UNITED STATED OF AMERICA
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
* * *
VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE
* * *
101st MEETING
* * *
THURSDAY,
FEBRUARY 17, 2005
* * *
The
Advisory Committee met at 8:30 a.m. in the Versailles Room of the Holiday Inn
Select, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Gary Overturf, Chair,
presiding.
This
transcript has not been edited or corrected, but appears as received from the
commercial transcribing service.
Accordingly the Food and Drug Administration makes no representation as
to its accuracy.
PRESENT:
GARY D. OVERTURF, M.D., Chair
NANCY COX, Ph.D., Consultant
MONICA M. FARLEY, M.D., Member
RUTH A. KARRON, M.D., Member
PRESENT (Continued):
PHILIP S. LaRUSSA, M.D., Member
DAVID MARKOVITZ, M.D., Member
PAMELA McINNES, D.D.S., Temporary Voting Member
ARNOLD MONTO, M.D., Temporary Voting Member
PETER PALESE, Ph.D., Consultant
STEPHEN PHILLIPS, D.O., M.P.H., Temporary Voting
Member
CINDY LYN PROVINCE, R.N., M.S.N., M.A., Consumer
Representative
BENJAMIN SCHWARTZ, M.D. (CPT)
STEVEN SELF, Ph.D., Member
WALTER ROYAL III, M.D., Member
MELINDA WHARTON, M.D., M.P.H., Temporary Voting
Member
BONNIE M. WORD, M.D., Member
CHRISTINE WALSH, R.N., Executive Secretary
FDA REPRESENTATIVES:
KATHRYN M. CARBONE, M.D.
MARY A. FOULKES, Ph.D.
RICHARD PASTOR, Ph.D.
RICHARD WALKER
FDA REPRESENTATIVES (Continued):
JERRY P. WEIR, Ph.D.
C O N T E N T
S
PAGE
Conflict of Interest Statement ................. 5
Open Public Hearing ............................ 6
Session II:
FDA Critical Path Initiative Update
Dr.
Jerry Weir .......................... 22
Dr.
Mary Foulkes ........................ 35
Section III:
Committee Presentation and
Presentation of Two Laboratories: ............. 55
Laboratory
of Biophysics:
Dr.
Richard Walker ................ 55
Dr.
Richard Pastor ................ 64
Laboratory
on Pediatrics and Respiratory
Disease:
Dr.
Jerry Weir .................... 75
P R O C E E D I
N G S
(8:38
a.m.)
CHAIRPERSON
OVERTURF: I'd like to call the meeting
to order for the second day of the Vaccines and Related Biological Products
Advisory Committee, February 17th.
I'll
turn the meeting over to Christine Walsh, who has some announcements.
MS.
WALSH: Good morning. This brief announcement is in addition to
the conflict of interest reading at the beginning of the meeting on February
16th and will be part of the public record for the Vaccines and Related
Biological Products Advisory Committee meeting on February 17, 2005.
This
announcement addresses conflicts of interest for sessions 2 and 3.
Drs.
Pamela McInnes, Stephen Phillips, Benjamin Schwartz, and Melinda Wharton have
been appointed as temporary voting members for these topics.
Meeting
participants were not screened for potential conflicts of interest for the
updates on FDA's critical path initiative and the presentation on the
Laboratory of Biophysics and the Laboratory of Pediatrics and Respiratory Viral
Diseases.
We
would like to note for the record that the agency is in the process of
selecting a non-voting industry representative for this committee.
That
ends the reading of the conflict of interest statement. Dr. Overturf, I turn the meeting over to
you.
CHAIRPERSON
OVERTURF: At this point we are going to
open the meeting to the open public hearing, and before we have any members
read, I'm going to read into the record the open public hearing announcement.
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, FDA believes that it is
important to understand the context of an individual's presentation.
For
this reason, the FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral 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 companies 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.
We
have one speaker in the open hearing, and I apologize if I don't pronounce this
completely right. Ms. Sadhana
Dhruvakumar will be representing the People for Ethical Treatment of Animals.
MS.
DHRUVAKUMAR: So I'm here to talk to you
about the reduction of animal years in the critical path to vaccines
specifically. You know, PETA is
definitely interested in reducing animal use where we can, but I'm glad to say
that the FDA also is very interested in this, especially within the context of
the critical path, and yesterday I was actually meeting at the Commissioner's
office covering some of these same topics and these same slides with Kathy
Carbone and people from the Commissioner's office, and I was getting a very
good reception, and I think that there is a lot of resonance with a lot of
things that are going on with the critical path in terms of, you know, deleting
some of these animal tests and moving past them.
So
I'm really happy to have a chance to be here and to present some of this
material to this advisory committee.
So
when you talk about how animals relate to the critical path, you know, as I
read that report, you know, a lot of it is about modernizing the development
path, and updating outdated tool kits and moving to modern technologies, and to
me a lot of that is kind of the same approach that we're taking where the
animals -- a lot of the outdated took kits consists of animal tests, and most
of the modern technologies are non-animal tests, but making that transition is
really hard.
The
critical path, as you know, addresses three main pillars: safety, utility, and manufacturing, and you
know, when it comes to safety, animal tests do not -- you know, they're
problematic. They're laborious, time
consuming, and we're not really sure that they're protecting us.
And
when it comes to the utility, animal models, obviously there are species
differences. You don't know how that
relates to humans. You may be searching
after targets that aren't relevant and especially when it comes to vaccines.
You
know, a lot of the animal potency testing has low producibility. We're not really sure how it relates to
humans, and also some of them are just designed so that they're not really
relevant. You know, like when you
inject rabies into a mouse's, you know, brain, it's not really a relevant route
of administration. So you're not really
sure what you're getting.
What
you mostly are getting, if anything, is a measure of consistency of something
that worked in a certain way before, but you don't really know how it relates
that well to humans.
And
when it comes to manufacturing, you know, there's an emphasis now more on
control technologies and in-process characterization, which I know is coming
across to vaccines as well, which is by nature biologicals are more, you know,
variable. But if we have more faith in
production consistency and more emphasis on that, I think we can reduce the
batch testing which has historically been done because we didn't have that
consistency, but we do need to delete those tests.
When
it comes to where animals are used in vaccine development and production, you
know, we do have it in the research stage, in the production stage, but most
importantly and our focus is on the routine batch control testing because it is
responsible for 80 percent of all animal use in the vaccine industry, and that
testing, when you compare it to the whole biomedical research industry accounts
for ten percent of all animal use, which is huge. It's ten million animals a year.
It's this routine testing of even a limited number of vaccines, and
that's why we see it as a great opportunity.
If
we can address this problem, there's a lot of potential for saving lives.
And
also the other thing that causes us concern is that the biological testing has
some of the most painful and distressful, you know, results to animals without
any kind of pain relief, especially with the vaccination challenge type
experiments.
So
there's this concept of the three Rs, which you may be familiar with: replacement, refinement, and reduction, as
an approach to, you know, eliminating animals and making research more humane. It was put forth in 1959 by Russell and
Burch.
So
when you think about that with respect to the vaccine batch control testing,
when it comes to replacement, the ideal really is to get to something like
antigen quantification where you do understand your protective antigen well
enough and that you can have an ELISA or something like that set up well enough
to detect the right antigen and the right confirmation.
It
takes understanding that, whereas a lot of the vaccines we have aren't
characterized well enough. We'd like to
get there, but in the meantime, also we can delete certain tests, such as
things that, you know, can be deleted due to production consistency, and we
don't really need it anymore. So it's
another way to go about it.
When
it comes to refinement, refinement refers to just making existing animal
experiments less painful, less disturbing to the animals. Non-lethal endpoints is one great approach
there where if you know that you've infected an animal, especially a control
animal, with a disease, rather than waiting for the animal to die which could
be prolonged and painful, you could identify some clinically relevant endpoint
that could be used to determine the disease, such as weight loss or loss of,
you know, neuromuscular coordination, and then you can euthanize the animal at
that point.
But
even that takes some amount of validation to understand what those endpoints
should be.
And
also vaccination plus serology or some measure of immune response obviously is
another way where you don't have to go to the challenge, which is one of the
worst aspects, and that is also considered a reduction because usually you get
more quantitative data out of that and you can reduce the number of animals.
Another
way to reduce is to move upstream in the production process and just focus on
if you could understand your adjuvant well enough, you can test the final bulk
on animals but not also have to test the final lot.
And
lastly, moving from a multi-dilution traditional approach to recognizing that
maybe single dilution gives us enough information.
So
then I just wanted to quickly move through.
You have this in your handouts.
I don't want to go over all of the material, but just I tried to bring
together some information that I think will be good background material, and
I'll just hit some highlights on each screen.
The
USDA Center for Veterinary Biologics there, you may be aware, is doing a lot in
this field. They feel like it is a real
priority there both in industry and within the regulatory part.
They
had a conference in April in Ames, Iowa that I attended, and there was a lot of
participation. People are very
interested in replacing animal testing within the vaccine industry. A lot of those people are vets, of course.
They've
presented to the U.S. Interagency Committee on validation of alternative
methods on some of the alternatives that they're developing, and they're also
trying to do rulemaking changes and changing the legislation and the regulation
itself to put the non-animal test on the same footing as the animal tests which
were never validated in the first place.
And they've also been doing some internal research.
The
biggest thing was I thought that they see that industry doesn't have the
financial incentive, even if they have the interest to develop the alternatives,
and that they have to kind of be the leader in that area.
There's
also the European Center for the Validation of Alternative Methods. That's a group of, you know, about 60 people
that's funded by the EU who develops and validates alternatives. So they've had a lot of workshops, nine
different workshops on this issue in the last ten years, and they've actually
developed and validated a lot of the tests that are out there.
And
so the next two slides are about regulatory bodies where they have changed the
regulations. They've accepted some new
tests. They've deleted some old
tests. That's in Europe and the World
Health Organization.
And
so these next two slides, I'm really not going to go over, but basically the
point is for each, you know, what I've done is tried to divide up the vaccines,
bacteria on one page, viral on the other, and then we've got the vaccine, the
traditional animal test and what alternatives, and then in parentheses which
bodies have accepted them.
And
what I don't have here is what CBER does, and actually I'm in the process of
getting that information. It's being
gathered as part of the other dialogue that I'm having, but we should hope that
we can bring everyone up to the same standard, especially when things have
already been validated.
And
it's really important in the vaccine industry especially because obviously it's
a very global industry. So if something
is still required in the U.S. that has been deleted or not required in Europe,
it's still going to be done because they want to be able to send it globally.
So
we need everyone to accept the same alternatives.
So
just my last slide is kind of thinking about opportunities for how we can
promote this kind of transition and change.
The FDA, I know CBER is already doing research on alternatives and
antigen based systems and things like that, but we really need to really better
define the pathogens, the vaccines, human based tissue engineering models that
will enable kind of human based research, define our adjuvants, that kind of
thing, and where the goal is, getting to the antigen quantification and to
rational vaccine design where we understand what we're doing well enough so
that we don't need animals as black boxes.
We
also want to be able to validate and
accept already whatever was on the last two slides I showed you that's
already accepted in other countries. We
want to be able to, you know, make sure
that those things are already accepted by CBER.
We
also want to promote people switching over existing products, which I think is
one of the hardest things. You've got
it licensed a certain way. You have to
put a certain amount of money, effort, research, and then you have to modify
your license. There's not a lot of
incentive for that, but somehow that needs to happen.
And
I'll obviously get the reviewers and researchers, you know, up to speed as well
as much as possible and for a consistency of approach.
And
lastly, we want to, you know, maybe organize.
I don't think there has been any, you know, CBER workshops on these
alternatives. Get that dialogue going
within CBER and more guidances around these things.
And
the last thought I want to leave you with was just, you know, I don't think in
like 100 years we'll be using animals in the way that we are for vaccine
testing. Hopefully we'll be way beyond
that, but we want to get there as quickly as possible and how can we do that?
That's
all I have. Thank you.
CHAIRPERSON
OVERTURF: Thank you.
Any
questions or discussion? Yes.
DR.
SELF: Yes. My comment is that the nature of the validation that we're
talking about seems to me to be really critical. When you refer to the fact that the validity of the current methods
are somewhat murky, maybe some of the approaches have been validated
technically, but certainly I think the connection to outcomes in humans that
would be really kind of the gold standard validation has perhaps not been
traced through very well.
And
my concern is that, on the one hand, that we would be replacing a set of methodologies
that aren't validated in a rigorous sense with another set that aren't
validated in a rigorous sense. And so
in part of the proposed changes, which I think are excellent, I see an
opportunity to really think through for each of these methods what really is
the validation that is required and how can the appropriate studies be designed
and conducted that would provide that kind of validation.
So
I would in this effort like to see, you know, perhaps more effort placed in
that particular area.
MS.
DHRUVAKUMAR: Can I respond to that?
I
think that's an excellent point. I
really think it's an opportunity to improve the science, you know, as we're
going about it. The only thing I would
caution, I mean, this is going on in terms of validation of, you know, other
types of tests that aren't related with ICCVAM and ECVAM, is you know not
trying to hold the newer, non-animal tests to such a high bar that we, you
know, wrap them up for so long that they can't even get out there, and also not
to use the animal tests as the gold standard for them because they aren't
validated. They shouldn't have to match
those tests.
But,
yeah, to definitely proceed ahead, define it better, but don't try to, you
know, make them 110 percent perfect before you replace something which is
really in some cases very suspect.
You
know, like for example the NIH test.
People know that it's generally very variable and not very good. There shouldn't be that high a bar, you
know, too high a bar to being considered better than that.
But,
yeah, a very good comment. Thank you.
CHAIRPERSON
OVERTURF: Thank you.
Yes,
one comment?
DR.
PROVINCE: Yes. As the consumer representative on this
committee, I do have a comment. I would
like to, first of all, just briefly
make a distinction that the presenter from PETA did not make in her
presentation, and that is the distinction between animal welfare and animal
rights. I won't belabor this point. I'll try to be brief.
But
many people don't realize there is a distinction between these two, and they
use the term synonymously. They are
not, in fact, synonymous. Animal
welfare is what we commonly think of as good care and humane treatment of
animals, and I think we can all buy into that as a good concept. Everyone of goodwill can.
However,
animal rights is something very different.
It is a philosophy which holds humans and animals are of equal or
similar value, and that I personally reject, and as a consumer representative,
I feel that it is important that I bring this to the table.
PETA
is such a group. It is an animal rights
group. They have the right to hold that
philosophy. However, I must say that as
much as I could say about PETA and their actions over the years, I won't do
that now, but what I will say is that although the reduction in the use of the
number of animals may be a worthwhile goal, if in some doing we can
simultaneously meet higher ethical obligations, I do want to state in the
strongest possible terms that our highest ethical obligations remain to the
human recipients of the vaccines recommended by this body.
Thank
you.
CHAIRPERSON
OVERTURF: Is there anyone else who
would like to make a presentation during this public hearing?
(No
response.)
CHAIRPERSON
OVERTURF: So I think we will close the
public hearing and go on with the agenda, and the first thing on the agenda
will be presented first by Dr. Jerry Weir on the FDA critical path initiative
update.
DR.
WEIR: Thank you and good morning.
On
March 16th, 2004, the FDA released a report entitled "Innovation
Stagnation: Challenges and Opportunity
on the Critical Path to Medical Products." In this report was described the urgent need to modernize the medical
product development process, the so-called critical path to make product
development more predictable and less costly.
In
this critical path initiative, the FDA will take the lead in development of a
national critical path opportunities list with the goal of coordinating,
developing, and/or disseminating solutions to scientific hurdles that are
impairing the efficiency of product development industry-wide.
If
you're interested more in the critical path initiative of the FDA, you can find
quite a lot of information on the FDA Website that is listed on this slide.
Now,
as part of this critical path initiative, CBER hosted a workshop on October
7th, 2004. The short title of this
workshop was "Working with Stakeholders on Scientific Opportunities for
Biologic Products."
The
participants in the workshop included representatives of industry, academia and
other government agencies, as well as the public, and in this workshop CBER
staff presented overviews of current and future scientific opportunities. These included presentations on cell tissue
and gene therapies, blood and blood products, manufacturing science,
statistics, risk management, and clinical trial design, as well as vaccines.
Following
these presentations, we had breakout sessions with panel discussions. So what I want to do today is basically give
you a very brief summary of what we presented at this CBER workshop. Dr. Kathy Carbone, who is the Associate
Director for Research at CBER, is in the audience, and she's available if
someone would like to know more about the FDA critical path or the background
to this workshop.
Following
my brief summary of the vaccines session of the workshop, Mary Foulkes, who is
also in the audience, will give a brief update on clinical trial design and
other statistical issues.
So
essentially what I'm going to do is just walk through and brief what we did at
this meeting.
We
started out in the vaccine sessions by presenting the types of laboratories
that we have at CBER in the Office of Vaccines, and these are listed on the
slide that you see here. In the
immediate Office of the Director of OVRR, we have a Standards and Testing
Section and an analytical chemistry staff.
We have two product divisions that conduct basic research most of which
is on the NIH campus.
In
the Division of Viral Products, we have laboratories of DNA viruses, retrovirus
research, hepatitis viruses, vector borne viral diseases, immunoregulation,
method development, and respiratory diseases.
In
the Division of Bacterial, Parasitic and Allergenic Products, we have
laboratories of immunobiochemistry, biophysics, enteric and sexually
transmitted diseases, bacterial polysaccharides, methods development and
quality control, microbacterial diseases, and cellular immunology, bacterial
toxins, and respiratory and special pathogens.
Now,
the type of research and laboratory activities that that take place in the
laboratories and the Office of Vaccines are designed in part to facilitate the
development and evaluation of new vaccines.
We considered this an important critical part of our mission.
To
do this we must anticipate and address the regulatory issues for new
products. These include very general
regulatory issues which are applicable to many products or product classes. I've given a couple of examples on this
slide.
For
example, cell substrate issues which apply to many different products,
especially viral vaccines, but also general regulatory issues, such as improved
test methods, which include better sensitivity, more reliable methods that are
applied to broad classes of products that we regulate.
But
also to facilitate the development and evaluation of new vaccines, we have to
address product specific issues. These
can include things like correlates of protection that are necessary for
efficacy evaluation; also include research design to improve assays that are
important for our evaluation, potency, efficacy assays.
Also
we have efforts for animal models for different vaccines that are necessary for
efficacy evaluation.
Now,
obviously to facilitate the development evaluation of new vaccines, all of our
research efforts have to be prioritized.
This is because we have to keep in mind the availability of the
necessary expertise that we have on hand.
We
also have to consider the appropriateness of the research effort. Who should do it? Should we do it in house?
Should industry be doing it? Is
someone else already doing it?
And
of course, as obviously you know, we have many competing demands on our time
and many responsibilities, and we always have to balance that with what we do
in the laboratory.
In
the next three slides I've listed just a few examples of research efforts that
are ongoing in the Office of Vaccines.
In the slide shown here, I have some examples of critical path efforts
that are ongoing in the general category of things that are applicable to many
vaccines.
For
example, we have several laboratory efforts ongoing and in the last few years
to develop alternative lot release tests.
Now, this is important because this can lead to increased product
availability. It can also in certain
circumstances reduce animal testing.
And
some specific examples that I've shown here are efforts that we've had over the
last few years on rabies potency assays, mumps neurovirulence assays, anthrax
potency, and diphtheria toxoid potency.
We've
also had quite a few efforts in the development of rapid microbial tests. These are important developments because
they can improve current products, as well as facilitate the evaluation of new
vaccines, particularly combination vaccines.
Development of new tests in this area can reduce the time and the amount
of product needed for testing.
And
finally, in this slide, I've listed the evaluation of novel cell substrates for
vaccine production. We have efforts
ongoing to develop new molecular methods to detect broad categories of
potential adventitious agents, as well as the development of new assays to
assess tumorgenecity and oncogenicity and to detect oncogenic viruses. All of these are important for the
evaluation of many products that we regulate.
In
the area of virtual vaccines, I've listed a few examples of critical path
efforts that we have for what I've called priority viral vaccines. Hepatitis C, we have efforts devoted to the
development of transgenic mouse models to study pathogenesis and evaluate vaccine
candidates.
In
the HIV field, we've been involved in the development of new assays to
distinguish vaccine response from actual HIV infection, as well as the
identification of target structures and epitopes for neutralizing antibodies.
In
the smallpox area, we've been involved in development of improved assays to
evaluate vaccine response, as well as the animal models necessary for the
evaluation of new vaccines.
For
West Nile virus, development of standardized immunological assays for vaccine
induced immunity. Poliovirus vaccine,
the development of animal models to evaluate efficacy of Sabi-derived IPV which
could become more important in the next few years, and of course, influenza
vaccines. We've been heavily involved
in the development and standardization of reference strains and reagents for
the evaluation of regular interpandemic as well as pandemic influenza vaccines.
Some
examples of critical path efforts that we have for priority bacterial vaccines
include several efforts in the anthrax area, development of animal models of
pathogenesis, development of serological assays, development of Ty21a vectors
for protective antigen, and of course establishing tools for genetic
manipulation of a pathogen.
In
the tuberculosis area, we've been involved in the discovery of novel antigens
with protective properties, as well as the evaluation of DNA vaccines.
Shigella,
the creation of Ty21 vectors for Shigella LPS.
In
the pneumococcus area, identification of the serological correlates of protection.
Meningitis,
the development of high efficiency conjugation technology, a well as
establishment of correlates of protection.
So
to summarize what we presented at this workshop, the Office of Vaccines
recognizes that there are numerous scientific, technical, and regulatory
challenges that must be addressed in the development of new and improved
vaccines. These include general
regulatory issues, as I've tried to point out, as well as very product specific
issues that we must address.
I've
also as a subheading listed that we all face the challenge of vaccine
development for emerging diseases.
We
think that OVR researcher reviewers have a major role in identifying and
anticipating such issues. It's up to us
and it's one of our major responsibilities to provide clear guidance regarding
the expectations for product development and licensure.
As
an example of this I've listed our involvement in producing and distributing
guidance documents. For example,
revised cell substrate guidance documents, as well as DNA vaccine guidance
documents are some that we've worked on in the last few years.
It
is also, we feel, necessary that CBER research activities are important to
address these issues with regulatory implications. This is both important for product development and product
evaluation, and if you think about it, product evaluation is part of product
development.
Okay. So in the afternoon, we had a vaccine
breakout session and a panel discussion.
I want to summarize that in the next two slides. Our list of panelists for the vaccine
sessions included our own Dr. Overturf from the University of New Mexico; Alan
Shaw from Merck; the late John La Montagne from NIH, the Deputy Director of
NIAID. We had Robert J. Reinhard from
the AIDS Vaccine Advocacy Coalition, as well as Laurie Norwood from the CBER
Office of Compliance and Biological quality.
Each
of these panelists started off the breakout session by providing their own
perspective of the entire vaccine development process. The floor was then opened to discussion, and
we had a brief summary of this discussion that was presented to the larger
group when we reconvened.
So,
in short, I've listed a few of what I thought were the overall themes of this
breakout session. In general, the panel
felt that the entire process of vaccine development should be reengineered. I actually that if I remember correctly,
this was John La Montagne's phrase, but almost everyone in the room agreed that
there were just many aspects of the current process of vaccine development that
were not optimal.
These
included complex and cumbersome IRB process, the burden of data management, the
lack of sharing of information about trial design, and again I remind you that
these are not CBER specific issues.
These were just issues related to the whole process of vaccine
development.
Many
in the audience and the panel thought that there was importance of establishing
and validating surrogate endpoints for vaccine trials. Everyone emphasized the importance of
communication both for CBER and for the Office of Vaccine to provide detailed
guidance for industry, but also there was a feeling that there should be more
guidance for those with limited experience in the vaccine development field.
There
was general consensus that there should be more long-term follow-up and post
licensure surveillance.
There
was also general consensus that CBER research did have a major role and can
assist in vaccine development. Topics
that were specifically mentioned included more preclinical studies, studies on
novel antigens, studies on adjuvants, vaccine delivery methods, as well as just
the overall rational vaccine design, including defining surrogate markers.
Finally,
the next steps in this process. For the
FDA critical path initiative, we will continue to compile an opportunities
list. There will undoubtedly be
additional workshops on specific diseases, products, and pathways.
For
CBER we will summarize and publish the discussions from the CBER workshop that
I have summarized, and we will use this information to develop future CBER
science priorities and agenda, and of course, we will continue to try to
communicate scientific advances in guidances, policies, and publications.
And
as I said, Mary Foulkes will now give you an overview of the statistics and
clinical design.
DR.
FOULKES: Okay. Thanks, Jerry.
Okay. Thank you very much.
As
Jerry mentioned, I'm Mary Foulkes from the Office of Biostatistics and
Epidemiology, and at the same workshop that Jerry mentioned, we had a breakout
session on statistical issues, risk management, and clinical trials design, and
I'm not going to summarize that in great detail, but I'm going to give you more
of sort of a holistic look as to how we approached the critical path.
I
don't often get a chance to quote Pasteur, and so I'm going to take that
opportunity. I really think that this
quote, "Chance favors the prepared mind," consolidates the entire
critical path opportunity that we have here, and another reason that I have for
pulling this particular quote is that "Chance" is the name of one of
the regular publications of the American Statistical Association. So it caught my eye for that reason as well.
If
my theoretical statistical colleagues will forgive me, I'm going to wildly
oversimplify the usual statistical approach to development of methodology. Usually there is a highly mathematical
development of the theory or a new model or a new method, and then there's a
search for an application to which it fits.
Well,
we see the critical path approach as really upending that process and
identifying areas where there exists no prior approach or no existing
approximation as a part of vaccine development or biological product
development and developing a mathematical or statistical methodology that fits
that need and finding a methodology because there is an application searching
for a methodology.
With
regard to the quantitative methods in general, we see the need as the whole
critical path concept maximizing efficiency while maintaining reliability, and
certainly within vaccine development there are many opportunities to approach
that by certainly improving the analytic approaches and by, as was mentioned by
Jerry, flexible study designs, and I'll get into that a little bit further.
Also,
there is a need for a transparency, for education of, as Jerry mentioned, of
vaccine developers, for example, who have maybe less experience than others in
the process.
Also,
transparency in terms of determining best practices for quantitative methods. In some instances there are multiple
practices available, but the particular best practices have yet to be
identified, and really the field is using a lot of variation in practices
without establishing a best practice.
There
also needs to be transparency in underlying assumptions. A lot of the quantitative methods are based
on assumptions or start with various assumptions at the beginning of the
process and are dependent upon those assumptions. Sometimes they are realistic assumptions. Sometimes they're simplistic assumptions,
and so there is an opportunity there to possibly improve the product
development and the contribution of quantitative methods.
The
list of CBER products I know you're all familiar with. With regard to vaccines, in particular, the
critical path is important because many vaccines are available to a huge target
population many, many times larger than the available data set for evaluating
that particular product for safety and efficacy.
Vaccines,
when they are made available, are administered to healthy people. They're also often evaluated in healthy
people, and that has implications for the risk-benefit assessment. Vaccines, when they are at all effective and
available publicly and universally and worldwide, can have a major public
health impact, as we all know, and again, as we all know, there is a growing
public safety concern, and just the existence of a safety concern can impact
vaccine coverage rates.
So
it's very important to address those.
So some of the things that Jerry has already mentioned, and I'm not
going to go into great detail in these, but some of the areas in which
quantitative methods can have an impact in improving product development and in
the entire critical path process in terms of study endpoints.
And
here's a short list of potential study endpoints, all of which have
implications for quantitative methods and for analytic approaches and for the
kind of inferences that can be made from them.
And those need to be assessed in a critical path context to see if there
aren't any opportunities for improvement in the definition of the study
endpoints and also in the analysis of the study endpoints and the inference
from those study endpoints.
Genomics
and proteomics is a very large and rapidly emerging area of research as can be
seen by the huge emphasis on genomics and proteomics this weekend at the AAAS
meeting downtown, which actually starts today downtown.
The
statistical practices for these areas are not yet well established, and this is
definitely an area for potential development.
There are lots, as you can imagine, multiplicity issues, multiple
plates, multiple SNPs, multiple everything.
There are lots of potential missing data issues. There are missing data issues elsewhere as
well, but particularly in the genomics/proteomics area, how one handles missing
data in terms of the analysis is very important. And there are certainly experimental design opportunities in this
context.
There
are statistical issues in manufacturing.
Particularly recently we've been dealing with issues of quality control
and blood collection, but there are also specific manufacturing issues related
to vaccines, as Jerry has already mentioned, vaccine lot consistency.
Now,
the flexible design issue. There are
opportunities to consider alternative experimental designs, clinical trial
designs, and these have been widely under discussion. For example, there was an FDA workshop just this spring. Sorry.
It was 2004 on flexible design, on adaptive designs. Adaptive designs, again, are being discussed
at the FDA Science Forum, and it's a very active area of research.
The
reasons that one might consider flexible design in the context of vaccine
development or any product development is that sometimes when the product
development process is speeded up a bit, there might not be a lot -- the amount
of learning curve that precedes, say, the Phase III clinical trial is
compressed such that your estimates of the initial parameters for that Phase
III clinical trial design might be less solid than we would prefer.
And
so there may be opportunities for interim modifications to the ongoing
design. Those have to be handled very
carefully and planned for and have implications for the analysis and the
interpretation. So it's an area that is
currently enjoying rapid development.
There
are also the traditional approaches, the group sequential designs, and so
forth, and there are new emerging approaches to consider. But this is a very active area for
statistical methodologic research, and the specifics of flexible designs for
biologics are obviously CBER regulates cutting edge products, and as I
mentioned earlier, we may have less information going into a Phase III design
than we might want, and we have the need for flexibility as the Phase III
clinical trial is progressing.
Again,
safety concerns. There may be a safety
concern that emerges in the course of a clinical trial that has impact or could
have impact on the trial design, and a flexible design might give the
opportunity to handle that.
With
regard to trial design and analysis, there are opportunities for improvement in
the process, improvements in handling non-inferiority trials, for example, and
obviously the ICH E10 already exists and gives us guidance in that arena, but
there certainly is room for improvement in the methodology there.
There
is a lot of room for improvement and activity.
There's a lot of activity in terms of handling missing data in
analyses. As with other areas of
analyses, there are multiple opportunities and multiple routes that one might
take, but there is no really identified, necessarily preferred analysis
approach. And so there's an opportunity
for improvement here.
With
high speed computing there are also opportunities for handling missing data
utilizing the high speed computing capabilities that we didn't have ten or 15
years ago and we have in our tool box today.
Another
area of methodologic development is data mining, and here CBER and other have
been using empirical based methods to try to apply those to, plus marketing
surveillance, and utilize the information that we get reported on adverse
events to identify areas of research and of concern with regard to vaccine
safety, in particular.
This
can be problematic because obviously false positive signals could have very
serious consequences, and so one has to utilize this information very, very
carefully and take into account the fact that it's based on our adverse event
reporting system, and other sources like that where under reporting may be a
serious problem. So that always has to
be in the back of your mind when analyzing these sorts of things.
Let
me go straight through to the summary.
We're approaching issues of risk analysis. This is an area where obviously we are in situations where we
have to make decisions, and the decision point comes in not necessarily as a
function of having complete data in front of you.
So
often you have to make decisions in the absence of full information, and this
is where risk analysis can play a role.
One can model the risks and identify influential parameters where we can
put our resources to clarifying those parameters, getting more information on
those parameters, possibly directing resources to gain more information in that
arena.
So
this is an area of development and an area that the critical path can consider
as part of its armamentarium, if you will.
So,
in summary, the quantitative sciences need to be considered as a part of
critical path, and have a role to contribute to improving the process of
product development and contributing to the critical path in terms of the
quantitative methods that I've outlined.
And
just in summary, that statisticians and epidemiologists need to be involved
just as much as anybody else in the identification of issues and encouragement
of involvement in development of new methodologies that improve product
development.
Thank
you. Any questions?
CHAIRPERSON
OVERTURF: Are there any questions or
points of discussion? Yes, Dr. Self.
DR.
SELF: I can't resist. Dr. Weir's slides mentioned in his summary
of the panel discussion the importance of establishing and validating surrogate
endpoints for vaccine trials. There's
been a lot of that work that's been done in other settings and without the most
optimistic results for actually achieving that. That's not something that is in your presentation. Could you just give a couple of minutes
thinking about where that sits with respect to vaccine?
DR.
FOULKES: Well, certainly, as I
indicated in the list of potential study endpoints, that study endpoints need
to be evaluated very, very carefully, and whenever we talk about surrogate
markers, I always have the tape of one of Dave DeMets' presentations in my head
where he has multiple, multiple examples of how we were misled by various
surrogate markers particularly in the field of cardiology, which is the source
of many of his examples.
So
we have those caveats in mind always, but there certainly is a potential for
surrogate markers, intermediate endpoints, biomarkers to be utilized should
they prove valid sources of information and valid bases on which to make
regulatory decisions, but that's a very large "if."
DR.
SELF: So a comment, and then one sort
of small question.
The
comment is even though your talk is targeted at clinical trial design, I guess
I would like to see the range of issues broadened to include preclinical
studies as well because that is a bridge that has not been built very well and
really needs to be. So I just raise
that on the radar screen.
DR.
FOULKES: Absolutely. The intention is not to exclude those.
DR.
SELF: Yeah. And then I found myself scratching my head a bit, and maybe this
is to Dr. Weir, in the reengineering of the vaccine development process. Listed here as Item No. 2 is burden of data
management. I don't know what that
means.
Could
you or somebody explain that one?
DR.
FOULKES: Jerry, if you want to, take
that, but I can jump in at one point that there is a perception, if not a
reality, and it probably in many cases is a reality, that the burden of data
management is too much of a burden, and I do think that there is room and
opportunity within the critical path.
In fact, this was one of the discussions in the breakout session that
the individual data items that are captured and collected and edited and stored
and constitute that particular burden need to be reevaluated in terms of do we
need this particular item and why do we need this particular item?
And
I think there is a lot of room for improvement there. There is a lot of room for efficiency, and os let me let Jerry
jump in.
DR.
WEIR: Well, I think you just summarized
it. That was the general feeling of
several people in the group, was that it was just an overwhelming amount of
data.
And
I think I remember that some questioned whether all of the data that was asked
to be collected was really necessary, and they talked about not only just the
sheer amounts, but how you manage it.
So it was just sort of a general feeling that it was just a big burden
in the running of large clinical trials.
But
like I said, I think May summarized it now.
DR.
FOULKES: May I just add that the FDA
for a number of years now has been discussing large, simple safety trials, and
one of the emphases in that discussion is the reduction of the data collected
to what is absolutely necessary.
Another
quote that I cut out of this talk is "make it as simple as possible, but
no simpler." And I think that
that's an area where we can make some improvements with regard to data
management.
CHAIRPERSON
OVERTURF: Dr. McInnes.
DR.
McINNES: Thank you.
I
also was having a dagger through my heart around this thing about burden of
data management, and I guess I understand a little bit better. It's around, I think, the issues or
challenge of appropriate data collection and then superb management of those
data that are deemed to be important, and I think we struggle so much with this
with all of the contractors and grantees who some resist the fact that this is
now 2005 and it's perhaps just not okay to have handwritten data in your lab
book.
I
mean, we are now in the very contemporary area and things have moved on. So I presume the burden issue is really
around the challenge of appropriate data collection and data management.
I'm
interested in the proceedings that come from the panel because I think
certainly with multi-center studies and with emerging disease issues where you
may only be capturing a few subjects at a large number of medical centers, for
example, the current IRB process is really very challenging in trying to
implement these multi-center studies, and I really think that's an area that we
need to tackle very seriously and together because it is proving to be very
difficult and impeding enrollment into very, very important studies.
I
also wanted to just make a pitch again, I think, the lack of specificity around
terminology of correlates and surrogates.
While there's a very small number of people who really understand the
difference between correlates and surrogates and some of those people who got
burned in those cardiology studies, I think these terms are tossed around quite
freely and people talk about correlates of protection and not necessarily
understanding that there may be some endpoint that you're measuring that has a
relationship to what you want to look at, but that you can't just measure A
instead of B and assume that it's a true surrogate.
And
I actually make a plea to this committee.
Maybe even some publication that could go back to definitions of
correlates and surrogates and something about what it really is and what it
isn't, in that I think very often we are measuring correlates and not
necessarily surrogates. I think this
vaccine development arena could really benefit from some of that work that has
been done really in drugs.
So
thank you.
CHAIRPERSON
OVERTURF: Dr. Schwartz.
DR.
SCHWARTZ: A comment and a
question. In the statistical
presentation, you talked about using data mining techniques and Bayesian
analyses and all of that. At CDC
they're obviously looking at the same things, both with respect to vaccine
safety as well as outbreak detection. I
don't know if you've been working with the statisticians at CDC --
DR.
FOULKES: Yes.
DR.
SCHWARTZ: -- but clearly, linking with other government scientists would be
useful for that.
The
question is at the end of Jerry's presentation it was mentioned how this new
information would come out in policies, guidances, publications, and there were
a lot of different aspects of the critical path that were talked about, and I'm
just wondering whether the vision is that as individual issues were addressed
there may be a particular guidance or particular publication about that
individual component of the pathway or whether it's kind of an end-to-end thing
where there would be some kind of guidance that would deal with the full range
of issues.
So
how do you see this coming out when decisions are made, when new approaches may
be validated? What will be the way that
then this will be translated into action in terms of vaccine development?
DR.
WEIR: I'm not sure I followed the
question, but were you referring to how we would decide to publish guidances on
specific topics?
DR.
SCHWARTZ: Well, I guess just more
clarity. There was such arrange of
topics that are being reviewed. Is this
something where you would, when a particular topic was addressed, you'd come
out with a guidance or a publication on that specific topic, or would it be to
complete an entire kind of end-to-end review as it were and to put it all
together then?
DR.
WEIR: Okay. I would have said the specific topic, but I think Kathy wants to
--
DR.
FOULKES: I think I understand what
you're getting at. These are all major
issues that are somewhat separable, and they all have scientific knowledge gaps
and tool gaps, et cetera. So as the
information comes across for a particular area, that would come out as a
guidance.
So
it might be an issue with a particular vaccine, a vaccine type, a type of
product, and as that information is gathered, it will come up as a guidance,
and keep in mind guidances are living documents. So even as more information is gathered, the guidances will be
updated so that the concept is to feed very quickly into the regulatory pathway
and make the advances clear as they come along.
CHAIRPERSON
OVERTURF: Are there any other
questions?
I
just wanted to make one comment. My
impression from the workshop was that a good number of the identified
difficulties in vaccine research were, if I could use a term, were pre-FDA, I
think, or post FDA, but they really didn't center there. They centered in places like local IRBs, the
recent expansion of HIPAA regulations and other kinds of problems which have
really had a tremendous disquieting impact unfortunately on particularly
collaborative research in vaccines.
And
it has not only been in vaccines, but it has obviously been in other drug
research as well, and I think one thing
the critical path might want to do is to really look deeper into and expand
into those areas because I don't know how the FDA could impact those areas, but
that would be an area that might facilitate more research more than just about
anything that I know of right now because those are the major problems. Because it starts right at your own
institution usually.
Were
there other points of discussion?
We
have to take a break because we have to get Dr. Palese on the phone. So is he expecting to be available precisely
at 10:05?
MS.
WALSH: No, I told him a little earlier.
CHAIRPERSON
OVERTURF: Okay. So how long do you want us to take a break?
MS.
WALSH: Ten minutes.
CHAIRPERSON
OVERTURF: All right. So we'll take a break and be back at ten
minutes till ten.
Okay. Thank you.
(Whereupon, the
foregoing matter went off the record at
9:35 a.m. and went back on the record at 9:55 a.m.)
CHAIRPERSON
OVERTURF: Please take your seats
because we have Dr. Palese on the telephone, and we need to begin the open committee discussion and presentation
of two laboratories.
The
first presentation will be an overview of the Laboratory of Biophysics and will
be presented by Dr. Richard Walker.
DR.
WALKER: Good morning. Actually for the next few minutes I won't
present an overview of the Laboratory of Biophysics, but I'll present an
overview of the Division of Bacterial, Parasitic and Allergenic Products, which
Biophysics Lab is a part, and so I'll try to give you a big picture, and then
Dr. Pasteur can go into the details of the Biophysics group.
What
I'd like to do is sort of hit three things:
give you a little bit of discussion of the challenge that our division
has to face, the way we're organized to meet that challenge, and then a little
bit about sort of what it's like to be a researcher or reviewer within this
division.
Okay. So our laboratory function, as you would
assume, is to assure safe and effective products for immunological control of
bacterial, parasitic and allergenic products that affect human health.
Our
task to do this involve research, as well as review. That's why we refer to our personnel as
researcher/reviewers. We are involved
not only in new products coming in, but also post licensure surveillance, and
also we are involved in many consultations with organizations that are
developing vaccines, as well as NIH and other organizations that are dealing
with various vaccine problems.
This
slide and the next slide are really not to go through all of the details of
what's written, but just to make a point that when our researcher/reviewers
begin working with a product, we take it from the beginning through the
end. So it's a lifetime arrangement
from pre-IND, where we might have a pre-IND meeting to help the sponsor work
out problems, to receiving the IND, a review of that, technical advice for
development of product assays and so forth.
Then
we go on through the clinical testing, the licensure process, continuing
back-and-forth dialogue with the sponsor, and then in the post licensure, our
work is not over. Like I said, it's a
lifetime arrangement when we're working with a vaccine or other immunological
product.
The
types of agents that we have to deal with, as you can get from the name of our
division, is very varied. We have
respiratory pathogens, sexually transmitted pathogens, other things like
malaria, special pathogens which really received a lot of emphasis recently,
those that could be bioterrorism agents.
We
also have diarrhea causing pathogens, other types of pathogens. If you look back, for example, to allergenic
products and skin test antigens. So see
we have a variety of things to deal with, and to do that, we have about 90
people in the division, and we're organized into eight laboratories. So we have the Office of the Director with
my administrative and regulatory staff, and then we have the various labs.
Two
of the labs, this being one, the Laboratory of Methods Development and Quality
Control, are more approach oriented.
The other six labs are more disease oriented. This first laboratory deals with things like methods for quality
control and serological assays, their development in animal models, and they
deal right now a lot with pertussis and anthrax.
The
Laboratory of Biophysics, which you're going to hear a lot more about in a few
minutes from Dr. Pastor, brings new techniques that allow us to do cutting edge
evaluation of vaccine products and understanding of the chemistry of these
vaccine products.
Now,
these other six laboratories are more pathogen or disease oriented. The Laboratory of Bacterial Polysaccharides
is actually just one that the Laboratory of Biophysics collaborates a lot with
because a lot of the technology like NMR and so forth that Biophysics has is
very beneficial to the people in this laboratory. Anyway, they're interested in characterizing the immune responses
to polysaccharide conjugate vaccines, standardization of methods, development
of new chemical methods to understand the chemistry of these vaccines and also
we've got some vaccine development studies going on there.
Laboratory
of Bacterial Toxins is, of course, another major area because we have botulinum
toxin, tetanus and diphtheria. So we
have to have experts dealing with those various toxin products.
I'm
not going to go through the details of these unless you want to go back to
that. I'm just trying to give you the
overview.
Laboratory
of Respiratory Special Pathogens, which is looking at virulence factors and
regulation of these virulence factors for things like plague, anthrax, and
pertussis.
Laboratory
of Microbacterial diseases and cellular immunology is dealing with various
promising antigens that might be useful against microbacterium, as well as
understanding the immunology of that disease.
There's also work in this group dealing with tularensis.
Laboratory
of Enteric and Sexually Transmitted Diseases primarily deals with various
enteric pathogens, like during the critical path thing you heard about, Ty21a
vaccine being a vector for Shigella.
That's some work that's going on in that group.
Laboratory
of Immunobiochemistry, studies allergen structure and function in the immune
responses to various allergens and trying to better understand processes in
allergen activity, as well as they do a lot of lot release work.
So
that's in a nutshell the division that we've put together to address the
bacterial and parasitic and allergenic products.
I
mentioned that we have about 90 percent in this division. I put this chart in because one of the
things that these site visit committees are asked to do is evaluate the people,
and so as part of that it's helpful to just sort of review how people are
sorted out or what terminology we use.
We
have sort of independent and non-independent pathways that people can take and
move up through various grades. One is
over here on the left where you start with staff fellow. This is moving towards a tenured position to
be a principal investigator, and these people are reviewed by the site visit
committees and tenure will be impacted very much by the comments of the site
visit committee as far as how they evaluate the work of these people.
We
also have another track for people who do not plan to be principal
investigators but are very capable of researchers in their own right, and
they're the support scientists and the staff scientists.
One
of the issues that we deal with is the funding for this research because in
addition to review, in addition to having facilities to do that, we have to
have laboratories and we have supplies and all of the things that go along with
research.
Salary
and overhead is part of base funding.
What actually comes down to us at the division level is really operating
money for expendables and equipment. We
have a general FDA appropriation which is really our division operating funds,
and we distribute that really on a per capita basis.
Recently
we've gotten counter-terrorism funds.
Those funds were useful in the last few years in actually adding to our
staff to be able to have a response to the issues of plague and anthrax and
some of those other bioterrorism agents.
Unfortunately,
we've ramped that program up, but money to support those programs has not
really stayed with us, and so a lot of that now comes out of our operating
funds.
There
are some extramural funds like the National Vaccine Program Office and a few
other sources maybe through CREDAs and some work that our people have to get
outside money. In fact, right now, most
of our research money is coming from the outside rather than these FDA funds.
In
the past we've had some money left at the end of the year, but that's also a
dwindling resource. So I'm just
painting the picture that we still have excellent people, and I think as many
of you know, they're doing high quality research and are turning out very
valuable information and really contributing to the scientific field, but
they're doing it on a shoestring.
Other
challenges and realities that face our researcher/reviewers, and some of these
may be true for other government, like NIH and so forth, the funding levels are
uncertain from year to year, and we have to depend on the appropriation
process. We're a very large
organization, and like any large organization we have bureaucratic hurdles, and
also we have to try to make sure that we don't have any appearance of a
conflict of interest. So we have to be
very careful. Sometimes it makes a lot
of paper work, and it keeps me busy.
The
other thing though is, of course, at the university and anywhere else, you have
other things like various committees and whatnot that take your time, and
bureaucratic hurdles. One thing that's
very unique that you should be aware of with relation to our researchers and
viewers at FDA is that their schedule is not totally capable of being planned
by them because timing of the work load could be determined to some extent by
the sponsor.
We
don't know when something is coming in, and ten we have to respond to it and
deal with it. So that's something
that's a conflict that anyone who does research and review work at FDA has to
deal with. So you have to be able to
juggle.
So
just to wind up, what I asked the site visit committee to do is in this case
for the people in the Laboratory of Biophysics is to review the individual, the
overall program, and then make comment on their current and future directions.
So
if there's any questions or clarifications you need now I can do that or we can
move on into the Laboratory of Biophysics. Anybody?
CHAIRPERSON
OVERTURF: Are there questions now or
should we just -- I think we'll proceed on to the overview of the laboratory.
DR.
PASTOR: Thank you.
This
is going to be a brief overview of the Laboratory of Biophysics. You all have these giant books if you chose
to read them with like more details, plus your handy-dandy disk of the whole
thing.
The
first slides are going to be more or less what I spoke about in the first part
of my talk, and then at the very end I'm going to go into a little bit to
summarize the rest of the talks.
The
Laboratory of Biophysics basically has four sections. There's a computational biophysics. I'm the leader of that part.
I'm Pastor. Rick Venable is in
it, as well as a postdoc. Then there's
a mass spectrometry and a protein chemistry section, a spectroscopy which is
NMR and light-scattering, and then an NMR theory part.
And
broadly speaking -- and I'll stay broad for a couple of slides and then be more
specific -- we basically use these tools for a biophysical characterization of
proteins and peptides, carbohydrates, DNA, membranes and micelles, essentially
all of your cellular components, and this has application to everything that
CBER regulates: vaccines, blood and therapeutics. Basically we work with almost everyone, and
just a couple of examples which you'll be seeing later of some of the molecules
we do.
And
as I said on the first slide, we use these tools. We have an array of actually mass spectrometers, NMRs up to 700
megahertz, which is quite a good machine, light-scattering, and modeling.
And
the characteristic that these things all have in common is that they're high
tech things. We use them center-wide,
and to really use it, you have to be an expert. Your average scientist can't walk in and start using a 700
megahertz NMR. I mean partly because
they're $1.3 million. So you're not
going to mess with it. "Can I
touch this?"
"No."
And
just kind of briefly, what is a characteristic of these methods? You can read them or look in the book
more. Basically mass spectrometry gets
the masses of each fragment. It works
very well on large proteins and mixtures.
NMR is really used to actually get the structure and conformations of
molecules. Light-scattering get sizes
quite well, and actually works with very large mixtures. A simulation gives you detail.
And
this last column is really sort of an interesting column in that it's like,
well, any technique, there are some things that you get, but some things that
you actually don't get from it, and we've tried to arrange the lab so that you
can almost pick your column and say, well, gee, you can't measure a large range
with NMR, but in fact, using light scattering you can.
So,
in fact, we've made a lot of effort to make sure that these techniques are
complementary. In fact, often we'll use
several of them on the same problem to map out the whole shebang, as well as
research, which you'll hear about in a little bit.
We
actually do a lot of regulatory work.
I'm involved in the LAL test kits and adjuvants, as are Boykins and Bull
and Rick Venable, and then each person -- you can read this -- acts as a
consultant often in INDs or PLAs or as things come up on these issues, and
that's quite frequent.
I
just step back and just remind you.
This is the risk analysis part of what we all think about. You know, what are the four things that
could happen with a product at lot release?
And it's, you know, a good product passes. A good product fails. A
bad product fails and a bad product passes.
That's your basic matrix.
And
of course, this is the sunshine one when the good guys get passed and the bad
guys get failed, but of course, it actually can happen that occasionally, and
you try to work against this, but real life says it's not perfect. You will have good product failing. A lot release test gave the result that
passed or that failed. That's the
alpha, right?
And
likewise a bad product will sometimes sneak in. And to sort of not realize that and think about it can lead you
astray, and you know, what's biophysics for?
Well, essentially if we understand these products better, if we make the
tests better, we can reduce those risks.
So
I think it has to start off with saying they're like our risks. What are they, and then by doing a better
job writing the biophysics in this case, we can lower those risks.
A
site visit, this was the schedule of the people. This is a list of the people who spoke at the site visit, and
each guy -- we're all guys here. So we
don't have to -- spoke about his area of expertise, and I spoke about the
membrane research I did, and in this slide I basically want to sort of target
in some since highlight as it regards vaccines. We do other stuff, but this is Vaccines Advisory. So you get vaccines.
So
I think one area that I've been working on, a large part of my research since I
came to CBER has been understanding how to really on a computer simulate pure
membrane. We're actually very close to
that now. You know, I showed results
that show we just about know how to do it.
So,
in fact, I've started now -- people in the group have started computer
simulations of the trehalose, which is a vaccine preservative, and we're trying
to understand using simulations just how trehalose keeps the membrane
stable. So I think that will ultimately
be where that goes, and I hope one of these days to say, well, we actually did
it. Here's how it happens. Vaccines are better because of this.
Daron
Freedberg, I spoke about his work on using an NMR technique called residual
bipolar coupling, which is a very precise technique that one can use to look at
the conformation of carbohydrates. The
goal there, at least the carbohydrate part of the research will actually
involve doing a very careful characterization of the conformations of the
polysaccharide vaccines.
So,
for example, a mixture of vaccine that has buffers or ions, it can actually
change the conformation. One can see
that exactly where it's changing it. It
could be important.
I
guess Scott Norris talked about light-scattering in general, and in fact, what
they just did recently is they were able to determine the extent of like a
conjugation of the meningococcal conjugate vaccine with light scattering, but
that data was used to help justify a Gates Foundation grant by the
polysaccharides group, and they got the money.
So that's actually working.
Tom
Bull spoke about a method that we worked out in the lab. For the first time we were actually able to
detect, you know, hydrogen bonding in a peptide directly, not because it looked
like a helix in CD, and in fact, we're applying that to carbohydrates now.
Rick
Venable, among other things, spoke about some conformational analysis he did on
the meningococcal polysaccharides.
Bob
Boykins, the mass spec guy, and he's a
protein chemist spoke about his work and multiple peptide conjugates unlike
malaria and anthrax vaccines.
So
you see from this slide, it's kind of busy now, but I hope it wasn't so bad
hearing it, how we're trying to take these really high powered methods and
actually solve problems in like vaccines.
So we do a lot of basic work, but we're, you know, applying it to real
live vaccines.
I
want to talk about one other area. In
the first slide I had said that the work is CBER-wide. Well, this is an example of that. In fact, it mostly happened sine the last
site visit. So it's hot news. We worked with the blood guys, and they had
problems in these blood substitutes.
Some weren't working, and so we applied all of the tools in the tool box
that were appropriate, mass spectrometry, modeling and light-scattering, and
one really cool thing was this. When they
were cross-linking that hemoglobin with raffinose, the way that's supposed to
work -- at least the manufacturer said it would bind to lysines, and it turns
out it just wasn't working. I mean it
was just all messed up.
And
so using mass spec, Boykins actually found fragments in which this raffinose
wasn't just binding to lysines. In
fact, it was binding to a cysteine right near the, you know, heme pocket.
And
Rick Venable, the modeler, then actually placed a cysteine where it was bound,
and said: well, you know, how close to
this heme pocket is it? What could it
do? The water is changing, you know,
and then you minimize it.
And
you know, to make kind of a long story short, you can really understand how
this would keep that molecule from actually undergoing the oxygen binding
transition, you know, T to R, and you know, they also thought it through, and
it really could explain how by perturbing that region of the molecule you can
accelerate release of iron and the degradation of the heme, and that might
actually, you know, give an underlying molecular basis on why this thing is
toxic.
So
that's what we did there. There were
two papers that came out of that. One
is already in press. So you see the
biophysics is highlighted in red. The
blood guys are important, too, you know, in biophysics, right?
So
the first one is the one I just spoke about.
It was with Bob and Rick.
There's a second one where we
use light-scattering, and that's submitted. So I'm actually very excited that the lab is work in this way
now.
The
last basic slide is the one thing that you have to make a vote on. I guess you can vote on lots of things, but
this I really want you to vote on. A
personnel action is a promotion of Rick Venable from a GS-13 to a GS-14.
I'd
just like to say that he's an outstanding scientist. He's been with the lab since 1985, almost 20 years, and he trains
the postdocs. He's been working with
like me on membranes. On almost all of
my important publications on like membranes have been with him.
He
actually provides computer modeling for anyone in the center who wants it, as
witnessed by that last slide I showed you, and he has his own program and a
conformation of carbohydrates. I just
said, "Well, you do this. You can
do it."
So
he's working as a PI in that regard even though he's not formally a PI. In fact he just did a paper with the
carbohydrate guys and the thing to know is like my name is not on that paper.
He
does a lot of other things at CBER.
He's a manager of the network, you know, takes care of a lot of things,
and then on NIH he's actually an extremely well known guy. He supports CHARMM, which is a computational
package that's used everywhere in the world basically.
And
lastly, he hasn't gotten a raise in over ten years. I think he deserves one.
So
thank you very much. Do you have any
questions for me or for Dr. Walker?
CHAIRPERSON
OVERTURF: Are there any questions
regarding the Laboratory of Biophysics?
DR.
PASTOR: Well, I thank you very much.
CHAIRPERSON
OVERTURF: Thank you, Dr. Pastor.
The
next presentation will be on an overview of the Laboratory of Pediatrics and
Respiratory Viral Diseases, and that's by Dr. Jerry Weir again.
DR.
WEIR: Thank you.
On
November 9th, 2004, we had a site visit of several research programs in the
Division of Viral Products. To give you
a quick background of the Division of Viral Products, there are seven
laboratories. I think I've listed them
already once today, but I'll do it again.
There's
the Laboratory of Hepatitis Viruses with Steve Feinstone as the Chief; the
Laboratory of Vector-Borne Viral Diseases with Lew Markoff as the Chief; the
Laboratory of Retrovirus Research, Hana Golding; Laboratory of DNA Viruses with
Andrew Lewis; the Laboratory of Pediatric and Respiratory Diseases with Roland
Levandowski as Acting Chief; Laboratory of Immunoregulation with Ira Berkower
as Chief; and the Laboratory of Methods Development with Konstantin Chumakov as
the Chief.
To
summarize briefly the mission and the functions of the Division of Viral
Products, we regulate viral vaccines and related biological products, insuring
their safety and efficacy for human use.
Part of our mission is also to facilitate the development, evaluation and
licensure of new viral vaccines that positively impact the public health.
In
support of this mission, we have numerous review and research activities. You've probably heard some of these before,
but briefly we review investigational new drug applications, biologics license
applications and supplements. We're
involved in lot release review and sometimes testing. We have extensive post marketing activities. For an example, I've listed biological
deviation reports. We participate with
the others in CBER in manufacturer inspections, and we actually have an
extensive role in consultation with other public health agencies, such as WHO,
CDC and NIBSC.
The
research activities that are ongoing as part of our seven laboratories span the
spectrum from very applied to very basic.
Examples of the type of research that we perform include studies on
viral pathogenesis, vaccine safety and efficacy, including cell substrates,
vaccine and viral vector evaluation, studies on the correlates of protection
that are necessary for our evaluation, reagent preparation, as you've heard
this week, influenza vaccines, methods development and evaluation, and research
efforts to vote it to emerging issues, for example, BSE, counterterrorism,
other things that come on the radar screen.
To
put the research program in perspective, at the present time we have a
full-time staff of about 75 in the Division of Viral Products. The entire staff of the division, counting
mostly postdocs, contract workers total somewhere in the neighborhood of 110 to
120 people. We have had some recent
reductions of full-time staff in FY '04 and '05.
In
FY '04, we had a budget of approximately $1 million to support these
researchers and these research efforts.
This was a slight decrease from FY '02 and '03, and at the present time,
we have supplemental funding in our laboratories from outside sources that is
now substantially and significantly greater than the internal funding that we
receive to support our activities.
We
expect continued budgetary challenges in FY '05 as well as '06.
On
November of '04, we had several laboratory teams reviewed as part of a site
visit. You all have briefing documents
and so I'm not going over this in detail.
I'm just going to list them for you.
The review of the influenza virus team which Roland Levandowski is the
head of this team, but also this includes Zhiping Ye.
The
major regulatory responsibilities of this group are obviously influenza
vaccines, including inactivated influenza virus vaccines, as well as live
attenuated virus vaccines. The areas of
research and the laboratory activities in this team include the
standardization, characterization, and development of influenza virus vaccines.
A
second program that was reviewed in November was the viral pathogenesis and
vaccine adverse reactions team. This is
headed by C.D. Atreya. The major
regulatory responsibilities for this group include review of measles, mumps,
and rubella vaccines, particularly the rubella part of that, and also review of
rotavirus vaccines which are under development.
The
areas of research in this group focus on the role of host factors and viral
pathogenesis, for example, primarily rubella and rotavirus.
And
third team that was reviewed in the site visit is the Neuroimmunopathogenesis
Team headed by Dr. Kathy Carbone. The
major regulatory responsibilities in this group also are in the areas of
measles, mumps, and rubella vaccines, particularly the mumps aspect of this,
and the areas of research that they focus on are vaccine neurotoxicity
pathogenesis and neural virulent safety test development. One example is the mumps neurovirulence test
that has been developed by Steve Rubin and Kathy in this group.
So
basically on November 9th, these groups, these individual teams were reviewed
by the site visit team. They were
evaluated for the progress both of the individuals in each team and the team
was assessed for its future directions that they presented.
And
that's all.
CHAIRPERSON
OVERTURF: Are there questions for Dr.
Weir? Everybody has read all of those
documents, I guess.
Okay. We're going to take a 30 minute break. Then we're going to come back and we'll be
almost an hour ahead, won't we?
All
right. So we'll take a 30 minute break
and start the final closed sessions which make the presentations, and then
we'll take the votes on these laboratories.
Okay.
MS.
WALSH: In 30 minutes we will begin our
closed session. This closed session is
closed to the public. We are asking the
public to leave the room at this time and take all of their possessions. Any briefcases, suitcases, or personal
belongings left in the room will be placed outside the door before we begin our
closed session.
For
the press, any media equipment that cannot be removed in the next 30 minutes
must have the power turned off. When the
closed session is over, you can come and remove any remaining equipment.
DR.
MARKOVITZ: Our luggage can stay in
here, I assume.
MS.
WALSH: Yes.
CHAIRPERSON
OVERTURF: Okay. We'll reconvene at 11 o'clock.
(Whereupon,
at 10:32 a.m., the open session of the above-entitled meeting was concluded.)