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.




                    BLOOD PRODUCTS ADVISORY



                   OFFICE SITE VISIT REVIEW

                    OF THE OFFICE OF BLOOD

                      RESEARCH AND REVIEW


(Open Session)











                                  July 22, 2005


                                  Gaithersburg Holiday Inn

                                  2 Montgomery Village Avenue

                                  Gaithersburg, Maryland












                        Proceedings By:


                    CASET Associates, Ltd.

                 10201 Lee Highway, Suite 180

                    Fairfax, Virginia 22030

                        (703) 352-0091

List of Participants:


                      James Allen, Chair


                         William Freas


                         Harvey Klein


                      Marcos Intaglietta


                        Donna DiMichele


                         Michael Busch


                         Harvey Alter


                        Suzette Priola


                       George Schreiber


                        Michael Strong


                        Peter Tomasulo


                          Ching Wang












                       TABLE OF CONTENTS




Welcome and Opening Remarks:  James Allen                5


Introduction and Charge to the Committee:  Karen Midthun 6


Overview of CBER Research Programs:  Kathryn M. Carbone 11


Overview, Office of Blood Research and Review:

  Jay Epstein                                           42


Overview of the Research Program of the Division of     79

Blood Applications:  Alan E. Williams


Overview of the Research Program of the Division of     96

Emerging and Transfusion Transmitted Diseases:

 Hira Nakhasi


Overview of the Research Program of the Division of    130

Hematology:  Basil Golding


Open Public Hearing                                    164

               P R O C E E D I N G S            (8:03 a.m.)

          DR. FREAS:  My name is Bill Freas.  I am the acting Executive Secretary for today's subcommittee meeting on the Blood Products Advisory Committee.  At this time, I would like to go around and introduce the guests seated at the table.

          I guess I started a few seconds too early.  In just a second I'll start my introductions, because if I go out of order, I will get a little confused.

          At the end of the table we have the court reporter.  Sitting next to the court reporter we have Dr. Harvey Alter.  He is chief of infectious diseases, Department of Transfusion Medicine, National Institutes of Health. 

          In the next chair, Dr. Busch is here and he will soon be joining us, Dr. Michael Busch, who is a vice president, research and scientific affairs, Blood Systems, Incorporated.

          Next we have Dr. Donna DiMichele.  She is associate professor of pediatrics and public health, Weill Medical College and Graduate School. 

          Next we have Dr. Marcos Intaglietta, professor of applied mechanics and bioengineering, University of California, San Diego.

          Around the corner of the table, we have Dr. Harvey Klein, chief, Department of Transfusion Medicine, National Institutes of Health.

          In the center of the table, we have our Chair, Dr. James Allen, president and CEO, American Social Health Association.

          Around the corner of the table we have Dr. Ching Wang, professor of chemistry and pharmaceutical chemistry, University of California-San Francisco.

          Next we have Dr. Peter Tomasulo, executive vice president, chief medical officer, Blood Systems Incorporated.

          Next we have Dr. Michael Strong, executive vice president and chief operating officer, Puget Sound Blood Center.

          Next we have Dr. George Schreiber, vice president, health studies, Westat, Rockville.

          At the end of the table we have Dr. Suzette Priola, senior investigator, Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories.

          FDA is continually changing and improving its advisory committee COI process.  Today we have from the ethics branch of FDA's office Miss Jenny Slaughter, to read the conflict of interest statement for the subcommittee meeting.  Miss Slaughter.

          MS. SLAUGHTER:  Thank you, Dr. Freas.  Good morning.  The Food and Drug Administration is convening today's meeting, a subcommittee to the Blood Products Advisory Committee, under the authority of the Federal Advisory Committee Act of 1972.  All members of the subcommittee are special government employees or regular federal employees from other agencies subject to federal conflict of interest laws and regulations. 

          FDA has determined that members of the subcommittee are in compliance with federal conflict of interest laws, including but not limited to 18 USC 208 and 21 USC 355 and 4.  Under 18 USC 208, which is applicable to all government agencies, and 21 USC 355, which is applicable only to FDA, Congress has authorized FDA to grant waivers to special government employees who have financial conflicts when it is determined that the agency's need for the particular individual services outweighs his or her financial conflict of interest.

          Members who are special government employees at today's meeting, including SGEs appointed as temporary voting members, have been screened for potential financial conflicts of their own, as well as those imputed to them, including those of their employer, spouse or minor child, and they will be related to the discussion of today's meeting.  These interests may include investments consulting, expert witness testimony, contracts, grants, cooperative research and development agreements, teaching, speaking and writing, patents and royalties, and primary employment.

          Today's agenda is devoted to the discussion and review of intramural research programs in the Office of Blood Research and Review.  In addition to the participation of today's subcommittee members, and pursuant to the authority granted under the committee charter, the director of FDA's Center for Biologics Evaluation and Research has appointed the following SGEs as temporary voting members:  Dr. Harvey Alter, Dr. Michael Busch, Dr. Marcos Intaglietta, Dr. Suzette Priola, Dr. Michael Strong, Dr. Peter Tomasulo, and Dr. C. C. Wang.

          In accordance with 18 USC Section 208.b.3, general matters have been granted to the following participants:  Dr. James Allen, Dr. Michael Busch, Dr. Donna DiMichele, Dr. Marcos Intaglietta, Dr. George Schreiber, Dr. Michael Strong and Dr. Peter Tomasulo.

          A copy of these waivers may be obtained by submitting a request to the agency's Freedom of Information Office, Room 12A30 of the Parklawn Building. 

          In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the record.

          Finally, with respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon. 

          This statement will be available for review at the registration table.  Thank you.

          DR. FREAS:  Thank you, Miss Slaughter.  Before I turn the microphone over to our Chair to start the meeting, I would like everybody to take a few seconds to check your cell phone, and please put it on the silent mode so it will be less disruptive to the meeting.

          Dr. Allen, I turn the meeting over to you.

           Agenda Item:  Welcome and Opening Remarks

          DR. ALLEN:  Thank you.  This is a unique opportunity.  This is the first review of this type that has been conducted, as I understand it, at the Food and Drug Administration.  We will be very helpful and very important to them as they go through their management review processes as they work with the Administration and Congress in developing budgets and setting priorities for future staff development and research opportunities.

          I want to thank each one of the committee members.  This is a big obligation.  It is not just a day out of your life.  I'm sure you have spent quite a bit of time reviewing the materials that FDA staff put together.  I possibly will be getting back in touch with you afterwards as we develop the report asking for your advice and ideas.

          We have a busy schedule ahead of us today.  We will be listening to reports.  We will be asking questions.  Later in the afternoon we will getting together and putting together our thoughts and summaries for presentation to the senior FDA staff at the end of the day.

          Currently scheduled, we run until five p.m.  In actual fact, we are going to need to truncate that.  I personally need to be out the door right at four p.m.  We will be looking for opportunities as we go through the day to shave a few minutes off here and there, so that we can try to wrap up no later than four p.m. this afternoon.

          As I indicated, this is the first of a series of processes that the FDA is going through.  Since it is the first, I want to invite each one of you, if you are not certain as we move through the day, and want to ask questions not just of the people who are making presentations, but of the senior FDA staff, to clarify the intent of what is needed, what do they need back, please feel free to do so.  I think this is a learning process for them as well as for us, and we want to give them the most useful set of materials that we can at the conclusion of this.

          So without taking more time, I would like to invite Dr. Karen Midthun, Deputy Director, Center for Biologics Evaluation and Research, to introduce our responsibilities and give the charge to the committee. 

    Agenda Item:  Introduction and Charge to the Committee

          DR. MIDTHUN:  Good morning, and welcome.  This activity is very, very important to us and a new one also, as Dr. Allen has pointed out.  Dr. Goodman, the Center director, regrets that he could not be here today, but again, I want to stress that this is an extremely important activity to him, and indeed this office level overview and input on the research program is something that has been initiated at his request.

          I am going to give some introductory comments about the Center, and then go over the charge to the committee today.  I want to stress that what we want is your input on the research and the substance of the research, rather than on management or organization thereof.  So I will move on to my first slide.

          I just want to go over the vision of CBER.  Essentially we believe that innovative technology advances public health, and that helps our mission, which is to protect and improve public health and individual health in the U.S. and where feasible, globally, to facilitate the development, approval and access to safe and effective products and promising new technologies, and to strengthen the Center for Biologics as a preeminent regulatory organization for biologics.

          The organization of the Center is that there are eight offices that report to the Center Director, Dr. Goodman.  A few of the offices is what we refer to as our product offices, the Office of Blood, which is the subject of today's meeting, the Office of Vaccines and the Office of Cell, Tissue and Gene Therapy.  Then we also have the Office of Compliance and Biologics Quality and the Office of Biostatistics and Epidemiology, which are very much involved in our regulatory and our review work, as well as research.  Then we have other offices that are also critical to our management, the Office of Management, the Office of Information Technology, and the Office of Communications, Training and Manufacturers Assistance.

          What are the products that are regulated at CBER?  They include blood, blood components, blood derivatives, vaccines, both preventive and therapeutic, allergenics, cell and gene therapies, tissues, xenotransplantation and related devices.

          Let's move on to the critical path research initiative.  Many of you have probably heard of that.  That is an agency-wide effort, and it is intended to identify and focus on regulatory and scientific opportunities to improve product development and availability, also to provide opportunity to promote and preserve the science base of the Center for Biologics and the FDA.  To this end, we at the Center for Biologics are seeking input to identify opportunities, collaborators and priorities.  We initiated a public workshop to this end this past October.  These site visits are an extension to try to get input at the office level into our activities, and also have a public process as part of setting our priorities.

          What is the unique role of FDA in the critical path?  FDA scientists are involved in the review during product development.  They see the successes, the failures, and the missed opportunities.  FDA guidance documents are science based.  They are intended to foster innovation and improve chances for success.  We believe strongly that scientific expertise in certain areas is critical to making informed decisions about the safety and effectiveness of products, and whether clinical studies of investigational products should proceed.

          The goal of today's review is -- what we are asking the subcommittee to do is to access the strengths, the weaknesses, the opportunities and the needs of the Office of Blood research program.  We want you to make recommendations that further the dynamic and responsive research programs that are intended to facilitate the development of safe and effective biological products.

          The objectives are to increase the visibility and transparency of how research programs are integrated into our regulatory process, to identify the contributions of the Office of Blood research to product development and availability, to determine the opportunities for research, expansion, direction and new collaborations, and to identify needs and strategies for future research, and also recommendations for attracting qualified science and medical experts to the Office of Blood research and review.

          Again, we believe that CBER has responsibility for some of our most important products -- blood, vaccines and tissues -- and we have a critical role in facilitating the development of innovative medical products that contribute to individual health, public health and counterterrorism, and as such, expertise, partnership and wise use of our resources are essential.  So we very much welcome and appreciate your input, and recognize the very large work that you have signed on to do, and we very much appreciate that.

          In closing, I would like to say, we are looking forward very much to your input on the research program.  The focus is the research rather than the management or the organization thereof.  We really want your input on the substance, so that we can use that to improve what we are doing.

          Thank you.

          DR. ALLEN:  Thank you, Dr. Midthun.  Any questions that any of the committee members would like to ask? 

          I thought your objectives slide was very helpful.  We may want to put that up later in the day as we go through our deliberations.

          DR. MIDTHUN:  Sure.  Thank you.

          DR. ALLEN:  Thank you.  Dr. Kathryn Carbone, associate director for research, is going to give us an overview of the CBER research programs.

       Agenda Item:  Overview of CBER Research Programs

          DR. CARBONE:  In your packet you have a copy of the slide.  You will see a nice picture of the Washington Monument.  This slide is provided by Dr. Goodman.  He makes the prettiest slides.  But we will move, rather than waste time with that.

          I am going to start today by saying, first of all, thank you.  I think we have tasked the members of our advisory committee with so many important things throughout the course of the year, and the thought that we added to both our internal committee members and Dr. Freas' office's hardworking folks, and the advisory committee as well as our guests yet another task, but we really appreciate the fact that you have agreed to come today and help us.  It is going to be very valuable and very important.  As we all know, science can't happen in a vacuum, and we welcome your input.

          Today I am going to start by explaining a little bit about what is the critical path FDA research initiative, and then follow with a little introduction of the overall research program at CBER, then start to drill down as we go through the various talks this morning.

          The critical path research was initiated through the Office of the Commissioner through the perception that, although biomedical research funding has grown exponentially, that the actual licensing of products was decreasing.  In CBER we have maintained a fairly active licensing output.  However, in certain areas, some of which are in this office and in other offices, we have still some gaps and ways to go to getting the science in place to do the regulation.  So the perception that we are simply throwing money at one side of the equation without preparing the pathway for licenses to occur was not going to be the solution.  We needed to cover both ends of the spectrum.

          What is a critical path?  Of course, we could not use translational research, which is a phrase that has great meaning and a different meaning to many people.  But we wanted to try and emphasize that there is this black box to many people.  Industry and FDA are very aware of the science of making a product, but in many cases, because we do deal in edge of the wedge and high biotech products, we are dealing with sponsors who don't necessarily know these pathways well.  In addition, we are dealing with products that don't have pathways, and ones that have to be created.

          So the basic path in developing a product is of course, the research leads to the prototype, preclinical testing to see if it is safe and worth going into people from an efficacy point of view.  Then clinically the product is tested.  If the testing looks good, then an application is provided and the FDA comes in here and works on the application to help evaluate the product.  Then if the product succeeds, it is approved.

          The critical path is focused on the last half of the pathway.  What many times happens is, something that looks wonderful in preclinical development gets through hundreds of millions of dollars of phase three trials, and suddenly doesn't look so good, and the development effort is for naught.  So the ability to earlier predict failures or, better yet, earlier predict the winners, would be a significant advance.  Sometimes products that can be made in a beaker can't be made in the hundreds of liters of development that need to be made for a commercial product, so those products fail.  Sometimes the clinical development is limited because the tests aren't available to evaluate the safety of these products.

          Many of these things occur in what is to most science a black box.  So a part of the effort of transparency is to talk about these problems, look at them as opportunities for solutions, and fix them so that products move forward in a more efficient fashion.

          There is a document put out.  It is highly relevant for the drug end of things.  Of course, the Office of Blood deals with a lot of interesting and unique aspects that aren't traditional for typical drugs.  But nonetheless, as a thought piece this is a very important document.

          It basically talks about identifying and focusing upon and managing the regulatory and scientific opportunities to improve product development, in other words, to identify potency and effectiveness standards, safety issues that need to be resolved early, and consistency in manufacturing quality.  This last one is probably the most neglected when it comes to early product development, particularly in terms of very high tech novel biological products, but great ideas and really promising products in a test tube are often still a far way away from knowing how to manufacture that product consistently, or even test it for consistency.  That will be discussed later today.

          These important scientific issues need to feed into policy and guidance.  As a result, the science base at the FDA is quite important to maintain.

          As Dr. Midthun was saying, why the FDA?  We review paperwork.  A lot of the science happens outside, and it will continue always to happen outside.  The problem is, in order to review the paperwork adequately and try and assist in the effective review, we need a science base here that can participate actively in the process. 

          So we view the critical path as a combination of FDA intramural science, FDA collaborating and externally leveraging, and extramural efforts, making the scientific community more aware of these issues, so that they get higher on the radar screen.

          To many people, science is a peripheral byproduct of regulation.  It is not part of our core mission.  I think the critical path document offered by Dr. Woodcock goes a long way to try and dispel that notion, but the scientific part of the review is integral to the process.  An application may come in, a problem that is identified, something that is otherwise holding up this application, scientific questions are raised.  They can be resolved  in academic, government or other sponsors and the FDA.  The science then feeds back, and is fed back often into advisory committees like this for public input.  Development of a public standard is put out.  Guidances and standards then communicate this to the outside world, and then the application moves forward, and future applications have a much clearer pathway.

          In 1998, a subcommittee for external review of CBER research -- CBER was the first center that underwent this review -- produced what was called the Korn report, which was distributed to the committee.  What we will talk about a little bit today is, although we are not completely unique in the agency in this regard, our center has probably the largest group of what we call the research reviewer.  I modified that to researcher regulator, since our researchers do much more than simply review.  I will talk about that in a minute.  The bottom line is that the same person handling the document and making an evaluation is the same person who can go to the lab and either work on a specific problem, or at least is familiar with the area.

          However, I don't want to leave anyone with the notion that all people who do very important regulatory work at CBER are lab scientists.  We have an outstanding cadre of regulatory scientists, clinical review scientists, and you will see some work presented today through Dr. Williams' division, that doesn't involve necessarily laboratory work, but it is still high quality science that results in better evaluations of products.

          Multi-tasking.  Having come from academia myself, the concept of multi-tasking was not a difficult one, since we all taught students and saw patients and worked in a lab.  That is what our people do at CBER.  In addition to doing research, and we target about 50 percent average time of the research regulator, they will be reviewing INDs and DOAs, helping in the development of policy and guidances, meeting with sponsors and advisory committees, participating in inspections, evaluating postmarketing and drug reaction information, risk assessments and the research performed relevant to this.  This view of the FDA's core mission gives them the opportunity to target research to solving some of the problems that they run into in the regulatory world.

          Part of our evaluation and review of research at CBER is further strengthening the bond between the fulltime regulatory scientists and clinical reviewers, and developing the team approach to the identification of the problems and scientific solutions we need.

          Mission relevance.  When I started, I started asking the research regulators to note which INDs and DOAs their research was applied to.  We collected hundreds of licensing applications and investigation of New Drug Applications to which their research was feeding into. 

          More than 50 percent of our research program is applicable to counterterrorism.  I say applicable, because we are not always working directly on an agent, but identified as an important issue in counterterrorism products.  The critical part of our research is to keep it in the public domain, so that what we do internally and with our partners is made public so that it benefits across the field in categories of products.

          I just want to delve down a little in how we manage our research products at CBER.  Basically we consider it important to evaluate both past achievements and future plans.  Those of you who have R0-1 grants understand the need to talk about both sides of the coin.

          As many of you are very familiar with, we have laboratory and investigator driven site visits right down at the bottom to make sure our scientists continue to be talented and interfacing with the external world, and their expertise recognized.  We also have an internal management review, which you may or may not be aware of, where they are yearly required to report their achievements and future plans.  This incudes publications, regulatory policy guidances.  This research QAQC is web based.  WE fold it into things like IRB approvals, AC-UC approvals, all sorts of -- the nitty-gritty of managing a research program.

          The Office of Research site visits.  This as you know is the first one.  We will be proceeding to Office of Cell, Tissue and Gene Therapies and Vaccines, coming shortly.  As part of this effort to team build, we are working on developing what we call subject expert teams.  This would be teams across office of people doing research to build a greater critical mass and improve communications across the offices so, for example, our retroviral experts in every different product office will be communicating as part of a product team.  Because the mission of the organization is regulation, we felt it is important to keep the administrative reporting within a product office.  However, it is also important to have our scientists with similar expertise communicating across the offices. 

          We provide researchers with limited intramural support.  Those of you with R0-1s know what one grant will get you, so we do what we can do to provide people with a modicum of support in terms of laboratory staff.  The vast majority of our people must compete for extramural sources of funding in order to support their research program.

          That said, we have instituted a research management grant review application process, so that our partners are selected are carefully reviewed for conflict of interest, et cetera.  We simply can't apply for NIH R0-1s with principal investigators, et cetera, but there are limited sources of funding that we are able to apply for, and pretty much our people have to do this in order to continue.

          CBER research.  This is going to be talked about in much greater detail, but today you will be highlighting in each of the divisions some of their achievements in supporting the regulatory mission, and some efforts that were instrumental in getting products through and protecting the public health as well.

          I wanted to come towards the end with a little bit of discussion of the vision Dr. Goodman and I and the leadership team have talked about, where CBER wants to go, where it can go.  We must of necessity be very focused in our efforts, and much of our work is delivered to us rather than something that we a priori decide to go after.  But nonetheless, this is just an example of initiatives that would be important for us to pursue.  However, that said, I also want to say that this part of the process is very important, to listen to our stakeholders as well as our advisors, to identify other areas that are very important that we should be attending to. 

          Developing and making available well-characterized cell banks for vaccines and biological productions would be a tremendous asset across the board.  Characterization of cell therapies and links of these cell therapy characterizations to standardized clinical outcomes, very important.  All sorts of new assay standards, biomarkers, surrogates for efficacy are desperately needed to move the products forward.  Method and validation of pathogen inactivation for products of interest to this office and others, and then trying to do multi pathogen detection methodologies.  Improving longevity in storage of animal and tissue for new vaccines, assay standards and reagents, and enhanced clinical trial design and analysis, this is an important contribution of our Office of Epidemiology and Statistics.

          So bottom line, our people are here today to seek your input.  I think they would welcome it.  They are a hardworking, talented group of people who have a very unique expertise, which is the attention to the scientific tools and knowledge that are needed to get products moved forward effectively and to protect the public health. 

          We are welcoming your input.  We really appreciate the opportunity to be transparent and to get your help in developing the areas of scientific expertise that we need to pursue.

          Thank you very much.

          DR. ALLEN:  Thank you, Dr. Carbone.  Any questions from the committee? 

          DR. WANG:  I fully agree that people who engage in regulatory affairs should be active scientists themselves.  Also, I am very impressed by the kind of research that is going on at CBER.

          I am just a little bit unclear how these individual research programs are initiated and approved, and how the internal resources are being allocated, how all these decisions were made.

          DR. CARBONE:  Currently the product offices make those decisions.  They do this in consultation with myself.  They receive the funding from Dr. Goodman.

          To the research program reporting, the individual is required to not only say what they did successfully, but what they plan to do in the next year, and all the supervisors must go and evaluate this program.  So the people who make the funding go through and evaluate the annual reports.

          In addition, there is a four-year cycle of site visits, where the person must present both what they have achieved and what they plan to do.  So we get external comment on their scientific input.  As a matter of fact, in one advisory committee, a question was asked about von Wilbern's factor research, whether we should pursue this, whether there was any value.  The experts on the site visit committee felt that there was a need for this kind of research, so that kind of input. 

          So that is a decision along the managerial chain of the product offices, but we get a lot of external input as well through the site visits, so it is a multiple source to decide.

          DR. ALLEN:  I think that was a very good question, Dr. Wang.  You may want to raise it again at the end of our discussions or at the end of the presentations.  It may be an issue that we would want to talk about and comment on during our review.

          Yes, Dr. Strong.

          DR. STRONG:  Along similar lines, these folks have a lot of responsibility, having to do with their own research, having to do with the regulatory process, having to balance that along with sit-in meetings like this all day long.  You mentioned that they have both internal and external support, or they are required to get external support.  I am wondering about the balance of that.  What is the percentage roughly of what they get supported internally versus what they have to get outside?

          DR. CARBONE:  It varies by office, but it can go from zero to 70 percent, depending.  For example, there was an issue where a public call came out through NIH about cell substrate applications.  Cell substrate is in an exact 100,000 percent alignment with what we do, and some of our people very successfully competed for those funds, which essentially gave them the opportunity to further their cell substrate work.  So this is the kind of application.

          All the applications are reviewed through the command chain, including myself, so that if the office director, division director or even myself feel that the work is outside the mission, the application doesn't get submitted.  Or we have a lawyer, Mr. Murphy, who starts the conflict of interest evaluation, and the offices have control of that as well, if there are any conflicts perceived.  That is even for the application process, before the money gets here there is another whole process for conflicts of interest.

          So the focus on target is maintained through this sort of application.  The application is reviewed before it is even out of here.  But the fact of the matter is, we want to do cell substrate research, looking at adventitious agent assays to evaluate cell substrates, making better test result substrates, which we can't do nearly as much without this external support.

          DR. STRONG:  So are you saying then that each individual investigator is judged on their own particular area as to what they are required to be supported externally or internally?

          DR. CARBONE:  There is no requirement.  It is simply a matter of what they can produce.  In other words, they can produce a little bit with the limited intramural support.  If they can get targeted funds to expand that, then with the approval of the office, they are permitted to.  But it has to stay in alignment with what they want to do.  It is a simple fact of life with the research resources here.

          DR. ALLEN:  But the source of external support is limited much more than it would be for most academic researchers.

          DR. CARBONE:  Yes, it is limited, what we can apply for, yes.

          DR. ALLEN:  Do you want to just quickly review where they can and cannot go for --

          DR. CARBONE:  Anything that is directly involving regulated industry would be difficult to achieve.  If it was permitted, it would require recusal of the person from any regulatory decision making, which we try to avoid, since we are limited in our personnel resources as well. 

          They can participate with academia, for example, if there is an academic partner.  The partner may be a principal investigator.  There is a cooperative research agreement, which is legislation that permits transfers of money for involving cooperative research, something like the Gates Foundation, although we are in discussions with them because of the technical ways of the research agreement, something that was viewed as non-sponsor focused, but more public health oriented. 

          As I mentioned, select initiatives through NIH intramural programs, often programs that NIH sends out to their intramural scientists, they will include FDA scientists as opportunities.

          DR. ALLEN:  But not NIH extramural?

          DR. CARBONE:  NIH extramurals are R0-1 funds now.  They can't do that.

          DR. ALTER:  This is on the same theme.  To me there is a little bit of a disconnect, as I talked over the last years to people working in FDA.  They are disheartened by cutbacks in their staffs, by cutbacks in their programs, that research is being diminished, and have sounded demoralized.  Then I read what is going on, and I am very impressed by the depth of what is going on, and by the high signs of it.  I am trying to figure out how that is happening.

          I am wondering, now that you are more transparent, now that the science is very directed to FDA issues, in a previous review I did, one of the problems was that the research going on was not totally relevant to the FDA mission.  But now it seems to me.

          DR. CARBONE:  Thank you.

          DR. ALTER:  So is one of the outcomes possibly that we would support Congress or whoever to give more to your research program, to recognize it as a legitimate endeavor?

          DR. CARBONE:  First of all, I want to recognize and appreciate the comment that you feel the research is more directed, because we have worked hard, not just to make it more directed, but to work with our scientists to better explain why it is connected, because sometimes this becomes unclear with the scientists in this proprietary black box.  I think they have worked hard to do that.

          We will take any support from anywhere we can get it, let me just say that, because things are truly in desperate times in the whole agency.  That said, I would really like to focus more today on the science topics, areas of expertise we need, projects that we are not doing that we should be, rather than talk about the funding, because in my opinion, coming from the extramural world, it is much more important to have something worth paying for first, and then taking that out and saying, this is valuable and then looking for ways to support it.

          Being an extramural scientist, I think that what I perceived here, coming here about ten years ago, was that our science is much more extramurally driven type science, in that we would have a mission.  We have a significant section, being as you know the first part on an R0-1, this is the way we are driven as well.  We are not here just for the science sake.  We want to do good science that is, I would say, applicable -- I don't like the basic or applied -- applicable to our regulatory mission.

          So I think first, the goal is to have good science worth supporting, that we can take and feel comfortable that the value is there.  Then at that point we will have to deal with how to get the funding.  It is a multi-level problem issue throughout the government all the way up through the FDA.  I think what you can help us with the most here today is to give us guidance as to make our scientific program really worth supporting.  That is where I would focus today.

          DR. DIMICHELE:  Thank you for that.  My question is related, but slightly different.  In academia, the 50-50 split, clinical, medicine research, is often very difficult to accomplish.  It is probably the most difficult position we ever put academicians in.

          What happens is that people who are in that split don't oftentimes have enough time to search out funding opportunities to see what is going on around them, look for opportunities for collaboration.  This is going to relate to one of the mandates that we have, that is, to help you attract scientists and people who are willing to do research in this kind of environment.

          So I have two questions.  The first is, with respect to funding, how does the Office of Research help its investigators not only go through all the regulatory stuff about approving funding, but look for funding opportunities, particularly since there are so many overlays of acceptability, and identify potentials for outside collaborations based on helping them understand what is going on out there.

          The second is, how are scientists coming into this environment trained in regulatory affairs, in terms of doing their mission?  That is not one of the things that you come out of med school or a Ph.D program really understanding how to do.  So how does a person come in here and learn how to do regulatory, and still do research?

          DR. CARBONE:  Those are very good questions.  In terms of the sources of funding, in the year and a half or two years I have been in this position, we have worked on many levels, we are beginning to work on trying to do that.  We have a very good web-based science -- it is called CBER research central, if you will; it is web-based. 

          Recently it came to light that there had been a discussion about joining Community of Science, which obviously provides search engines, grants and opportunities, which provide the big universe, to pare down to what we can apply for.

          I will be frank with you, the cost was prohibitive and we couldn't afford it.  But the good news is, it turns out that through other avenues, we were able to link up with NIH, and we now can join Community of Science through that avenue.  So investigators and associates for research in each office were provided with the information, and it is also on our website.  So that is a first step to get the universe.

          I have held little town hall meetings about site visit presentations and how to go about this.  There is a planned town hall meeting about how to write a grant.  We have little internal grants that, after individuals apply within the Center, I request that anybody who would like to meet and discuss their grant applications, say they didn't get funding.  In many cases it is simply one of those, you have 30 people and three opportunities for funding, but in many cases there are problems with titles, things from people that aren't trained in writing grants. 

          Then we seek larger partners.  We are working with the agency to develop funding.  Sometimes the problem is not the funding agency is inappropriate; there is no mechanism to receive those funds for research.  So we are working with the Office of the Commissioner.  We have sent forward a proposal that they are evaluating for different approaches to opportunities to get specifically research funding.

          One of the other things is the push-pull, unfortunately, as you noted about the time spent writing grants and trying to get the funds and do the work of the grant, the regulatory work.  One of the things is that in some respects, our people are developing an appreciation for us, again, having come from extramural NIH salary support, and supportive of a biologist or a technician and a postdoc, is one R0-1.  So in essence, we aren't requiring people in any way to go out and get those funds.

          What we do need help with is the supply money, which is usually smaller pots of money, smaller grant efforts.  I think as we get -- we are trying to raise institutional partnering.  We have a leveraging page, for example.  We have just put up where successful applications have gone, to give our scientists an idea where they can go, that other people have gone successfully.

          But I think part of the problem that we have to deal with is that often when we approach even the smaller sources of funding, the foundations, et cetera, they say, we don't fund federal scientists.  We explain we are not receiving intramural NIH funding, et cetera.  But these are bridges that we are working on to cover.  That is an active effort and that will be continuing.  It is a big part of my job. 

          The second thing is training.  That is a very good question.  The only place people really get good regulatory review training is at the FDA.  They come here and we train them.  We have several courses.  I think that highlights one of the -- in my opinion -- very important aspects of this research program.  Because our researchers actually review the questions that arise, if only I had a surrogate marker, we could drop this clinical study from 30,000 kids down to 3,000 if we had a surrogate marker of efficacy; if only we had a way of characterizing this product, I would know that these three studies were comparable.  Those questions come to the fore.

          One of the things that we have worked on is, there always was a collegial way for a regulatory scientist or a clinical reviewer to feed into the research agenda.  Pick up the phone, they work together, we identify problems together.  What we are doing now is making a formal bridge, so that we are going to bring together the regulatory divisions with the research regulatory divisions, and develop a yearly process for identification of problems.

          Essentially our regulatory scientists and clinical reviewers will be identifying research problems as well to feed into our research program.  But having us act not just as consultants in theory, but being faced with the regulatory problems really helps identify the bang for the buck.  I think our people, to their great credit, like academic scientists.  When funding levels get tight, they get very focused, very goal oriented, outcomes oriented, and have to pare down what they do to become the most essential to what we need.

          Does that answer your question somewhat?  There will be more time later.

          DR. BUSCH:  You answered many of my questions really well, but the intramural question of intramural funding that NIH has available, I'm not clear on to what extent your people are qualified to apply for those funds.

          DR. CARBONE:  When I am in intramural, it would be not the intramural funding that they are based on, but they will put forward for their Institutes occasionally intramural calls, if you will, for grants.  So these are grant applications that occur within intramural NIH for intramural NIH scientists.  Occasionally we may apply for those as a federal agency.  If we receive funds from NIH, they have to come from the intramural NIH pot.  So this is not the baseline lab budgets intramural money, this is an occasional call for grants. 

          They have them for AIDS.  They recently did this cell substrate call.  Very isolated, small pots.

          DR. ALTER:  Just a comment on that.  Last week I sat on a bioterrorism review, which is an extra pot of NIH money, and I would say that about a quarter of the applications were from FDA.

          DR. KLEIN:  One of the research things that is a little different for the FDA than for other areas is the area of evolving urgent public health needs, as an example, West Nile virus, the need to do regulatory work with a real short time line, or VSIG that we heard about yesterday, needing to find surrogate markers, and do some important research work in a very short time frame.

          How are funds and resources found and allocated to do those kinds of things, which come up on a fairly regular basis, clearly are important for our national public health.

          DR. CARBONE:  That is a very good question.  I think one of our strengths, and one of the reasons for having intramural research is the ability to flex quickly.  You see this as well in extramural science.  As funding goes up for this and down for that, people flex, but it is on a much longer time frame.  So our people just expect that if there is an emergency, they may have to literally drop what they are doing in one area and work on a higher priority area.  Sometimes it is simply a matter of transferring the same funds you would otherwise be spending on area A, your baseline activities to the new area.

          When available, when possible, Dr. Goodman has provided funding for high priority or urgent issue processes.  But the work gets done if we have to rob from Peter to pay Paul in the intramural program.  We just don't have a great deal of flexibility.  But when there are funds available, we try and fund -- for example, center-wide resources is our core facility, which provides a baseline of support for everybody that does DNA sequencing, peptide sequencing, DNA synthesis, et cetera.  We have mass spec available through that analysis.  So when we can support them in some way to get the job done quicker, our scientists are able to flex.

          The good news of having the scientists in house is, they often see, even if it is a few weeks' notice, problems coming down the pike that they can prepare for.  But they do a fabulous job of flexing as they need to.  We have had scientists go from virus A to virus B when virus A regulatory issues become lesser and virus B is going up.  They will switch their programs, and create a new program.  They will do it even on a shorter notice if need be for issues like West Nile.

          We try and find money, but sometimes it is simply taking money from their current research and shifting it over. 

          DR. TOMASULO:  Is there any capacity to support your needed research programs outside the FDA?  So for example, taking from Harvey's question, something comes up and you just don't have the resources to pursue the issue, can you go to some other institution and support?

          DR. CARBONE:  Well, when you say baseline, no, it is not an option.  In other words, we have a very dedicated staff, and when there is a public health issue, we do it, we handle it.

          For example, HHS will come up with additional support for a particular problem that is high priority.  When you talk about getting money outside, it is a question that is often posed, why don't you just have NIH do your research.  Whenever you go to somewhere else, it is their priorities that are important.  What we try to do is find partners like the cell substrate, where their priority and our priority are identical, or at least very close.  Going to the outside necessitates that we must put them ahead of us if you are getting funding, unless it is for example a special pot that HHS provides for us for a particular issue.

          The timing is the other issue.  If we are talking truly the urgent, urgent things, we don't have a lot of time to go carrying a banner around.  So we look for opportunities wherever we can to align.  But we have to always remember when we get money from the outside -- in some respects this distresses us when we get money from the outside; we are responding to their priorities, not ours.  We try and find them aligned when we do it. 

          DR. ALLEN:  Let me just comment on that also.  I think it is also fair to say that the NIH process is not geared towards identifying urgent emerging problems and responding to them quickly.  The process for both intramural and especially extramural research is a very long one, and it is just a different mechanism.

          This has been a good discussion.  I have got just one additional question going back to one of your slides, where you identified among the total priorities the high percentage of research that has some relationship to bioterrorism.  For FDA, I think that bothers me.  It is not that it is unimportant; it is just that there is -- most of our lives and most of our needs and medical issues have little to do with bioterrorism.  While we want to be prepared and not shortchange bioterrorism issues and threats in any way, that should not be the primary driver of decisions and resource allocations.

          DR. CARBONE:  Let me comment on that.  When I say bioterrorism, of course, we are talking about products used to treat or prevent bioterrorism.  Interestingly, our role, like the CDC's, is quite different from NIH.  When preparedness is needed for particular products that may be coming down the pike, we have to prepare.  So in essence, we are obligated due to our public health mission to deal with things like -- and I would include bioterrorism/emerging infectious disease.  This is perhaps where you get what you are concerned about a little addressed, because many of the things we are going -- bioterrorism agents are agents which, whether they are released intentionally or unintentionally, are problematic.  So we have to often deal with them as say improvements in vaccines, improvements in end points, dealing with the animal efficacy rule.  These are all things that would happen for SARS as well as smallpox.  It really doesn't matter whether it is released intentionally or unintentionally.

          Again, we always try and multi-task so that what we do for a bioterrorism product is going to feed into our overall improvement for any product in that area.  We take our marching orders if you will from the Department, and that is appropriate.  They are organizing all the agencies.  They have seen fit to provide us with some additional pots of money to deal with emerging infectious diseases and bioterrorism products, or products designed to deal with bioterrorism.  So in a sense, by having bioterrorism or bioterrorism  relevant activities, we are dealing with the priorities that HHS has set for us, which are appropriate.

          This is part of the problem with trying to be specific.  Sometimes there are proprietary issues, and we can't delve into the details. But be assured that when we do this, some long term value is always sought, so that we always align some greater technological advance that will help a range of products, while we are dealing with a specific bioterrorism product.  For example, our regular flu program, yearly flu program, has benefitted from having funds for the pandemic flu program.  We were able to create a BSL-3 plus devoted to influenza because we had those funds. 

          So I understand completely what you are saying.  We try and make sure we get a good bang for the buck.

          DR. ALLEN:  I know you do.

          DR. ALTER:  Good comment.  One way you might save some money would be to turn the air conditioning down. 

          DR. CARBONE:  I agree.  My nose is cold.

          DR. ALLEN:  This is the second request for that.  This is a private facility.  The downside to that, Harvey, is that we did that yesterday morning, and by mid-afternoon, the temperature in here was -- Dr. Strong.

          DR. STRONG:  I get the feeling that we can probably keep you up here all day long.  Obviously there is a lot of interest in policy, and we are going to be getting to the science.

          We got on the subject to bioterrorism.  The sister agency is CDC, and we have mentioned NIH.  What is the interface with CDC relative to the kinds of things we just talked about?

          DR. CARBONE:  There is a tremendous amount of interaction, if you will.  CDC is often oriented more oriented towards surveillance and diagnosis.  We would be relied upon to deal with the products needed when something was identified; we have to be prepared with the products.

          I think a good example of a collaborative effort was, when SARS was identified as a problem by public health agencies, we met with the CDC and talked about -- as the isolates came in and they were interested in distributing an isolate to various potential sponsors for manufacturing a vaccine, they met with the FDA.  We talked about the kind of GMP, the kind of history of the virus itself, the tracking of the virus, making the virus stock, how to do that in such a way that the virus they distribute could legitimately for our purposes serve as a vaccine seed or at least, a vaccine reference.  That is a tremendous time saver in the collaboration.

          If for example they had sent out a virus without history or one that had been through a very dangerous history, then somebody turning around and trying to use this to manufacture or develop a vaccine would have had to go back to the drawing board, et cetera.  By collaborating together on that effort, we knew the manufacturer on the product side.  They clearly know how to grow viruses, and knew about the SARS and the epidemiology.  So that would be an example of where we would collaborate together to serve the public health in flu.  There is a tremendous collaboration between both the laboratory and the public health area.  So we work quite closely.

          But they are not product oriented from the point of view of product quality testing, et cetera.  That is the side that we take care of.

          DR. ALLEN:  Just one quick comment, or it is sort of a question, and then we will move on.  Let me use the fire department analogy.  If you have got a diverse community, volunteer fire departments might work.  You have an urgent need; people from around the countryside drop whatever they are doing and go.

          I think within an urban environment, it is well recognized that that is not the most effective way to handle it, so we have developed fire departments, and we don't expect the firemen to be putting out fires all the time.  We expect them to be ready.  They train and do other things.

          Is it fair to say that the federal government doesn't view the FDA as needing that extra capacity, the ability to have people there with sufficient flexibility in their schedule and resources to absorb the emergency issues and the urgent issues, in the way that one would expect a fire department to be prepared?

          DR. CARBONE:  I would like to back up a little and just say that I think one of our goals is to prepare for fires, that is exactly right.  In science in particular, we can't just simply drop dead now and have the science tomorrow.  We have to have a five-year look.

          This is in part why we are pulling together the office's cross-office, so they can have discussions about downstream what we need for the baseline.  So what people do here is deal with the baseline applications, the baseline science that we need to do, and then they insert on that the emerging and urgent issues.

          As far as the view from the outside world, I think that prior to the critical path, there was simply not much discussion about research and FDA in the same sentence.  I think some people found that surprising.  The first question I am asked is, is there research?  I didn't know there was research at the FDA.  The second question is, why is there research at the FDA?

          So I won't say there is a government position on it, but I will say that I think that part of Dr. Goodman's goal in being transparent, part of all our goals, is to talk about the research, to show the value, to make it more valuable, so have people understand that having a paid fire department in this case would be a wise investment.

          DR. ALLEN:  Thank you.  This has I think been a very good discussion and an opening for our day.

          Our next presentation is Dr. Jay Epstein, who will be director of the Office of Blood Research and Review.  He will be giving us an overview of the office, including mission and structure, regulatory activities and priorities and research program instruction.  I think we can truncate then some of the questions overall.  We were to have a few minutes for discussion among all of the people.  We can do that to the extent that there is a need, but I think what we have just gone through has been a very helpful introduction. 

          Dr. Epstein.

  Agenda Item:  Overview, Office of Blood Research and Review

          DR. EPSTEIN:  Thank you very much, Jim, and good morning, everyone.  My pleasant task is to provide you with an overview of the research program in the Office of Blood Research and Review, which I direct.  I hope that I will be able to illuminate you regarding our goals and objectives, structure and governance, and then to illustrate how our process works with examples of our historic and current activities.

          Dr. Midthun already reviewed for you the vision for CBER.  I won't repeat that, except to say that we believe that the functions within our office are conforming to the overall vision of CBER.  We are the primary FDA component responsible for facilitating the development, approval and access to safe and effective blood products.  More specifically, we perform scientific functions related to the regulatory of blood derived and recombinant analogous products, medical devices that are used to test, collect, process or store donated blood, and additionally, under an understanding with our sister Center for Devices and Radiological Health, we are the responsible component for regulatory of retroviral diagnostic tests. 

          I think that is an interesting point, why did that happen.  It happened that we had virology laboratories when the AIDS agent was discovered, and therefore we were in the unique position to be able to deal with characterization, standardization and assay validation, because we had these experts in wet labs.

          Additionally, as Dr. Carbone has illuminated, we collaborate in larger CBER programs.  Some of these include tissue safety, for example, validating a diagnostic on a cadaveric blood sample, xenotransplantation, HIV immunology, vaccine development, et cetera.  Some of this will be illustrated in later talks.

          Now, we are organized in the Office of Blood into the immediate office, myself, Dr. Goldsmith is my deputy, I have a director for regulatory affairs, and Dr. Tabor was our director for medical affairs, associate director, but he has just retired.  We have three product divisions, the Division of Emerging and Transfusion Transmitted Diseases, Dr. Nakhasi will present to you, Division of Hematology, Dr. Golding will present, and Division of Blood Applications, and Dr. Williams will present.  I also have a small staff that deals with our policy process.

          You have heard already that we have this dual function of science and regulation, which we believe we harmonize.  But just to give you a feeling of the kind of spectrum of regulatory work, we receive all the kinds of application that exist in the FDA.  We use every regulatory mechanism that exists under the PHS Act and the FD&C Act.  In a typical year, we have a variety of different kinds of application which have required review times under either the Prescription Drug User Fee Act or the Medical Device User Fee Act.

          This was in calendar year 2004, what was received and what was completed.  You can see that we essentially completed about a year's incoming in relation to a year's work, so we just treaded water with our nose just a little bit above the tide.

          I can't really illustrate for you what this is in terms of a workload demand, but I can tell you that it represents easily 80 percent of the work output of the office is the review work.

          The question is always, why do we do research at FDA in general and the Office of Blood Research and Review in particular.  As has been said already in other words, we believe we are in a unique position to identify cross-cutting issues by virtue of our regulatory responsibility and the things that we see confidentially.  This also gives us a unique opportunity to coordinate effort across the spectrum of blood issues and among diverse industries that are involved with the manufacturing of blood and blood products.  After all, we are in a position to understand the manufacturing and quality of a device like a screening test at the same time as to understand what the user's need is before say automation or data handling or high throughput.  So we occupy that unique role.

          This is in the areas of product characteristic and safety and efficacy determinations, and also supply impacts, which is not rarely understood, but we are mindful of trying to make sure that needed products are in fact available and available timely.

          We are able to resolve scientific questions critical to regulation, as has been said, standard setting, which can be targets for technology development, certainly the development of surrogate markers to facilitate clinical trials.  Sometimes it is more basic understanding of mechanism of action, so that we have a rational approach toward product validation or clinical study.

          We believe also that having a supported scientific enterprise enhances the quality of our scientific review,  obviously when we are engaged directly in the kind of problem solving that I described, but also more generally because this way we have sophisticated regulators who understand the cutting edge products that come into our office and center.

          Then additionally, having the research program maintains our capacity to investigate product failures.  This is important for work that we do.  A year does not go by where there are not novel questions raised about products that are not working as we thought that they would, especially in the blood system.  Where we are talking about millions of component transfusions, it is important to rapidly solve these problems, and when we can't do it ourselves, at least is makes us effective collaborators.

          How are we organized, and what is the mechanism of oversight?  Our research is organized in parallel with the product review responsibilities down to the branch level.  In the next slides I will show you how that is organized down to the division, and in the divisional presentations you will get a little bit more of a flavor of this direct linkage.

          Of course, as the office director, I allocate the funds.  The power of the purse is the power to direct, and so I do survey the scene and surface regulatory issues, identify overarching priorities, and fund the programs accordingly.

          However, I have to tell you that the direct oversight of research in its details, that is to say, assuring its quality, making sure that the fellows are properly progressing, that the monies are wisely spent, that kind of oversight is primarily at the division level under the direction of the division directors who of course talk to me quite frequently.

          Coordination across CBER is accomplished through our acting liaison for research, who is presently one of my division directors, Dr. Nakhasi.  He cooperates with the other division directors.  Dr. Carbone leads this effort, and we do have a formalized structure which has regular meetings and reviews research issues across CBER as a whole.  It is our goal to establish an associate director for research, or perhaps combine that with the associate directorship for medical affairs to further tighten this linkage to the mission.  We are not quite there yet, but I would say it has been no detriment because Dr. Nakhasi, wearing a third hat, has done a very highly effective job of insuring coordination with the larger CBER.

          Additionally, we have a very formal system of publication review, where there have to be two peer reviewers for every publication.  It has to be signed off by the division director, and then I will review and sign off on the publication.  This serves the dual function of keeping me well apprised of the output that we are producing, as well as giving me the opportunity to look at quality and direction.

          Additionally, as has been said, and I won't belabor it, all the laboratories are on a periodic external site visit schedule, once every four years.  That function is integral to all scientific tenuring.  In other words, if you get a permanent job as a research scientist, you have to have been peer reviewed, and additionally, promotions go through that process.  The opinion of the site visit is integrated into the promotion decision.

          So as I promised you a moment ago, I will try to show you some of the correlation of product responsibilities and areas of research at the division level. 

          First and I guess arbitrarily, we have the Division of Emerging and Transfusion Transmitted Diseases.  The product responsibilities in this division include retroviral donor screening and diagnostic tests as I have said, so it is not just blood screens, it is all retroviral diagnostics, HIV, HTLV; hepatitis donor screening tests, emerging viral agents and tests for bacterial, parasitic and unconventional agents.  This roughly also reflects the branch structure.

          So how do the areas of research correlate?  We are engaged in epidemiology, pathogenesis and diagnostic methodology for retroviruses and hepatitis agents -- HIV, HTLV, HBV, HCV, HAVE.  These are all active programs.  In terms of emerging agents, we have developed a program in West Nile virus detection, looking at assays as well as metrics of inactivity, and we invested very heavily -- we are fortunate to have David Asher, who is a world class scientist in this area, who investigates detection and decontamination of TSE agents, including classic CJD and virion CJD.

          We have a program which is active in cross-cutting issues of parasitic vaccine development, which is a scientific gap, and we are, as has been said, firemen, and we deal ad hoc with emerging issues.  In recent times, these have included vaccinia, whether there is viremia after vaccination, and whether there are false positive donor screens after vaccination, transmissibility or detectability of HVA, the blood threat or lack of threat from SARS, the significance of SENV.  Much of this is also done in collaboration with partners at NIH and CDC.  So I think it is rather self evident that there is in fact correlation.

          In a similar vein, this is now the Division of Hematology.  The product responsibilities include plasma derived products, immunoglobulin, immunoglobulin intravenous albumin, coagulation products, et cetera, blood and blood component collection devices, including aphoresis equipment, hemoglobin based oxygen carrying solutions and plasma expanders, and bacterial detection devices.  Why they live in Hematology instead of Emerging and Transfusion Transmitted Diseases is because this issue surfaced in conjunction with platelet safety, and platelets are regulated as a blood component in our Laboratory of Cellular Hematology.

          So the areas of research, we are engaged in the characterization and standardization of plasma derivatives.  In fact, we have been engaged in that since the 1950s, and continue to be world leaders in this area; functional studies of platelets and studies on platelet safety, chemistry and mechanism of toxicity of hemoglobin based oxygen carrying solutions, investigation and standardization of bacteria detection methods, and a cross-cutting activity in HIV vaccine immunology, because we have a very strong science base in immunology, not surprisingly, in the Division of Hematology.

          Then in the Division of Blood Applications, the product responsibilities include blood and plasma licenses, blood establish software, and blood grouping and HLA reagents.  The areas of research here include donor related epidemiology, validation of donor questionnaires, monitoring of shortages of products and reagents, quality controls for blood components, and a little bit of wet laboratory work investigating the specificity of new blood grouping agents, for example, those based on monoclonal as opposed to polyclonal antibodies.

          Again, I think it is evident that there is in fact correlation.

          By way of the bird's eye view and historical perspective, I am going to summarize briefly some of our regulatory and research accomplishments that are highly pertinent even today.

          First of all, what are some of the things we have done for you lately, in the last say year and a half?  In the area of product development and approval, we have brought forward approval of rapid test for HIV-1 and HIV-2, both on blood samples and on oral fluid; the first barcode scanner for matching the unit with the recipient as a way to reduce medical errors of mismatch at the bedside; the first approval of a computer assisted self administered interview system, which is believed based on behavioral research to be a more accurate way to elicit donor histories, various new immunohematology and anti-RHD and immunoglobulin IV products.  The tests for West Nile are still under development.  Development has been supported through our laboratory activity, and we issued multiple guidances, and we have approved initially quality control and most recently, a system including release testing to control for bacterial contamination of platelets.

          On the area of guidance and rulemaking, the barcode rule was an FDA wide rule applying to pharmacy products, but it included a section on requiring machine readable code for blood products.  We have published a draft uniform history questionnaire, which will go a long way towards standardizing the donor history taking process.  That was a collaborative effort including the FDA, both as a driver and as a collaborator in studies to validate these questionnaires.

          We have published guidance on the requirement now to screen the blood supply with nucleic acid tests for HIV and hepatitis-C, and we have done a publication on the clinical trial standard.  We had a previous one on safety and now one on efficacy of oxygen therapeutics to facilitate progress in that area, and of course, many guidances on West Nile screening recently, updated in June.

          Additionally, we have sponsored and cosponsored a large number of public workshops.  These of course are oriented toward problem solving, looking at the conditions of plasma freezing and how that relates to plasma quality, the issue of novel approaches toward platelet evaluation, creating a more uniform standard against which to look at novel platelet products, a workshop closely looking at safety and efficacy considerations for immune globulin intravenous with the goal of figuring out ways to be more economical or smaller sized studies with the patients, better use for example of statistically modeled historical controls, potentially looking at surrogate markers for efficacy for some indications, et cetera.

          We cosponsored with the Society of Gene Amplification and Technology working group a symposium looking at NAT standards for a very large number of transmissible agents.  Likewise we were the sponsor or co-sponsor of the Plasma Fraction Association and Paul Ehrlich Institute annual workshop on NAT.  This is a workshop on updates in transmissible disease.

          We cosponsored with the Department of Health and Human Services a workshop on rare plasma protein disorders, to try to foster progress in that area, both at the clinical level and to streamline regulation, and just two days ago, we had a workshop on leukocyte reduction, critically examining the issue of whether there is a general medical benefit for universal leukocyte reduction, the various issues in terms of standardization and quality control of products labelled as leukocyte reduced, and some updates on the development of filtration schemes to remove prions from blood products, including cellular products.

          Additionally in the area of review management, which will be addressed in a bit more detail by Dr. Williams, we have been bringing forward what you might call management innovations.  If you will excuse me, maybe it is really management science.  These are office operating procedures for the review of the various categories of application, like the device 5-10K, the biologics license application and so on, and supplement industry meetings, checklists for aphoresis components, et cetera.

          We have been very busy bringing about a GMP mind set to our review operation, and correspondingly, we have been bringing forth an initiative working toward external accreditation of our laboratory activities, including review of risk assessments and statistical models and other methodological approaches.

          You have already seen this.  The overarching framework is that we have a goal that our research in the blood program should conform to the needs of critical path to be facilitators of product development.

          Here are some historical examples of how we feel we have done that with our research.  In the 1950s we were critically involved solving problems of the stability of albumin, what stabilizers worked, and how many you had to use.  In the 1960s we played a major role in developing standardization of clotting factor potency, both through the development of biologic reference materials and through the development of reference assays.  In the 1970s our laboratories were critically involved in solving the problem of hypotension from plasma protein fraction, a preparation similar but less pure than albumin.  One of our scientists discovered that it was due to the presence of a precalicrene activator.

          In the 1980s, we became very concerned with the HIV safety of plasma fractions, and contributed fundamentally to the literature on HIV clearance and inactivation in derivative manufacturing.

          In the 1990s, we had this outbreak of hepatitis-C from  two immune globulin products subsequent to the introduction of highly sensitive screening for HCV antibodies.  We were instrumental in bringing forward very quickly assays that could detect HCV in the products.  Then we had lot release so that only the products with undetectable RNA could be released, and also validating the pathogen inactivation strategies that are now uniformly in place for the licensed human derived blood derivatives.

          Some examples of things that are ongoing in the present decade.  Refinements to standards for NAT for HIV and HCV, investigations of the toxicity of hemoglobin solutions, a model called Transnet for monitoring blood shortages, and as you have already heard, contributions toward the quality assurance and sensitivity standards for donor screening for West Nile virus.   

          Now, some of our research highlights are enumerated on this slide.  I am not going to have time to talk about them, but some of them you will hear about in greater depth in the divisional presentations.  But this is to give you the broad brush, what is the sort of work that we are doing in the labs.

          Development of reference reagents, examples, HIV and West Nile.  Evaluation of the diagnostic significance of emerging HIV variants.  This is now recognized as a significant issue worldwide.  The point is, how does it affect the sensitivity of our current diagnostics.  Development of an oligonucleotide chip to detect blood-borne pathogens, including so-called conventional agents and also candidate bioterror agents, development of a candidate NAT test for detection of malaria, investigation of possible viremia after smallpox vaccination, the effect of smallpox vaccination on donor screening tests, mainly specificity, establishment of standards for thrombin and anti-D immunoglobulin, a murine model to study the pharmacogenomics of Factor 9 in relation to development of inhibitors, mechanism of toxicity of various hemoglobin based oxygen carrying solutions, a modeling of TSE decontamination methods, TSE risk assessment for plasma derivatives, both the one that came from the U.K. under IND, and then to examine all the U.S. derivatives, tracking systems to examine fatalities and look for clues, cognitive evaluation of the donor history questionnaire, and statistical quality control methods for blood components.  I have already touched on some of these, and you will hear more.

          What I want to do in my remaining slides is attempt to illustrate for you how we think that the critical path model and mind set works.  You will hear about some of these in greater detail in a minute.

          First of all, we identify a critical path problem or opportunity.  Detection of blood-borne pathogens, obviously an issue.  What is the issue?  It is the need for the development and evaluation of technologies and methods that can screen blood donors for a large number of pathogens simultaneously.  There are only two ways out here, either to bring forward effective pathogen reduction or clearance or inactivation strategies, or to have an ever-increasing number of tests.  If we are in the paradigm of an ever increasing number of tests, finding ways to consolidate them becomes critical to operations in the blood center.

          What we have done?  Our humble effort is to develop and evaluate a prototype multiplex nucleic acid based test and micro array for blood donor screening, and to develop and provide FDA referenced panels and materials to spur industry development in this area.  The outcome has been to identify critical parameters for assay development, for example, what kind of primers can you mix with diverse agents so they work under the same reaction conditions.

          We have developed standardized panels that are being used as a target for industry to assess different assays, and we have already brought forth proof of concept for novel assay development.  This is just a graphic illustration which Dr. Nakhasi will review, but it is a gene chip which can concurrently detect and confirm multiple conventional and unconventional pathogens.

          Another example, counterterrorism, the safety of the smallpox vaccination.  The issue is that smallpox vaccination can cause life threatening complications in immune deficient individuals, and that the efficacy of vaccinia immune globulin, a primary prophylactic and therapeutic, cannot be tested in humans.  You don't give people vaccinia in order to do these studies.

          So what has been the approach?  The approach has been to develop a SKD mouse model to test the efficacy of immunoglobulin.  The outcome was a transfer of this methodology to industry and the incorporation of this model helped provide a pathway for the licensure of the first vaccinia immunoglobulin intravenous product which was the first counterterrorism biologic approved by CBER.  It is a model of how we are trying to use our labs to solve regulatory problems.

          This is an illustration.  If you prophylax with vaccinia immunoglobulin intravenous, you can convert from 100 percent fatality to 100 percent survival, based on the timing of administration.

          Another example, hemoglobin based oxygen carriers.  The problem is that blood availability for trauma victims in rural areas and in disaster situations including war and terrorism attacks is limited.  However, the toxicity of the early generation of hemoglobin based oxygen carrying solutions turns out to be unacceptable.  These products cause generically vasoconstriction, very high blood pressure and multi organ system damage.  The actions at CBER, at OBRR, were to attempt to identify the link between the oxidative chemistry of a given hemoglobin and its toxicity.  We developed an endothelial cell animal based model system to promote the understanding of blood substitute toxicity.  The outcome is that preclinical testing is now becoming more predictive of clinical performance, and it has led to the design of a second generation of hemoglobin based blood substitutes that are now in clinical trials.

          Just to be more specific, one of our investigators, Abdul Aliyash, is credited with co-discovery of this mechanism of free hemoglobin bonding nitric oxide and therefore inhibiting the vascular relaxation that nitric oxide otherwise mediates.

          Another example is monitoring of supply availability during shortages and emergencies.  There is no rapid and reliable mechanism currently to objectively assess the blood component reagent or other supply shortages during regional or national emergencies.

          What did we do?  In Dr. Williams' group, he led an effort to develop and pilot a monitoring system called Transnet, which is a web based system to permit direct reporting of shortages and their medical impact from all U.S. blood centers and transfusion services.  This is as opposed to previous, very cumbersome, very expensive services that were based on daily funding of sentinel sites.

          The outcome is that this program was piloted and is planned to be incorporated into a blood monitoring system at the departmental Secretary's operating center that is activated in the emergency.

          The future of course is part of your purview -- where are we headed and do we have the right focus.  Some of the potential critical opportunities that we recognize include the following:  Development of nucleic acid based or other technologies for the detection of bacteria and parasites and blood components, investigating the potential of nanoparticle based diagnostics for multiple detection of blood-borne and counterterrorism agents, investigating the diagnostic implications of variants or so-called mutants of HIV and HPV respectively, developing diagnostic and donor screening assays for transmissible spongiform encephalopathies, or at least developing standard materials that can be used to assess those that come forward.  You will hear a little bit about this in a few minutes from Dr. Golding, the establishment of cell lines expressing -- receptors, which is a novel approach to detecting microbial components in blood and plasma derived products.

          In the area of blood product safety, we believe it is important to do animal inoculation studies to evaluate the infectivity of blood units that have low titers of West Nile virus with and without antibodies, developing or further developing animal models to predict the immunogenecity of clotting factors eight and nine, and the continued development of standards such as the standard for NAT assays for human -- virus B19.

          In the area of blood product potency, we are about safety, purity, potency.  I should have said that.  That is our mission under the Public Health Service Act, so developing an animal model to test functionality of candidate modified platelet products and developing standards for additional plasma derived products, for example, alpha-1 proteinase inhibitor.

          So my conclusions from this bird's-eye view are, and I hope I have convinced you, that research is critical to the mission of my office, that mission related research facilitates product development on the model of critical path, and that our research program is focused on regulatory concerns related to product safety and efficacy, and that these include the prevention and control of blood-borne infections through testing, inactivation and removal of pathogens, the characterization and standardization of blood products and methodology development for product review and product surveillance.

          So please accept my personal thanks for your contribution at this site visit.  I look forward to your comments and report.  Thank you.

          DR. ALLEN:  Thank you, Jay, that was a wonderful overview.  Questions? 

          DR. WANG:  I am very impressed by all the programs you are engaging in, but I got an impression that many of these programs are out of your own initiatives rather than in response to any claim in the applications that you tried to validate.  How do you separate these two, and how many percent of your effort is to develop methodology or use your methodology to check on the application's claim?  And how many are you involved in developing your own diagnostic methods or even the vaccine development?

          DR. EPSTEIN:  It is a fair question.  It is hard to give you a hard and fast number.  My back of the envelope estimate is that about 30 percent of our effort is what you might call preparation for the future, building infrastructures.  So for example, we investigated for a period of years very heavily in gene based technology for pathogen detection before there were any product applications.  But I think that really, the bulk of it does derive from regulatory issues that do surface. 

          Clearly in the area of West Nile virus, the development of standards so that we had targets for the sensitivity of the NAT assay development, characterization of variance to look for virus drift, so that we would know whether NAT assays, which of course are very, very highly sequence specific, would be robust.  That evolved from a product issue.

          Similarly, I think that the vaccinia research all came in the wake of concern over possible bioterrorism from use of a smallpox agent, and we became aware in anticipation of the need to have available vaccinia immune globulin intravenous product.  Then we were immediately confronted with the issue that there was no way to measure the potency.

          So I think there is a balance.  It is certainly true that a lot of what we do is generated from within, but it is generated on the basis of our perception of where do we need to be in two years, where do we need to be in five years.  It is because we are sensitive to the public health need, we are sensitive to what is in the product pipeline in anticipation of an actual product review.

          In fact, you really don't want to wait for an application to first be asking the question of what to develop at the laboratory.  You want to be doing that at a much earlier stage.  I think that is why that cartoon of the critical path shows the research engagement starting at a much earlier stage of the product development pipeline.  It is precisely because we have to recognize problems at an early stage to be in a position to contribute meaningfully at a later stage.

          So I would say that your observation is correct, but that there is still a long term linkage which is a very real one.

          DR. DIMICHELE:  Jay, I want to give you my compliments on all the work that you do.  We are very impressed.

          One of the questions I have, and I think maybe you are the proper person to address this to, when I am reading about everything that is going on, and having read through the site visit materials, one of the questions I would have is, when you look at the Laboratory of Plasma Derivatives is doing, because they are in charge of gamma globulins, they are very interested in serology and therefore get into a lot of infectious disease issues, and then you look at what the Department of Emerging and Transmissible Diseases are doing, and a lot of times they are working on the same organisms, but from a different perspective.

          One of the things that I didn't get a good sense of from reading and looking at what the collaborations are is, how much collaboration across for instance these two laboratories or these two divisions would be and how is that fostered within your oversight.

          DR. EPSTEIN:  Yes, thank you, that is a very insightful question.  I appreciate your kind words.

          Well, things kind of grow organically in science.  What happens is, you are involved in a question or an issue, and you find yourself also dabbling in somebody else's domain.  I think that what we do, because we review current activities, and we do it collectively, and certainly things are recorded at my level, we do recognize both the needs and the opportunities for collaborative effort.

          I think that there are certain things that cause it to happen.  For example, Dr. Carbone described the Center-level interoffice cooperative grant program that is run out of Dr. Goodman's office.  Those tend to be projects that are cross cutting and where the different groups must collaborate in order to receive funding.

          A good example of that is in transmissible spongiform encephalopathy.  So for instance, our lead group is Dr. Asher's group, which is in the branch of bacterial, parasitic and unconventional agents.  But the question of where do prions bind in blood components, and where are they, research along that line was done by Dr. Vostel, who is in the Division of Hematology.  The groups clearly work together.

          The issues related to say HCV in plasma derivatives or parvovirus have been managed with sharing of technology, bacterial detection.  Our review group includes individuals from the Laboratory of Cellular Hematology and Hematology, but also bacterial, parasitic and unconventional agents in DTD.

          So we do this.  The process however I would say is not so highly formalized.  It more depends upon the fact that we do talk to each other, we do present our work to each other, and because I am aware of what is going on in the different components of the program, I will just say to people, you guys need to cooperate on this.  And the Division directors do also talk to each other.

          It hasn't been mentioned before, but we have scientific seminars in each of the divisions.  Those are weekly events.  Often they are outside speakers, but just as often they are the researchers in house.  That is another opportunity where people listen to each other's work and can recognize opportunities and needs for cooperation.

          So it does happen, but I'm not going to say it happens through a formal process.

          DR. STRONG:  Jay, in your fifth or sixth slide you had the regulatory work output.  You commented that 80 percent of your effort was review.  So I am trying to balance these numbers.  It is supposed to be 50-50 research and regulatory.  How do you manage that exercise of distribution of work?

          DR. EPSTEIN:  You have to understand that not everyone is a researcher.  When we say the 50-50 model, we are talking about the subset of people who are using research resources.  Those individuals are expected to do 50 percent of their laboratory work and 50 percent review, and they do.  But they are not the larger number of our organization, they are a subset. 

          I know we don't want to talk primarily about the resources.  I can comment on that, if you wish.  So the reason for this is the balance.  Most of our staff are in fact not research reviewers.  They are regulatory scientists and various kinds of support staff.  The 50=50 mix is the researchers.  Everybody else is 110 percent.

          DR. ALLEN:  I was adding up, it looked like it was about 120 percent.  You didn't add in the administrative tasks.

          DR. ALTER:  Jay, I see a parallel.  You could be the head of the National Cancer Institute.  You would have then two mechanisms.  You would have extramural R0-1 initiatives, investigator initiatives, and you could have an RFP saying, I want you to do this, give me your plans.

          So how much of your operation is, an investigator says I would like to study this, and it sort of fits in our mission?  Or you say, this is what we need to look at, come up with an idea in that realm.

          DR. EPSTEIN:  Again, it is a difficult question to answer.  Because our researchers are regulators, much of what they propose to do is rooted in the questions they find significant, based on the regulatory work. 

          So a fine example of that is HIV variance.  We have to decide whether the assays are sensitive to the variants that are circulating in our country and worldwide, because they may be brought in.  Dr. Hewlett at her own initiative recognized the opportunity for a collaboration in Cameroon.  Why Cameroon?  Because it is the world's hotspot for new HIV strains and recombinants.  So you could say, isn't that investigator initiated?  Well, yes, it is.  But is it mission related?  Yes, it is. 

          I think that the way this process works is that because we control the laboratory support, the branches and the sections have to review with the director and ultimately with me just exactly what they are embarking on, so we do scrutinize it. 

          Now, how much of that is grass roots versus top down?  I would say that I will sometimes simply direct the work.  I will just say, we need to develop an assay for X, or we need to develop a standard for Y, or we need to solve this problem. 

          Also, much of that comes organically from what is happening in the field.  If we have problems with hemolysis, with diversion pouches or white particulates in red cells, is it top down or is it bottom up?  There is recognition, and there is willingness to embark on a project, but I am also going to tell people, you have to jump on this yesterday.  u have to jump on this yesterday.

          So it does work both ways.  But I think the leavening is that all of the initiatives are scrutinized at the managerial level.  So we know what people are embarking on and why.  So because it is a dialogue, it is hard to tease out what was a mandate and what was an initiative.  It is because we have the group process in deciding what we do, so it is very hard to dissect that out.

          So I can't give a number.  I would find that very hard.

          DR. BUSCH:  Jay, your group working in development diagnostic or vaccine development makes a lot o sense in terms of them understanding what is coming at you.  But is there another motivation?  If you discover some new sequence that is particularly effective at capturing -- is there any capacity to patent within your organization?  Or is that a motivation at all for the investigators?

          DR. EPSTEIN:  I think that it is not the prime motivation.  We have certainly patented inventions.  We have that right.  We don't own the royalties.  We own only a small share of royalties if there ever are royalties.  But we can patent invention.

          I would say that most of the time when that happens, it is a spinoff.  So for example, one of our researchers, Dr. Sebastian Wan, has been very interested in HIV replication.  He made the discovery that there is a significant regulatory role of extracellular TAT, and it therefore became a potential vaccine or pharmacologic intervention target.  I believe he has pursued patenting; he might have to clarify that for me.

          So I would say that the prime motivation wasn't -- I have to discover something I can patent.  The prime motivation was, I am trying to solve this problem, but then a discovery gets made and a patent is possible.

          We encourage that, but I think that the focus of the organization as a whole really is the public health mission.  That is what motivates people on a daily level, and it is how they orient their activity.  If we make discoveries, that is great.  Similarly, the discovery about the mechanism of toxicity of hemoglobin based oxygen carriers.  That is marvelous, but why it happened is that people were trying to solve a mission related problem, and I would say that it is a sort of a spinoff.

          But yes, we can patent.  I'm sure people don't mind it if they get a patent.

          DR. INTAGLIETTA:  Dr. Epstein, thank you very much for your exhaustive presentation of the extraordinary research accomplishment of your division.

          I am quite familiar with the work of Abdul Aliyash in identifying the toxicity of hemoglobin solutions.  I should say that indeed, that has become an international standard, and is widely recognized.

          You made a really interesting comment in saying that you have to identify where you want to be in the research and in addressing problems that might arise.  I got the impression that this to some extent mostly depends on your own intuition of where this want to be situation and location is going to be.  I was wondering whether a more structured approach to this might not also help in identifying where to go. 

          I was wondering whether it has ever been considered, for instance, the establishment of an advisory board or some sort of a mechanism by which to collect these perceived needs that your institution has to address in the future, because indeed, in some cases they might be just guesses.  Of course there is good science, but you do have from what I gather a rather directed mission to accomplish.

          So my question is, would it help to establish some sort of a structured mechanism to identify where you should be in the future.

          DR. EPSTEIN:  I think that is a very helpful comment.  Dr. Carbone may want to comment on this.  I think that we are moving in that direction.  In fact, today's site visit is an effort in that direction, because we have invited you to comment on the direction.

          Outside input I think would be very helpful to us.  We do have as you know advisory committees.  The Department of Health and Human Services advisory committee on blood safety and availability has at least in the area of emerging infectious disease taken up the question of the national approach including the agency approach.  I think that we will benefit from some direction out of that process.

          But I feel that you have made a very construction suggestion.  It is in our thinking, but we haven't really utilized such a process.  But Kathy, would you like to comment, because I know it is part of where we are headed?

          DR. CARBONE:  I would, just briefly.  I think that is something Dr. Goodman and I discussed in where we are heading.  For example, the October meeting was a meeting of stakeholders and sponsors broken down by office to collect needs and ideas for the future, et cetera.  So that was the initiation of the process.  I think this is also on the way, where we are, and then of course the future.  So I think that is clearly on the books, discussing approaching that.

          I will use an example.  There is an element of intuition and guessing, you are absolutely right.  But I think part of the issue with what we can generate -- not that we don't need input, we certainly do -- is the example of SARS.  When SARS came down the pike, we knew that there would be a vaccine proposed, and we knew the organism.  Fortunately, we had somebody who was an expert in their previous life, and we met as a group across offices, and we talked about what would be needed to deal with the vaccine, also blood products.  There was immune therapy.

          One of our investigators immediately -- a vaccine specialist, immediately said, if we are going to make a vaccine, then it is going to be inactivated vaccine.  We know that this organism is difficult to inactivate.  And set about working on different product procedures for inactivation, documenting inactivation, all the things we would have to review if a vaccine came in, identified ways to inactivate the virus.  Just recently this has proven to be valuable to potential sponsors.  This information has been published and transmitted, and we have gotten queries in this area that other groups interested in the vaccine have had problems inactivating the virus.

          So this is an example where the experience and regulation of a vaccine plus combined within the expert area and the scientific, identifies and quickly crystallizes key issues. 

          So that said, we agree completely about external process as well, and that is in the works.

          DR. WANG:  My imagination is running a little wild here.  Suppose that out of your own initiation you successfully develop a diagnostic kit, or even a vaccine.  Will you patent it, license it to a company, and then eventually an application will come to you for approval?

          DR. EPSTEIN:  Well, that is an issue.  When we have cooperative research and development agreements, CRADA's, the individuals involved with the CRADA obviously cannot be the reviewers.  So there is an issue of recusal in that kind of situation.

          We do participate with the NIH program of technology transfer.  Even if we patent something, we can through the government license it to manufacturers.  But certainly the individuals who were involved in that level would not be the reviewers.

          So the answer is, we hope to have enough people on board who are knowledgeable enough to review things that they didn't themselves develop.  We recognize that that would be an unacceptable conflict of interest.

          But on the other hand, there is a lot of more general work with which we can engage, and we can utilize CRADA's where we feel we have enough staff to deal with eventual reviews.

          DR. PRIOLA:  I want to return for a moment to Dr. Intaglietta's suggestion and the discussion earlier about flexibility of the research at FDA, that you can respond rapidly to newly developed situations. 

          If you are going down the path of having an advisory committee or something like this to help you determine where research should be guided, how would that affect that flexibility?  I think that is a very important aspect of what you are able to do.    DR. EPSTEIN:   I think part of how it would help is if we can support the basic scientific disciplines critical to our work, then it enhances our flexibility. 

          I think that Dr. Carbone hit the nail on the head when she said that we flex a lot, and we rob Peter to pay Paul.  It is when we have urgent situations, we do address them.  We cannot always address them by continuing all of our previous work.  So sometimes things get put on the back burner while we address an issue  that is more pressing.

          I think though that over the long haul, having better insight into program goals and targets with the benefit of outside input would only benefit the program, because we would be better structured to deal with things that are emerging.  It would be rather unusual to find that their infrastructure was not relevant.

          An example in my own lief, I came here as an I.D. doc, and I started working in vaccine development, and I was working on herpes viruses.  But then AIDS came along.  CMV was a big issue in AIDS, especially early on with gay men, and so it was pertinent to be working on CMV.  But meanwhile I was learning the skills that I was later able to adapt to HIV.  That was done virtually overnight when the agent was discovered.

          So I think that to the extent that having a supported infrastructure, albeit targeted, would make us more robust as a scientific program, we would end up being better equipped yet to flex.

          I will say though that as external funding under grants increases, it becomes a little bit difficult, because you must do what is under your grant.  But people do get very creative in finding mechanisms that are cross cutting.  If you bring in a technology such as the gene chip, it isn't so difficult to introduce another primer set.  You have already got the infrastructure for the system, and then you are able to flex.  So that is the kind of thing that goes on.

          So I don't actually see those things as mutually inhibitory.  I think the one fosters the other. 

          We are at this point about a half an hour behind.  I think it has been a very rich discussion.  Dr. Tomasulo, if it is pertinent, go ahead, but we really do need to move on.  But as I said, I think this has been a very important and rich discussion, and I hesitated to cut it off.

          DR. TOMASULO:  Jay, picking up on Marcos' where you want to be question, can you talk a little bit about monitoring blood shortages, and what is the ultimate outcome that you expect from that activity, and what products are included in it?  I believe you monitor plasma derivatives as well as blood products.  Can you talk a little bit about that?

          DR. EPSTEIN:  Yes, sure.  We are not the manufacturers.  The government doesn't make anybody make anything.  We can sometimes do it under contracts; it is rare.  So we have a privatized system.  So the ultimate responsibility to make and distribute products lies with the manufacturers who we also regulate.

          We see our goals as oversight in order to recognize and characterize problems and address them from the federal point of view to the extent feasible, which may be simply providing information.  It might be at times providing regulatory alternatives, for instance, flexibility in changing licensed laboratories.

          Our ability to monitor shortages is established in regulatory authorities.  We have shortage officers, and we do have a role and responsibility to respond, heavy emphasis on respond, to shortage reports.  We feel that we are additionally being proactive in monitoring and helping to avert shortages under the more general mandate that that is part of safety.  Lack of adequacy of products is a public health safety issue.

          So we are not generally speaking charged with surveillance of product distributions.  We do that more in a reactive mode.  So for example, with the issues of immunoglobulin and other derivatives that have gone back over the recent decades, we do have authority to require periodic reporting of U.S. distributions of products.  We have exercised that authority to bring about a system where the fractionators give us a monthly report of their distributions, and we have persuaded them to make aggregated data public.

          We have as I have already mentioned developed a system for more acute monitoring of shortage system wide for components, reagents, devices, to monitor the blood system.  The responsibility for that surveillance has been taken over by the Department, and it doesn't reside with FDA.  In other words, we are not primarily in the business of supply surveillance -- safety surveillance, yes, supply surveillance, not exactly. 

          So we play a role, and our objective then is to find truth and find ways to mitigate problems.  We have many, many ways that we can mitigate problems.  We can first of all provide information, so people know what is going on.  Secondly, we can provide alerts.  For example, we can provide web postings or letters to physicians indicating that products are in shortage, and you may want to be mindful of certain things.  For example, where can you go get product, or what are the approved indications and how might you wish to consider that in your prioritization of clinical use.

          Additionally, at times we can make product more available by say accelerating a review of a product, accelerating review of a facility to bring it online.  We can at times offer variances for time limited or temporary granting of alternative procedures.  So we do those kinds of things.  Or we can permit for example importation of products under IND, as long as they meet adequate safety and efficacy standards at the IND level. 

          So there are a lot of things that we can do.  I would have to say though, it is more in the reactive mode in the area of supply.

          DR. ALLEN:  Thank you very much, Dr. Epstein.  Let's go ahead and take our 9:30 break at this point.  I would ask that we make it a very short break.  I would like to have Dr. Williams ready to make his presentation in ten minutes.

          (Brief recess.)

          DR. ALLEN:  The next presenter from the divisions will be Dr. Alan Williams, who will give us an overview of the research programs in the Division of Blood Applications.

        Agenda Item:  Overview of the Research Program

             of the Division of Blood Applications

          DR. WILLIAMS:  Thank you, Jim.  What I will start with is an introduction to the Division of Blood Applications, and then go through some of the initiatives in the review process itself within the office.  In fact, the review process for applications is within the critical path, and I would argue a very important element within the critical path.  Then we will go through some other critical path related activities in our division, including standards development and some of the epidemiologic studies we have been involved with.

          I think two things I want to have you keep in mind throughout the talk.  Many of the things I am going to mention, particularly with respect to the managed review process, is that these are office wide efforts, and everyone within the office has worked together very hard to make our review process more efficient.  Then secondly, some of the research things that you will see.  A couple of our staff members have joined FDA within the past five years, and there are some transitional things that involve collaborations from our previous lives.

          So our principal staff, and those arguably most involved in some of the critical path work.  I direct the Division, ably assisted by Dr. Sharon Orton.  Dr. Orton also serves as the acting chief of the Blood and Plasma Branch.  We have a Devices Review Branch, headed by Charyl Kochman, a Regulatory Product Management Branch headed by Dr. Sian Najar, and we have medical officers who work on things like medical evaluations of reports that come into us, as well as some of the surveillance activities that I will mention.  And I wanted to specifically mention Judy Saraldi, who just recently has taken up a quality assurance monitoring role within our office, and helps look at our review processes as well as several other elements from a quality standpoint.

          I will tell you a little bit more about our branches in this slide.  As you saw from Dr. Epstein's slide, we look at a lot of applications.  The bottom left is the number of license supplements review.  That wasn't a typographical error.  We actually do look at between 800 and 1,000 license supplements from blood and plasma establishments, many related to SOP changes from the establishments.  These are done within our Blood and Plasma Branch in this Division.  It looks at both blood establishment licenses and supplements as well as source plasma collection licenses and supplements.

          Within our Device Review Branch, we deal with a fairly focused area of devices, specifically blood establishment computer software, and this includes ancillary software that interfaces with the primary blood establishment software component.  These are finally called BECs.  They also review in vitro diagnostics or IVDs related to immunohematology.  This can be everything from ABL grouping to HLA typing, and some of the identification systems related to patients and blood identifiers.

          Thirdly, we have our Regulatory Project Management Branch.  This branch is responsible for managing the regulatory applications from the time they come in the door, getting them logged in, and through the review divisions, where the scientific reviews related to the disciplines of hematology and infectious disease are actually done by our laboratory divisions, which will follow.

          We manage the applications, manage the review process in large part, define the regulatory paradigm that will define how those applications are reviewed.  Then we also serve as the primary interface with the sponsor of that application.

          To give you a little more detail about some of the review management initiatives that Dr. Epstein introduced, the goal is an OBRR-wide improvement in our process, including the time line to review, the efficiency of the process, the consistency of the reviews and the management, and the documentation related to the decisions that have been made in the regulatory process.

          This is certainly a good thing to do anyhow, but certainly we are motivated somewhat by the new MDUFMA and PDUFA 3 regulations, which define some pretty ambitious time lines for the review process. 

          I think some major accomplishments have been made in the initiatives in the area of documentation of our procedures, making sure that if a telecon or other sponsor interaction actually contributed through a review division, that that is well represented in our archival record for that review.

          We improved the sponsor meeting paradigm so that instead of saving some decision making to a pre-meeting just before the actual sponsor meeting, we try to get a front-end loading to the review of the questions that have come in from the sponsors, have our position well established, and wherever possible share that with the sponsor ahead of time, often in hopes of pre-empting a face to face meeting and saving everyone's time.

          We have participated in an assertive effort to develop guidance documents faster and to close out those that have been published in draft, and get those issued as final.  Some of you are aware, it is a very complicated process from initial scientific development of a document to actually getting it out the door at the agency, but we have I think worked as a Center very hard to get these documents developed and published, and many of them are well along the way.

          The question was raised earlier about training of our staff and particularly our reviewers and our reviewer researchers.  I think this is one area where there has been a particularly strong improvement over the past two years.  Center wise, there has been an initiation of a regulatory management update, coordinated by CBER as a whole.  This is a monthly training session on review processes and some of the elements that have been changed at the Center level with respect to efficient management of applications and meeting our legal requirements. 

          Then we also within the office have developed a monthly regulatory forum.  This is an area that provides us an opportunity as an office, even though we are in three different geographic locations, to sit down together and hash over any problems or any regulatory issues or management issues that we are having.  This has been a particularly useful program in terms of developing our new paradigm for sponsor meetings and training staff as a whole.

          Last in this list, we have developed internal review management metrics to try to put some definition and teeth into the review process as a whole.

          This next slide on a little cartoon shows a life cycle of a generic application that comes into our office.  This could be a BLA, a 510K IND, whatever.  The application comes in, we have a document control center that logs it into their database as being received, and then within a very short time, a process that has also been improved recently, we receive the application in the office and assign it an identifier within our regulatory database.  Then copies of this application are distributed to the reviewers.  The reviewers take a quick look to see if the submission qualifies for review, has sufficient elements for review, and we issue a filing letter to the sponsor saying that we accept this for review, and you will be hearing from us. 

          Then the process of review itself starts, and what we define as a new element is the mid-cycle of the review process. The idea here is again to front-load the process, with the target of identifying all major review issues by mid-cycle, then strategizing interactions with the sponsors that will take place in the second half of the review with the goal of having those solved and in approval at the end of that first cycle.

          What we have done is worked toward that goal, but also established a metric, so that at the mid-cycle review meeting for all of our applications, we maintain a database with the help of our regulatory project management staff that documents the date of the mid-cycle meeting, the attendance of the discipline reviewers at the meeting.  The reviewers are expected to have a written discipline review that has been concurred by their supervisor available at that meeting.  Again, it is not a completely exhaustive review.  It is identifying major elements, major showstoppers that might be a part of that review. 

          At that meeting, as I said, the future actions are strategized on toward a final action. 

          In terms of the final action itself, we are working under very aggressive time lines with MDUFMA and PDUFA 3.  We have established a metric called T minus ten.  This again is a goal, so that sponsor interactions and final review memos are complete and documented at ten days before our final action date, when notification to the sponsor needs to go out the door.  We do track that, how successful we are at doing that, and it gives us a little breathing room if we need a day or two to finalize a decision, but it serves as a worthy target.  The goal here obviously is to maintain an on-time performance for completing our applications, but also to have the management signoff at the branch, the division and the office level as necessary done in sufficient time that the managers have enough time to review everything that does go out.

          I think these metrics have been very helpful, if not the results of the metrics themselves, certainly the presence of the metrics has gone a long way towards helping us review the process.

          After the tragic events of the fall of 2001, we did have an emphasis on emergency response and our BTCT related responses.  This is one of the areas where I think DBA had a major role, but an office-wide effort.  We developed an internal SOP for responding to crises, which defines staff responsibilities and backup.  It defines when to initiate and document a response, when to end a response.  It defined our contacts for both internal and external communications in time of crisis.

          We have with the Center and really all of HHS developed our continuity of operations plan, which is under Presidential directive.  It is called a COOP.  It allows us to continue operations off site in the event that we need to, and we have staff defined who would be prepared to continue our functions at a different location.

          Then finally, in anticipation of an event, we have given up-front proactive thought to agents which could be used as part of a BT or CT related exposure, and developed our baseline information that we would need, our baseline contacts, both internal and external, and given preliminary thought to what policy actions might result from a specific event.

          Our Division like the other two divisions as well has a lot of external liaison activities.  Many of these are with our colleagues at the AABB, and their standing task forces and committees.  These include the -- I'll just mention a couple, the indoor organizational donor history task force, with which we have been working closely to get an accepted donor questionnaire that is standardized and cognitively tested available to the field.  We have the primary representatives to the standards committee and the technical manual committee, and their indoor organizational task force on disaster response.  We have also produced a chapter in Dr. Harmoning's textbook overviewing the regulatory policies related to blood transfusion.

          A few examples of our critical path activities.  We mentioned the Immunohematology Branch and their reagents and platforms.  This is an area of critical path related to definition of standards, and I would say, standards related to products.  A lot of our activity within the Division relates to process and SOP review rather than products, but in this branch it is products.

          Dr. Epstein mentioned that in many cases, particularly for immunohematologic reagents, you may face a situation where a reagent is in short supply anyhow, and a manufacturer is considering ceasing production or in some other way the reagent may potentially come short.  NTIS would be a good example of this.  We may have to scramble quickly to help look at a potential replacement reagent, and both through wet laboratory work and review of data determine whether the specificity is sufficient to cover the territory that that original reagent would have supplied.

          Also, changes in platforms like infectious disease IDVs, the immunohematology reagents, some of the procedures are manuals, some are technological, and we have to facilitate movement between platforms.

          Blood establishment computer software.  As Dr. Epstein mentioned, we have been particularly interested in and supportive of computer assisted donor screening systems.  The AIDS related behavioral literature does support that computer assisted screening of subjects does give a better, more precise response to medical information.  Some of these systems have now been made available to the public and are in use in donor centers today.

          In addition, radio frequency identification technology is rapidly making its way known.  We have been looking at some of the consensus standards for interference and compatibility, and reviewing their relevance to our devices.

          In terms of procedures, we have had a several-year program now to look at the statistical basis of quality control for biologicals.  This has been in close collaboration with our colleagues in the Office of Biostatistics and Epidemiology.  As you will recall from the regulations both in the U.S. and elsewhere in the world, quality control is often defined as one percent or N equals four per month.  That is a reachable quality control system, but it is hard to define just what that says in terms of defining a product and the extent to which it meets standards.  However, if you can define a product as 95 percent of the product meets a standard with 95 percent confidence, that gives you much more of a definition of what you have.

          There are various statistical approaches to get there.  Binomial is one, which is a feasible approach for blood products, and scan statistics is a recent one that we have been looking at, and are eventually going to introduce as an FDA accepted way of producing a standardized quality control paradigm.

          In terms of blood safety and adequacy, there are two elements that I think are important.  We don't carry the responsibility right now for overseeing the availability of blood in the country, that is in the Office of Public Health Science under the Assistant Secretary.  We do have the responsibility for making sure that when we put a policy in place, that we aren't jeopardizing the adequacy of supply.  So what we need to do is maintain an informed balance between regulatory intervention and blood supply adequacy. 

          I would say every major policy that emerges has had that cost versus donor loss consideration made very carefully, and often vetted with this committee or a similar public advisory committee.  This involves risk modeling, and in some cases just scraping whatever data we can to assess whatever impact a donor deferral policy might have.

          This is an older one, but this is the basic comparison between a donor travel survey conducted on a multi-center basis among ten blood centers, which was used to define the theoretical risk reductions for dietary exposure to virion CJD for travelers to the United Kingdom versus blood supply loss. 

          This is the basis of one of the earliest decisions related to virion CJD deferral, which deferred on the basis of a six-month exposure in the U.K.  We knew we would lose 2.2 percent of donors, and had an 86 percent risk reduction.  This was used subsequently for policies afterwards as well.

          The second area is, improve emergency preparedness through accurate assessment of blood shortages.  This is a Transnet system that Jay said a few words about, a web-based reporting system, which is going to be applied to blood and blood components, reagents and supplies specifically targeted to transfusion services, because they are the best indicator of when you really have an acute problem.

          I think an important thing that is built into this system is not only where a product is short, but what is the medical impact of that shortage, anything from delay of a necessary procedure to use of Rh positive blood in an Rh negative patient when you wouldn't normally do so.

          It has the capability to be turned on and off as needed.  You might turn it on in a holiday period or in the summertime, or in a time of crisis.  It was made available to DHHS essentially as a turnkey system, and they have announced their intention to make this one arm of the basis system in the Secretary's operations command center.

          Just an example of what I meant as far as the medical relevance of a shortage, we piloted this in the winter of 2002-2003.  It just coincidentally happened at a time when we had a very severe holiday related blood shortage.  So we were able to not only document the shortage, but get some indicator in our ten participating sites of what the medical impact of that shortage was. 

          So out of the 191 transfusion service reporting days that were part of the pilot study, there were no delays of emergency or elective surgery.  Eleven sites made use of their strategic reserve, one delay of medically necessary treatment, and 24 transfusion service days in which Rh negative patients were transfused with Rh positive blood when they most likely otherwise would not have been.  So I think it is important to get the impact of a shortage, as well as the fact that a shortage exists.

          Improvements to donor screening I won't go into in detail.  Just to say that I think some of us in this room have been founding members of this effort.  It has been a long haul, six or seven years now.  I think we have approached the point where we have a standardized donor questionnaire.  It has been cognitively tested for the first time in history, and we are on the verge of having that as an FDA acceptable questionnaire used potentially throughout the country.  We are actively working toward doing the same sort of a qualification on an abbreviated process for repeat donors.

          There has been some very elegant laboratory work done on West Nile in our office, but also, I wanted to mention our participation in some targeted epidemiologic studies.  West Nile is one of those.  In collaboration with the American Red Cross, Dr. Orton in our group conducted a case control study of West Nile, seropositive donors versus controls for NAT symptoms, and produced data which helped support a recent decision that we could discontinue the donor symptom screening question of headache with fever.

          This question originally rose out of some preliminary studies with donors who were implicated in transmission of the virus in early CDC studies, but it was found that particularly in the presence of NAT testing that this question was no longer predictive.

          This is one of the transitional studies I mentioned.  We were involved in some survey research with the NHLBI red study.  Donation incentives are common, but data addressing incentive impact on a motivation of a donor to show up at the blood center and donate are quite limited.

          This is some survey research.  The bottom line is, we found that heath related incentives are very motivating, particularly things like availability of a blood credit which many donors think they have, but in fact may not, cholesterol testing, and other health related testing, even things like PSA testing, are very encouraging to donors.

          On the other hand, compensatory type incentives, while they are attractive to younger donors, also appear to turn off about seven to nine percent of the overall donor population, which is something to keep in mind.

          Similar epidemiologic study of HIV incident infection.  Recent HIV exposure is of interest, because individuals who have incident HIV exposure have presumably just gone through a blood donor screening process, and it is interesting to know how that process may have missed a risk factor.  The bottom line is, incident HCV infection has a high association with injecting drug use, just as prevalent infection does.

          White particulate matter was an issue of concern a little over a year ago.  In early 2003, there was an observation of abnormal white particles in red cell units.  The bottom line is, our Division collaborated with some blood centers to look in depth at adverse event reports from transfusion services in some instances where we know units with particulate matter had been issued and received, and there was an absence of adverse event reports, which helped us to a conclusion that this was most likely an event that did not jeopardize blood safety.

          We have ongoing surveillance using the databases that are available to us.  Fatalities both in donors and recipients are reportable to the FDA.  We had a blood product advisory deliberation in December of 2003 in response to an apparent blip in donor fatalities, and some intense work between CBER staff and AABB donor fatality task force.  We recognized that simply defining the period of time after transfusion that would be allowed as an inclusion criteria clarified this quite a bit.  The numbers both from those high years of 2002 and 2003 as well as in 2004 were considerably lowered and more consistent when more carefully defined.

          Similarly, there is ongoing work looking at recipient fatalities.  Transfusion associated lung injury was the leading fatality cause in 2002 and 2003.  In response to this recognition, FDA issued a dear doctor alert to help increase the recognition of this as a post transfusion event. 

          This is a bar chart showing the contribution of TRALI to total fatalities, and you can see that after the issuance of that dear doctor letter, one without looking at it more carefully could perhaps assume that the increased recognition improved the reporting of TRALI related events.

          Just some closing thoughts.  Our staff in the Division of Blood Applications have worked in concert both with internal and external collaborators to successfully identify and pursue some unique critical path opportunities with a multidisciplinary response that has involved epidemiology, modeling, behavioral science, management science, if you will.  I think we have been able to make some key measurable advances to public health and to transfusion safety.

          Thank you.

          DR. ALLEN:  Thank you, Dr. Williams.  I am going to defer questions for Dr. Williams and the other presenters until we have had a chance to do all of them.  If you have got a critical question with regard to clarification of a point, you may ask it.  But otherwise, in terms of general questions and discussion we are going to defer. 

          Our next presenter is Dr. Hira Nakhasi, who is Director of the Division of Emerging and Transfusion Transmitted Diseases.  He is going to give us an overview of the research program for DETTD.

        Agenda Item:  Overview of the Research Program

          of the Division of Emerging and Transfusion

                     Transmitted Diseases

          DR. NAKHASI:  Thank you, Dr. Allen.  Thank you very much to all the committee members for coming over here and listening to what we will be presenting to you, and all the audience who is here to listen to what the research program is.

          First of all, by way of introduction, my goal here is to present to you the scope, mission, regulatory relevance and public health impact of the DETTD research program.  I will provide you with several examples of our accomplishments, and how that goal is met.  Both Kathy and Jay did an excellent job and you did an excellent job of asking the questions clarifying what is the purpose of today's program.  I will try to provide you with examples of how those fit into what the goals are set in to begin with.

          First of all, examples which will directly impact our regulatory mission, and how does it fit into FDA's critical path initiative, which has been described already, and how we are planning as part of our future needs.

          In the interest of time, I will not give you all the detailed examples from every principal investigator in our group.  However, the books which we have provided to you will have an extensive elaboration of that.  I will highlight some of the major examples, and then from there we will go forward.

          We have also in the audience some PIs whose research work I will be presenting.  If there are specific technical questions, I will be directing those questions to them.  Otherwise I will try to answer as much as possible.

          With that introduction, I would like you to sit back, relax and enjoy the talk.

          First of all, the organization of the Division of Emerging and Transfusion Transmitted Diseases.  The Division is organized into three research laboratories and one fulltime branch.  This was organized recently.  The laboratories having organized as Dr. Epstein pointed out to you earlier on products and what type of research and product responsibilities these labs have, and what type of research they did do.

          In addition to that, as I said, we have fulltime reviewers which have interaction -- the dotted lines show the interaction with each of these branches.  The purpose of this is to have a cadre of people who can interact with all these groups, as well as, they are responsible for the process as well as the review of science.

          In addition to that, we have a small laboratory which is the product testing laboratory, and Dr. Bisswas is head of that.  These are the people who test all the lots of any products which are licensed before they go on to the market.

          The head of the Laboratory of Molecular Biology is Dr. Hewett.  The head of the Laboratory of Hepatitis and Related Emerging Agents is Dr. Kaplan, and Bacterial, Parasitic and Unconventional Agents is Dr. David Asher, and the Product Review Branch, Dr. Elliot Cowan.  In my immediate office, myself and Dr. Meade, who many of you know.

          The mission of this Division is to proactively insure the safety of the blood supply.  How do we do that?  Through regulation of blood screening and diagnostic testing to detect infections which contaminate blood and blood products.  In addition to that, we evaluate new technologies for rapid and flexible screening of blood supply, and develop policies for the guidance of use of tests and diagnostic products, and also the implementation.

          So with that responsibility, we plan and conduct research on disease pathogens of various blood-borne agents.  We test the safety of these tests for these blood-borne pathogens, and in addition to that, we have an added responsibility, because of the unique expertise, CBER-wide expertise in the Division, to the development of biomarkers for vaccine safety and blood-borne agents.  I will elaborate that point further, why we are doing those kind of studies in our Division.

          In addition to the broad based approach, we also have responsibilities for testing, for approval of investigational tests, and surveillance of licensed products.  We develop materials for testing, and which have been already spoken many times.  The members of the Division conduct inspections for these manufacturing facilities.  We have done consultations with other agencies and government components for other issues such as CDC and NIH, HRSA, CMS.  We have an outreach, where we discuss the safety and efficacy of blood donor screening tests, such as forums like this Blood Products Advisory Committee, tissue, spongiform advisory committee meeting, and Department of Health and Human Services blood safety and availability committee.

          The regulatory output for '04 for our Division was approximately 540 applications we reviewed, which included biological license applications, supplements, amendments and reports, and PMAs and 5-10Ks and IDEs.  In addition to that, our group performed thousands of test kits and performed several inspections.

          From the research output in '04, in our Division there are nine principal investigators, and the research publication in the period of '04 were 41.

          As you heard the mantra for the critical path all along this morning.  Really our mission is to follow the critical path challenge for the blood products to insure the blood products safety, efficacy, availability, while minimizing the destruction to the blood system.  So based on that, I will then provide you examples, how that mission is achieved. 

          But before we do that, I just want to show you a chart illustrating the point, what impact has this testing of the blood donors with agents such as HIV and HCV over the year have reduced significantly with this transmission.  So therefore, it just speaks volumes by itself.

          So how did we prioritize research priorities in the Division?  We have three broad categories.  One is blood safety and availability, which is related to the retroviral testing of these various agents, both present in the blood system or emerging such as SARS, vaccinia and others, or West Nile virus or vaccine safety for blood-borne parasitic agents as well as HIV and hepatitis agents.  I will discuss in detail why we do that.  And other issues such as manufacturing issues because of the unique expertise of Dr. Asher and his group in our Division, which goes across the whole CBER regarding the detection, decontamination and issues for screening assays.

          The first topic of my discussion would be blood safety and availability.  I will show you what is the impact on the U.S. public health, what are the regulatory challenges for us, and then give you the examples.

          The impact on the U.S. public health is because millions of units are transfused annually, and there is a risk of transmission of these agents through it.  However, since the introduction of tests, the risk has gone significantly down.

          However, there are new and emerging pathogens which constantly threaten the blood supply, such as the emergence of the drug resistance as a common variant of HIV or HBV mutants, and how those mutants impact our ability for testing or currently existing licensed tests; emerging pathogens such as West Nile virus, SARS and BT agents, existing parasitic agents which we know, many of them are transmissible, and we don't have any tests available for those assays; potential blood donors which are exposed to this, such as TSE agents, or for those for which we do not have tests available, and which results in a significant loss in the donor population, and therefore it becomes an issue of blood availability.

          Also, some of the people who have -- on the basis of certain other tests, and how those can be re-entered, such as the ones you heard yesterday with the proposal for -- therefore, the regulatory and scientific challenge based on those public health impacts is to evaluate sensitivity and specificity of such donor screening, as well as diagnostic tests for retroviruses, donor screening tests for hepatitis, West Nile, bacterial, all those agents out there, and to maintain the safety of the blood supply by assessing the efficacy of thes existing screening tests or the diagnostic tests, whether they are capable to identify new and emerging agents, and also gaps in knowledge for critical path development of protective blood screening tests for parasites.  The purpose is not to develop assays, it is to have a proof of concept or what we would call a gap in knowledge, so that the information that we have can be useful for evaluating future tests for these agents.

          Some of the examples in the blood safety and availability category.  This is the Hillard group laboratory.  The question she asked was, can currently HIV licensed tests identify retroviral variants.  As Dr. Epstein pointed out, this came out by looking at the tests and based on her research in this area of HIV diagnostics, it became important for her to evaluate performance of FDA licensed assays with new variants. 

          So a study was initiated in Cameroon, because as Dr. Epstein pointed out, it is the heart of recombinance, it is a country with evolving HIV diversity.  What she found out is, one of the recombinant, which is the major recombinant form, CRF-02AG, were not reliably detected by some NAT -- so therefore it raises a very important issue, that we need to have extended national and global surveillance of emerging HIV and other human retroviral variants, as well as, we need to develop certain standards of the reference panels which include all these recombinants or the variants, so that in future tests we may identify them.  A very important contribution.

          Similarly, the other contribution in the area of HIV and sensitivity of existing HIV assays.  This is work from Dr. Sabash Dawin's group.  The question he was asking was, currently existing HIV western blot assays, how can we enhance the sensitivity of these by modifying the conjugates, poly enzyme conjugates, by making certain modifications.  Again, it came from his experience as a peptide chemist, and knowing the chemistry of these things.  So if we can modify those conjugates, you can enhance the same tests, now you can enhance the sensitivity of these tests.

          What does it do?  By modifying the conjugates, he could increase the sensitivity of the western blot assay, and such conjugates could then enhance the detection of antibody early on.  Let's say the current assays detect as early as 22 days.  With new enhanced sensitivity, you could detect early on, therefore you can reduce the direct impact on the public health.

          Another important example is the performance of the West Nile screening assay.  As many of you know, the epidemic of West Nile has been going on for the last four or five years.  It became very clear in the very beginning that this agent is transmitted through blood.  We need to have an assay for screening this agent and for validating those tests we need to develop reference panels.  Dr. Mario Rios in the group developed in collaboration with industry and other academicians, two isolates of West Nile virus, genetically characterized them, did the biological characterization such as detecting the titer viral load, and then subjected it to seven different labs and different assays, and based on those analyses, they formulated -- when they were distributed to different laboratories, and based on the FDA's standard of 100 copies per ml, most assays had a satisfactory performance.  Again, a direct impact on the validation of these assays.

          The other important issue in the West Nile virus transmission is the question whether the blood samples which cannot be detected by current screening assays and are antibody positive, but sometimes many of them can be such a viral load that they can only be detected by individual NAT, are they infectious.  She asked the question, since she could not do it in animal studies, to see if first of all in the human primary cell cultures she developed, and asked the question whether such samples can be infectious.

          Most of you heard yesterday her presentation.  I don't want to give you the whole data, but the result was that the presence of antibody reduces in some cases but does not eliminate viral factor in vitro.  Mind you, this is an in vitro study, and we had a significant discussion about how does it translate in vivo and whether we need to do those in vitro studies at the moment.

          It raises a concern for potential risk for transmission until we have those studies.  Therefore, she is planning to do in vitro effective studies to investigate in vivo.  So therefore, the question is, what do we see in the field, what questions we can recognize from looking at these problems post test, and how we can solve these problems.

          The other good example is the example of comparing the sensitivity of HBV with the HVG assays for acute HVG infection.  This study was done a couple of years ago by Dr. Bisswas and Dr. Tabor.  They tried to compare several HVG assays licensed or not licensed at that time, and compared the sensitivity of that assay with the HVG mini-pool NAT or HVG single NAT, and to see that whether NVG mini-pool NAT will enhance the sensitivity of licensed NVG assays, and therefore reduce the window period.

          The outcome of that was a small sensitivity increase of pool NAT versus NVG assays -- results in a marginal increase in safety, but the important observation was, the implementation of a single donation of NAT will most likely increase the safety of the blood supply.  This issue was discussed last year in VPAC, and based on that, the recommendation was made that HVG pooled NAT is not recommended, but it can be used, because it can have small sensitivity -- but the important thing is to move towards the single unit NAT.

          As I said, not only the existing or emerging pathogens, but there are other pathogens.  Two years back, as many of you know, we were hit with an onslaught of new emerging pathogens, West Nile virus, SARS, monkey pox, name any of those.  So at that time, the issues were becoming very important for us, whether those agents were having any impact on our blood supply and an impact on the blood safety.  Also, in spite of not having a test available, can currently available inactivation processes inactivate such agents as for example SARS and therefore insure the blood safety.            Dr. Taylor in the Division has done the study.  She showed that using solvent detergent, which is the currently available technology, can inactivate SARS virus, and therefore it insured the safety of blood for transfusion and blood products.

          Another example is another agent which is emerging which is present all the time, malaria parasite.  We don't have a malaria parasite assay out there, and this is becoming more and more important because of immigration from these areas, and people coming from this.  In the country there is some transmission going on, so what kind of tests will be developed?  Again, this is a proactive example, if the test comes out tomorrow, will we be able to evaluate that test?  Dr. Kumar in the Division developed a test using PCR assay, and also a microarray test which showed a detection limit of one parasite per microliter of blood, and also, not only can it detect the plasmodium -- the major cause, but other species which are also contributing to the malaria infection, can detect other species.  So an example of being proactive to what things can come down the pike.

          Another example is TSE detection.  Currently available detection is immunohistochemical staining of these tissues.  It is very subjective because it is just visual observation.  Dr. Asher's group developed an assay called quantitative marker for metric analysis, i.e., computerized digital analysis such as here shown.  This is a control slide, this is a histochemical slide which is stained, and then using QMA analysis, you can enhance the computerized digital image and therefore it will improve the predictability and the sensitivity of TSE detection.  Again, a very important contribution.

          As Dr. Epstein pointed out to you, as more and more agents become available, blood-borne agents that affect the safety of the blood supply, we do not have the luxury of each individual agent to be screened individually.  So there is a way to detect these agents in a multiplex format, or simultaneously.  The rationale is, increasing the number of agents that threaten the blood supply, limited blood sample for detection.  Therefore, what happens if you do so many tests there is a problem with error rate, and we need rapid detection sometimes and simultaneous detection.

          So based on that, in my laboratory we developed a multiplex detection, a blood-borne pathogen chip, which has oligonucleotides corresponding to many of these agents such as bacteria, parasite, bioterrorism viruses and agents, and the regular blood-borne viruses like West Nile and HIV.  This whole chip has all of the oligonucleotides.  It has also the controls at the end.  We can show that simultaneously using three primer pair sets, we can detect three of these agents, and the sensitivity was 50 cells per ml.

          The purpose here again was that we could detect three agents simultaneously, and also to understand if there are some more applications which come to us, what are the problems, then they will try to multiplex three or four or five, since we have seen that there are some problems, and we cannot keep on doing N number of multiplexes.  So there is a certain limit with this kind of technology.

          In the same thing, we are now looking at the new technologies like nanotechnology and multiplexing, and Dr. Hiller's group is looking at that.  Also, in collaboration with people in the industry, we are trying to see how using mass spectrometry we can detect those agents rapidly and simultaneously.

          The second topic of discussion today is the vaccine safety of these blood-borne pathogens.  The reason why we are looking in the Office of Blood is because of the CBER wide unique expertise in some of the blood-borne pathogens.  It profiles the need for all CBER wide.  For example, in parasitic agents, this is the only laboratory in the CBER which builds with malaria and other things, so therefore it becomes a CBER-wide unique expertise. Something like hepatitis-A, these are experts only in the Office of Blood primarily because these are blood related issues, but we can also ask the question for the safety of the vaccine related issues.

          The unique issues with the vaccine and blood product safety are testing for agents in vaccines of blood donors, because that becomes also a question.  An example which was given previously also, there was a notion that we will be vaccinating en masse by vaccination.  The question came up immediately, what is the viremia in those donors, can those donors be also used because it became a blood safety availability issue.  The studies were done by Dr. Hiller's group to show that is no viremia with these vaccines, and also, those people who got the vaccine, testing their blood did not impact the sensitivity of other existing tests.

          So therefore, it is very important to know how to respond, not only because of the blood related issues, but also cross-cutting with the vaccine issues.  Also, the role of therapeutic vaccines.  I will show you an example of that, and again, more importantly, the gaps in knowledge for critical path development of these vaccines.

          The question was asked earlier, are we in the business of developing vaccines.  No, we are not developing vaccines.  The goal here is to have a proof of concept, to show that when a vaccine is available, what are the issues, what are the safety issues, what are the biomarkers which we can look at which will determine the safety of those issues.  So therefore, the question is not developing the vaccine, but to have a proof of concept.  Also, it is very important for people in house to know those issues, because when these applications come to us, we should be able to evaluate when keeping any biological product in concentration.

          What is the impact on the U.S. public health?  As many of you know, the millions of American travelers and thousands of U.S. troops are deployed in all these parasitic endemic areas.  There is an increased rate of immigration, which raises the concern for potential for transmission.  Known cases of transmission have occurred through these agents.  There are a significant number of potential donors because we don't have any tests, and therefore it becomes a blood availability issue.  There are no vaccines available at this time.  There is a lot of effort going on in industry to develop various methodologies for these vaccines, especially the parasitic vaccines.  Similarly for the HIV and HCV vaccines; those efforts have focused on specific areas, because we know that millions of these HIV and HCV cases are worldwide and there is no safe and effective vaccine available at this time.

          So the regulatory and scientific challenges for us are the assessment of safety and development of biomarkers for effective parasite vaccines, cell culture for some of these hepatitis viruses, because many of these viruses cannot be grown, and therefore there is a very strong hurdle for developing of these vaccines for these agents, such as HCV, hepatitis and others.  Assessment of the efficacy of viral therapeutic vaccines such as HIV and West Nile, and selection of markers for donor screening in the vaccines, as I pointed out when I gave you an example of the vaccine.

          This study was done in my laboratory.  We showed that in looking at the leishmania vaccine as an example here, by altering one of the essential genes which is important for the growth, this parasite cannot grow in the form which is infectious.  For example, this showed you the parasites in the macro phase, the wild type, and this is the attenuated wild type, and you can see one or two parasites.  So what it shows us is that by modifying, attenuating the gene by genetic manipulation, we could reduce the integrity of in vitro by gene dilution, and therefore it raises the important issue that such vaccine candidates can be used as vaccines on the outside.  There is a lot of effort going on outside which is looking at various forms of how to develop these parasitic vaccines.  Traditional methodologies such as subunit vaccines or recombinant proteins have not really been fruitful so far.

          My point was not in the developing of vaccines, but to show what are the safety issues. If a person comes up with this kind of a vaccine candidate, and there are examples out there which they are trying to develop such type of vaccines, what are the safety issues with that in vaccine development.

          Our group showed that if we took this attenuated parasite and then analyzed the expression of the genes in this parasite, we could find out there were several genes which are affected, expressions lower or improved, and expression of those genes can then be used as a biomarker for the vaccine safety.  If you take this vaccine and inject it into animals or into people, you want to monitor whether that vaccine is still attenuated or not.  By looking at the expression of these genes, that can be one of the markers.

          In the area of malaria vaccines, a lot of effort has been going on in outside developing various methodologies, and also the issues of vaccine safety, and also whether these vaccines are biologically effective or not.  Dr. Kumar in the group has been working on this issue, where he took the approach of developing a multiple antigen peptide vaccine which has various epitopes which are in both the humeral and the cellular response, different proteins at various life cycles.  It has been shown from the literature and what is out there that a malaria vaccine which will be only good which will represent different stages of life cycle.

          What he did was, he developed this multiple antigen peptide and then looked in mice at different genetic background and found that there was a good humeral as well as cellular response, from moderate to high.  This is the humeral, this is the cellular response.  He compared the two mice with the same genetic background, except one that is a B6 and HLA-2, which is a human HLA-2 gene, which could get the protection in the sporicide inhibition assay.  So the response could protect the sporicide inhibition, but could not do in the B6 mice. 

          So the issues are very important issues, because one would think when you have got a good response it will be protective.  However, his analysis showed that it is not uniform.  A very important issue for the safety issue.

          Another example is the developing cell lines which can grow these hepatitis viruses.  I can give you an example here of hepatitis-A virus.  Dr. Kaplan's group has shown that he has developed a cell line where wild type hepatitis-A virus can be grown.  Now this cell culture system provides us a very effective tool for making modification in the virus genome and then asking the question how that virus application can be attenuated, as well as, it also provides us a diagnostic tool to detect blood products which are infectious and therefore, this will be a very important contribution.

          The other area of vaccine related issues which are coming out, standing out from the work done in the laboratory, looking at the blood product, how it can be impacted in other areas.  This is a slide showing work done by Dr. Darmon, where he showed that PAT protein enhances the viral replication. 

          This is a -- formation assay here, and he showed that there are certain epitopes in this protein which enhance the replication of the virus, such as the epitope 21 to 40 and 53 to 68.  So therefore, using those epitopes, one can use as a therapeutic vaccine to prevent further infection, and therefore could be used as a therapeutic vaccine.  So therefore, a very important observation which could be applied in the vaccine area, HIV vaccine area.

          The last issue, not least, is the manufacturing issues, especially focusing in the TSE issue.  Again, the U.S. public health impact, millions of Americans who have visited or lived in the United Kingdom and other countries and have got exposed to these TSE agents.  We do not know how many people there are.  There is uncertainty about the incubation period of these things, and the TSE contamination of blood products has shown to be causing fatal infections.  There are now documented cases of transmitted cases.

          The manufacturing issue.  The regulatory and scientific challenge for us is to establish criteria for accepting TSE infective -- claims in the biological products, whether it is a blood product or a vaccine product or any other product, establish the criteria for accepting TSE infectivity in the contamination claims.  The issue is, when this manufacturing is done, the probability is that the instruments and other things can be contaminated, so what are the ways we can validate those decontamination claims.  Most importantly, gaps in the knowledge for the development of the TSE detection assays that Dr. Epstein had pointed out earlier also.

          This is to give you an example of what the TSE prion diseases look like.  This is control prion in infected brain, and this is early case of CJD, late stage of CJD, and VCJD, which has a different pattern of format, and this shows you the immunohistochemical staining in the lymph nodes.

          The issue is, are all the prions infectious.  The discovery made by Dr. Picardos has shown that not all prion proteins are infectious, because the prion proteins are protein sensitive, and they generate protease insensitive.  So they become resistant to protease digestion.  You can see both the high molecular and low molecular advance.

          What his data showed is that prion protein infectivity is only associated with the high molecular advance, not with the low molecular protein resistant forms such as the example he gives, GSS, which only generates the lower molecular weight forms.  It was shown in animal experiment in transgenic animals that this does not cause the disease. 

          Therefore, what is the significance?  This becomes very important from a diagnostic point of view, because if there was an ELISA assay which will pick up all the forms, we will know that it may be infectious.  But having this kind of assay, which is the western blot assay here, we can distinguish that not all prion proteins are infectious, and therefore it could be important for looking at the animal derived materials.

          The other example is, I am showing the decontamination of the procedures.  Dr. Asher's group, what they did was, they validated WHO recommended TSE contamination protocols which included treatment of sodium hydroxide or sodium hypochloride plus autoclaving.  They took a scrapie vein from mouse, put it onto needles on glass plates, and then subjected it to this treatment.  What they found was that this treatment effectively removes, and therefore this is a validated assay. 

          So in summary, where are we going?  The future directions for us are to come to validation of new technologies to allow rapid, sensitive, multiple detection of new and emerging blood-borne pathogens.  Look for how the prevalence and diagnostic significance of HIV variants, HIV mutants, will impact our ability to screen those agents.  Focusing on the emerging pathogens such as West Nile virus and other agents, God knows what, that are coming down the pike, looking at the infectivity of blood, looking for standard development for validation of those assays.  Then in the area of CJD-VCJD, the contamination and detection is another area where we are focusing.  The development of biomarkers to predict vaccine safety and the attenuated parasite, similarly focusing on the assays for developing the cell culture system for hepatitis to evaluate both the blood product and vaccine safety, and similarly in the area of viral therapeutic vaccines, see how future vaccines could be developed based on the studies done.

          So in summary, the mission relevant research in ETD, in the areas of viral, parasitic and TSE diseases, improves not only OBRR's but CBER's as a whole ability to evaluate the safety and efficacy of blood and blood products and vaccines.  I just want you to take this message home, that that is the whole purpose of my presentation, and the purpose of our being in the Division of Emerging Transfusion Transmitted Diseases.

          Last but not least, I would like to acknowledge the folks, because I am only the messenger here, so I am just giving you the examples of all the principal investigators.  Some of them I did not present, some of them I did.  I apologize to those who I did not, but the point was here to show the examples to see how is our research important for our mission relevance.

          The area of safety and efficacy of human retroviruses, West Nile, smallpox, donor screening and diagnostic assays, Dr. Hiller, Sawash Darvon, Andrew Dayton and Mario Rios are the PIs, that is the work presented from their group.  The safety and efficacy of donor screening assays for hepatitis and emerging viruses, the PIs in that group are Dr. Kaplan, Dr. Taylor, Dr. Tabor and Dr. Bisswas, whose present work I presented here.  Safety  of blood from the risk of transmission of parasitic agents and safety of such vaccines incudes my group, Dr. Kumar and Dr. Alan Debberman, and the safety of biologics from transmission of TSE en cephalopathies, Dr. David Asher and Dr. Pickard.

          Thank you very much for your attention.

          DR. ALLEN:  Thank you, Dr. Nakhasi.  I am convinced.  And bonus credit for coming in with the green light still on. 

          DR. DIMICHELE:  I know we are trying to save questions for the end, but I just want one clarification question.  Just help me understand the critical path issues.  Let's say we have three pathogens.  We have West Nile, malaria, leishmania.  For West Nile as West Nile was emerging, the emphasis went into diagnostic testing, not vaccines.  Then very rapidly we had a diagnostic test.

          Now, with malaria and leishmania, the approach -- since we don't have diagnostic tests, right now the approach is into vaccines.  I am just trying to understand from a critical path standpoint how those kind of decisions are made.  And as a corollary to that, for instance, let's say you develop a malaria vaccine, how are we going to use that vaccine, let's say, license that out to someone who makes vaccines, how do we use that vaccine to then protect the American blood supply from malaria? 

          DR. NAKHASI:  I think that is a very good question.  I think you point in the right direction.  In the area of parasitic diseases, you said they are not having an immediate impact.  As you saw I gave you an example of both detection as well as vaccine.  We also are focusing our efforts not only just for vaccine safety, but for the diagnostic areas.

          Now, because there was minimal effort, we had to put a lot of effort in the West Nile area.  The second question is, once we have a vaccine, how do we go ahead with this technology.  Again, here the point I was trying to make is not really develop a vaccine, it is to have a proof of concept with regard to the issues which are relevant to the safety of that vaccine.  Tomorrow when the vaccine comes on our door, we as reviewers should be able to ask a specific question, should be able to review the aspects of the safety issues.

          The example that I gave you for malaria, even though the humeral response was good, the biological response was not with this approach.  So therefore, we know a vaccine comes, we are up to the part of knowing that there could be.  So if we do develop a vaccine, as Jay and Kathy pointed out to you, there are ways to transfer technology and things like that, and those people who are involved in that project will not be able to review that, so therefore, the conflict is not there.

          But the important point here, the take-home message, is not -- our role is not to develop a vaccine.  It is to insure what are the issues that the vaccine production -- it is like a safety issue or biomarker issues.

          DR. DIMICHELE:  But if I could just extend my question for a second, in the meantime you are focusing on vaccine, and thinking that at some point you might be evaluating vaccines, and now are going to be in a better position to evaluate vaccines.  So how will that translate back into public safety?  Do you envision for instance everybody going overseas being vaccinated against malaria, so when they come back, there is no chance of having malaria enter the blood supply, and therefore be at risk to other people?  Is that the thinking?

          I am just trying to understand what the public health strategy is, because obviously you have that in mind, I am assuming.

          DR. NAKHASI:  Of course.  Before that, I think Kathy Carbone is trying to --

          DR. CARBONE:  I am going to let Hira off the hook a little bit.  Given our incredibly thin level of expertise, Hira has to with his Division deal with Center priorities, not just blood priorities.  Since we have no malaria, leishmania, TSEs as far as expertise in the Office of Vaccines as a Center priority, he group must address both blood and vaccine issues.

          As far as how a vaccine is used and how we envision, something to keep in mind is, the FDA regulates what is presented to it.  We also try and be proactive, try and support the public health, but one could ask the same question, if you have a licensed product A, why bother dealing with B, C, D, E, F?  Because we have to.

          I agree with some of your thoughts and concerns about how you would utilize the malaria vaccine, et cetera, but from the point of view of a malaria vaccine that would be useful for troops going overseas, et cetera, the fact is, if it is presented to us, we have to deal with it, and we have to know how to deal with it.

          But I do want to let him off the hook a little bit in terms of prioritizing, because he is forced to do things for the entire Center that may not be directly on target for blood.

          DR. DIMICHELE:  I just wanted to clarify that.  My line of questioning was not critical.  It was more trying to understand just how it fit into the processes.  That is all I was trying to do.

          DR. CARBONE:  I am trying to help him with it.

          DR. WANG:  I have a similar question on the same line.  Many, many good evaluative methodologies developed, but I am not clear about the application aspect.  Are you applying all these methodologies in house in checking on all the products, or are you just publishing it, or actually trying to push for everybody to use it?  Are they truly on the cutting edge among all the methodologies that are available at this point?

          DR. NAKHASI:  That is again a good question, how do we apply.  First of all, obviously we publish these studies.  It just makes us ready for eventualities, when these things come up.  There are ways by which one could then see that the technology modification, for example, the example I gave about the HIV enhancing the sensitivity of the modification.

          So there are issues by which people have thought about they come to us per application, and they discuss this at the pre-IND stage.  We provide them the information, because we have seen the failures and successes.  Therefore from that vantage point of view, we go ahead and then provide advice so that you can avoid those pitfalls, don't go this way, go this way.  That again only comes from our experience on doing the research.

          Jay, you wanted to say something?

          DR. EPSTEIN:  Back on the earlier point about vaccine work versus blood problem targeted work, when I recruited a new director  in the Division of Emerging and Transfusion Transmitted Diseases, Hira was our lead candidate.  But I knew full well that his background in CBER was vaccine research, and that that was critical to CBER.

          So the point is, you had asked earlier, what is top down, what is grass roots.  Part of the agreement when Hira was hired was that work in his group would concurrently look at issues highly focused on blood such as diagnostics.  So what you would find is that in many of the branches working on vaccine, there are always concomitant projects looking at issues that are more directly blood safety related.  That is how we have managed that arrangement with responsibilities for CBER versus responsibilities of the blood program.

          So I think we shouldn't overstate the immediate relevance to the blood program of the vaccine research, although there are some very good historical examples such as the plasma derived hepatitis-B vaccine which was in fact developed in the forerunner of the blood office; it was then the Division of Blood and Blood Products.  There you had a very direct relationship between a vaccine made from blood, which also protected the general population but in particular reduced the hepatitis-B risk from donors, as you have more vaccinated donors, which has finally come to pass.

          But that link is not always there, to be honest.  However, direction of the work insures that there will always be relevant projects.

          DR. SCHREIBER:  I guess I have the same uncomfortableness with the pathway as I have been hearing.  One of the problems that I have is, I think there is a lot of very important research done, but I am not quite sure how useful the research is in terms of FDA.

          For example, we talked about the vaccine, and you talked about using biomarkers.  It would seem to me for the community who are working on vaccines that the follow-through for the pathway should be that if you have an application, FDA will accept these markers as a measure of efficiency.  But what I am hearing is that that gets out into the literature, and it is up to somebody to pick that up and say, here are some markers and we will use this, as opposed to a policy.     The same thing with Indira's work, where there  might be some HIV variance missed.

          What I don't hear is that you take that information and go back to the manufacturers of the test and try to either push them into the direction to make changes, or you do something that affects FDA policy.

          DR. NAKHASI:  I'm sorry if I didn't make that point clear.  We do that.  I think the purpose again, as I pointed out to Dr. Wang, that the efforts which we do many times develop into policies.  For example, for HBV NAT, when we did the HBSAG and the comparison with the HBV NAT, that was the policy -- the results of that research became a policy, that at this point HBV NAT cannot be recommended.  So that was from that.

          Similarly, for the other issues, we develop the guidance documents.  Unfortunately, these guidance documents take a little longer time to come out, but whatever research efforts are done internally, they are put into some form or other into guidance form so that it is available to the people when they are looking at it.

          For example, these biomarkers.  Definitely this is a study that has not been published.  Therefore these issues become much more concrete.  It will be important for us to develop a guidance which we could then use for the purposes of the manufacturers.

          DR. ALLEN:  I think your question in general, George, is of the type that this afternoon we will need to wrestle with, with the advice certainly of FDA senior staff.  But I think those are the issues that we need to deal with.

          DR. ALTER:  I agree with the statement that we can't keep chasing each agent with a separate test.  If we don't go the inactivation route, which would be the most preferable if it became practical, the multiplex idea is a very relevant and practical issue.

          I was interested to see you already have some data on gene arrays.  We have been trying to do that.  I have spoken to Rausch, and I was surprised that Rausch who is pushing it still feels this is much more difficult than they initially conceived.  We are finding it very difficult to develop.

          So I was wondering, is the data that you seem to already have data, where does that stand, and how easy is it to do?  And is it relevant?

          DR. NAKHASI:  I think that is a good point again.  I think there are limitations to every -- when you do it in the laboratory versus when you go into large scale.  What we wanted to show, there is proof of concept, that it is achievable.

          The thing is that multiplexing is already on the way.  You have HIV, HCV multiplexing two agents.  There are more agents trying to be putting together some things in detection.  So the question is what are the issues in there, focus on the issues.  If we put more than two or three primers in there, will they affect the sensitivity and specificity of that assay.  I think that is where we are putting our focus; whether the microarray technology  as such can be translated, that needs to be seen.

          But I think the important thing is to understand the basic science and the issues relevant to that. I think that is where our focus is.

          DR. ALTER:  Can you get sensitivity out of the microarray?

          DR. NAKHASI:  I showed you 50 cells, what we can do at this time.  But obviously we need to get much higher sensitivity, because there are certain issues which we are still working on.

          DR. KLEIN:  At the risk of being accused of throwing you a softball, I think it may be a little unfair to say you showed data on leishmania and vaccine, but aren't you also involved in the testing aspect of that, knowing that you need some expertise there, and there in fact is a test, but it is not yet ready for prime time in terms of screening?

          DR. NAKHASI:  Sure.

          DR. KLEIN:  So it is not either-or, really.

          DR. NAKHASI:  No, no, it is not either-or, it is both.  I think that is the thing.  It is not either-or.  That is why I pointed out that we are doing both areas.  It is not only just the vaccine issue and not only the blood.  All these issues came out because there are separate other vaccine issues, but these are much more relevant to blood product issues, and those came from not only the screening and the diagnostics, but the vaccination.

          DR. KLEIN:  Because this is in fact an issue of importance to blood transfusion today, and one that the Blood Products Advisory Committee has pointed out in the past.

          DR. NAKHASI:  Absolutely, thank you very much.

          DR. CARBONE:  I hear circulating around this common theme of how does it relate, how does it feed back.  I just wanted to do a cycle that we work off of.  One is, we can't tell you often the specific product or issue that this came from.  We can't tell you, it is proprietary.  So what we do is, if we see this popping up in several different applications, we pick up the problem, we work on it. 

          I believe your data already is published on this multiplexing.  We will put this out in the public domain, not taking any proprietary data, but taking the problem and working on it.  It now is out in the public domain in a publication or a guidance, so that new sponsors circulating through can look at this information and say, ah-ha, here is a possible avenue, here is something they showed didn't work.

          So this is a way of communicating across a whole field of products.  That is the whole point about critical path.  What we do is unlike a sponsor's effort to solve a problem that might be between the sponsor and the FDA.  We can take a problem you see routinely and put something in the public domain or in a guidance and help the entire field move ahead.  Unfortunately, the direct link we simply can't say because it is proprietary information.

          DR. ALLEN:  We have got a couple more requests for questions.  Let me just remind you that we need to get our last presentation in and then come back to the more general questions.

          DR. WANG:  There is one point I am still not very clear.  When you draw the guideline, are you just drawing it based on your own research results and new methodology, or are you covering the entire field, all the new development methodology including proprietary information from individual companies, to come out with the best testing methodology to recommend to the public?  How do you do this, or is it just from your own view?

          DR. NAKHASI:  There are several layers into that.  One is what we know out there and where the areas of improvements, the areas of need, we focus on that.  Also, some of it comes from -- because you can't cover the whole waterfront here, and also it comes from the particular research area, where the particular individual person is focused on, and sees how connections can be made to the other needs.  So it is a combination of that.

          DR. ALTER:  Just a quick observation.  It seems to me that the time line for the critical pathway is identical to the time line to adjusting the air conditioning.  It is still freezing.

          DR. ALLEN:  I want you to graph that into a slide for us.

With that pertinent observation, we will move on to our third division overview.  Dr. Basil Golding, who is director of the Division of Hematology, will provide us with an overview of the research program for that division.  Dr. Golding.

        Agenda Item:  Overview of the Research Program

                 of the Division of Hematology

          DR. GOLDING:  Good morning.  I would also like to thank the committee and the audience for this opportunity to present the research that is being performed in the Division of Hematology.  I am particularly proud to do so, because I think the research is of high quality.  I think my charge here today is to show you this research in its best light, so you can make your own decisions about the quality.

          The Division of Hematology has an organization which is shown on the slide.  We have a Laboratory of Biochemistry and Vascular Biology headed by Dr. Aliyash, the Laboratory of Cellular Hematology headed by Dr. Vastow, a Laboratory of Hemostasis which has an acting lab chief, Ten Lee.  The Laboratory of Plasma Derivatives is headed by Dr. Dorothy Scott, and the Clinical Review Branch is headed by Dr. Silverman.  So we are four research review units and a clinical review branch, and we do have weekly seminars, and a lot of databases with the review branch which provides us their insight into the gaps in the research that we need to do.

          Each branch has a certain number of PIs that are distributed as follows.  I will be inclined to present the work of these PIs, these principal investigators.  I should point out that you have asked questions about resources.  Nearly all these PIs are heavily involved -- all of them, I should say, are heavily involved in review work; at least 50 percent of the time is in review.  The support staffs are one or two people, and the review staff is also heavily involved in review work, except for the occasions where people are able to generate outside money and use that money to hire postdocs and other technical assistants that can then be fulltime workers.  We have been able to generate two other PIs, Dr. Rular and Dr. Scott.  We were able to successfully apply for biodefense money from the National Institute of Allergies and Infectious Diseases.  Other PIs over the years including myself have obtained intramural grants from the NIH for AIDS research and from the Office of Women's Health.

          The money for those grants is hard to come by, it is getting harder to come by.  We have dwindling resources.  If we had a graph plotting out budgets over the last five to ten years, you would see a line going down.  There has been a lot of mention of the critical path.  I would like to point out that the critical pathway has not been funded by Congress or by anybody else.  While it is highly endorsed by CBER and I think by the FDA, we haven't seen any money to support that program.  So when we identify gaps and we want to be flexible in dealing with problems, we drop everything else and we do what needs to be done, but I think it is getting increasingly more difficult to do that and I'm not sure how long the situation will continue to be feasible to do that if the resources continue to decrease.

          The scope of regulation in our Division is very broad.  We look at similar components of blood such as platelets, red cells and so on.  We look at plasma derived proteins and analogous recombinant proteins such as Factor VIII.  What I would like to point out that if you think about it from an academic discipline point of view, the scientists in our Division are very diverse.  The reason for that is that the scheme which is used to make products from plasma can be used to make products that are regulated by our division.  We need that expertise in one Division because the manufacturing process and the scientific questions arising from that are all related to this process and the products that can come out as a result of that process.

          The clinical indications are diverse and include bleeding disorders, shock, hypovolemia, infectious diseases often associated with immunological deficits, and replacement therapy in congenital or acquired deficiencies related to coagulation factors, but also other plasma protein deficiencies that you will see in a moment.

          Our research priorities are in terms of resolving problems that are critical path related, and we divide them into these three headings.  As was pointed out before, the mission of the FDA is to assure safety and effectiveness of products, and we now have the additional change of being involved and engaged in counterterrorism review and research. 

          From a safety point of view I am going to give you a few examples which relate to product toxicity.  The one I am going to talk about is hemoglobin based oxygen carriers.  I am going to talk a little bit about contaminants of plasma derived products, particularly microbial contaminants, and also mention some research related to hepatitis-C virus transmission.  In terms of efficacy, if I have time I will talk about the standards that have been developed in our Division and that are critical for the regulation of these products, assays that have been developed to look at potency for many of our products, and animal models.  The example I have is for platelets.  In counterterrorism the two agents that we focus on are anthrax and smallpox, which I think are highest on the list.  We have looked at these in terms of in vitro assays of potency and animal models.

          I would just concur with what has been said already, that by engaging in a lot of these areas, we have developed a scientific expertise that allows us to regulate these products effectively.

          Dr. Epstein mentioned this work, so I can go through these slides quickly and maybe save a little bit of time in my presentation.  The public impact is clear in situations where red cells are not available.  The regulatory and scientific challenges relating to that; what we found with our products is that it is very important to establish what the structure-function relationship is.  Because hemoglobin by itself is toxic, it has to be modified in order to be used as a product, and we found that it is very important to look at these chemical modifications in a lot of detail.  The example that I will give you will show that.  We have also been involved in developing -- in vitro and in vivo assays for looking at efficacy and safety of these products.

          One of the first generation hemoglobins was made by cross linking with hemoglobin using oxidized -- these assays were done in the laboratory of Dr. Aliyash.  When we looked at normal red cells and hemoglobin we get a very nice curve.  With this product, we were finding a non-sigmoidal oxygen equilibrium that was non-saturating and was non-cooperative, and it was not sensitive to pH changes.

          Detailed investigation of the structure of the hemoglobin revealed the exact nature of the abnormality of this hemoglobin.  The molecule consists of a heme and a protein part.  The heme part was studied by EPR and the normal heme is shown here.  It facilitates the movement of iron in a vertical plane up and down as oxygen is down in an unrestricted manner.

          When we looked at this molecule, we found that this molecule was asymmetric, that the iron instead of moving up and down moved towards one of the nitrogen atoms and we think as a result of that destabilizes this molecule.

          The protein part of the molecule normally binds oxygen and moves back and forth into an oxidized and non-oxidized state.  When it is oxidized it is termed a relaxed state and gives up oxygen quite easily.  In contrast, when we looked at the abnormal protein, when oxidized it moved into a locked state and was not able to be easily reversed into the tense state, and this also explains why this hemoglobin did not function normally.

          Looking at it from -- this is a crystal structure of a hemoglobin molecule.  What the company thought they would be able to do is cross with these lysines and stabilize the molecule.  What we found by various mass spec -- that it modified some systems, and that this resulted in the abnormal function of the molecule.  This particular system, C-93, is in very close proximity to the iron in the heme group, and probably explains why we noticed that abnormality in the heme.

          What these studies have done is, we have looked at a particular hemoglobin, but we now have a framework of looking at these modified hemoglobins, and we know how to approach this.  This was published, and anybody in the field can now benefit from this knowledge in characterizing and developing their hemoglobin products.  It also gives us a handle on looking at these products before we get started into clinical trials, and hopefully trying to improve the field so that the second generation products are more likely to succeed.

          This was work done by Dr. Gula, who is also in Dr. Aliyash's group.  What we noticed is that a lot of the first generation hemoglobins were associated with particularly vascular toxicity.  So what Dr. Gula set up was an endothelial culture system.  This is a -- endothelial cells shown as contrast.  He looked to see what happens when he took one of the first generation hemoglobins and incubated it with oxidation compounds, which will happen in ischemia and trauma.  What we found is some of the cells were floating on the surface, and when we did a -- for apoptosis, we found that these cells were undergoing programmed cell death.  So clearly this is an assay that could be used to assess hemoglobins in the future.  We are trying to correlate the assay with in vivo toxicity.

          The next project that I will go through very quickly, one of the products that we regulate is alpha-1 proteanase inhibitor.  Most patients with hereditary deficiency develop -- in the third and fourth decade of life, and about 15 percent develop severe liver disease.  Such deficient patients can obviously benefit from augmentation therapy.

          The challenge to us is, we notice that these products do have problems with polymerization and aggregation, and we think this could be related to -- this is work done in Dr. Schaeke's lab.  The crystal structure of alpha-1 PI is known by other work.  The first theory was proposed based on indirect evidence is that due to manufacturing, alpha-1 PI does become partially unfolded due to various treatment.  For example, heat treatment for viral inactivation can unfold this molecule partially.  The theory was that this flexible loop, as the molecule become unfolded could then insert itself into the beta sheath of the next alpha-1 PI, so we would get a head to toe polymer formation.  That was work described in the literature as how polymerization occurs.

          In Dr. Schaeke's lab, what they did is a series of experiments, and I am only showing one of them, and this is published, where they took one that was partially unfolded and incubated it in buffer for various periods of time, and then passed it through a -- HPLC and got the following tracings.  For a short incubation, what you see is a monomer peak, a dimer peak and some polymer formation.  When you left alpha-1 PI in buffer for a longer period of time, the monomer peak remained the same.  There was no difference in concentration of the monomer peak, but the dimer peak started to shrink, and you started to get very high level of polymer formation.  So based on this and other data, they came forth with the following proposal, that you first got dimer formation, and the dimers then combined to form high molecular weight polymers, and this is the more direct explanation of why polymers occurred.

          What are the implications?  We have here a new understanding of polymer-1 formation.  This knowledge can be used to minimize unfolding of monomers and dimer formation during manufacturing, for example, by adding appropriate stabilizers during heat treatment.  In the future, this work will investigate the conformational change in the dimers that result in spontaneous polymerization.

          Immunoglobulin intravenous.  This is work done from my own lab.  We have been aware for a long time of the issues with patients with this product.  A very high percentage have developed a reaction, some of them severe, but definitely causing the patients to complain about fever, headaches, chills, indicating or suggesting at least a prior inflammatory reaction.  This product when it is made undergoes sterile filtration, so the product does not have any bacteria, but we know from the manufacturing that upstream there is some bio burden, and it is very likely that microbial components are -- in the product, and we do find LPS and bacterial DNA in the product, and there are strict limits as to how much of this is allowed.

          So our concern is still about -- we would like to find out how to detect other bacterial components and maybe devise mechanisms to reduce this contamination to improve the product safety profile.

          What are the regulatory challenges?  The need for rapid high-throughput assays to detect microbial components in these products.  By the way, this is a cross-cutting issue, because many of the products made in CBER could end up with microbial components, so I am only talking about our Division, but I think this could have CBER wide implications.  So what we are trying to do is to adopt cell lines to express receptors as a detector system for microbial components.

          Our immune systems have evolved so we know the immune systems have a whole array of TEL receptors on their surface that can recognize most pathogens that are out there.  What we are trying to do is to take these TEL receptors and use them as a detection system for microbial contaminants.

          So for example, it is known that LPS will bind to TEL-4, lipopeptides bind to TEL-2.  This is on the cell surface.  Within the cell there are other TEL receptors that are sensitive to bacteria components such as doubled-stranded and single-stranded RNA, and are also sensitive to bacterial DNA.  All these TEL receptors signal NF kappa-B to the nucleus, and what I am going to show you in the next slide is that we are going to use this by introducing the reporter gene into the detection cell line that has NF kappa-B regulation, and -- acting as a reporter.

          So we double transvect these cells.  These are 293 cells, transvected either with one of the TEL receptors, but co-transvected with the NF kappa-B reporter gene, so when these cells are activated, a -- signal can be detected. 

          If we now look at different microbial components, -- is a component of the cell wall of gram positive bacteria, we get a really strong signal when we have TLR-2 on the surface.  When LPS is used as a ligand, we get a strong signal of TLR-4 containing cell line, and when CPG oligonucleotide is used, which is highly represented in bacterial DNA, we get a strong signal in these cells.

          The outcomes we have shown with cell lines expressing TLR, and we are going to try and develop cell lines with multiple TLR and the reporter gene can detect microbial components.  These cell lines will be used to develop a record high-throughput system for testing immunoglobulin products and other CBER products for microbial contaminants.

          This is the Laboratory of Cellular Hematology.  They regulate similar components such as platelets.  The public health impact, ten million platelet units are transfused annually in the United States.  Transfusion of sub-optimal products leads to decreased circulation and the need for more transfusions, increased risk of infection and allo-immunization.

          The regulatory and scientific challenge I am going to be talking about is to develop a test for efficacy.  In vitro tests are informative but not predictive, and the in vivo test is an in vivo survival of radiolabeled platelets in humans, which is burdensome. 

          The other project that I am just going to allude to but not show any data is that we think there is a real problem that platelets and other cell components give rise to micro particles which can be associated with adverse events to these products.

          So in terms of platelets, this is using immune deficiency SKD mice that don't have much of an immune response.  If we now take normal platelets and we infuse them into normal mice, they are very quickly cleared.  In contrast, if we infuse them into SKD mice, they are cleared over a period of time which we think can be used to measure survival time of human platelets.

          This is a proof of concept experiment.  We took one day and seven day old human platelets to see if these mice could detect the difference.  This is percentage of platelets.  What you find is, the one day platelets have a very nice survival time, but then when you start to look at the seven day platelets it is much reduced in the SKD mice.  So this in vivo assay could be used to measure human platelet survival and used for product development.

          What I haven't shown you for lack of time is, we have also developed a cytometric assay to measure micro particle and platelet products.  This will enable us to determine whether micro particles in products are associated with adverse events such as thrombosis and inflammation.  He has published some of this work.

          In terms of viral detection and antiviral antibodies in immune globulins, this is one of the areas of close connection between our group and the other division, Dr. Nakhasi's division, in terms of emerging viral diseases.  The public health impact, an estimated two million Americans suffer from hepatitis-C infection.  About 70 percent of them go on to develop chronic hepatitis, and liver fibrosis, cirrhosis and hepatocellular carcinoma.

          The regulatory challenges relate to screening plasma for hepatitis-C, measuring hepatitis-C viral neutralizing antibodies in preparations that would have hepatitis-c immuno globulin.  There is no -- currently in in vitro system there is no animal model available for looking at HCV infectivity.  There are a few labs that can now grow HCV in vitro, but this is very difficult.  I am told recently chimpanzee was the only model.

          This is a system developed working with Dr. Fizelle at the NIH.  They developed a system, and Dr. Yu has been working with them to neutralize the system to answer some of our research regulatory questions.

          Very briefly, what they were able to do is make these pseudo particles by using HCV envelop protein, structured proteins from HIV and green fluorescent protein into these cells, and the cells will then release these pseudo particles.  When you take the pseudo particles and add them to liver cells, the HA-7 cell line, if these cells can successfully enter the HA-7 cell, in other words, they have a functional HCV envelope, then you get this green fluorescence which can be easily detected by flow cytometry.  If on the other hand you incubate these pseudo particles with a neutralizing antibody, you should prevent the entry and infection of those cells.

          So these are experiments done by Dr. Yu in collaboration with Dr. Fizelle.  What they show is that there is a correlation with what she had previously shown in the chimpanzee and the pseudo particle assay.  She took a control immune globulin that did not have any anti-HCV, that had been treated with solvent detergent so it should not have any RNA from the product, but then challenged the chimps with HCV.  This product could not protect the chimps.  It had a low titer antibody and could not protect.  When she took a high titer antibody which was also inactivated and again challenged the chimps with viable HCV, this high titer antibody could protect the chimps.      So the pseudo particle assays are being correlated.

          If you take immune globulin preparation that has not been used at this point in time but was made many years ago, and this preparation was not virally inactivated, does have RNA, but because it would have a high titer antibody, it was not infectious.  So even though there was virus here, this antibody was protected.

          There was an interesting story that emerged in the '90s that I am not going to have time to tell you about, but just to say one fact.  Before viral inactivation was instituted, it was thought that the immune globulin safety could be enhanced by having an ELISA assay to screen out any positive units by ELISA.  So in other words, if there were antibody positives, you would assume there may be an infectious risk until those products were removed.  But unfortunately what happened, some of the products got by that had no antibody, but they did have virus.  So as a result there were a large number of transmissions from one particular product.

          So what Dr. Yu did in this study is to correlate that data in terms of hepatitis transmission and the pseudo particle assay.  She works now with lots that were made quite a long time but they were not screened, in other words, they had antibody against hepatitis-C virus.  There was no evidence of hepatitis transmission.  In contrast, when the screening took place, what that effectively did is make sure that there was no antibody in the product, and then we started to see cases of transmission.  So again, a correlation of this pseudo particle assay showing that when antibody is present in humans, you don't get transmission, when antibody is absent, you do get transmission.

          In effect, the HCV neutralization in the pseudo particle assay correlates with infection or lack of infection in chimps, and the pseudo particle assay can be used in a neutralization assay, which will facilitate development of new hepatitis-C and immune globulin products.  Future plans include identification and characterization of neutralizing epitopes.

          A major public health issue is patients who receive Factor VIII and Factor IX developed inhibitory antibodies.  These neutralizing antibodies to coagulation factors complicate the use of Factor VIII and Factor IX, and in hemophiliacs, about 20 percent of the patients have this problem. 

          What are some of the research regulatory challenges?  Understanding the genetic factors that control whether patients make antibodies to Factor VIII and Factor IX, and developing preclinical models to predict product safety and efficacy.  Those two issues are intertwined.

          What Dr. Laser has done is, using genetically well characterized inbred mice, he has shown that there is a high correlation to certain genes and development of inhibitory antibodies.  These genes are the MHC genes mainly, but to a lesser extent T-cell receptor genes, the zinc alpha-2 glucoprotein-1 gene, and that these influenced the antibody response, and that MHC genes and to a lesser extent cytokine genes such as IL-10 and interferon gamma control the antibody response to Factor IX.  This was to Factor VIII. 

          He has also shown, using the hemophiliac dog model, that the Chapel Hill hemophiliac dogs have a genetic defect identical to that in about 40 percent of humans.  So if you look at a normal dog, this is a tissue analysis, and you see the color distribution is different, indicating a DNA rearrangement.  In fact, this is an inversion which very closely mimics the human defect.  In addition, the bleeding phenotype is identical to human hemophilia A, and the dogs making antibodies were treated with dog Factor VIII.

          The outcomes of mouse genetic studies provide clues for problems of genetic predisposition to induction of inhibitory antibodies in humans.  The Chapel Hill hemophiliac dogs are an ideal model for preclinical evaluation of products with potential to induce inhibitory antibody. 

          In the field of counterterrorism, one focus is anthrax.  This is obviously a major threat to public health and security, and the same goes for smallpox, which poses a potential bioterrorism threat.  Widespread vaccination is expected to cause fatalities in susceptible individuals who have progressive -- this occurs in immune compromised people or eczema vaccinatum, which occurs in people who have eczema or atypic dermatitis.

          What are the regulatory and scientific challenges to developing in vitro and in vivo models to assist the efficacy of the products that we think will be coming down the line?  These are anthrax immune globulins, and you have already seen vaccinia immune globulins.

          So in terms of anthrax, in the 2001 outbreak, five out of 11 patients died in spite of intensive antibiotic treatment.  So combined antibodies from anti-anthrax antibodies may improve survival.  The antibody targets the bacillus, antibodies target the toxin.

          Very quickly we will go through this model because we like the research.  Anthrax has three plasmids which call for a particular antigen which forms a hiptomeric pull, which allows the edema factor or lethal factor toxin to enter the molecule and to cause cell lysis and also to induce edema. 

          For proof of concept of an animal immune globulin, we did some pilot studies in sheep.  The sheep were immunized with various anthrax antigens with protective antigen, a lethal factor for the stem strain, which is a strain which is used for agricultural vaccine purposes.  The sheep were immunized, the antibodies were purified, and the purified antibodies were tested for ability to protect these mice from a lethal challenge of anthrax.

          This is some of our results which have been published.  If you look at the survival of the mice, if you treat them with a control antibody the mice die; if you treat them with just the antibody by itself, some of the mice survive after 11 days.  If you treat with an antibiotic by itself, some of the mice survive, but if you use the combination you get almost 100 percent survival.  So this is just the proof of concept that using this approach could potentially improve survival in patients.

          In terms of other in vitro assays, Dr. Dabul developed, using the endothelial assay that I described for the hemoglobin, showed that if you make a monolayer of endothelial cells and you pass a current through it, it is highly resistant because it is a confluent layer, but as the layer starts to break down, you get decreased resistance.  So if you treat with lethal toxin, the resistance decreases, but if you incubate together with anthrax immune globulin, you decrease the effect of the lethal toxin to a large extent.

          The other target of lethal toxin is the MEP kinase -- and MEP-1 belongs to this signal transaction pathway.  If you treat cells with lethal toxin, it cleaves the product, and you cannot protect this product.  On the other hand, if you add anthrax immune globulin, you block the effects of lethal toxin.

          Just to mention in terms of collaborations, this work was done in collaboration with the CDC, and they provided us with the anthrax immune globulin.

          The outcomes.  Proof of concept that polyclonal antibodies made in animals can protect against anthrax toxins, and in the process we have established in house, in vitro and in vivo assays for testing the efficacy of anthrax immune globulin products.

          Vaccinia immune globulins.  This is work done in Dr. Scott's lab.  The complications of smallpox vaccination as I have already mentioned, you can get progressive vaccinia in immune compromised people.  Historically the vaccinia immune globulin that was licensed many years ago reduced fatality from 100 percent to 50 percent, and in cases of eczema vaccinatum, the VIG reduced fatality from 30 percent to three percent. 

          What are the scientific and regulatory challenges?  How can efficacy and potency for VIG products be assessed, and there is clearly a need for animal models for severe vaccinia and for that case were eczema vaccinated.  What Dr. Scott's lab has been able to do is develop a mouse model for vaccinia.  These are SKD mice that are immunodeficient.  If you scarify one in the same way that you would scarify a human after shaving off the hair, you would find that you get these lesions developing over this time period.  These are non-healing.  Eventually the virus spreads systematically and these mice die.

          This is some data from her lab showing mouse survival over days.  If you challenge the mice with two different doses of virus, they die.  Dr. Itsing showed pre-exposure prophylaxis, this is post exposure prophylaxis.  If you inject the VIG on different days post exposure, you can improve the survival and the extent of survival depends on the viral challenge.

          The SKD model can be used to demonstrate that VIG can reduce -- both in pre and post exposure treatment.  This SKD model was adopted by industry in support of licensure of one of the products.

          I am going to try and save a little bit of time by not going through this in detail.  Just to mention that our Division has worked over the years with international and national agencies to develop a whole host of standards which facilitate testing and licensure of products and assuring the consistency of products that are already licensed.

          There are examples here of Factor VIII, thrombin and immune globulin standards, MET standards, and you can see again a connection between our division and Dr. Nakhasi's division.  So in terms of future directions, I am not going to mention future directions for products that I have already discussed.  I mentioned them earlier.

          So in terms of safety, studying the association of immune globulin products on pro inflammatory cytokine responses, and we have some preliminary data suggesting that IL-15 is involved, developing MET and infectivity assays to determine and quantify hepatitis-C and D-19 viruses, and to look at variance in particular in plasma derived products, and to look at hemoglobin products, hopefully second generation products having preclinical models to evaluate oxidative stress and vaso activity.

          In terms of efficacy, developing an alpha-1 PI standard which hopefully will be also adopted by the World Health Organization, identifying and characterizing HCV neutralizing epitopes, and enriching antibodies which have neutralizing ability; assessing neutralizing antibodies to HAVB-19 and HBV and other viral pathogens by in vitro culture systems.  We have identified this as a gap, and we are now trying to set up a program to look at this, and one of the first projects will be to develop another assay for evaluation of activity of this factor.

          In terms of counterterrorism, anthrax from -- these will be human antibodies from trans-chromosomal cows will be tested for protective antibodies by in vitro neutralization of toxin using macrophaged based and endothelial assays, and also in mouse models which I described earlier, and in terms of vaccinia, already we have preliminary data that this is going to work, to develop a mouse model for eczema vaccinatum.

          Thank you very much for your attention.  This has not been exhaustive, but I hope it has also not been exhausting.

          DR. ALLEN:  Thank you, Dr. Golding.  It is 12:30.  Let's take a few questions for Dr. Golding as we did for Dr. Nakhasi.  We will also open it up more generally for questions to Dr. Williams, since we didn't do that directly at that point in time.  We are having an open public hearing.  I am aware of only one speaker.  We do need to break for lunch by about one o'clock or at the latest, a few minutes after one.  So questions?

          DR. KLEIN:  Are there data to suggest to suggest that the headaches and other adverse effects of VIG are in fact due to tiny levels of bacterial contaminants that would be picked up with the -- receptor assay?

          DR. GOLDING:  Well, there are a lot of anecdotal reports about immune globulin preparations containing some cytokines such as tumor necrosis factor.  There are also some reports that some patients who get the product develop these.

          I would say based ont the literature, I would be hard pressed to make a firm statement.  I think the issue is that many of the products that we regulate in CBER such as for example vaccines that cannot be sterile filtered or cell gene products that cannot always be sterile filtered, that there is a high likelihood that many of those do contain.  We do know that the IGIVs that are licensed, we find that it is below the level.  We do find DNA from bacterial DNA by PCR techniques.

          Now, where this directly affects the product in terms of the adverse effects, I think it is possible.  But I don't have direct proof, and I don't think the literature has direct proof on that matter.

          DR. ALTER:  Not a question, but I just feel I have to comment.  I think this beautiful presentation is a great example of why the FDA should be doing research.  You had eight or nine areas; every one of them was addressing a specific issue that was relevant, and the basic research in some of these things is remarkable.  The hemoglobin work, the endothelial cell cultures, I think this is a model.  If you have to present to some funding agency of why the FDA is doing it and what they are doing, this is a good example.

          DR. GOLDING:  Thank you, Dr. Alter.  Just to point out that we aren't related.

          DR. WANG:  I want to second what Harvey said.  It is a tremendous amount of accomplishment by 11 researchers.  It is really very impressive.

          I am wondering how many publications on average per year you have generated.  Number two, what is the most forefront research among all these subject matters that you consider really on the cutting edge at this point?

          DR. GOLDING:  We looked at the number of publications, and we don't want to shame the other divisions by showing the number.  No, that is not true.  But each principal investigator has two or more publications per year.  Some years they have more, some years they have fewer.  But I would point out that the staff is pretty -- some of the investigators have maybe one or two support staff, and in some of the cases the support staff are also heavily involved also with review work. 

          The quality of the papers is also important.  You were asking about cutting edge.  My answer to that would be, look at the journals we are publishing in -- Blood, PNAS and other high impact journals.  So I am not going to choose which ones are at the forefront.  I think they are all at the forefront.  I think that all of these PIs should be supported, fully supported.

          DR. BUSCH:  I also agree, it is excellent work, and a good example of how you can be prescient and get into a field early and then deliver over the years.  The hemoglobin oxygen carrier work defined the mechanism of the hypertension phenomenon, et cetera.  What you are doing now in terms of getting into these micro particles, I think that is going to prove to be a very important area, and very appropriate.

          My question though is with respect to pathogen inactivation of cellular components.  That same kind of work, unfortunately what seems to be evolving is the current first-generation pathogen reduction methods seem to be facing challenges.  I am curious as to whether in your division or within CBER there is a program, a basic science or developmental program that would help solve those problems that were are seeing in pathogen inactivation, and where in CBER those products are both reviewed and research is being initiated to help that field evolve.

          DR. GOLDING:  I absolutely agree with you that pathogen inactivation is important, from the CBER point of view and from our point of view.  We have seen quite a few applications in this regard, for cellular therapies and much earlier on for the others.

          What we are really focused on is for the proteins and for the cells, how has the pathogen inactivation process altered the product.  So our focus has been in looking at the safety and efficacy of the product once a cell or a protein has been treated.  The assay that I described in terms of cell assays, for example, and looking at platelets, for example, I think if you get pathogen inactivation and you want to know if your platelets would still function normally, I think having in vivo and in vitro assays will help develop that field.  That is where I think our contribution lies.

          DR. TOMASULO:  It seems to me that some of the research you are doing now could lead to requirements that you would impose on manufacturers that submit products to you, and even that some of the work could stop at your laboratory and done in theirs.  Could you talk about that a little bit?

          DR. GOLDING:  I think that is a very interesting question, and not so easy to answer.  I think it is better to deal with a concrete example.  Let's take hemoglobins because we discussed that quite a lot.  The first generation hemoglobins were produced.  The manufacturers from their perspective, they want a product that they can make and get into clinical trials and market as quickly as possible.

          What we found is that the chemistry is very complicated.  I am not faulting the manufacturers for not doing this.  I think it is very sophisticated techniques that are required to unravel what was really going on.  But once you started to see the effects in humans, in the trials that were ongoing, it was necessary for the FDA to say first of all, some of those trials have to stop and that product cannot go forward.

          But what are the lessons learned from that?  Then go back to the molecule and find out what is going on.  I think what you are asking is, if a new product is developing -- just say we did this very early on for this particular product, hypothetical, and we can't know these things early on, but we have been doing something that is a concern to you or a concern to the manufacturers.

          I will argue, if we had the foresight to know that these products were going to have the problems that they had, that it would have been in the public health interest at least that we did have all of these problems, that they didn't go into clinical trials, and that we were further along in our second generation.

          I think a lot of times, we investigated these products which weren't that well characterized, and as a result we don't have a product on the market yet.

          DR. TOMASULO:  I guess I was more thinking of the observations you were making about the immunoglobulin preparations, for example, the neutralizing antibodies.  This is something that the manufacturers can monitor, can follow, and it is almost like it has been translated into another area and should be handed off to them.  I don't know if that is true.

          DR. GOLDING:  I think that is also an important question.  I think in this particular area, a lot of it is due to the specifics.  If you want to develop a product, clearly you need to have a potency assay.  The hepatitis-C virus as you know has been very difficult to -- it has been very difficult for people to get the potency assay in place.  We have seen this as a stumbling block for the development of that particular product.

          I think ten years ago, many people could have come up with the idea that we need that product.  We don't have the product.  I think what Dr. Yu's group has done is -- they have been very alert to the situation that we need this immunoassay, and as soon as the techniques become available, we need to work with whichever collaborators we can find to develop it.  Having knowledge of the technology, as Dr. Nakhasi said several times, once we are engaged in the research, we understand what is involved in the assay, what are the pitfalls.  So I think for us to develop those assays would be very helpful.

          One other very quick example.  When we started to see transmission of HCV, that was a major public health issue, and what Dr. Yu's lab was able to do is very quickly, working with others like Dr. Hewlett, set up PCR assays to measure HCV.  Companies didn't have that assay in place.  The companies sent teams of people to make the assay in her lab, and then went back to the companies, and that allowed us to release the product so that it was available.

          So if we weren't aware of the problems and we weren't doing these things, I think we could go on for a long time, but there are many examples where I think there would be a public health deficiency because we were unable to do the work.

          DR. TOMASULO:  I'm not suggesting that it wasn't very, very important for you to do this, or to continue doing it.  I am just questioning how you transfer the obligation to take advantage of what you have learned on to the manufactures, and then you plan your future directions to develop another ground-breaking observation.

          DR. GOLDING:  I think in practice what has happened is that we communicated to the manufacturer as soon as we knew how to do things that, you could do this, and guided them and transferred the technology very willingly to the manufacturers, in the case of the HCV PCR, in the case of the SKD model for approval of an immune globulin.  So I think we do it, but I don't think we have an SOP that tells us, this is how you are supposed to do it.

          DR. ALTER:  The people in the, quote, know in the hepatitis field, myself one of them, say this is a no-brainer.  You take anti-HCV positive people out of the blood supply, why are you allowing them to donate into an immune globulin product?  The FDA said, wait, this product seems to be safe.  Maybe if we manipulate it, something is going to happen, and sure enough, something happened.  Finally we talked them into it, and finally something happened.  Then they went ahead and figured out why it happened.  It is a beautiful story of them being there at the beginning and figuring it out at the end.  Another reason why you have to have knowledgeable people inside the agency.

          DR. ALLEN:  I think the question you raise, certainly if you look at the perspective of the people who claim government is too large, we need to have as much as possible back out at the industry and so on, they would use the kind of question that you raised as to why it shouldn't be done here, shouldn't be done at the FDA or a government agency, the responsibility should be out there.  I think Dr. Golding has answered very well, and we will later this afternoon, I hope, get further into -- with others on the staff get into discussion about these, because I think answering that question is part of what the agency needs in terms of developing its response and moving forward.

          DR. TOMASULO:  I don't consider myself in the camp that you just described.  I have a feeling my question was a little misinterpreted.  I'm sorry that I wasn't clear.  I was really talking more about planning future directions for this incredibly productive set of investigators than criticizing what was done in the past. 

          DR. ALLEN:  I certainly didn't interpret it as criticism, nor do I think Dr. Golding did.  It is a very good question, because when you have got very limited resources, you want to develop things to a certain stage, and then if appropriate let others pick it up from there, and you take your limited resources and move on into other directions.

          It is a very important theoretical discussion that we need to enjoin here as part of the final conclusions of our report, I think.

          DR. DIMICHELE:  In listening to both presentations, which were both outstanding, one of the things that struck me emerged from one of the recent workshops that was held on rare plasma protein disorders.  Certainly at that workshop we were focusing on FDA from a regulatory standpoint, and the issue of clinical trial ad clinical trial design, et cetera.

          But I think we missed a very important point.  In looking at for instance back to the vaccines for malaria and leishmania, looking at the work that is being done in alpha-1 PI, which was certainly up there in terms of rare disorders, it struck me that potentially part of the FDA agenda and part of its priorities could be, if it is not already, and maybe you are using it as a priority, the issue of doing some of the basic research in some of these rare disorders.  Asking industry to make these products, oftentimes they are balking at some of the work that needs to go in, some of the preliminary work, because of the cost.

          But certainly this is work that is being done, and being done well, by the FDA.  Can the issue of rare disorders, where we are unlikely to get the work done by industry or by more profit driven operatives, maybe bringing that into the FDA and using that as a priority, is that something that could be considered?

          DR. GOLDING:  I think it should be considered.  I think that part of what you have seen over and over again is public health impact and how many cases of this disease are in the public.  So I think again, it is a question of how much resources you have in terms of personnel and what the issues are.

          I personally believe that what you are suggesting is something we should think about seriously.  I think within the agency, it is something we should discuss in terms of funding.

          I think one of the important things from your question and from our own thinking is to identify areas where the FDA or somebody like FDA is going to do the research.  It is not going to be done because there is not commercial interest.  Partly what happened with counterterrorism to some extent that is true, because government funding is driving what we do regarding counterterrorism.  But I think an important ingredient of all of this is the resources.  I think if the funding was there, I think we would find that the FDA would be interested in doing this.

          DR. NAKHASI:  I think the industry does not see it from their perspective.  Down the way, these are important public health issues.  We need to focus on that. I think it is a very valid point, and I appreciate that very much.  There is not much interest in those areas, because industry looks at it, bottom line is the profit and how much they can sell.  But from the other perspective, we need to focus on that.  I think as Dr. Golding said, we should be focusing on the broad issues and the sub-issues which aren't at the top of the priority list, but down the road may become priorities.

               Agenda Item:  Open Public Hearing

          DR. ALLEN:  Other important questions at this point, or should we -- if not, let's move on to the open public hearing.  I am aware of only one speaker who wants to speak, Dr. Selso Bianko from America's Blood Centers.  If there are any other people who wish to speak, would you please give a note to Dr. Freas with your name and so on, and we will allocate a brief time.

          I need to read an open public hearing meeting for general matters meetings.  This is one of my important responsibilities as the Chair. 

          Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making.  To insure such transparency at the open public hearing session of the advisory committee meeting, FDA believes it is important to understand the context of the individual's presentation.  For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or open statement to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting.

          For example, the financial information may include the company's or group's payment of your travel lodging or other expenses in connection with your attendance at the meeting.  Likewise, FDA encourages you at the beginning of your statement to advise the committee, if you do not have any such financial relationships, if you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

          Dr. Bianko.

          DR. BIANKO:  I am Selso Bianko.  I am with America's Blood Centers.  I am a fulltime employee of America's Blood Centers.  I want to disclose another conflict of interest.  My wife works at CBER in research.  However, this is not going to influence what I say.

          In the public record, it is the position of America's Blood Centers, and it is a written position that was submitted recently to the docket regarding the critical path and comments that were submitted by America's Blood Centers.

          I want to be brief.  I want us to show our support for science at CBER.  We fought very hard a few years ago, and it was the intent showed by some in Congress to remove the regulation of diagnostics from CBER and move them to a less strict system.  We went to Congress and we succeeded in moving the process. 

          We are very concerned about resources for research at the FDA.  We try very hard to raise our voices to see if we can increase that.  We confront similar things.  Dr. DiMichele raised very well the issue of diseases and things that are done for which there is no substantial commercial interest.  We are all not-for-profit organizations.  There is no venture capitalist knocking at our doors to do the research that is needed in many basic aspects of research.

          In terms of recommendations and things that I would ask FDA to do, I think the first issue is communications.  What we are seeing today is something that the public doesn't see normally.  I haven't seen anywhere such an aggregated compiled representation of the research that goes on at CBER.  I would like to see these more publicized.  I think that will help the future and the funding and all those things.

          I would like to have more dialogue.  The committee is asking wonderful questions about priorities, for instance, how they are set, how they are done.  I would like you to ask the regulators for the priorities for the things that they are missing.  We are hit with issues like were mentioned here, of hemolysis with filters or white particulate matters and all that, and there are very few people in our field that have laboratories or that are set up to deal with what seems to be a very low class science, almost, to look at white particulate matter, that has disrupted the entire blood system in the country for a period, and for which nobody was prepared to address with research.

          Finally, we want to encourage the FDA whenever they can to suit the science as a basis for regulations.  Sometimes we see a predominance of issues like the precautionary principle and all that, that ignores science, running a lot of what we do.  It is beautiful to see when science helps regulation, and we really support that approach.

          Thank you.

          DR. ALLEN:  Thank you, Dr. Bianko.  We have one other speaker, Kate Gregory, American Association of Blood Banks.

          DR. GREGORY:  Thank you.  I think I would like to echo what Selso just said.  AABB certainly supports the idea of FDA being involved in research.  You saw some of the long list of things that we have been collaborating with FDA on, and we very much appreciate being able to do that.  We hope we are helpful to them, and they certainly are helpful to us. 

          I think this sort of meeting is very important.  I sort of knew a lot of what was going on, but seeing it all pulled together like this makes more of an impact, and certainly is something that should be communicated not only to the general public, but to the industry and people that you work with.  I think they are not always as aware of it as they should be.

          Finally, I would also like to echo Selso's comments on communications.  Sometimes I think you may work somewhat in a vacuum, in that you are working on things and you don't necessarily communicate it, or communicate it as quickly as we would like you to.

          For example, one of the things you talked about this morning is how long it takes to get guidance out.  We realize you have a lot of constraints and you have to do things in a certain way, but it is somewhat frustrating when you are working on a guidance, and it seems to take years before we can get to that resolution.

          I would also like to echo, we do like your decisions based on science, and that research is very important to helping you make those decisions.

          DR. ALLEN:  Thank you very much.

          DR. TOMASULO:  I would just like to ask Ms. Gregory, do you have any relatives who work in the --

          MS. GREGORY:  No.

          DR. ALLEN:  Other questions or comments at this period?  If not, we will break for lunch.  I would like to ask everybody to be back here ready to go in 45 minutes.  We will lay out a slightly revised timetable for the afternoon at that point.

          DR. FREAS:  This does conclude the open public portion of this subcommittee meeting.  When we meet in the afternoon, it will be in closed session, so please do not leave any packages or anything on your seats.  We do have to clear the room.  Anything left in the room will be placed outside by the table.

          Thank you.

(The meeting recessed for lunch, to reconvene at 1:50 p.m.)