FOOD AND DRUG ADMINISTRATION

P R O C E E D I N G S (8:20 a.m.)

Agenda Item: Welcome, Statement of Conflict of Interest, Announcements.

MR. JEHN: I am going to go ahead and begin here. Mr. Chairperson, members of the committee, invited guests, consultants and public participants, I would like to welcome you to the 85th meeting of the Blood Products Advisory Committee. I am Donald Jehn, the executive secretary for this meeting.

The entire meeting is open to the public today. At this time, I would like to introduce the individuals seated at the head table for today's first session.

Starting over to my right here, and going counterclockwise around the table, we have Dr. Kenrad Nelson, professor of epidemiology from Johns Hopkins. Dr. Quinn will be seated next to him when he arrives. He is also from Johns Hopkins.

Dr. Samuel Doppelt is the chief of the department of orthopedic surgery, Cambridge Hospital. Dr. Henry Cryer III, chief of trauma and critical care, UCLA.

Dr. Schreiber, vice president of health studies, Westat. Dr. Roshni Kulkarni, professor and director of pediatric and adolescent hematology oncology, Michigan State University. Dr. William Duffell, Jr., director of government affairs, regulatory affairs, quality systems, Gambro.

Coming over to this side now, we have Judith Baker, consumer representative, regional coordinator, federal hemophilia treatment center, region IX, Children's Hospital, Los Angeles.

Next to her, Dr. Adrian Di Bisceglie, professor of medicine, chief of hepatology at St. Louis University School of Medicine.

Dr. Suman Laal, assistant professor, department of pathology, New York University School of Medicine, Dr. Frederick Siegal, medical director, comprehensive HIV center, St. Vincent's Hospital, Manhattan.

Dr. Catherine Manno, professor of pediatrics, Children's Hospital, Philadelphia. Dr. Matthew Kuehnert, assistant director for blood safety, division of viral and rickettsial diseases, CDC.

Dr. Donna Whittaker, director of Robertson Blood Center, Fort Hood, Texas. Dr. Irma Szymanski, here to my immediate right, professor of pathology emerita, University of Massachusetts Medical Center. Dr. Harvey Klein, chief of the department of transfusion medicine, NIH.

Dr. Donna DiMichele, she will be acting chair for topic I discussion. She is the assistant professor of pediatrics and public health, Weill Medical College and Graduate School of Medical Science, Cornell.

Our regular BPAC chair, Dr. James Allen, president and CEO, American Social Health Administration, Research Triangle.

There are two committee members not present for the meeting, Dr. Quirolo and Dr. Katz. I would like to thank the members and consultants for attending this meeting.

Before we begin, Dr. Epstein, can I have you forward? There are four retiring members of the committee that we are going to recognize these individuals.

Could we have Dr. DiMichele, Dr. Doppelt, Dr. Klein and Dr. Laal to step forward? Thank you.

DR. EPSTEIN: Let me just remark that it is a bittersweet honor to give these awards to our outgoing committee members.

We deeply appreciate the effort that each of you have provided on our behalf, and in the interests of the public health.

We know that this participation represents a certain degree of personal sacrifice, reading long documents, sitting in a chair long hours, and scratching your brain for all of us. So, these are small tokens of our appreciation, which I am very pleased to hand to you. So, I guess one at a time.

First, to Dr. Harvey Klein, with our deep appreciation. [Award given, photograph taken, applause.]

This is to Dr. Donna DiMichele, again, with our great thanks. [Award given, photograph taken, applause.]

Dr. Samuel Doppelt, again, thank you very much. [Award given, photograph taken, applause.]

Dr. Laal will receive hers later. Thank you.

MR. JEHN: Before I turn the meeting over to the chair, I have a conflict of interest statement to read. Bear with me. It is a little lengthy.

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 of 1972.

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

The following information on the status of this advisory committee's compliance with federal ethics and conflict of interest laws, including, but not limited to, 18 USC Section 201, and 21 USC Section 355(n)(4) has been provided to participants in today's meeting, and to the public.

FDA has determined that members of this 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 USC Section 208, and 21 USC, Section 355(n)(4).

Under 18 USC Section 208, applicable to all government agencies, and 21 USC Section 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 special expertise, section 355.

Members and consultants of the committee who are special government employees at today's meeting, including special government employees appointed at 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 discussions of approaches to over-the-counter home use HIV test kits, and the discussions of alpha-1 protease inhibitor products.

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

Today's agenda for topic I includes review and discussion of the approaches of over-the-counter home use HIV test kits. For topic II, the committee will review and discuss alpha-1 protease inhibitor products.

In accordance with 18 USC Section 208(b)(3), waivers have been granted to the following special government employees: Dr. Donna DiMichele, topics one and two, Dr. Catherine Manno, topic two.

In addition, Dr. James Allen has recused himself from the discussion of topic one related to HIV home test kits.

A copy of the written waiver statement may be obtained by submitting a written request to the agency's freedom of information office, Room 12-A-30 of the Parklawn Building.

With regard to FDA's guest speakers, the agency has determined that the information provided by these speakers is essential.

The following information is being made public to allow the public to objectively evaluate any presentation and/or comments made by the speakers.

Dr. Mark Brantly is professor of medicine, molecular genetics and microbiology and alpha-1 research professor, University of Florida, Gainesville.

Dr. Bernard Branson is associate director for laboratory diagnostics, division of HIV/AIDS prevention, CDC, Atlanta.

Dr. Devery Ann Howerton is chief, laboratory practice, evaluation and genomics branch, coordinating center for health information and services, CDC, Atlanta.

Dr. Joseph Inungo is professor, school of health sciences, Central Michigan University.

Dr. Hans Peter Schwarz is associate professor of medicine, vice president, global preclinical research and development, Baxter Bioscience, Vienna, Austria.

Dr. Sue Sutton-Jones is senior vice president, regulatory affairs and quality assurance, OraSure Technologies.

Any guest speakers will not participate in the committee deliberations, nor will they vote. 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. William Duffell, Jr., is serving as the industry representative, acting on behalf of all related industry, and is employed by Gambro BCT. 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 members and consultants that, if the discussions involve any other products or firms not already on the agenda, for which an 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. Dr. Allen, I turn it over to you.

DR. ALLEN: Thank you, Mr. Jehn. I would like to add my welcome to all the committee members, and my thanks to the retiring members. It has been wonderful working with you, and we will miss you.

We have a very full agenda today. We are going to do one more retirement here.

DR. EPSTEIN: I would like to call Dr. Suman Laal up at this time and, once again, please step forward, to thank you personally for your service to this committee and, again, this is an expression of appreciation on behalf of all of us and the public health. [Award given, photograph taken, applause.]

DR. ALLEN: Jay, I think we will have to come up with another name for retirement, because there are no retiring members on this panel.

We do have a very busy schedule today. During topic one, from which I will recuse myself, we have got a number of open hearing speakers, as well as our regularly scheduled speakers.

I would just like to remind everyone today, please keep to your allotted time. It is essential that we have adequate time for the committee to have full discussion and to ask questions, and to seek the information that we need in order to provide the proper advice to the Food and Drug Administration.

For the updates this morning, rather than running through each of the updates in sequence and then having time for discussion, I am going to allow time for discussion immediately after each one, because each topic is so different.

So, we will move straight into the first discussion item, which is a west nile virus update by Dr. Hira Nakhasi of the FDA and Dr. Theresa Smith of the CDC.

Agenda Item: Committee Updates: West Nile Virus Update.

DR. NAKHASI: Good morning, everybody. The first speaker always has to be on time, I guess. So, I will try my best to be on time, and also just to give you a quick update on the epidemic of 2005, the west nile virus epidemic of 2005, and our efforts to see how things are moving. Also, Dr. Theresa Smith will talk from the CDC perspective.

Now, the background here, if you were not here for the last three years, then I think you should be looking at this slide.

However, if you were here for the last three years, at every BPAC, I have been talking the same thing. I just want to briefly say that West Nile is a single stranded RNA virus, a flavivirus.

It is mosquito borne. Eighty percent of infection is asymptomatic, 20 percent develop mild fever, and approximately one in 150 infections result in meningitis or encephalitis.

Old people like me are at risk for neurological diseases for a period two weeks prior to symptoms, and can last more than a month, which was a new revelation during the course of this epidemic.

In 2002, when the first outbreak -- not the first outbreak, the first transmission cases -- occurred, and in that time we realized that west nile can be transmitted through blood and transplantation and other sources. However, the magnitude of risk is still unknown through the transmission. Virus titers of this blood is much lower than the other known viruses, like HIV, HCV, and IgM can persist, that antibody can persist, up to two years. However, there is no chronic stage.

This is the progression of the epidemic, west nile epidemic, in the Americas. You can see the United States started in 1999, Canada 2000, spread to Mexico in 2002, and Central American in 2003, and then to the Caribbean.

This just gives you the overall human cases over the period of time. What you see is here, that the epidemic started in 1999 and reached a peak in 2003, and the last two years it has sort of plateaued here.

You will hear more about the epidemic from Theresa. This is year, 2005, as of now, most of the states in the lower 48 states, they are human cases, but still, Washington, northeastern and some places in Virginia you still have only avian activity but not the human activity.

This is to give you an idea of how many cases of the blood donors this years. As of November 374 cases in blood donors that were detected by testing. Again, you can see it is spread out all over the place.

This just gives you an idea how we progressed since we started testing the blood as of July 1, 2003, using Genprobe and Roche tests.

The first year, in 2003, we found 880 donors who had reported to the CDC arbonet and, at that time, there were six confirmed transfusion transmitted cases. However, out of six, four out of six had very low viremia.

In 2004, we saw a dramatic decrease in the number of cases from approximately 880 to 224. Again, I want to emphasize that this is mini-pool NAT and, during this season, we started to also, in certain areas, where the incidence and prevalence of these cases was much higher, the industry introduced the individual NAT testing.

Last year we found one reported case of transfusion transmitted cases. However, that was only detected by ID NAT and it happened in a situation right before the ID Nat was instituted in that area.

This area, as of now, October 1, 2005, we saw a little bit of an increase in the number of cases, 374 so far, and it has already petered out. In the last couple of weeks we see one or two cases every week. Again, the peak was between late August, early September.

Again, this year, mini-pool NAT and ID NAT was instituted in mild cases, where the high cases, where the prevalence was much higher, the ID NAT was started right away.

Fortunately, so far we have no reported transfusion transmitted cases this year. However, there were three cases of transmission through transplantation.

As you know, we have issued several guidances over a period of time in 2002 and 2003, and now this year we issued a revised guidance, basically to update what is happening with the epidemic, and to keep on changing the donor deferral periods.

This year we show, under the new revised guidance of 2005, basically says the epidemic season starts between May 1 and November 30.

The reason I am saying May 1, for the last several years we have seen it coming earlier and earlier, except this year, where it started a little bit late, and last year it started toward the middle of April, end of April kind of a thing.

So, we said, if the cases are during that epidemic season, donors of suspected west nile infection, or diagnosed with west nile infection, should be deferred for 120 days.

What we found out is that the studies showed last year that, in some of the donors during the epidemic period, could be up to 104. Mind you, it was only one case, but there were some cases that were beyond 28 days, and the earlier guidance said 28 days, because that was based on the studies in the 1950s.

We found out that in some cases -- again, mind you, this is low level of virus in the presence of antibodies. So, we do not know whether that is infectious or not.

So, we decided that it would be 120 days deferral, would be fine. Donors would be deferred on the basis of investigational tests, and blood establishments, at their own discretion, may enter such donors after 120 days after the reactive donation, i.e., that they may not have to test them again before entering.

Earlier we had suggested that, before re-entering, they should be tested. However, the FDA recommends that we still would like to be tested those who are re-entered, be tested by ID NAT on a follow up sample during the 120 days, which will provide useful additional scientific information on the duration of west nile viremia.

Still it is evolving. The first year we thought it was only 28 days, the next year we found out 49, 50 days. Last year we found that one of the cases was 104 days.

So, it will be important to find out how long the viremic period is, because this is an evolving situation. If such a follow up sample is reactive for west nile virus, the FDA recommends that the donor be deferred for an additional 120 days from the day the sample was taken.

So, we still are continuing working closely with the test kit manufacturers to expedite the licensure, and we still are having the meetings bi-weekly during the season with the AABB task force, and I am really thankful for them, in collaboration with CDC and NIH. So, we monitor the epidemic and then make a course correction if that is needed.

So, in having this story told so far, there are still gaps in knowledge, which we in the FDA are working on. A couple of things, one is the genetic variation in west nile strains.

Even though there is limited data, I will show you some data that there may be some variation, but the question is, why are we studying that? Is it important because it may have impact on the west nile assays?

Then also, an important issue still remains whether there is any residual risk of west nile infection in the presence of antibodies. That means, those people who have low titer virus by mini-pool or ID NAT, and are having antibodies, are they infectious.

I think those studies, we want to ask those questions. So, Maria Rios' lab in FDA has collected several of these isolates, 25 in total, from various periods of the epidemic, and sequenced the structural gene, and five of them have completely sequenced the complete genome.

What she found out, and others found out, was that there was a genetic shift between 1999 and 2001 and 2002 in the sequences, at least in the structural regions. So, there was a major shift there, that 55 percent of the oral isolates in 2002 had changes, whereas 85 percent had a different group of isolates in 2003.

However, between 2005 and 2002, the majority of the nucleotide changes were in U to C and A to G, and a small number of mutations also have so far not affected the testing. So, thank God for that.

She also did in vitro infective study samples, which were mini-pool NAT positive or ID NAT positive and antibody positive or mini-pool NAT negative or ID NAT positive.

What she found out, 10 out of 16 samples, when she infected these blood samples onto viral or macrophage cells, she could see the virus replication.

That doesn't mean that virus is infectious, and it doesn't mean that it can be transmitted, but it tells you that it is infectious.

Although in vitro infective does not imply infective in vivo, it demonstrates the presence of live virus and, therefore, raises some concerns about a potential risk for transfusion transmission.

I should hasten to say that, so far, we have not seen any transfusion transmitted cases from samples, if they were antibody positive samples. So far, in real life, we have not seen that.

There remains a potential for that, even though it is low. So, what we are trying to do now is doing it in non-human primate studies as well as small animals, to see whether these samples are infectious.

With that, I think I will acknowledge my colleagues at CDC, the AABB task force, other organizations -- ABC, ARC, BSL, Roche, GenProbe, Department of Defense and FDA colleagues. Thank you very much.

We are doing a tag team, and Theresa can talk and if you have any questions, then we can come together.

Agenda Item: West Nile Virus Update.

DR. SMITH: Thank you for letting me tell you about the west nile virus epidemiology and surveillance update for 2005.

I will skip virology this year, since Dr. Nakhasi covered it so well but, like last year, I will go ahead and discuss the epidemiology of west nile in the United States quickly from 1999 and then, more fully, a brief review of last year and how things have gone this year. Then we will discus what we have seen in blood donations. As marked on this slide, all data, including 2005, was in Arbonet as of 11-1-05.

The data that we are going to be looking at is from Arbonet, a national arbovirus surveillance system. It is a web based passive system begun in 2000 in response to the new epidemic in the United States.

It includes 57 area health departments that report over the internet to the division of vector borne infectious diseases.

It includes both animal and environmental data in the form of mosquito, bird, horse and other animal surveillance, and human cases.

Human cases have a great deal of information collected, including age, sex, race, ethnicity, residence, clinical illness, onset date and outcome, blood or organ donation or receipt.

You may have seen some of these maps over time. This gives a sense of when we first saw this virus, and when we have seen activity in environment versus activity in humans.

You will notice we have something like areas in our country where we only see transmission in the environment and not yet any human cases, and the rest of the country has experienced human cases.

In 2004, we saw a great deal of activity down in the southwest. While it had been there before, it was the first time that we saw a lot of human cases.

During this year, we see that area continues to have quite a few human cases, and it is becoming a little denser in terms of the counties that become affected by west nile.

This is a quick reminder that all the data that you are looking at revolves around reports that come in, and that is always going to lag behind the actual onset.

So, in orange you see the onset of cases. In green you see the reporting of cases. So, what you see today is not going to look the same when we finalize this year's data.

Here you can again see that we have started with relatively few cases in 1999. Our peak year was in 2003. The last two years have been fairly level.

So far this year, we have had 2,581 case reports in 42 states. Of those, 1053 have been neuroinvasive disease.

West nile fever has accounted for 1,368. There have been 83 deaths. Of those 83 deaths, we have information on the age of those people in 78 cases. The median age was 78 with an age range of 36 to 98.

There were six states with cases that were greater than 100 in number. California has 824 so far, Arizona has 102. These together account for nearly two thirds of all the cases in the United States.

We have been collecting data on screened blood since 2003, when 6.2 million units were screened. Eight hundred eighteen presumptive viremic donors were recognized.

Of those, six ultimately developed west nile non-invasive disease, 137 developed west nile fever, and six were related to transfusion associated transmission of west nile.

In 2004, 8.2 million units were screened, 224 presumptive viremic donors were recognized, of which four developed west nile neuroinvasive disease, 66 developed west nile fever, and there was one transfusion associated transmission.

In this year, we of course don't know how many will be screened by the end of the year. So far, we have seen 375 presumptive viremic donors. Three have developed west nile neuroinvasive disease, 82 have developed west nile fever, and there have been no transfusion associated transmissions this year.

Here is the map from 2003 showing that the predominance of the presumptive viremic donors were in the midwestern and high plains states.

Last year, where we see a little more scattering of where the presumptive viremic donors were found, although some of the highest density areas were where the newest activity was in the southwest.

This year, you again see some scattering, but there also are some little clusters. It looks like the Missouri valley, Texas and California would be the areas that we have seen the most activity in.

In 2004, again, 224 cases were reported in 29 states -- California, Arizona, Colorado and Texas being the most common places to find presumptive viremic donors last year.

This year, we have had more presumptive viremic donors -- 374 -- in 30 states, with California, Texas, Nebraska and Louisiana being the most common places to find presumptive viremic donors this year.

During this year we have had six investigations. As of last night, four are now negative and two are pending plasma return from Switzerland.

We did have one organ transplantation transmission. In the past, organ transplantation transmission has also been associated with transfusion associated transmission. This year it was likely to be a mosquito borne infection in the donor.

There was potentially a febrile illness in that person, but that was a history that was not obtained prior to their donation.

Later, again, after there was recognized to be a problem, it was found that the day before donation, this person was IGM positive for west nile, although PCR negative.

Three of the four organ recipients became PCR positive, and two became ill. Here is a quite time line of what occurred.

On the top you see information that was available at these dates. So, on August 16 there were known to be west nile positive mosquitoes in a park in the area where this person lived.

On the 23rd, this person was injured and required surgery. On the 26th, they were declared brain dead, and on the 28th organ recovery and transplantation occurred.

On the bottom you see information that was available only after an investigation occurred. It was found that there was a possibility of a febrile illness before this gentleman's injury, and blood that was recovered from the 27th of August was found to be PCR negative and IGG positive for west nile.

In summary, west nile activity has continued over most of the continental United States. It has continued its westward expansion insofar as it has increased its presence in many of the counties in the southwest.

The full season of transmission in California occurred for the first time in this last year. Now human cases have been reported from all states except Alaska, Hawaii, Maine and Washington.

The risk of west nile virus transfusion associated transmission remains unknown. We continue to investigate possible transfusion associated transmissions, as we will next year. We have only two pending this year.

As we have seen from this last occurrence, the transfusion associated transmission is less likely to cause organ transplant related west nile virus transmissions than it was before we started our work in looking at the blood.

I would also like to point out that there are some areas of the United States that appear to be remaining important spots for transmission.

Here the Missouri Valley appears to be a consistent area since it first became involved in west nile. This may be something that we need to continue watching.

Each year we learn more about where this organism wants to live and transmit the most. Thank you. Any questions?

DR. ALLEN: Questions or comments for either Dr. Nakhasi or Dr. Smith?

MS. BAKER: A question. Is there any west nile transmission surveillance activity in the U.S. Pacific jurisdictions?

DR. SMITH: I am sorry, I don't think I understood that question.

MS. BAKER: We have the territory of Guam, and there are two other Pacific jurisdictions that are affiliated with the United States, and three others that are less affiliated. I wondered if they were involved in surveillance.

DR. SMITH: Puerto Rico is. The others have not been very active, simply because there is little evidence that it is going to get across that ocean again very quickly.

Over time, we are going to need to be able to make sure