P R O C E E D I N G S (8:04 a.m.)

Agenda Item: Welcome.

MR. JEHN: We would like to welcome you all to this 87th Blood Products Advisory Committee meeting. I am Donald Jehn, the executive secretary for the meeting.

Today's meeting is open to the public until approximately 3:30 p.m. At this time, I would like to have the committee members go around the table and just introduce themselves briefly, giving their name.

[Introductions made around table.]

MR. JEHN: Thank you. Before we begin, the committee members not in attendance today will be Dr. Quinn, Dr. Szymanski and Dr. Manno. Again, I would like to thank you all for attending this meeting.

Dr. DiBisceglie actually is a new member for his first time here at the meeting.

At this time, I would like to have Dr. Allen and Dr. Epstein come up to the podium here.

DR. EPSTEIN: Jim, it is my bittersweet pleasure to award you a plaque in honor of the service that you have rendered to this committee both as a member and then as a chairperson, from February 2002 to September 2006. It seems like only yesterday.

I just want to express the thanks for the Food and Drug Administration to you for this generous service on your part.

You have set a high standard as a chairperson and we are very grateful for all the effort that you have put into this enterprise on behalf of the health and safety of the American people.

To a certain extent, it is premature to give you a plaque first thing in the day, because we still have a meeting ahead and we are not through with you yet, Jim. Again, our very sincere thanks.

[Applause.]

MR. JEHN: thank you, Dr. Epstein. Before we start with the meeting, I have a conflict of interest disclosure statement to read.

The Food and Drug Administration, FDA, is convening today's meeting of the Blood Products Advisory Committee under the authority of the Federal Advisory Committee Act, FACA, of 1972.

With the exception of the industry representative, all members and consultants of the committee are special government employees, SGEs, or regular federal employees from other agencies, and are subject to the federal conflict of interest laws and regulations.

The following information on the status of this advisory committee's compliance with federal ethics and conflicts of interest laws, including but not limited to 18 US Code, section 208 and 21 US Code 355(n)(4), is being provided to participants in today's meeting and to the public.

FDA has determined that members of the advisory committee and consultants to the committee are in compliance with the federal ethics and conflict of interest laws, including but not limited to 18 US Code Section 208 and 21 US Code Section 355(n)(4).

Under 18 US Code 208, applicable to all government agencies, and 21 US Code 355(n)(4), applicable to certain FDA committees, congress has authorized FDA to grant waivers to special government employees who have financial conflicts when it is determined that the agency's need for a particular individual's services outweighs his or her potential financial conflict of interest, section 208, and where participation is necessary to afford essential expertise, section 355.

Members and consultants of the committee who are special government employees at today's meeting, including special government employees appointed as temporary voting members, have been screened for potential financial conflicts of interest of their own, as well as those imputed to them, including those of their employer, spouse or minor child, related to the discussions on July 13 of topic I, a product approval discussion and recommendation of the safety and efficacy of hepatitis B IGIV for the prevention of recurrent HPV disease, after orthotopic liver transplantation, sponsored by Nabi Biopharmaceuticals, and topic 2, a general matters discussion, an overview of the research programs of the laboratory of bacterial, parasitic and unconventional agents, division of emerging transfusion transmitted diseases, office of blood research and review.

These interests may include investments, consulting, expert witness testimony, contracts, grants, CRADAs, teaching, speaking, writing, patents and royalties, and primary employment.

Today's agenda also includes updates on various topics. In accordance with 18 US Code Section 208(b)(3) no waivers were required for the discussion on July 13.

In addition, there may be regulated industry and other outside organization speakers making presentations. These speakers may have financial interests associated with their employer and with other regulated firms.

The FDA asks, in the interests of fairness, that they address any current or previous financial involvement with any firm whose product they may wish to comment upon. These individuals were not screened by FDA for conflicts of interest.

Dr. Louis Katz is serving as the industry rep acting on behalf of all related industry and is employed by the Mississippi Valley Regional Blood Center. Industry representatives are not special government employees and do not vote.

This conflict of interest statement will be available for review at the registration table. We would like to remind the members and consultants that if the discussions involved any of the products and firms not already on the agenda for which the FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from such involvement, and their exclusion will be noted for the record.

FDA encourages all other participants to advise the committee of any financial relationships that you may have with any sponsor, products, direct competitors and firms that could be affected by the discussions.

Thank you. Right now I will turn it over to Dr. Allen, the chair.

DR. ALLEN: Thank you, Don. I just want to note that there will be a quiz on the applicable CFRs before we break for lunch today. So, be prepared.

We have got a busy agenda this morning. We are going to start with a number of committee updates. The first will be a summary of the May 9-10, 2006 meeting of the department's advisory committee on blood safety and availability by Dr. Holmberg. Welcome.

Agenda Item: Summary of May 9-10, 2006 Meeting of the DHHS Advisory Committee on Blood Safety and Availability.

DR. HOLMBERG: Thank you, Dr. Allen. Also, I would like to comment from Health and Human Services, and thank you for your services over the last year.

The important information that comes from the BPAC and goes up through the department is very critical, and we thank you very much for your service.

The advisory committee for blood safety and availability addressed an issue at the May meeting as far as what the strategic plan should be for the upcoming years.

One of the things that we catch ourselves in very often is the idea of where are we going. Very often, not only in the government but also in private industry, there has to be some sort of a realignment of priorities, and also the direction of different people.

One of the things I learned when I was in the private sector --and I realize I have a colleague in the back of the room that knows probably what this really means -- but poshun(?) is a Japanese word that means going in one direction, sort of like a compass point.

That is the whole idea, is to try to move blood safety and availability together in one direction. The goal of that is obviously for blood safety. We also know that, with availability, if the blood is not available, then it is also a safety issue.

As you all know, Secretary Thompson resigned over a year ago and Secretary Leavitt was confirmed to take his place.

One of the things that Secretary Leavitt put together was a 500-day plan, a 500-day horizon. His comment to the department was, the President of the United States has given me a clear mission, to help Americans live longer, healthier and better lives, and to do it in a way that protects our economic competitiveness as a nation.

Secretary Leavitt put together actually some vision statements and visions that he saw the department going in and that he would like to see us accomplish.

There were quite a few different guiding principle for reaching those various missions. That is, first of all, the care for the truly needy, foster self reliance, national standards, neighborhood solutions, collaboration, not polarization, solutions that transcend political boundaries, market before mandates, protect privacy, science for facts, process for priorities, reward results not programs, change a heart change a nation, and value life.

There are six elements of the plan. First of all, to transform the health care system, to modernize medicare and medicaid, advance medical research, secure the homeland, protect life, family and human dignity, and improve the human conditions around the world.

So, the question at the May meeting was, how does the blood safety and availability complement the Secretary's 500-day plan.

One of the things we do in my office -- and I say office with a small o because I am in the office of public health and science in the office of the Secretary, but blood safety and availability is responsible for convening groups and obtaining consensus on issues.

For instance, in collaboration with FDA yesterday we had a very good workshop on malaria and trying to convene people together to be transparent in a lot of our thoughts, and also to develop policy and also products.

The first part of the plan was, what can be done to improve blood safety and availability as part of transformation of the health care system.

First of all, the committee felt that we really needed to have strong guidelines and direction as far as process for policy.

We also needed to look at what were transfusion practice, donor recruitment, retention, and a big one that we have been talking about for years and we feel we are behind the power curve when it comes to looking at other countries, especially other developed countries, is where are we with biovigilance.

As you see, it is biovigilance, not hemavigilance. Hemavigilance, a lot of the developed countries have undertaken hemavigilance to look at just the blood system.

We see it not only being the blood, but to be broader than the blood, being biovigilance to include organs, tissues, progenitor cells included in that biovigilance.

The next issue is, what can be done to modernize medicare and medicaid as it pertains to blood safety and availability.

Dr. Sandler is in the audience here and he is one of our committee members. He represents the hospitals. Primarily, one of the things that we hear all the time is the reimbursement issues.

Definitely, with modernization of medicare and medicaid, with the medicare modernization act, there have been significant changes.

Even as I speak this morning, there are plans later today to have a hearing at Ways and Means Committee on the part B plan of medicare, the MMA, and especially looking at the average sales price for various drugs and pharmaceuticals, such as the IGIV.

So, the committee looked at the reimbursement issues. I must say that what we did was, we actually had working groups break down.

We closed the meeting actually during the meeting and had working groups then convene to work on each one of these issues to come up with thoughts.

Advanced medical research, what research needs to be targeted to improve blood safety and availability. One of the things that was very interesting about even the committee, the working group, I should say, but a working group that addressed this issue, was that several members of the committee were also part of the NHLBI strategic planning the day before.

So, we really got some good input as far as what NHLBI was doing, and also some of the blood priorities that were being set forth with NHLBI.

I have to say that NHLBI, although they are not officially represented on the committee, they are in the audience at every one of our meetings.

So, they do hear where the blood community is going and looking forward to different research aspects of that.

The committee really felt that there needed to be prioritization funding for promising new technologies and also a strategic research agenda.

Secure the homeland. You know, every time we do have a disaster, especially after 9-11, we learn more and more.

As I tell people with Katrina, from lat year, there was enough that everybody could take blame. I like to say, instead of taking blame, let's take responsibility for what happened or didn't happen.

So, really, what this working group did was look at the integration of the blood plasma system into the public health infrastructure.

Because we do not have a nationalized blood program, we do have a private heuristic approach to supplying blood within this country.

So, therefore, blood is really not a critical infrastructure, but it is a critical element of the health care infrastructure. Also, what we looked at was risk communication and disaster planning.

One of the issues that the committee had not identified back in September of last year when the elements of the strategic plan were put together, were improve the human conditions around the world.

I must say that, although this is not officially part of the strategic plan as proposed by, or recommended by, the advisory committee for blood safety and availability, one of the things is that we are very involved in trying to improve conditions around the world, especially in the developing countries.

One good example of that is the activity that Health and Human Services and also the State Department is doing with the PEPFAR in Africa and the Caribbean.

So, what is the process that we move forward? Firs of all, we have to draft a strategic plan. We have the various elements of the plan, a lot of critical thinking that has gone into the plan.

Now we have to put it into words and we also have to draft a tactical work plan, and this will be re-submitted to the committee and then submitted to the Secretary and then we will implement it.

Now, what is the time line on all this? I can't tell you right at the present time. Like everything else, we have a lot to do with very little sources.

So, we are moving ahead on this and hopefully in the net couple of months we will be able to present something to the committee and have the committee look at that. Thank you very much.

DR. ALLEN: Thank you, Dr. Holmberg. Questions from the committee? Okay, thank you, Dr. Holmberg. We will move on then to our second presentation which is a summary of the July 12, 2006 FDA workshop -- that was yesterday -- on testing for malarian infections in blood donors, by Dr. Kumar.

Agenda Item: Summary of July 12, 2006 FDA Workshop on Testing for Malarial Infections in Blood Donors.

DR. KUMAR: Thank you and good morning. This workshop happened yesterday. So, I was trying to work on this last midnight. So, I hope you will bear with me if it is not very organized.

As you see here, we called for this workshop on testing for malarial infections in blood donors. Just before I get into that, I think a little bit of background is in order.

As I said, it is a little bit disorganized here. So, I will jump two slides and then come back here. So, some background here.

The incidence of transfusion transmitted malaria in the United States is at an all time low. We get about one case every other year.

Also, currently, there is no laboratory test that could be used to screen blood donors for malarian infections. So, how do we protect the blood supply from malarian infections?

It is done through donor deferral policies, based on the travel, residence or history of malaria of prospective donors.

In the process, we do lose a lot of donors. There are approximately 150,000 people are deferred every year, donors deferred every year.

So, now efforts are being made on how to make it better. So, we have various screening tests available. So, we started looking around recently. There are good reasons why we don't have available tests. We will go into that in a second.

Before we go into that, some European countries and Australia in the last few years, have started to test deferred malarial by an ELISA that detects antibodies to only two of the four malarial strains.

I would like to remind you that, in this country, at least in the past, we have found all four species of plasma malaria.

So, briefly, in the United Kingdom, individuals who had malaria or a history of prior residence in endemic countries, are deferred indefinitely.

That is in the absence of this test. Now they cannot donate blood once they have this class. All prospective donors are deferred for one year.

So, basically, travelers are deferred for one year. Then they are tested with this ELISA and, if they are negative for antibodies, they allow them to donate blood, but they are not tested for at least six months after they return. In France, what they do is, they test four months after they return from an endemic area.

So, with that in mind, we called this workshop with a very specific question in mind. So, we asked for public discussion of scientific development that might allow us to implement donor testing from early infections as part of a pre-donation testing, others as follow up testing to reduce the donors who are deferred for the risk of malarial infection.

So, we came up with these questions. We did a lot of deliberations and we wanted to get some clear matters out of this workshop. So, we asked these questions.

So, what are the main sources of the infection that is in the U.S. population. Precisely what are the donor populations that are causing transfusion transmission of malaria in the United States, and mostly looking at the current populations.

What are the risks and benefits that would be of implementing a blood donor screening test in lieu of risk-based deferrals. That is what we are doing now, apparently.

Available and emerging technologies to test blood donors for malarial infections. That is keeping the future in mind also.

Then potential effect of implementing such a test. If we do a model of universal testing for all blood donors -- that is, everybody is tested -- or do we test only a targeted population for people who either had a history of malaria or a possible exposure to malaria.

So, I would just like to use the workshop data base to tell you what we got out of this workshop. So, Dr. Goodman gave the welcoming remarks, and Dr. Nakhasi delivered the introduction and overview of the workshop.

Then we had three scientific chairs and one round table discussion. I am not going into the details of this. Basically, we looked at the global problem of malarial infection and how has it affected the U.S. blood supply here.

I am going to present a summary of a few of the talks here, the ones I targeted for today. This is the talk from Dr. Monica Parise at CDC.

So, the picture that is emerging now, that in the past we used to get the donors that used to have malaria, half of them used to be U.S. travelers, malaria-naive travelers, and the other half used to be immigrants coming from other countries.

Now the demographics are changing. What we are finding now is that travel to Africa accounts for only .6 percent of the U.S. travel in 2003 data, but 66 percent of all malarial infections in this country, clinical cases, were caused by these travelers, the people who went to Africa, and 59 percent of these cases were falciparum cases.

So, most of the malaria that is in this country is coming from Africa, which is not surprising. For the last 15 years or so, 17 years, 93 percent of malarial deaths in U.S. travelers were due to falciparum, and 73 of those were acquired in subSaharan Africa.

Again, looking at the transfusion transmission issues especially, since 1990, more than 15 years of data, there are 16 cases there. So, less than one case more recently every year.

One of the donors was a U.S. traveler who went to Kenya. One was an immigrant who had lived in this country for a long time, was visiting family and friends in Africa. The others were immigrants.

So, out of those 14 infections, 12 of 14 were acquired in Africa and 71 percent were falciparum. So, that showed us very clearly -- and this is one thing we got out of this workshop -- the group of the donors that we need to target most are the immigrants coming from subSaharan Africa, probably born there or have lived long term there. So, that is one thing.

So, the second session mostly targeted on testing for malarial infection but still looking at what technologies are available, the current ones and even the future ones.

So, this is a talk by Newmarket Labs. It is a company in the United Kingdom that made the ELISA test that is sold in Europe and Australia. It is the test that they use currently.

It is based on two malarial antigens only from two species, plasmodium faliparum and plasmodium vivax. So, this is the test that is currently used. It is based on their sensitivity claims currently that there is 94 percent sensitivity for falciparum, 100 percent for vivax.

Now they are working on a new one. So, what they are finding is more antigens are better. So, if there is only one antigen, the sensitivity is 70 percent. That is the falciparum antigen.

If there are two antigens, the sensitivity increased slightly, three antigens, it becomes 82 percent, four antigens brings the sensitivity to 99 percent. So, they come to us with this was the test that probably would be more appealing to us.

I gave a talk yesterday. I had been asked this question repeatedly, why there is no DNA based test. That is what is used for most of the viral infections for blood safety.

First of all, the malaria parasite is highly infectious. There is some report that a single infected red cell can cause an infection. So, how does one look for one infected red cell in a unit of blood. So, it is a sampling issue here.

What we concluded was, I presented that most of the people I read, that sensitivity is not an issue. We can detect up to two parasites in an ml of blood. The problem is that it still leaves an unknown amount of parasites in a unit of blood.

So, the other biggest problem is in the asymptomatic donors, those are the ones who mostly transmit malaria, we don't know what is the minimum number of parasite burden that is there. So, that is the biggest road block.

So, we are testing for something that we don't know what the sensitivity should be. So, what are the possible solutions?

One is to have a technology that could concentrate parasites, that is, find one infected red cell in a whole unit of blood.

Well, that would be nice if you could achieve that. Then if we could find out about the parasite burden in the infected donors who are asymptomatic carriers. The concept was there that probably the technology is not there right now for implementation.

The third session was more about hearing about the actual experience of testing in the United Kingdom, in France, and some data was presented by Dr. Susan Stramer from the American Red Cross.

Actually, this was a very rewarding session there. Then David Leiby presented. I am just going to go through two talks very quickly here.

So, Professor Chiodini, this is the data looking at the at risk populations. The people that had clinical malaria had come back from an endemic area and were travelers.

So, in 2004 they tested close to 43,000. Around 1,200 were repeat positives. So, in this year they found about 2.8 percent of the donors. This is the at risk population here. Those are people who have been otherwise deferred. So, there is a net gain of close to 97 or 98 percent in terms of donors here.

In 2005, they had more samples to test, and the activity stayed in the same range, but slightly came down, around two percent.

So, they got 98 percent of the donors back who would have been otherwise deferred. This year so far, until June, they have tested close to 12,000 donors and, again, they are staying in the range of two percent.

Professor Garraud from France told of the French experience there. They have tested close to 75,000 donors. Again, this population is people who were travelers, that had been in malaria endemic areas.

They are finding the activity in about 3.5 percent. So, the rest are negative, and this is the donor gains for them, again.

Surprisingly, the other two people who presented their extensive data, they seemed to be very happy with the test. There were no complaints.

So, this is Dr. Susan Stramer from the American Red Cross. She had her own data. She presented the American Red Cross experience, how many donors had been deferred because of malaria risk each year.

So, how much burden was the donor deferral policy. That is the other way to view it. So, we have the data for five years here, and the mean donation rate of 1.69.

So, travel related deferrals were close to 2.4 million deferrals, something close to here, and this is the number of units they calculated lost, close to 400,000 units.

Residents were 25,000, or this number has shifted. This is the percent loss. So, one percent loss in terms of the total blood donations among travelers. The residents is 1.69 percent. The total lost, they are calculating, is around 1.2 percent of the donors are lost because of malaria deferrals.

So, this is their own data, but the numbers seem to be the most number of donors we are losing are in this traveler group here.

That is where everybody's eyes are. Those are the donors people want back in the blood banking industry and that is where we have got to focus also. I think we have heard the message very loud and clear now.

Falciparum, we have a lot of data with the Australian experience, and because I time I have to summarize it.

So, I think they have been doing it only for eight or nine months. They have already screened around 36,000 donors and close to two percent reactive. So, the numbers from France, from the United Kingdom and Australia, they add up.

I would like to present some interesting data from the American Red Cross again. So, here is just data, the same ELISA here. He tested in non-deferred donors, a little over 3,000, 3,200 cases here, suing non-deferred donors.

So, nobody reported they had any risk of -- they were qualified as non-malaria risk donors, accepted as non-malaria donors here.

What he found was, surprisingly, the one time 21 cases were there, the secondary reaction was 11 donors here. Interestingly -- and I found it very intriguing -- they went back and looked at the history of these donors here, and I think that is telling us something.

Our of these 11 donors, two had no travel history at all. Two of the donors were born in Africa, lived there a long time.

One had traveled to an endemic area in malaria, and four people had been previously treated for malaria more than three years ago, and at least three of them had lived or were born in Africa.

So, these are the donors who slipped through the system. Probably they were completely safe from malaria. None of them caused transfer in terms of malaria, but this is what happened, 11 people.

So, out of level, two had no travel history, but nine of them had some sort of exposure to malaria, risk of malaria, which was not otherwise detected. So, they are doing more follow up, the serology and PCR based on data from CDA.

Then came the round table discussion. Personally, I found that the most rewarding. Jay Epstein moderated this session.

These are the questions that were put there. I don't think I will have time to go through them individually, but they were basically based on the sessions that we had previously.

So, these were the take home messages, at least what I got from here. So, the majority of the clinical infections and transmission transmitted malaria area coming from the donors who were born in or lived in Africa. So, those are the people we need to pay clear attention to.

There were serious doubts expressed over current donor deferral policy, about one year deferral for all travelers, especially those going to resorts in Mexico and clubs in the Caribbean. So, there is a lot of noise being made about those travelers here. So, we have to consider how we can help there, or whether we can have a test that can help to alleviate the situation there.

The parasite detections, I think everybody is in agreement right now the technology, although it is very good, it is not being fit to screen donors for malaria infection, just because of inherent problems there of sampling.

Antibody testing, the experience in the United Kingdom, France and Australia has found it to be satisfactory based on detection of two out of four species, and what we can do about antibody based screening in this country.

So, we asked two very specific questions. Jay Epstein put two very specific questions to the panel. For universal testing, I think there was a mixed response. at least I didn't get a clear message, but people want to keep the issue alive. Nobody wants to close the issue here.

Especially I think I heard at least one comment that we need to be careful already that the universal testing supposes there are malarial infections in the United States. So, that may be the way to go, then.

Testing in at risk populations, also, I think we need to collect more data for the geographic based distribution, and the species that is prevalent, to decide what number of the species should be presented in the test before we can think about this a little further.

Then some members expressed concerns regarding logistics, how they will configure their data base to fit in with the target of screening in the at risk population. I think that is it. I will stop here, and obviously we will prepare a much more in depth, thoughtful summary. I was finishing this talk at 1:00 o'clock in the morning.

DR. ALLEN: Thank you, Dr. Kumar. Questions from the committee about the workshop or the report that we just heard?

It is obviously an area that is going to receive a lot of attention and I think the committee looks forward to a more complete report coming back, as well as research on ways to deal with this issue. Thank you.

MR. ALTER: One other important thing I thought that came out is, one, we probably would not be able to get rid of the questions, but hopefully we could simplify the questions and just say which country you went to, not where, when and how in the country.

Secondly, that if testing was added to the questions, that if it is done after the fact, it would not really help.

By the time you got the testing, the donor to come back and the testing done, you wouldn't save much time off the one year deferral.

So, if testing is done, it would have to be that you were able to draw the donor at the time they gave a positive question response.

Then, if the donor was antibody negative that unit could be used and, if not, it would be discarded. This would require big changes in computerization and how to track this special group of donors.

DR. ALLEN: Yes, gain, the algorithms that will be developed would be an interesting challenge, I am sure.

DR. KUEHNERT: I just wanted to mention that, unlike most infectious disease issues we talk about, this was more a discussion about improving availability and looking at safety trade offs, rather than the other way around, which is usually talk about availability trade offs and needing to increase safety.

It seems that the efficiency of the deferrals are really the issue and the more that we can increase that efficiency, I think the better this issue will be addressed.

We had some discussions about malaria risk mapping and trying to look at the areas of highest risk as really the ones that need the most focus.

As long as the trends continue, as far as the epidemiology, then all of that will still have the same frame.

I was struck by some of the slides which showed that really what was driving the decrease in casing was the decreasing immigration.

So, if there was a spiking immigration, you probably would see a change in the risk profile concerning transfusion transmitted malaria. So, that is probably what needs to be watched.

DR. ALLEN: And the immigration being considerably more important than just most business or pleasure travel.

DR. KUEHNERT: I mean, the traveler is what is driving things now because there isn't the immigration issue, but if that came back and there was an increase in immigration, then you would see both of those issues have much more equal weight. Right now it is the travelers because of the decrease in immigration, at least the way I saw it.

DR. ALTER: The main goal of the meeting was to give Mexico back to Dr. Katz.

DR. ALLEN: Other questions or comments? Thank you, Dr. Kumar. The third presentation is the committee report on the office of blood research and review site visit, the review of intramural research, and I have the pleasure of giving the summary.

Agenda Item: Committee Report on the Office of Blood Research and Review Site Visit, Review of Intramural Research.

DR. ALLEN: Good morning. I don't know if they scheduled this purposely for my last committee meeting or not.

I had the pleasure almost a year ago, July 22, to chair the review committee for the office of blood research and review, review of intramural research.

The committee was composed of a broad base of people with various background and experience, including committee members, those with basic science research backgrounds, clinical research backgrounds, blood collection experience and backgrounds, as well as industry backgrounds. The committee members are listed on the right.

The purpose of the review was a periodic review of progress and performance of the OBRR research program. In fact, this was the first one structured in this way, however.

The intent was an over-arching summary of the research program's goals and support. It is not a focused review of individual investigators and their work, which is done through a separate review process.

To conduct a review, we did the following things. We evaluated background information about OBRR and its function within the Center for Biologics Evaluation and Research.

We studied written research program descriptions, voluminous materials. Actually, I think we had a couple of binders of materials.

We did have a chance to review the report on the research programs at CBER that had been conducted back in 1998.

We looked at the curriculum vitae of the investigators. We looked at selected publications and then we had oral presentations, questions and discussion in an all day process.

I just quickly go through the 1998 report because I think it has useful background information. At that time the review committee strongly endorsed, first, the fundamental need for basic science research at OBRR to support its regulatory mission and, second, adequate funding of the research program to assure its success and its ability to attract first rate scientists.

I think it is not a secret that, even at that point in 1998, there were significant concerns expressed about the level of financial support through congressional appropriations, and the need to find acceptable alternative sources of funding for the research program activities.

By way of background, OBRR maintains an active laboratory research program. It is integral to FDA's critical path research initiative.

It is mission focused to enhance OBRR's regulatory functions and is primarily targeted at current regulatory issues, but with the flexibility to respond to new regulatory concerns and safety issues.

I think we will hear next a report on that, as we listen to the west nile virus update which, again, obviously was a problem that was not a problem that was anticipated and planned for prospectively. That is an example of the kind of flexibility that the OBRR needs in this arena.

The principal investigators and senior research staff at OBRR expected to spend about half their time on research activities and about half their time on regulatory activities.

That, in fact, is a balance that is rarely achieved. It does not account for regulatory time frames and priorities which take precedence very frequently, and it certainly does not account for other significant and time consuming activities such as management and administration within a complex structure at the FDA.

Evidence of the research program's success, just some brief summary statements. In total, the senior scientists in OBRR regulatorily publish more than 50 articles per year, most of it in the peer reviewed literature.

They have abstracts accepted at scientific meetings. There are progress assessments on external laboratory site visits, which uniformly, during the period of time I have bene here, have uniformly been very favorable, and commend the work that is accomplished and the scientists accomplishing that work.

OBRR staff sponsor and organize workshops on specific topics of importance, such as the malaria workshop we just heard about.

From this intramural research review, overall, in summary, OBRR research programs merit high grades for depth and quality of research.

Research agendas have been diversified and productive. Research programs are directly applicable to the FDA's critical path of biologics product development.

In comparison with the 1998 CBER review, the OBRR research programs were believed to definitely have improved in terms of focus and relevance to mission, quality of the research being conducted, and the diversity of funding sources, for example, through developing innovative alternative funding sources and establishing collaborations, which were an important way of getting the resources to accomplish the work that needed to be done.

Let me, as this point, go through the recommendations from the committee. First, the OBRR intramural research site review committee strongly supports the FDA's continued emphasis on the importance of having a strong intramural research program to support its critical path program for effective and efficient regulatory activities.

Having experienced and active research scientists involved, both in the regulatory process, and in the development and evaluation of scientific knowledge critical to the support of the regulatory activities is both sound and an essential component of the regulatory process, a process that facilitates the approval of biological products, and protects the health and safety of the American public.

Two. The OBRR senior management and the research scientists are highly commended for the depth and quality of the research program that was presented at this review, especially considering that each investigator is simultaneously responsible for a huge regulatory work load.

Both divisions, the division of emerging and transfusion transmissible diseases, and the division of hematology, have developed productive and diversified research agendas that have increased in value over the years despite both budget and personnel restrictions, and both divisions have contributed to the critical path program.

Three. The issue of sufficient time and qualified personnel to conduct the research remains important. The environment must be competitive to be able to attract outstanding young scientists, and to retain more senior scientists as principal investigators and regulators.

These issues are critical to the continuation of an effective and productive research program that supports the FDA's regulatory mission.

Four. Among the most critical issues facing the OBRR research program is funding to support the basic activities, including reagents, supplies and adequate equipment.

The meager budget available to OBRR through congressional appropriations to support research directly is totally inadequate to conduct even a significant part of the wide range of important program priorities for which the office is responsible.

Five. Other options to increase the research budget through resources outside the FDA, although difficult and time consuming for OBRR staff, are essential.

Opportunities for collaboration and to seek acceptable funding sources must be pursued, although this must be done within the confines of the research priorities established by OBRR.

Just to emphasize this point, obviously FDA can't go to the regulated industry and seek direct support for research activities.

Alternatively, unlike NIH supported scientists who have research ideas that they want to pursue, regardless of the specific mission, the FDA is very tightly constrained in terms of the direction of the research and the research priorities. These obviously limit the funding potential also.

Six. Adequate laboratory space and equipment are clearly essential components of a strong and product research program.

The inability to assure these in the future could have a definite impact on future research activities. These issues need to be addressed as funding is sought to support the research program.

Seven. As was noted during the presentations and discussions, it is imperative that OBRR have the flexibility, capacity and resources to address new scientific and regulatory issues that become apparent at any point in time, perhaps as a crisis.

Planning for these is difficult, especially when OBRR is also being faced with decisions about trying to develop a more focused research program.

These issues must be factored into the decisions that the agency needs to make about future research program directions.

Eight. Given the current realities of the research funding limits, the committee recommends that OBRR must decide whether it should try to maintain a broader array of research activities that attempt to address the responsibilities within its mandate, or whether it should focus on a smaller number of research topics and priorities, allowing staff to develop greater expertise and critical mass in fewer areas.

If this model is adopted -- that is, a more focused, limited research program, OBRR could define a research matrix based on the potential for collaborating effectively with academia or industry through contracts and other mechanisms.

The committee recognizes that this approach also requires funds and other resources that may not be included in the budget.

This is a difficult recommendation. I think it clearly shows how the committee was, I don't want to say split, but was not necessarily unanimous in whether the focus should be a very tight, controlled, here are the areas that we give the highest priority to, or whether it should try to cover the broad array of responsibilities that OBRR has.

Nine. A related issue is the need for OBRR to define the best mechanism for identifying research priorities to be pursued, either through intramural research or outsourcing. A good mechanism may already be in place, but it was not discussed with the committee.

Ten. OBRR needs to be attentive to the potential or perception of bias introduced into the regulatory process by intramural research findings that are portrayed as FDA policy positions when, in fact, they are not formal policy positions.

Eleven. The visibility of the OBRR research program is an important aspect of its broader acceptance and support.

Despite the meritorious work that is accomplished, there seems to be little appreciation outside the FDA for the extent and quality and importance of the work that is being accomplished.

It is important for OBRR to define and exploit opportunities to expand their visibility. Certainly information available through the new web site may be one opportunity, as are workshops, scientific presentations and publications and other venues.

Every opportunity should be taken to provide strong links between the research program activities and the regulatory capabilities that this research supports.

I will add here that I think it is obviously incumbent on each one of us, who are not FDA staff, to try to get the importance of this message across to congressional leaders and funders.

Twelve. To directly enhance funding to support research activities, OBRR should work with FDA and department leaders to identify creative funding mechanisms.

Establishing a research endowment fund, for example, that could be funded by major philanthropic organizations, private donors and regulated industry might be one example.

There certainly are examples of this kind of activity both at the NIH and the Centers for Disease Control, where there was congressional authorization to establish outside endowment funds and foundations to support research and other activities that were not directly supportable or supported by appropriate monies. I think this might be a model that should be pursued by the FDA, and there are others also.

Finally, the committee strongly supports the FDA's emphasis on a strong intramural research program to support its critical path initiative for effective and efficient regulatory activities, and adequate funding and other resources, including outstanding staff, are essential to support OBRR's research program and the FDA's critical path initiative.

The critical path, in turn, facilitates the important licensure and regulatory activities of OBRR and, as we all know, that certainly protects the health and safety of Americans, and it is an extremely important funding. Thank you.

I would be glad to take any questions from the committee or supporting other comments that want to be made. Dr. Goodman.

DR. GOODMAN: I would just like to make a few general comments. First of all, I think your efforts were some time ago and we have thanked you, but I would like to thank you again.

This is very, very important and we take it very seriously. A major goal for FDA is not only to have a science based organization that uses the best science to make our important decisions for the health and safety of the American people, but also, as Dr. Von Eshenbach has said, a science led organization.

So, we recognize that. That said, there are many, many challenges, as you said. I will just make a few general comments.

One is that the positive feedback is very much appreciated and important and, as you said, we need to do a lot more with our partners to be sure people understand what FDA's role is, what FDA science is, how that is science, meets different needs, than academic or NIH science, but how we work together with those partners. So, I agree with you.

I also want to say that it is good to hear that your independent assessment is that there has been progress since 1998, and we also feel within the last couple of years.

I think that has been from input we have gotten as well as from soul searching within the agency. A few comments that, as most people are aware, the federal budget is quite tight.

We get new very important priorities, such as issues in national defense, pandemic influenza, that end up causing needs for money to flow in those areas at times when total monies might not increase.

So, we are faced with continuing challenges. So, we do need to do a number of the things, and are doing a number of the things that your committee suggests.

There is even increased leveraging, as you said, working with NIH, working with other partners, et cetera, and that can make a big difference.

The outside funding has increased, but an important issue there -- this gets to management of the program -- is that we are sure that that stays with our mission, that we use outside relationships to solve the important issues that are part of our regulatory responsibility, and we are trying to do that.

What else was I going to say? Having you guys look at this program as a whole is part of something that we are very committed to doing and we want to do it regularly, not just from 1998 to 2006, but on a more frequent basis, and we are working out a process for doing that.

One of the things that we have done -- I think you heard some about this -- is we have had a retreat and a research working group of our scientists come up with ideas and approaches to how to deal with all these challenges and how better to manage our processes.

We have reinvigorated and are reshaping our resource processes within our center, the research priority setting and resource processes.

We can give you more of a report on it another time, but what is important is, the key elements of that are going to be regular stakeholder input -- and that is both external stakeholders such as yourself -- but also internal stakeholders.

We have internal stakeholders. For example, our full time reviewers are stakeholders in the research process.

They have ideas of things that are important from their review activities, and it is also important for them to understand the current science.

So, we sort of empower -- we have a person in each office who is an associate director of research for that office, just like Dr. Carbone is for the whole center.

We have created a new structure that empowers those individuals and they, and the office directors, in each of the offices, are going to basically set research agendas for those offices and prioritize and have resources, limited resources, focused in those kinds of areas, based on an objective assessment of what the needs are and what the available resources are.

What we are aiming for is to have, in essence, periodic development and reexamination of a research agenda, which we will bring and share with our stakeholders and publicly, and probably including through the BPAC, to again get input, and to then look at how are we making progress on that, what are we leaving out, what are new areas that we need to deal with and, given the limited resources, are we focusing them well.

So, we would like to come and, I think, update you on that. That process is being operationalized right now by those people themselves, not by me. We are going to look at what they come up with and be sure it meets these needs.

The other comment I would make -- and it just occurred to me listening to your presentation, but we had talked about it before when we had received the report.

We are doing this in the other offices, too. So, it is important people realize it is an across the center process.

I already asked our teams in each office to look at the reports they get from the advisory committees and use those in their planning processes.

In other words, they may not be able to accept or do everything you want, or they may have other reasons to have other views of some things, but we need to address all the things that have been brought up.

I would like to think of a formal way, whether we create a report or just come back, maybe, Kathy and report to you, for each of the offices to say, here is how we are resounding to the suggestions and ideas. Here is where we are with each of these things in detail.

So, I would like to put some time aside at a future advisory committee meeting to do that. One of the things that drives me crazy, that drives committees even crazier, is when people do good work and, because everybody is busy and because there aren't enough resources or whatever, it is sort of the tree falls in the forest but nobody hears it.

Well, we can't guarantee that we can make the forest whole again, but we can hear it and we will very much do our best and value your input.

I think I have said enough, but I really do appreciate -- it is helpful to me to hear where we are making progress.

It is helpful to me to hear other people's ideas of how we ought to be approaching these challenges, and we want to keep you engaged in that, and we very much appreciate your support.

Another comment I would make -- because this hasn't been part of the normal way of doing things -- is in your committee meetings today, if you identify what are essentially scientific issues that aren't being resolved -- and we have colleagues at NIH, we have colleagues in industry and academic -- that can be part of our process.

Identifying and solving those can be important. So, even from a single advisory committee meeting on a single topic, we would not object to hearing, well, gee, if we knew a protective level of X antigen, would we be here today, and how can we get to that point and who would be the right partners and how do we move that forward.

I would just like to say that we are open to scientific input in virtually any way possible, and to use it in solving problems.

The other thing is the critical path initiative. I am working very hard, we all support it. Again, the issue of financial support for it is a challenge, but our view is also that, for some of these areas where the public doesn't immediately think of this kind of research, like transfusion medicine, blood safety, I think it is very important, and you can really help us in articulating that those are important issues for this initiative to address, and we are certainly working on that within the government.

As we talk to people within the congress and explain what some of the unmet scientific needs are there and how meeting them can help the American people keep safe and accessible blood and blood products.

That was too long, but I think I actually had something to say and I really, again, appreciate your thoughtfulness, both in that report and in sharing your general feelings with us. So, thank you very much.

DR. ALLEN: Thank you, Jack. Dr. Alter?

DR. ALTER: I thought, Jim, you did a superb job of summarizing the process, even though you are just a lame duck at this point. It was very good.

I was on both these reviews over that time period and the change was really palpable. I just want to reemphasize how much more focused it had become and how much better the science had become because of the focusing, I think.

It was just amazing how much had actually been done, given the regulatory work load. I don't know how it was done, but it was. So, very, very good.

DR. HOOFNAGLE: I am Jay Hoofnagle. I am from the National Institutes of Health. I am in charge of funding of liver disease grants.

One of the frustrations I have always felt is that the intramural FDA cannot apply for NIH grants. I think the administrative reason for that is that they are part of HHS, as we are.

We have other parts of the government that can apply for NIH grants, like the agriculture department. We do fund labs in the agriculture department.

I think this is one potential help that might come to the intramural programs if they could. We actually have funded some FDA investigators indirectly through academic subcontracts to the FDA, and there are certainly outstanding scientists there who could compete in our already tight system.

I think that might be one solution to this problem of shortage of research funding, perhaps more palatable than applying to industry through foundations.

DR. ALLEN: Thank you. I appreciate that comment. Again, those of us around the table should see what can be done with that kind of suggestion as well as the FDA staff, although they may be restricted in terms of how they can hold their hands out to congress. Thank you. I think that is important. Other comments or questions?

MS. BAKER: Thank you for the excellent report. Are the summary recommendations available to the public in any fashion?

DR. ALLEN: I will let Dr. Carbone answer that.

DR. CARBONE: They were publicly presented at the last BPAC. So, they are part of the public record in that format, and we also plan to put them publicly available in an easier format on the web site. We will include the summary report as well.

MR. JEHN: Actually, the whole report will be posted on the web after this meeting.

DR. ALLEN: Other questions and comments? Okay, our last update will be west nile virus 2006, and I don't know if one would characterize it as a whimper.

Agenda Item: West Nile Virus Update.

DR. RIOS: Good morning. I will be giving you an update on the west nile. The United States is currently experiencing the eighth consecutive epidemic of west nile.

The first human case was actually reported to the CDC earlier this year. There have been close to 20,000 human cases so far reported to the CDC, with close to 800 fatalities.

According to CDC's estimation, for each neuroinvasive disease of west nile viral infection, there are between 150 and 300 infections for each case of neurological disease.

So, it is estimated that the minimum of 1.3 million to 2.5 million of infection has occurred in the past seven years.

In 2003, west nile was begun to be screened for the safety of the blood supply. There have been 1,600 interdicted units, or more than that, which led to the prevention of transfusion of those units and consequently transmission by blood of between 1,600 to over 3,000 cases potentially transmitted by transfusion.

There have been 30 cases definitely confirmed of transmission of west nile by blood transfusion. twenty-three of them were prior to the implementation of NAT screening and six were after implementation under IND in the mini pools of six or 16 which, when we had some changes in the blood industry, changes in the strategy of testing, it declined to one, and last year there were none. There are some inconclusive cases that were due either to the lack of follow up or the lack of a specimen.

The human season for west nile in 1999 was rather short, and it steadily increased over the years. In 2005, it was all year long. The first report was January 2 and the last one to the CDC was December 16.

This year we have already had reports early this year to the CDC. According to the standard reports, there are between eight and 10 cases of blood donors reactive to west nile, either confirmed or to be confirmed.

To give you a brief history of the west nile and the blood safety story, in 2002, it was identified that west nile was a risk for blood safety.

There were initiatives taken by FDA, the office of blood in CBER, and calls for test development. That led to a strong collaboration, actually before never seen, between government, academia, industry, test kit manufacturers and the blood establishments. Shortly after that the test was developed and implemented nationwide under IND for the summer of 2003.

The platform for these tests were in pools of plasma from donations of six to 16 samples. That surely led to interdiction of reactive units, in 2003, over 1,000 reactive units made by asymptomatic donors, since west nile, most of the infections are asymptomatics.

In the same year, the evaluation for the suitability of mini pool tests of six or 16 for the west nile was performed by the blood centers, and identified that 75 percent of the infected units only were detected by mini pool NAT and another 25 percent were undetected.

So, the approach was that, in 2004 and 2005, during the peak epidemic or between spring and fall, ID NAT was to replace mini pool NAT in the specific areas where there was a high activity of human west nile virus cases, and that obviously led to increased safety of the blood supply.

The status of assays right now, FDA has licensed the first west nile NAT assay for testing volunteer blood donors.

Also, these assays are licensed for organ and tissue. The submission was in January and the approval was in December 2005.

There are INDs currently ongoing on the testing of the blood. The current consideration for assay implementations are as follows:

We recognize that performing NAT assays actually involves a very complex pooling and testing system. So, we are considering recommending the implementation of a licensed assay for west nile within six months from the date of the publication of a notice in the Federal Register announcing the availability of the final guidance.

Our current considerations and tests, as you saw in these slides that I have shown before, the occurrence of west nile activities all year round.

West nile has become endemic in the United States as declared by CDC last year, with the intensity of activity occurring between the spring and fall of each year.

So, in screening volunteer donors for whole blood and blood components for transfusion, we have improved the safety of the nation's blood supply.

So, we are considering to recommend that west nile screening by mini pool NAT should be performed the year round, with implementation of ID NAT in the specific geographic areas where west nile activity is high.

We are also considering that the criteria to trigger ID NAT in a given geographical area into mini pool NAT should be defined and validated by the centers based on their incidence rates.

We also are considering recommending the confirmation of initial reactive units in the index donation by