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.