority, the issue of doing some of
the basic research in some of these rare disorders. Asking industry to make these products, oftentimes they are
balking at some of the work that needs to go in, some of the preliminary work,
because of the cost.
But
certainly this is work that is being done, and being done well, by the
FDA. Can the issue of rare disorders,
where we are unlikely to get the work done by industry or by more profit driven
operatives, maybe bringing that into the FDA and using that as a priority, is
that something that could be considered?
DR.
GOLDING: I think it should be
considered. I think that part of what
you have seen over and over again is public health impact and how many cases of
this disease are in the public. So I
think again, it is a question of how much resources you have in terms of
personnel and what the issues are.
I
personally believe that what you are suggesting is something we should think
about seriously. I think within the
agency, it is something we should discuss in terms of funding.
I
think one of the important things from your question and from our own thinking
is to identify areas where the FDA or somebody like FDA is going to do the
research. It is not going to be done
because there is not commercial interest.
Partly what happened with counterterrorism to some extent that is true,
because government funding is driving what we do regarding
counterterrorism. But I think an important
ingredient of all of this is the resources.
I think if the funding was there, I think we would find that the FDA
would be interested in doing this.
DR.
NAKHASI: I think the industry does not
see it from their perspective. Down the
way, these are important public health issues.
We need to focus on that. I think it is a very valid point, and I
appreciate that very much. There is not
much interest in those areas, because industry looks at it, bottom line is the
profit and how much they can sell. But
from the other perspective, we need to focus on that. I think as Dr. Golding said, we should be focusing on the broad
issues and the sub-issues which aren't at the top of the priority list, but
down the road may become priorities.
Agenda Item: Open Public Hearing
DR.
ALLEN: Other important questions at
this point, or should we -- if not, let's move on to the open public
hearing. I am aware of only one speaker
who wants to speak, Dr. Selso Bianko from America's Blood Centers. If there are any other people who wish to
speak, would you please give a note to Dr. Freas with your name and so on, and
we will allocate a brief time.
I
need to read an open public hearing meeting for general matters meetings. This is one of my important responsibilities
as the Chair.
Both
the Food and Drug Administration and the public believe in a transparent
process for information gathering and decision making. To insure such transparency at the open
public hearing session of the advisory committee meeting, FDA believes it is
important to understand the context of the individual's presentation. For this reason, FDA encourages you, the
open public hearing speaker, at the beginning of your written or open statement
to advise the committee of any financial relationship that you may have with
any company or any group that is likely to be impacted by the topic of this
meeting.
For
example, the financial information may include the company's or group's payment
of your travel lodging or other expenses in connection with your attendance at
the meeting. Likewise, FDA encourages
you at the beginning of your statement to advise the committee, if you do not
have any such financial relationships, if you choose not to address this issue
of financial relationships at the beginning of your statement, it will not
preclude you from speaking.
Dr.
Bianko.
DR.
BIANKO: I am Selso Bianko. I am with America's Blood Centers. I am a fulltime employee of America's Blood
Centers. I want to disclose another
conflict of interest. My wife works at
CBER in research. However, this is not
going to influence what I say.
In
the public record, it is the position of America's Blood Centers, and it is a
written position that was submitted recently to the docket regarding the
critical path and comments that were submitted by America's Blood Centers.
I
want to be brief. I want us to show our
support for science at CBER. We fought
very hard a few years ago, and it was the intent showed by some in Congress to
remove the regulation of diagnostics from CBER and move them to a less strict
system. We went to Congress and we
succeeded in moving the process.
We
are very concerned about resources for research at the FDA. We try very hard to raise our voices to see
if we can increase that. We confront
similar things. Dr. DiMichele raised
very well the issue of diseases and things that are done for which there is no
substantial commercial interest. We are
all not-for-profit organizations. There
is no venture capitalist knocking at our doors to do the research that is
needed in many basic aspects of research.
In
terms of recommendations and things that I would ask FDA to do, I think the
first issue is communications. What we
are seeing today is something that the public doesn't see normally. I haven't seen anywhere such an aggregated
compiled representation of the research that goes on at CBER. I would like to see these more
publicized. I think that will help the
future and the funding and all those things.
I
would like to have more dialogue. The
committee is asking wonderful questions about priorities, for instance, how
they are set, how they are done. I
would like you to ask the regulators for the priorities for the things that
they are missing. We are hit with
issues like were mentioned here, of hemolysis with filters or white particulate
matters and all that, and there are very few people in our field that have
laboratories or that are set up to deal with what seems to be a very low class
science, almost, to look at white particulate matter, that has disrupted the
entire blood system in the country for a period, and for which nobody was
prepared to address with research.
Finally,
we want to encourage the FDA whenever they can to suit the science as a basis
for regulations. Sometimes we see a
predominance of issues like the precautionary principle and all that, that
ignores science, running a lot of what we do.
It is beautiful to see when science helps regulation, and we really
support that approach.
Thank
you.
DR.
ALLEN: Thank you, Dr. Bianko. We have one other speaker, Kate Gregory,
American Association of Blood Banks.
DR.
GREGORY: Thank you. I think I would like to echo what Selso just
said. AABB certainly supports the idea
of FDA being involved in research. You
saw some of the long list of things that we have been collaborating with FDA
on, and we very much appreciate being able to do that. We hope we are helpful to them, and they
certainly are helpful to us.
I
think this sort of meeting is very important.
I sort of knew a lot of what was going on, but seeing it all pulled
together like this makes more of an impact, and certainly is something that
should be communicated not only to the general public, but to the industry and
people that you work with. I think they
are not always as aware of it as they should be.
Finally,
I would also like to echo Selso's comments on communications. Sometimes I think you may work somewhat in a
vacuum, in that you are working on things and you don't necessarily communicate
it, or communicate it as quickly as we would like you to.
For
example, one of the things you talked about this morning is how long it takes
to get guidance out. We realize you
have a lot of constraints and you have to do things in a certain way, but it is
somewhat frustrating when you are working on a guidance, and it seems to take
years before we can get to that resolution.
I
would also like to echo, we do like your decisions based on science, and that
research is very important to helping you make those decisions.
DR.
ALLEN: Thank you very much.
DR.
TOMASULO: I would just like to ask Ms.
Gregory, do you have any relatives who work in the --
MS.
GREGORY: No.
DR.
ALLEN: Other questions or comments at
this period? If not, we will break for
lunch. I would like to ask everybody to
be back here ready to go in 45 minutes.
We will lay out a slightly revised timetable for the afternoon at that
point.
DR.
FREAS: This does conclude the open
public portion of this subcommittee meeting.
When we meet in the afternoon, it will be in closed session, so please
do not leave any packages or anything on your seats. We do have to clear the room.
Anything left in the room will be placed outside by the table.
Thank
you.
(The meeting recessed for lunch, to reconvene at
1:50 p.m.)