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 that they have the capacity for surveillance, but right now, no.

DR. CRYER: Is there a clinical difference in the course of the disease in the transplant patient that is immunosuppressed?

DR. SMITH: It appears so, but it is a little hard to tell because we have had so few to look at. There is no reason to believe that all four people didn't receive an organ that was capable of transmitting west nile virus, yet only three actually seemed to have any evidence that the transmission occurred.

Of those three, only two people got sick, but one of the people that did not get sick had a rather prolonged course of having at least PCR positive blood, and that may not be something that is due to their transplant, per se.

Just as the blood donor had long-term PCR positive blood, it is hard to tell whether or not that had to do with transplant or just some people are capable of having a little longer term viremia. I wish I could tell you more than that. Those are the things we are looking at, though.

DR. ALLEN: Are organ donors, at this point, routinely tested for west nile virus in most circumstances or not?

DR. SMITH: No, the test that we have been using on blood has only been given an IND for that purpose at this point, is my understanding.

DR. DUFFELL: I am curious about your thoughts about the drop in numbers from 2003. Is this an indication that this was almost like a medical fad at the moment, that people were looking for this, noticing it and reporting it, and then the interest in it has dropped off? Has the reporting system changed in some way that might account for the dramatic drop in numbers?

DR. SMITH: It is difficult to tell, but there does appear to be a point at which west nile becomes entrenched in an area in a way that it has covered a certain geography, it is capable of being in the mosquitoes, in the birds, in the humans, but the majority of people have never seen it. The majority of birds have never seen it. So, all are susceptible.

Why that decreases, whether it is a change in the mosquitoes, the birds or the humans is a little difficult. There is certainly evidence that, once west nile virus is introduced into an area, that people are much more careful about using mosquito sprays when they go out to garden, and wearing long sleeves and long pants.

It is also possible that birds become resistant to the transmission, making it impossible, then, for the mosquitoes to continue the cycle as efficiently each year.

I don't think it is merely a surveillance artifact. I think this is a matter of the rather complex work that goes into supporting a transmission cycle like this in nature.

DR. NAKHASI: I just wanted to make another point here. I don't think it is that interest in the surveillance has dropped.

I think as you see in the blood area, the testing has been going on year round, in most of the blood centers. You can see, when you did the number of cases in 2003 were more than 800, and last year were 224, and this year a little bit more.

Obviously, it is fluctuating, but what was happening, I think what Theresa said, that was the first time it was a full blown epidemic going through mosquitoes, a new population of mosquitoes were being infected and, once it established, and birds were infected, birds were dying.

It is known in the literature that, once the birds and other people get infected, they may develop resistance, and therefore you may see a drop in the human cases.

DR. ALLEN: Other questions? If not, we do need to move on. Thank you very much. Our next presentation, by Dr. Paul Mied, Food and Drug Administration Draft Guidance on NAT testing for HIV-1 and hepatitis C viruses, testing, product disposition, donor deferral and reentry.

Agenda Item: Draft Guidance on NAT for HIV-1 and HCV: Testing, Product Disposition and donor Deferral and Re-entry.

DR. MIED: Thank you, Dr. Allen. This morning, I would like to very briefly provide an update on comments FDA has received to the docket for our draft guidance on NAT for HIV-1 and HCV, testing, product disposition, and donor deferral and reentry.

This draft NAT guidance for industry was published on July 27, 2005, for comment purposes only. The 90-day comment period closed on October 25, 2005.

This guidance provides recommendations to blood and plasma establishments that have implemented, or are implementing, a licensed HIV-1 and HCV NAT method for source plasma or whole blood.

This guidance contains generalized testing algorithms, to be used when NAT reactive results are obtained on a pool of samples, or on individual samples of source plasma or plasma from whole blood donations.

Now, these testing recommendations deal with a NAT reactive result only, and they are independent of those for serology testing that were in the 1992 HIV memo, and the 1993 HCV memo to blood establishments.

Currently approved tests on master pools of donor samples, or on individual donor samples for HIV-1 RNA and HCV RNA may be either multiplex NAT for the simultaneous detection of HIV-1 RNA, and/or HCV RNA, or separate NAT tests for the RNA of the two viruses.

Now, the draft guidance includes six different testing algorithms that cover all of these testing situations.

The recommendations on testing, product disposition and donor deferral address the actions to be taken when an individual donor sample is reactive on a multiplex HIV-1 HCV NAT, after a negative antibody screening test, and when a master pool is reactive on a multiplex HIV-1 HCV NAT, and that reactive master pool is then resolved down to the level of the reactive individual donation by testing sub-pools and/or by testing individual donor samples.

The recommendations also address the actions to be taken when an individual donor sample is reactive on a separate HIV-1 or HCV NAT after a negative antibody screening test, and when a master pool is reactive on a separate HIV-1 or HCV NAT, and that reactive master pool is then resolved down to the level of the reactive individual donation by testing sub-pools, and/or by testing individual donor samples.

Now, in the guidance, we refer to an individual NAT for the separate viruses HIV-1 and HCV, but one of the comments that we received was to change this terminology to separate NAT, and I found it helpful to do that, at least for this presentation.

Some of the highlights of the recommendations in the draft guidance on testing and donor and unit management are, we recommend actions to be taken regarding the unit and the donor and for look back, product retrieval and recipient notification, at each point in the testing algorithm.

When an individual donor sample is reactive on a multiplex HIV-1 HCV NAT, we are recommending deferral of the donor whether or not one of the discriminatory NAT tests is reactive.

In accordance with a previous recommendation by the blood products advisory committee, we recommend that a non-reactive NAT on subpools or on individual donations be definitive for release on all units in those non-reactive subpools, or for release of those non-reactive individual donations.

For look back, the recommendations indicate, for product retrieval only, or recipient notification also, should be done.

Now, here is a generalized algorithm for using the multiplex NAT, that combines all the testing algorithms that are in the draft guidance into one algorithm.

It refers to a situation in which, whether you are resolving a reactive master pool down to the reactive subpool, and then down to the individual donation level, or you are screening individual donations in the first place, and you have a reactive individual donation on the multiplex NAT.

Units in all non-reactive subpools and all non-reactive individual donations may be released, and we recommend running discriminatory NAT tests on the individual donation, and discarding the unit, and deferring the donor when one or both of those discriminatory NAT tests is reactive.

When both discriminatory NAT tests are non-reactive -- that is, when there is a NDR or a non-discriminated reactive result -- we are offered the option of performing an additional NAT at this point, and discarding the unit and deferring the donor, regardless of the results of that additional NAT.

The result does indicate whether you should perform product retrieval and also initiate transfusion recipient notification when the result is reactive, or just do product retrieval when the result is non-reactive.

Now, some of the major comments to the docket that we have received that address the testing and unit and donor management recommendations in the guidance include a question about the need to investigate each occurrence of a NAT reactive unresolved master pool, that is, when all of the subpools or the individual donations subsequently test non-reactive.

Also, a question about the need to defer donors with NAT reactive results of the individual donation, when both of the discriminatory NAT tests are non-reactive.

These are the donors with an NDR or a non-discriminated active result. The argument being made here is that the vast majority of these NDRs are false positive. There is also a request for us to define the time frame for look back for HIV and HCV in this document.

Now, this draft guidance also contains algorithms for donor reentry for HIV and HCV that combine NAT and serologic test results obtained on the donor.

This is the recommended reentry algorithm for the three classes of donors deferred because of HIV-1 test results.

Here is the first class of donors who were individual donation NAT reactive but serology negative, the second class of donors who were not non-reactive, HIV-1, 2, combi-EIA repeatedly reactive, western blot or IFA indeterminate or negative, and the third class of donors, who were negative on the other tests, but were repeatedly reactive on the HIV-1 P24 EIA, with a neutralization test that was positive or indeterminate.

We are recommending that, after eight weeks, you conduct non-donation testing on a follow up sample from the donor, using an HIV-1 NAT and an anti-HIV-1, 2 EIA.

If the HIV-1 NAT is non-reactive and the anti-HIV-1, 2 EIA is negative, the donor may be reentered. That is, the donor is eligible to donate in the future, provided, of course, the donor meets all donor eligibility criteria.

Some of the major comments to the docket that we have received that address the recommendations for donor reentry for HIV in the guidance include the suggestion that there be an additional waiting period for a donor who tests NAT reactive during that eight week deferral period. We had recommended that that donor be permanently deferred.

That we clarify the conditions for reentry of donors who were deferred because of their HIV-2 test results.

That we clarify the requirements for Group O sensitivity for the individual sample NAT, and for the EIA on the follow up sample, and that we permit reentry for donors who initially had an invalid or an unreadable western blot.

This is the recommended reentry algorithm for the two classes of donors deferred because of HCV test results. Here is the first class of donors, who were NAT reactive, serology negative, and the second class of donors, who were NAT non-reactive, HCV EIA repeatedly reactive, RIBA indeterminant or negative.

We are recommending that, after six months, you conduct non-donation testing on a follow up sample from the donor using an HCV NAT and anti-HCV EIA.

If the HCV NAT is non-reactive, and the anti-HCV EIA is negative, the donor may be reentered. That is, the donor is eligible to donate in the future, provided all other criteria are met.

Lastly, some of the major comments to the docket that we have received that address the recommendations for donor reentry for HCV in the guidance include the suggestion that there be an additional waiting period for a donor who tests NAT reactive during that six month deferral period.

That we clarify the requisite sensitivity for the HCV EIA used to test that follow up sample, and that an additional six-month waiting period be permitted for donors who are anti-HCV EIA repeatedly reactive on the follow up sample, and for whom the RIBA test is persistently indeterminant.

We will carefully consider and discuss these and other comments submitted to the docket, and it is FDA's intention to revise the draft guidance and to issue final guidance as soon as possible. I think I will stop there and take any questions you might have.

DR. CRYER: How many are we talking about? How many donors in the donor pool would this affect?

DR. MIED: How many would be re-enterable? The estimate I have is about three years old, and it comes from one of the blood organizations.

We are talking about, assuming eight million different donors per year, possibly re-entering with these HIV and HCV algorithms, on the order of 14,000.

For NAT false positivity, it is at about one to 20,000. So, we are talking about maybe reentering 400 false positive NAT donors out of those eight million. Again, those are three or four year old estimates.

DR. ALLEN: My comment, as I have followed this, I think you have done a superb job. It is a very logical sequence.

One can argue about the parameters somewhat, which I think are reflected in the comments that have come into the docket.

My concern is, have you received comments from people at the working level within blood collection centers, who are going to have to apply these, because it is an extraordinarily complex algorithm.

As you go through the process of finalization, I would hope that would be a consideration that you would seek from the blood collection industry.

Certainly, one would hope also that the software manufacturers would try to write this algorithm into the computer based software that is used in the blood collection centers, that would help simplify this. I am just concerned with the complexity of the algorithm.

DR. MIED: Yes, Dr. Allen, most of the major comments that I showed this morning are from the blood organizations themselves.

DR. DI MICHELE: I just have one question. I am just looking at the algorithm for the multiplex screening that is reactive.

Then we go on to do discriminatory NATS. If they are non-reactive, it just seems that, if they are reactive, we go on to destroy, relabel units, notify donors and do look back.

Then, if they are non-reactive for both HIV and HCV, you either destroy and relabel the units anyway, or perform another sample. Then, whether the sample is reactive or not, you go on to do the same thing anyway? Is that correct?

DR. MIED: The difference there, on the additional NAT, the difference -- the additional NAT, which they have the option of performing, if that is reactive, they are performing the full look back, whereas, if they are non-reactive, we only recommend retrieval of prior collections, and not recipient notification. The difference there also is that a donor who is reactive on the additional NAT is no eligible for reentry.

DR. DI MICHELE: So, whether or not they are non-reactive on discriminatory tests, they are still removed.

DR. MIED: Yes, that is correct. This is a point of discussion, as I mentioned. The argument is that the vast majority of these are false positives.

However, we have in the guidance the conservative approach to defer all of those donors, but they are re-enterable, with the exception of those who have a reactive additional NAT.

DR. ALLEN: Other questions or comments? Well, we look forward to hearing how this continues, and to having another update in the future.

Our third update topic will be presented by Dr. David Asher, the FDA summary of the transmissible spongiform encephalopathy advisory committee, which met on Halloween.

Agenda Item: Summary of the TSEAC Meeting held on October 31, 2005.

DR. ASHER: And a frightening experience it was. I was just asked to do this talk on Tuesday, and I can't summarize eight hours of action-packed committee meeting in 10 minutes.

What I tried to do was put as much of the salient information as possible into a handout that was provided to the committee.

Unfortunately, I only made 75 copies and I was so tired I couldn't figure out how to reload the electric stapler, but this will be -- the other thing I have to warn you is that this is not a cleared presentation. So, it really shouldn't be cited as authoritative information. A cleared version will be appearing on the web site.

We had the 18th meeting of the TSE advisory committee on Monday. There were four issues covered, two interesting informational issues that time doesn't permit discussing, and two decisional issues.

One is asking advice on further development of a risk assessment for variant CJD and plasma derived factor 8, an extension of an assessment that was done for factor 11 in the year.

The second was a discussion of validation criteria and possible label claims for devices purported to remove TSE infectivity from blood components.

What I propose to do is to concentrate on the first few slides, which may need some explanation, whereas the last slide summarizing the advice of the committee should be reasonably self explanatory from the handout.

What prompts both of these issues, of course, is the striking observation in the United Kingdom that variant CJD has almost certainly been transmitted by transfusions of non-leukoreduced red blood cell concentrates to two of a very small number of recipients, a difference that is quite striking between this and sporadic CJD, which has never been convincingly documented as transmitted by blood, although the fear of that exists.

I do want to point out right at the outset that there is no case of variant CJD in the United Kingdom or anywhere else that has been attributed to use of a plasma derivative, human plasma derivative, regardless of the amounts of product used.

There are now 185 cases of variant CJD, the vast majority of them in the United Kingdom. The concern is that five or six of those cases have occurred in people in other countries who acquired the infection in the United Kingdom, one of whom was only there for about 26 or 27 days, and three days in France.

In addition, there are other BSE countries where exposure might occur, particularly France, where there have now been 15 cases, several of whom have been blood donors.

These travelers, of course, carry their infections with them to their home countries, where they pose some risk of transmitting disease to recipients of their blood.

As you know, there are deferral policies in place to reduce that risk for people who spent considerable periods of time in the United Kingdom and longer periods of time in France and other countries.

In addition, we know that we have had a very small BSE risk in our own country. There has only been one native borne cow, over 500,000 sick cows screened.

So, we think the risk of endogenous BSE in this country must be very small indeed. The main risk is from people who were exposed in those countries where there has been a lot of BSE.

To evaluate these risks, Steve Anderson, our risk assessor, with Hong Yang, has set up a risk assessment breaking down the elements of risk into four modules.

Two of them involve the source of plasma, the second, the ability of processing to reduce the infectivity, and the third exposure from the use of the product.

It turns out that each of these elements is surrounded by considerable uncertainty and is very difficult to model, and it was to improve the information to be used in the assumptions for this model that we asked for advice from the committee.

The prevalence of variant CJD in U.S donors is largely controlled by the prevalence of CJD in the United Kingdom.

There are problems in evaluating both that prevalence and our own prevalence. That is, however, a critical driver of risk.

A second driver of risk is reduction by processing. Plasma pool size does not appear to be a highly important factor, but reduction by the manufacturing process and, to a somewhat lesser extent, the amount of infectivity potentially present in the plasma are important.

In addition, it has been very difficult to estimate -- surprisingly difficult to estimate -- the amount of plasma derivative that an individual patient has used.

There are two sources of risk in the donor population in the United States. One is those people who should have been deferred but, for some reason, were not. The second is those people who are suitable blood donors, but nonetheless might have been infected.

We know that, if you defer for people who are in the United Kingdom for three months, that it is possible to be infected in considerably less than three months. Yet, we can't defer everybody who has ever visited the United Kingdom, because we would be deferring perhaps 25 percent of blood donors, and even more in east coast areas.

So, there is an analysis of prevalence in the United States relative to the United Kingdom. Estimating prevalence in the United Kingdom turns out to be surprisingly difficult.

There are two methods that have been used to estimate it, and they give quite disparate estimates. One is predictive models based on the number of UK cases actually observed, and the other is an estimate based on a survey of appendices removed from patients in the United Kingdom.

The models of the first sort have estimated a maximum, in more recent estimates, an estimate of, oh, 2,500 cases in the entire United Kingdom, tops.

Studies looking for the accumulation of abnormal prion protein in lymphoid tissue of the appendix have predicted about 13,000 cases incubating variant Creutzfeld Jakob's disease in the United Kingdom.

Those are possibly low estimates, because we know that earlier in infection the appendix is likely to be negative.

We know that blood of these patients contains the agent as long as three years before onset of signs, clinical signs, but we don't know how much longer, and we don't know the exact incubation periods for most people. Nine to 12 years seems to be a reasonable number. We don't know the maximum.

We don't know how many people with less susceptible genotypes might be infected, but we think that some of them surely are infected, and their blood probably contains the infectious agent as well.

The advice from the committee was to use empirical prevalence values based on the tissue survey, allowing for preclinical and subclinical infectious status in donors of all prion protein encoding genotypes.

Our second source of uncertainty has to do with screening out unsuitable donors. Estimates from analogous donor screening situations, like the HIV risk donors, suggested that questionnaires might be as high as 99 percent sensitive, perhaps 90 percent more conservative, but the committee was quite uneasy about that, and recommended considering only 85 percent sensitivity of the screening.

They were concerned, as we are, that we have no direct data about travel histories of source plasma donors. We have been using extrapolations from a travel survey for doors of whole blood.

Donors of source plasma are younger, give more plasma, are thought to be poorer, and it would be desirable to have specific data.

Another area of uncertainty is in how much infectivity to consider potentially present in the blood of donors.

All the information for that comes from animal models. Our proposal was to consider a minimum of .1 infectious dose per ml -- that is one dose per 10 mls -- more likely 10 doses per ml, with a maximum of 310, because that is the highest value in the published literature.

The published literature shows models all over, and to assume that the blood was infectious from the time that the donor became infected until the donor died.

Estimates of the actual amount of infectivity in the blood of rodents, however, tend to cluster together somewhere between two and 30 infectious doses per ml.

This study was from mice, this study from hamsters, that showed a mean of 10 infectivity appeared about halfway through the incubation period.

The committee agreed that, based on rodent data, 10 doses per ml of blood was most likely, and a minimum of 1.1 prudent. They offered mixed advice on upper levels of infectivity.

Pool size, bimodal with a peak at 20,000, a peak at 60,000, the committee agreed, and agreed that we use three different ranges for the reduction in infectivity by different classes of products, anywhere from a minimum of two log reduction to a maximum of nine log reduction, although that would be overkill for removing infectivity.

They agreed that the CDC data bases for factor eight use are the best available data, but they encourage, especially for von Willobraun's disease, collecting better data, and FDA has a plan for doing that.

They shared our concern that some experimental data suggests that cumulative, repeated exposures to small amounts of infectivity may increase the risk of infection, and of course they could be considered a model for those users of plasma derivatives who use them repeatedly. They agreed with our plan to estimate a risk per year rather than a risk per dose.

A special concern to the committee as well as to us is risk communication. The risk of transmission by plasma derivatives, of course, is entirely theoretical.

It is very difficult to communicate small and highly uncertain risks of this sort, and a concern that the notification itself might cause patient anxiety and health care provider anxiety.

It would be terrible if dentists started refusing to take care of people with a history of the use of plasma derivatives, simply because we had told them they were at some small, uncertain risk of this disease, and it was felt that participation of the patient groups in setting plans for risk communication would be helpful.

There won't be time to go through the plasma filtration. We had a very interesting presentation from UK authorities who are going to do independent evaluation of any European, Council of Europe, marked plasma component filtration device that is going to be marketed there with a claim for reduction of TSE infectivity.

They are going to require at least three log reduction in a spiking study, evidence that at least red cells maintain their functionality.

Three manufacturers, one with a Council of Europe marked filer, and two with interesting matrices, presented promising results.

The committee suggested a few modifications to our criteria, greater than three log reduction of spiked infectivity, removal of all detectable infectivity from endogenously infected animal blood, at least two animal models using two strains of agents.

One of those should be derived from either a cow with BSE or a human with variant CJD rodent adapted, and functionality of filtered components should be demonstrated.

They also noted that it would be desirable to demonstrate that any device would remove all endogenous infectivity from whole units of blood from large animals.

At the moment, the sheep is the only large animal demonstrated to have infected blood, although I think primates will eventually become available, since bioassays in sheep are generally not feasible.

They felt that, if sensitivity of transgenic mice to sheep infectivity were demonstrated, they would be an acceptable, although a huge number of mice would be required, and the expense would be considerable. I think that I can stop there. Thank you.

DR. ALLEN: Thank you, Dr. Allen. Questions or comments on this topic? For anyone who is not following it, it is a very complex and confusing area, but one in which a lot of new data continues to emerge rapidly.

Just one comment quickly. With the order of presentations to the advisory committee, it should be noted that, already with the presentation of data on efficacy of filtration to remove the prions from units of blood or plasma, the work that is being done there, we may have a device being presented that would claim to reduce risk, before there is any test to identify risk in the potential units of blood or plasma. So, this presents an interesting conundrum in terms of regulatory issues.

DR. SZYMANSKI: A questions about travelers to the United Kingdom who are going to be refused as donors. If that traveler is a vegetarian, is that considered at all?

DR. ASHER: Yes, the question is, is a question of vegetarianism considered in suitability of blood donors. First, let me say that travel to the United Kingdom after 1996 is no longer considered a deferral factor, because the agency is convinced that a full range of food chain protections put into place then should be effective in protecting against significant exposure to BSE agent.

The answer about vegetarianism is no, it is not considered. The reason for that is that dietary histories, particularly long after the fact, have to be considered relatively unreliable.

Also, people have different understandings of what it means to be a vegetarian. Many people who are self proclaimed vegetarians have, in the past, consumed beef.

One of the patients in North America came from a family that, I believe, were practicing vegetarians. So, vegetarianism is a sometimes thing, and it just can't be evaluated critically in the setting of a blood program.

DR. NELSON: How many cases were in the United Kingdom in the last year of the 158?

DR. ASHER: In the last year, just a handful. The cases are dropping in the United Kingdom.

DR. NELSON: So, the numbers are still going down, and it seems that the estimate of 12,000 is perhaps too high.

DR. ASHER: It is reassuring as far as it goes. The problem is that all the cases in the United Kingdom, all the clinical cases, have been in people who were homozygous for methionine at codon 129 of the prion protein encoding gene.

Now, that genotype is known in other forms of CJD to increase susceptibility in shortened incubation period. The problem is that people with other genotypes are susceptible to other types of CJD.

The second transfusion transmitted case, who died -- well, it was a woman who died at, I think, 81 of a ruptured aortic aneurism, had evidence of preclinical CJD.

The most likely scenario is, had she lived longer, she would have come down with symptomatic disease, which is what happens with other forms of CJD in people with those genotypes.

I understand that the last case of kuru was seen in New Guinea in 1999, and then suddenly they start reporting cases in people of the less susceptible genotype almost 15 years after the exposure.

How long the blood is infectious in variant CJD in those people during that period of time is not clear, just another example of the extreme uncertainties surrounding this.

DR. NELSON: About 40 percent of the population has a susceptible genotype, as I understand it.

DR. ASHER: Has the most susceptible genotype. The advice of the committee and of the UK authorities, is to consider all persons potentially susceptible to infection. Hopefully, the attack rate will be lower and the incubation period will be longer, but we still have the problem of what to do with infectious blood from people who are clinically normal. So, it is a mixed picture.

DR. ALLEN: Okay, any other questions or comments? We will move on then. Dr. Jerry Holmberg, executive secretary of the advisory committee on blood safety and availability, will present a summary of the department's recent meetings.

Agenda Item: Summary of the DHHS Advisory Committee on Blood Safety and Availability.

DR. HOLMBERG: As Dr. Asher mentioned, it is difficult to cram a two days presentation into 10 minutes. So, I will try to move as fast as possible.

Just a point of clarification, Mr. Chair. I understand you wanted a little update on the hurricane response. Is that still desirable, or should I move forward?

DR. ALLEN: Go ahead and move forward.

DR. HOLMBERG: Some of the issues that were discussed at the most recent Advisory Committee for Blood Safety and Availability were issues relating to the varicella zoster immune globulin, immune globulin intravenous, and a strategic plan for improving the blood safety against known and unknown transfusion transmitted complications in the 21st Century.

As far as the issue with the VZIG, there is a potential shortfall. There is a use rate of about 200 vials per month, which should probably take us through the end of January.

Also, one of the things that most recently the Advisory Committee on Immune Practices has recommended, recommendations may lead to the use of IGIV as an alternate product until there is an availability of VZIG.

That leads me to the next issue that was discussed, and that is the IGIV issue. I hope you like my slide here. I thought this front coming in here was a good analogy to what is happening. Is this a perfect storm, or is this just a market adjustment to the MMA, the Medicare Modernization Act.

I would like to dwell a lot of time on the waterfall here. This was a picture taken during my trip to Puerto Rico this summer, but I just put that in there as an analogy of what is really happening in the market place.

That is one thing, that the BPAC usually doesn't get involved, or isn't permitted to get involved with the issue of economics, and basically your charge is to look at the science attributed to the various products that are put before you.

The Secretary's advisory committee can look at different aspects, including the ethical use and the economics.

One of the things that we have found -- and I like to put this as a waterfall or a cascade, is that we have the manufacturers contributing their products.

We have seen, over the last couple of years, a consolidation of the manufacturers and also, with the manufacturers, they have also consolidated the number of distributors.

So, you also have primary and secondary distributors and then, at the hospital level, you have the distribution of that, to either the hospital, which is under the reimbursement as the DRGs, the physicians offices, which are under the part B, and then the hospital outpatient.

Well, if we look at how reimbursement is handled, what we have is, we have the manufacturers reporting their wholesale and their sales prices to CMS, and this is on a regular basis, that they are reporting to CMS for a recalculation.

IGIV is one of the very few drugs that actually is monitored on a regular basis for price, and it is adjusted on a quarterly basis. Unfortunately, that adjustment lags behind the quarter.

Most recently, in the medicare modernization act that took place in January of this year, the calculation was changed to average sales price plus six percent. As of this quarter, that is going for a -- liquid is going for $56 a gram.

However, right at the present time, hospitals, outpatients, are being reimbursed at average wholesale price at 83 percent, which is about $80 a gram.

So, you can see that there is a disparity there and, what happens, there is going to be a shift in service. So, we have seen a shift in service.

One of the things also that we identify is that the distributor in the calculation that is mandated by congress -- and this is a statutory requirement -- is that the MMA look at the price coming from the manufacturer and not the distributor.

This is where the problem exists, in that the distributors are not part of the calculation for reimbursement.

As a consequence, you have the primary distributor for the manufacturer who is selling under contract and the secondary and gray market that is selling in a spot market scenario.

If I can put it in a different way, we have the manufacturers who have been very diligent at increasing their inventories.

In the past, the manufacturers have had months and months of inventory. In an economic move, they cut back and, for a while, we were under a yellow light system, meaning that there was about a five week supply of IGIV.

However, in the last two months, since August, we have actually had a green light situation, meaning that there is a greater than five week supply of IGIV.

We also have the reimbursement issue which, as of October 28, the lyophilized was about $45.57, and the liquid was at $56.30. This is for doctor office reimbursement.

So, as I mentioned before, in the last slide, there is a shift in service. So, we have seen a shift in service from the physician offices to the outpatient setting.

Then, on the other side, we have the demand issue. We have the labeled use of the product. We have the evidence based use, that CMS has about 30 different evidence based clinical entities that they will reimburse for, and then you have the non-evidence based use of the product.

We have quite a problem here, trying to address all those issues. What we have seen, just to quickly go through this -- I have talked about all of this -- is that the industry has consolidated, there has been a change in business practice, there has been a market correction, reduction in inventory, a smaller number of distributors.

What we have found is that there are sufficient supplies of IGIV for patients who need treatment. I was on the phone quite a bit this week tracking the various complaints of availability.

Every place that I called said, yes, there is product available. It is just that when you get it from the secondary or the gray market, some of the physicians' offices are paying up to $160 a gram.

What we also found was is that it suggests that, under the allocation system, that the physicians might best serve the patients by communicating their supply needs directly to the manufacturer, and also ensure that IVIG treatment is prioritized toward FDA labeled use, and those diseases are clinical conditions that have been shown to benefit from the use of IVIG based on evidence of safety and efficacy.

What we have done within the department is we have looked, or we actually have posted -- this is my web site if you would like to go to the advisory committee for blood safety and availability.

We do have a statement there on the IGIV. We also have posted the CBER number and a place where you can report shortages to CBER.

Also, if there is denial of medicare coverage, then that can be reported directly to medicare. What we also have posted there is a page from PPTA that lists all five manufacturers with their 800 numbers, and that will -- each one of the manufacturers has agreed to have an emergency supply inventory of IVIG.

So, if there is a need, the physician can call directly to the medical director at the manufacturer, and discuss the case, and request the product.

As I just mentioned, hot lines have been established. The department has also looked at the possibility of doing an evidence based medicine study, and that is still under investigation.

However, we are looking at the CMS reimbursement. We are monitoring the cost. Once again, I have to say that this is an issue that is statutory.

Congress has said, these are the calculations that you will use to determine the rate of reimbursement. So, there is very little that we can do as far as the reimbursement, and right now we are just constantly monitoring what is the situation.

However, there is an IG assistance in looking at the problem and trying to identify areas where we can step in.

Well, the committee looked at all that and, after new input from patients, medical professionals, distributors and manufacturers, the committee remained highly concerned that persistent disruption in access to IGIV, which includes a progressive shift to treatment in a hospital, continues to compromise quality of care to many patients.

In particular, the committee believes the transfer to a hospital may impair continuity of care by their usual medical provider and may add otherwise unnecessary cost, logistical complexity, and nosocomial infectious risk.

The committee further is concerned that a change to the hospital outpatient reimbursement to ASP plus eight, effective January 2006, will further aggravate an already difficult situation, and that this shift will not be sustainable.

They recommended to the secretary that an increased reimbursement for non-hospital IGIV therapy, to a level consistent with current marketing practice.

Consider and reclassify IGIV as a biological response modifier, consider declaring a public health emergency to address short term problems.

Modify the current plan to change hospital outpatient reimbursement to ASP plus eight in January 2006, in such a way as to prevent any sudden or large decrease in reimbursement.

Reexamine whether the current IGIV supplies are meeting patient needs, and work with congress to establish a long term stable and sustainable structure.

We are continuing to investigate this. Areas where we can have impact we are looking at. However, there are some areas, such as what congress is willing to do, and what congress has already put in the MMA. Whether the MMA is going to be opened up again for discussion this year is debatable.

The other thing that we looked at was a strategic plan for the 21st Century. The committee recognized that blood is a critical element of modern medical care, and ensuring an adequate supply of safe blood is a national responsibility.

Although there have been dramatic improvements in blood safety and availability in the United States in the last two decades, the committee finds that there are compelling needs for improvement in some areas:

Minimizing destruction of the supply, and the supply of access to blood products and their analogs;

Meeting the product development needs for patients with rare disorders;

Timely funding to ensure appropriate utilization of new technologies;

Integrating presently fragmented systems for monitoring blood safety and availability;

Aligning reimbursement and funding policies with product approvals and other decisions intended to optimize blood safety and availability;

Modifying reimbursement policies, as needed, to sustain access to blood products and their analogs for all patient groups, e.g., IGIV;

Reassessing policies and their related interventions based on the evaluation of their impacts;

Intensifying efforts -- the committee recommended doing these things to intensify efforts to influence clinical practices related to blood transfusion and alternate therapies based on scientific evidence.

Accelerating responses to threats -- patient specimen/unit misidentification -- for which there are available interventions.

Utilizing formal risk communication strategies targeted to blood donors, patients and care providers, to enhance scientific comprehension and public trust.

Also, pursuing opportunities to enhance public health in the management of blood donors.

Promoting comprehensive disaster planning,including sustaining the inventories necessary for an effective crisis response.

Establishing a proactive, prioritized and goal-oriented research agenda, utilizing formal assessment tools more routinely in policy development and decision making.

Further clarifying the respective roles of government agencies and the private sector in management and oversight of the blood system.

The plan should include and encompass: structured process for policy and decision making; integration of blood systems within the public health infrastructure; surveillance of adverse events related to blood donations and transfusions; risk communication; error prevention in blood collection centers, transfusion services and in clinical transfusion settings; donor recruitment and retention; clinical practice standards for transfusion; strategic research agenda; disaster planning; stable and sustainable reimbursement; funding for promising new technology.

I believe I will call it there, but these recommendations have been forwarded to the secretary for consideration.

If these are approved by the secretary, we will be working within the department to put together a strategic plan to encompass the recommendations that the secretary approves. Are there any questions?

DR. ALLEN: Thank you, Dr. Holmberg. Questions or comments? It is an ambitious plan. I assume it is unfunded.

DR. HOLMBERG: Unfunded and, right now, we have 94 years to accomplish that.

DR. ALLEN: Thank you very much for the update. Our final update for this morning will be reentry of donors deferred based on anti-hepatitis B cor test results. Dr. Gerardo Kaplan from the FDA will start, and Dr. Susan Stramer from the American Red Cross will provide a brief statement also.

Agenda Item: Re-entry of Donors Deferred Based on anti-HBc Test Results.

DR. KAPLAN: Good morning. I will give you an update on reentry of donors deferred on anti-hepatitis B cor test results.

The issue here is that the FDA would like to update the committee on the proposed algorithms that will allow reentry of donors deferred for testing repeatedly reactive for antibodies to hepatitis B cor antigen on more than one occasion.

As a historic perspective, the 1991 guidance indicated that donations for transfusions should be tested for anti-hepatitis B cor antigen. Only negative units should be transfused.

The donor should be indefinitely deferred when they tested reactive more than once, and that reentry algorithms were not recommended at that time, because there was no supplemental test for anti-hepatitis B cor.

One of the main consequences of the screening was that anti-hepatitis B donors contribute to the safety of the blood supply.

However, many donors have been indefinitely deferred because of potential false positive anti-hepatitis B results.

The considerations for reentry is that reentry will be permitted only on the premise that historical tests for anti-hepatitis B cor antigens were false positives, and that there is no evidence for past or present hepatitis B virus infection.

In a 1999 BPAC presentation, the FDA and AABB presented to BPAC similar reentry algorithms, based on negative test results for surface, anti-cor and anti-hepatitis B surface antigens.

The committee did not recommend reentry because some of the American Red Cross data showed that there were some hepatitis B surface antigen and hepatitis B cor negative samples with hepatitis B DNA reactives, using an experimental NAT.

There was another BPAC presentation in a 2004 meeting, where FDA presented to BPAC the following reentry algorithm, based on test results for surface, anti-cor, and hepatitis B NAT.

The committee did not vote on the proposed reentry because there was a lack of data to evaluate its use. This algorithm basically said that, although the donor has been indefinitely deferred because of having tested repeated reactive for anti-cor on more than one occasion, there may be reentry if, after a minimum of eight weeks subsequent to the lest repeat reactive anti-cor test, a new sample is collected from the donor and these samples test negative for the three markers, basically surface antigen, anti-cor, and hepatitis B NAT in FDA licensed assays.

When a donor presents at the blood center to donate, subsequent to the negative test for, again, the three markers -- surface antigen, anti-cor and hepatitis B NAT, and all donor suitability criteria for donors of whole blood and components are fulfilled.

The good news is that companies have developed two key tests, and the FDA has approved them. There was an approval in April of 2005 of the Roche Cobas AmpliScreen hepatitis B NAT for screening donations in mini-pool and individual donation format.

Roche also presented some data to BPAC indicating that it is possible to enhance the sensitivity of the ID test.

FDA also, in October 2005, the Abbott PRISM anti-cor test for screening donations was approved. This test uses a different technology than other currently licensed assays, and could be used for the reentry algorithm.

So, the FDA is looking forward to reviewing that data to validate the proposed reentry algorithm for anti-hepatitis cor repeat reactive donors, and the good news is that today we are going to hear a talk by Dr. Susan Stramer from American Red Cross, and she will provide some of this data. This concludes my presentation.

DR. ALLEN: Very quickly, any questions for Dr. Kaplan at this point? Okay.

Agenda Item: Re-entry of Donors Deferred Based on anti-HBc Test Results.

MS. STRAMER: Good morning. While my handouts are being handed out and we are loading my presentation, I will thank the committee for this opportunity to present an update of what I presented at the October 21, 2004 BPAC, and also to declare my conflicts of interest.

I am a current employee of the American Red Cross, and I am a former employee of Abbott Laboratories and, as such, I still have Abbott stocks, but that shouldn't influence my judgement of scientific data.

I would like to first acknowledge my collaborators at National Genetics Institute, NGI, and Abbott Laboratories. As I mentioned, this is an update from the October 21 meeting of last year, about a year ago.

So, the questions -- so, relative to what I presented in October, the historical and current repeat reactive rates for FDA licensed anti-cor tests range from .4 to 1.6 percent. This is basically a historical number.

False positivity, as already mentioned, is high on these tests, ranging from 25 to 87 percent reported, varying depending on the specificity of the test used.

As mentioned, there is no confirmatory or supplemental test available, and as such, we have a two time allowance for donors to donate and be repeat reactive before they are permanently deferred.

I presented last time the impact of a repeat reactive notification on first time donors, and whether this prevents them from returning for their second donation.

If you look at what the Red Cross has in our data base for the numbers of anti-cor deferred donors, who lack other markers for deferral, from the period of time that we have formal tracking, it is greater than 200,000.

If you go back to the numbers since February 1987, and try to estimate a nationwide number, we know there is probably greater than a half million.

So, the question is, can an algorithm be validated to reenter deferred donors who are falsely anti-cor reactive. If so, what would be the yield of such a reentry algorithm.

BPAC, last October, did provide unanimous support for the validation of the reentry algorithm as provided by FDA and outlined by Dr. Kaplan.

We will test a follow up sample greater than or equal to 56 days by a highly sensitive HBV NAT, or DAN assay, having less than or equal to 10 copies per ml.

We also would retest the sample by a second or more specific anti-cor assay. We would, of course, also do an FDA licensed, HBSAG assay, and all tests must be non-reactive and the donor have no other causes for deferral, and the donor would then be eligible for reentry.

What I showed at the last BPAC, relative to how successful reentry would be based on the same test, what I used was a model saying how many donors were one time reactive, and then came back a second time and were reactive again.

So, looking at a data base from the year 2000 that included 6.5 million donations from about four million donors, the overall repeat reactive rate at that time was 6.4 percent.

The important point here is that 75 percent of donors who were reactive one time because two times reactive on their next donation, with another 13 percent accrual over the next three years.

That doesn't bode very well for the efficacy of the two times reentry algorithm based on the same test. If you look at the split between first time and repeat donors, one would assume that, in these first time donors, most of these represent true HBV infection.

These represent probably an overall mixture of false positivity as I mentioned, and true positive HBV infection.

So, what we -- the AABB and the industry -- had recommended was that an anti-cor reentry algorithm would be projected to have a higher yield if a different test was introduced.

The blood system would then have to convert to that new test, rather than testing these donors over and over again with the same tests, and finding the same false positives.

This slide shows you the repeat reactive rate over about the last 10 years at the Red Cross. We are running now at about a .4 percent repeat reactive rate. That is for all donors.

Over time, the repeat reactive rates have come down significantly. So, we have culled out the true positive donors and, since most of our donors are repeat donors, that is possible.

Now, one interesting piece of information is, if you switch tests, how much of your false positivity will be reduced.

So, this slide was provided to me by Hema-Quebec, courtesy of Dr. Gile Delage. It shows you here that, when they introduced HBC screening in Quebec, they introduced it on the Ortho platform.

Then, in April, they converted to the Abbott PRISM platform What you can see, if you take an overall mean, after a first culling period and then a stabilized repeat reactive rate of just under one percent, they convert it to PRISM and then they stabilized it just under .6 percent for .4 or 40 percent decrease.

You can see that there was quite an impact by changing tests, and this is actually the test, the European version of PRISM that does not contain the reducing agent that eliminates false positivity.

So, what we did, in 2001, to look at the possibility and to follow up, do anti-cor donors really have DNA associated with them, we took 3,000 anti-cor repeat reactive unlinked donations, and we tested them for HBV DNA and NGI.

These were surplus NAT samples. So, they were handled under proper conditions, and to limit contamination. The criteria for inclusion was non-reactive by all other test methods.

There was no pre-selection for first time or two time anti-cor repeat reactives. We just took the tubes out of our NAT laboratories.

From projections of numbers of donors who were two times reactive, of this 3,000 -- which is why I chose a large number -- it was to enrich the population so we would have enough donors in here who represented truly deferred donors, and we would project 708 of these 3,000 were actually two time cor-deferred donors.

So, when we tested these samples on the NGI net, ultraqual assay, the eight reaction test -- that is, the sample is extracted and processed eight times.

We used a .2 ml input and, if there is reactivity in any of the eight tests, the test is interpreted as positive.

The sensitivity was 9 IUs per ml, which converts to 31 copies per ml. We saw 19 of 3,000, or just under one percent, samples reactive.

The samples had low reactivity for DNA. Eleven of the 19 had less than 100 copies per ml. With an average of the eight reactions, how many were positive? An average of just under two.

Eight of the 19 samples had viral loads between 100 and 500 copies per ml, with about a 300 copy per ml mean, and the average number of reactions of the eight reactive was just about five.

So, in red, this slide is shown frequently. It shows you how this data, the .3 percent anti-cor positive rate, compares with other published studies, either the Roche clinical trial or a rat study showing what the frequency of DNA positivity is in isolated anti-cor reactives.

So, the purpose of me standing here today is to tell you the updated results when we tested these 3,000 samples which were characterized by DNA testing.

When we tested them by the Abbott PRISM anti-cor assay, using the licensed lots -- that is, post-licensure, which Gerardo said just happened, so these data are hot off the press, I just got the data last night.

The study was initiated following the qualification of the samples and PPTs, which hadn't been qualified on the PRISM system previously, and availability, as I mentioned, of licensed lots.

The assumption going into the testing is that the 19 HPV DNA positives that I mentioned would all be PRISM anti-cor reactive.

Also, what we wanted to know was, how many eligible donors we would yield for reentry after testing the anti-cor non-reactive. That is, how many samples would be anti-cor nonreactive by the PRISM and were DNA negative.

This testing, as I mentioned, is completed. We are doing further studies to investigate anti-cor IGM reactivity of the cor reactives, and to look at anti-surface for scientific interest, as sample volume allows.

So, these are the results. If you look at the NGI sample tests, we tested 3,000 samples. Actually, it came out to 2,999. I am off by one. Seven were QNS for the PRISM testing, leaving a total in this table of 2,992.

In red are the NGI DNA positive results, and all 19 were positive on PRISM cor. All 19 were strongly positive for anti-cor antibodies on the PRISM assay. The mean S to CO was a .14.

I should mention, in the PRISM test, which is a competitive inhibition assay, sample S to COs less than or equal to one are reactive. Sample S to COs greater than one are negative. So, here you look for a low signal to cut off ratio.

So, a .14 is a very strong mean, and the range of these 19 samples, their PRISM reactivity ranged from .02 to .49.

Of the samples that tested DNA negative, what were the PRISM results? Eighty percent of the total actually retained reactivity by PRISM.

So, using the Ortho test, as we do, in combination with the PRISM test, we only have 21 percent of donors who were deferred due to anti-cor reactivity, who would be predicted to be eligible for re-entry if they passed the follow up testing.

These are the 19 samples. Although you might not be able to see this, I highlighted in red -- these are the triplicate signal to cut off ratios, initial reactives are repeated in duplicated.

The values are very consistent, and the values above .14, which was the mean, are highlighted in blue, and there were only five such samples.

So, in summary and to conclude -- and then I just have one more slide after this -- preliminary data indicate the feasibility of an anti-cor reentry algorithm.

That is, all 19 HBV DNA positive samples were detected as reactive by PRISM anti-cor assay. All 19 of these samples were strongly anti-cor reactive, and I already highlighted their reactivities.

The caveat of this study is that the yield of reentry is probably dependent on the prior assay. I showed you, for our 1X, 2X anti-cor deferral study, that we only yielded 25 percent for going from Ortho to Ortho.

In this pilot study, I only showed you a 21 percent yield. Then, from the Hema Quebec study, I showed you a 40 percent yield going from Ortho to PRISM.

I don't have any data, if you were using the prior Abbott EIA called Corzon, what that yield would be going forward, going to PRISM.

I would like to just end with subsequent studies other than completing the study I just described. Currently we are doing a study of anti-cor repeat reactive samples with the National Genetics Institute, that is testing them all for HBV DNA.

Of approximately 5,000 deferred donors that we had over the last year -- that is, 2X cor reactive with anti-cor as their only deferral criterion -- we have invited these 5,000 donors to provide a follow up sample under NGI's HBV IND.

This was before the FDA had the proposed algorithm. So, we tested these by HBV DNA, HB SAG anti-cor, Ortho, anti-cor, and the PRISM anti-cor results are pending, as well as anti-HBS.

A study similar to this we will convert to the Roche's IND using the more sensitive method that Gerardo presented.

Of these study results to date, only 10 percent -- again, relatively low yield -- of these 5,000 deferred donors have provided a follow up sample.

Sixty-six percent, or numbers that are consistent with those I have shown, do have evidence of past HBV infection, leaving 44 percent eligible for reentry, assuming they don't show reactivity on the PRISM test.

Due to low participation rates, if you multiply out all the numbers, our yield of these 5,000 donors has only been a reentry rate of 4.4 percent. That is all the comments I have. Thank you.

DR. ALLEN: Thank you, Dr. Stramer. Questions or comments either for Dr. Kaplan or Dr. Stramer? This is certainly good to have this data, and I think at least I am a little surprised by the results that you just presented.

DR. STRAMER: The relatively low yield?

DR. ALLEN: Yes. As you said, the science is the science. So, that is very good, and we continue to learn more about hepatitis B infection.

DR. NELSON: Are donors now being screened for cor using PRISM?

DR. STRAMER: No, the PRISM cor test was just licensed on October 13.

DR. NELSON: So, presumably they will be.

DR. STRAMER: Yes, some blood centers are gearing up. The first date of implementation that I heard was December 5, but you know, validation, et cetera, et cetera, is required.

DR. ALLEN: Other questions on this topic?

DR. SZYMANSKI: I just wanted to point out that anti-surface hepatitis B surface antibody is not a reason for deferral, whereas the cor antibody is, I guess, because then you have more infectivity present if you have anti-cor antibody.

I just have noticed that sometimes our donors who have been recently vaccinated for hepatitis B also converted to anti-cor positivity.

DR. STRAMER: That is probably because they were vaccinated having had prior HBV infection, and this is a secondary or amanastic response to the vaccine. That has been seen before.

DR. SCHREIBER: Another elegant presentation, thank you, Susan. What the time between them being invited back for the re-testing and their initial tests?

DR. STRAMER: For the 5,000 in the last slide I showed?

DR. SCHREIBER: Yes.

DR. STRAMER: Immediately. Certainly, when we are inviting them back for a study, the message we can give them is not as strong as saying, if you come back for the study you may be re-enterable.

So, moving forward, hopefully after we do the validation studies and we are doing this real time, hopefully our yields will improve. The regions, to do a study, aren't that excited, as they would be to get their donors back.

DR. NELSON: I wonder if anybody has ever done a study where they do repeated DNA testing on a cor? In other words, the levels may be fairly low, but I wondered if they bounce around, those that are PRISM positive.

DR. STREAMER: Most likely they do, but in the reentry algorithm, they would have to be nonreactive, by the anti-cor.

DR. ALLEN: That is probably a study that is more likely to be done in the future than to have been accomplished in the past, and perhaps could be done on the reds data or other sources.

DR. NELSON: There may be some PRISM false positives as well.

DR. STRAMER: Of course there will be. There is no test without false positivity.

DR. ALLEN: An important object lesson to take on. Okay, we will bring this committee update session to a close. We are, at this point, running almost a half an hour behind. Good discussion.

I am going to turn the gavel over to Dr. DiMichele for the next session after a 10-minute biological break. Please keep your discussions to a minimum. Back in here ready to start in 10 minutes.

[Brief recess.]

DR. DI MICHELE: Good morning, everyone. My name is Donna DiMichele. I am a committee member and serving as the chair for this particular session.

In that capacity and without further ado, I would like to ask Dr. Elliott Cowan to provide the introduction and the questions to the committee on our topic for this morning, which is approaches to over-the-counter home use HIV test kits.

Agenda Item: Approaches to Over-the-Counter Home-Use HIV Test Kits. Introduction and Questions to the Committee.

DR. COWAN: Thank you very much. I think I am stating the obvious when I say there has been considerable expectation surrounding this meeting, and for good reason.

Knowledge of one's HIV status is one of the most important weapons we have against the epidemic, and HIV tests and testing are at its core.

As we begin what promises to be an extraordinary session, I wanted to make clear from the outset why we are here.

Within the past several months, a sponsor approached FDA to market its HIV test kit for home use. In response, FDA is taking a carefully measured approach.

As a first step, the agency felt that input on what information should be provided to validate a home use HIV test kit is critical to our decision making process, and that input is necessary before we consider over-the-counter claims for HIV home use test kits.

For that reason, we are bringing those issues before the BPAC in this public forum. Let me be clear, however, that consideration of HIV test kits for home use is a multi-step process.

Contrary to what you may have seen or heard recently, we are not going to be evaluating an HIV test for approval today.

An evaluation will come in the future only after we have established the criteria by which to evaluate these tests for their intended use, and when a company decides to apply for over-the-counter status.

At that point, the FDA will determine if the test kit meets the statutory and regulatory requirements for approval, determining that the device is safe and effective for its intended use. That analysis will be a determination of whether the benefits outweigh the risks.

Let me turn, then, to the matters at hand. The purpose of this session is that FDA is seeking advice regarding the conditions necessary to support the approval of a home use HIV test kit.

In particular, we are asking the committee to consider what studies are needed to validate test accuracy, test interpretation and medical follow up based on the provision of informational material in place of a trained test operator and counselor.

My role is to provide an introduction to this session to orient you, the committee. To do this, I am going to give you information on prior public discussions of home use HIV tests, a history of point-of-care testing for HIV, concentrating on rapid HIV testing, issues to be addressed for home use HIV test kits, an overview of this session, and finally the questions that you will be considering at the end.

Let me start with some definitions. Home use tests are tests that are used at home by untrained persons without the help of a health care professional.

There are two types of home use tests. The first is a home use collection kit, in which you take your own sample, mail it to a laboratory and get your result over the phone.

There are also home use test kits, and these are those in which you take your own sample, test the sample, and read your own test result.

There are some currently approved home collection kits, and those include tests for detection of hepatitis C infection as well as HIV. I will come back to the HIV in just a couple of minutes.

There are home use test kits which are for fecal occult blood, glucose, cholesterol, pregnancy, prothrombin time, just as a few examples.

At the same time, I need to let you know that there are no previously approved home use test kits for infectious diseases.

Again, home use test kits are different from home use HIV collection kits. For the home use collection kit, the specimen is collected by the test subject, the test is performed and interpreted by a trained operator in a certified laboratory, and the individual asking for testing receives live counseling.

In contrast, with a home use test kit, the specimen is collected by the test subject and, in this case, the test is performed and interpreted by the test subject.

So, there is a lack of trained operator, there is lack of live pre-test counseling and post-test counseling at the time that the test result is provided, and there is a lack of medical referral.

Let me turn now to some of the previous discussions that we have had in considerations of home use tests.

Starting in 1986 -- you can see there is some history here -- companies first expressed interest in developing and marketing home use blood collection kits for HIV testing.

At that time, FDA and AIDS advocacy groups raised public health concerns about test accuracy in the hands of untrained individuals, and the way users would be notified of their test results, particularly centering around areas of patient confidentiality, and adequacy of telephone counseling.

Counseling is a central issue. It is deemed critical to ensure that HIV infected people understand what HIV infection means, and receive important information about recommended treatment and coping methods.

In March of 1988, FDA notified, by letter, manufacturers and other interested parties, of requirements for the approval of these test systems, and this was based on consultation with U.S. public health agencies, our sister agencies, and public sector advisory groups.

This led, in February 1989, February 17, 1989, to a Federal Register Notice, in which FDA published its criteria for HIV specimen collection systems, and stated that these systems would be available only for professional use, and that results of testing should be reported to public health care providers for reporting an interpretation of the test result to the person requesting the test, as well as counseling the individual. In other words, the test result was not to be reported directly to the individual. There were other requirements as well, such as use of licensed HIV tests and some other requirements.

In this Federal Register notice, there was also an announcement of a public meeting to discuss the collection and shipping of blood specimens by lay persons, return of results directly to the person from whom the sample was collecting, counseling outside of the medical health care environment, availability of blood collection systems over the counter, as well as kits for collection and home testing of blood for evidence of HIV infection.

The meeting was held on April 6, 1989. At this session, invited speakers spoke to the issues of regulatory issues.

We heard from CDHR, the Center for Devices and Radiologic Health, their experience in home testing, speakers on counseling, ethical issues, as well as experience among the states.

There was extensive discussion on risks and benefits of blood collection kits and home use test kits, which I will get to in more detail a little bit later.

This led, in turn, to a Federal Register notice on July 30, 1990, in which FDA had stated that they had considered the data and comments from the April 1989 meeting and, on the basis of that, decided that HIV specimen collection kits should remain for professional use only.

At the same time, we stated our willingness to work with manufacturers on requirements for premarket approval application to review data for home collection kits, opening a door.

That same month, BPAC met to consider the approval of a premarket approval application from a sponsor for its home collection system.

The committee recommended against the approval of that particular application, citing the fact that the application lacked sufficient data, and the questions remained regarding possible problems with a variety of issues, including confirmatory testing, the counseling issues, as well as compliance with state requirements in maintaining confidentiality.

Between 1990 and 1994, FDA discussed over-the-counter specimen collection kits extensively with other public health service agencies, and also with product sponsors.

During that time, there was a change in circumstances. We saw advances in technology which translated into a potential for improved accuracy of these tests.

We saw a change in treatment methods. We saw the availability of therapy for asymptomatic individuals, so that people who had a reactive test result have the ability to be treated and to maintain a life with infection.

We also saw the public's increasing desire for greater involvement in personal health care decisions. In June of 1994, BPAC met again to reexamine home use specimen collection systems, and there was an agreement that there was a benefit to having alternative means of reaching previously unreachable populations for HIV testing, and that that outweighed the potential risks of such a system.

At the same time, concerns were expressed about accessibility of a home use specimen collection kit for target groups, adequacy of counseling, while maintaining confidentiality. and effectiveness of education and follow up.

There was a recommendation from BPAC At the time for pilot studies to evaluate these studies. One more Federal Register notice.

On February 23, 1995, FDA notified the public that it was revising its guidance for specimen collection kits labeled for HIV antibody testing set forth in the February 1989 notice, that over-the-counter specimen collection kit systems may be approvable, and listed specific kinds of data that sponsors would need to submit for the review of the safety and effectiveness of these products.

However, it did not address kits for home testing, home test kits, in other words, for evidence of HIV infection.

This notice led eventually to the approval of two home specimen collection kits in 1996, one of which was the original test that BPAC had considered in 1990.

So, what has changed since 1995? One is the technology. We now have tests that have an extremely low risk of an incorrect result, and tests that are unaffected by changes in operating conditions or conditions that could affect the integrity of the specimen.

These tests are simple to use. They don't require special storage conditions. The results are available within 20 minutes and, in one case, uses an oral fluid specimen, which would eliminate concerns that were previously expressed concerning biohazardous conditions. In other words, there is no blood to be collected and no sharps. We also have more experience with these tests in non-traditional testing settings.

There is the concept that early detection translates into better outcomes. Again, with the increased availability of treatment regimens, early identification before the onset of symptoms can translate into better outcomes. Finally, there are changes in social awareness of HIV infection.

Let me turn now to some nuts and bolts of HIV testing. Traditional HIV testing requires two visits to a clinic or health care provider, one to provide the sample and the other to receive the test result, normally about a week later. It could be a little bit less, or it could be up to two weeks.

CDC has estimated that each year approximately 8,000 positive individuals do not return to receive their test results.

Contrast this with point of care testing, in which the test provides a test result in a relatively short time, so that only a single visit is required.

These tests come under the category of what we refer to as rapid HIV tests, again, tests that provide results within 20 minutes, require few steps to perform, have a visual readout, no special storage conditions or instrumentation is required. They detect antibodies to HIV, and these tests are used for diagnostic purposes only, not for blood donor screening. At this point in time, FDA has approved four tests in this category.

The performance standards for rapid HIV tests were discussed at yet another BPAC meeting on June 15, 2000. Performance standards, and the clinical trial and non-clinical requirements were discussed and concurred upon by BPAC at that time.

In terms of performance, it was determined that the sensitivity of these tests should be 98 percent, as well as a specificity of 98 percent.

The important consideration here is that this is a statistical number. Ninety-eight percent is the lower bound of the 95 percent confidence interval. It is not a point estimate.

This translates into tests that are very accurate. The next two slides are going to give you some examples regarding the four tests that are available now.

So, the four tests that are available are OraQuick from OraSure, Reveal from Admira, Unigold from Trinity Biotech, and Multispot from Biorad.

Looking at the numbers here, with the different types of specimens that could be analyzed using these tests -- whole blood, plasma, serum, oral fluid -- you can see greater than 99 percent sensitivity, and these figures are point estimates from clinical trial data that were submitted in support of the product approval.

Likewise, for specificity, the numbers are exceptionally good, specificity being the ability of the test to tell someone he or she is not infected when that is truly the case.

Regarding the interpretation of these tests, a non-reactive rapid test result is considered to be a negative result or, as a reactive result, is considered to be preliminary positive.

That is, all reactive results should be confirmed using an appropriate supplemental test, and this is consistent with the concept that FDA has abided by over the years that, although screening test results are highly accurate, the test results should be confirmed by supplemental testing.

In discussions on the role of rapid HIV tests in facilitating HIV testing, it was recognized that, even though these tests were simple to use, it is critical that a quality management system be in place to assure that testing was being performed properly, and you will be hearing more about this later from one of our speakers.

With an eye to this, and with concerns that rapid HIV tests could be used improperly, FDA approved rapid HIV tests with a series of sales and use restrictions.

The first is that sale is restricted to clinical laboratories that have an adequate quality assurance program, and where there is assurance that operators will receive and use the instructional materials.

Secondly, the test is approved for use only by an agent of the clinical laboratory, that is, they are not approved for self testing.

Test subjects must receive a subject information pamphlet and pretest counseling prior to specimen collection, and appropriate counseling when test results are provided.

These tests are not approved to screen blood or tissue donors, and a customer letter is included with all kits that are purchased which states, by purchasing this device, you are doing so as an agent of a clinical laboratory and agree that you or any of your consignees will abide by the restrictions on the sale, distribution and use of the device.

Access to rapid HIV test has been an issue that has been discussed also over the years, and the central question here is who is permitted to use these rapid HIV tests.

This is governed by something referred to as CLIA, the Clinical Laboratory Improvement Amendments of 1988. What CLIA does is, it categorizes tests on the basis of their complexity.

So, tests can fall into one of three categories, high complexity, moderate or waived. Waive tests are free of many of the requirements under CLIA for oversight, when these tests are run.

To perform CLIA waived tests, the entity must do one of only a few things. One is, enroll in the CLIA program, obtain a certificate of waiver, pay a biennial fee, follow the manufacturer's instructions, and meet state requirements.

Contrast that with moderate and high complexity tests in which there are requirements for training for each of the individuals who are running the tests, as well as a number of other requirements, including inspections of the facility.

The sponsor must apply for CLIA waiver. It is not granted automatically. An application is made to FDA after initial approval, and results of studies must be supplied to demonstrate that the device is simple and accurate in the hands of intended users.

By the way, CMS, the Center for Medicare and Medicaid Services, is also involved in the CLIA and is involved in the inspections and much of the program as well.

As far as the HIV testing goes, what is the impact of CLIA waiver? What it has the potential to do is that, again, subjects can be notified of their test result without the need to be recontacted or the need for a second visit, and fewer laboratory restrictions permit potentially wider use.

BPAC discussed this issue on June 14, 2001. There are now two tests that have received CLIA waiver, each of the two tests for two different types of specimens.

OraQuick has received a CLIA waiver for its use with whole blood, which was granted on January 31, 2003. Subsequently, for use with oral fluid, on June 25, 2004.

The Trinity Uni-Gold test was granted a CLIA waiver for use with venepuncture and finger stick specimens as well. On your handouts, there is a bit of a typo. The second Uni-Gold reference should read finger stick, instead of another venepuncture.

I should also make mention of the fact that the sales and use restrictions, which I was discussing before, also apply to the CLIA waive tests.

Now, turning to some of the recurring themes that we have heard over the years -- and you will be hearing more about this, I am sure, over the course of the day.

There are a number of benefits. Number one is, anonymous testing potentially leads to more people knowing their HIV status.

Secondly, earlier diagnosis can translate into earlier intervention and better outcomes for the patient. The home use test kit would empower consumers in making their own health are decisions.

There is the potential impact on behavior and public health. In other words, knowledge of HIV status can lead to change in behaviors that would have resulted in infections, thereby limiting the spread of the virus and having a potentially significant impact on public health.

There are also, of course, a number of risks that have been repeatedly coming up over the years regarding home use HIV test kits.

Inappropriate use of the test or test result. It is absolutely critical to understand the limits of HIV tests.

In tests that we are discussing here, these are tests that detect the presence of antibodies to HIV. These antibodies are a response to the infection by the immune system of the individual, and this response can take about two months.

Therefore, an individual concerned about a possible HIV exposure within a week could very well be infected with HIV, but would test negative.

Actually, there is no approved or licensed HIV test that has the ability to detect infection within a week after exposure.

Continued high risk behavior with a false sense of security of the negative test result would then result in transmission of the virus to others.

There is a potential for adverse outcomes obtaining a test result without live counseling. Concerns have been expressed over the years about the psychological effects of receiving a positive HIV test result without the benefit of live counseling. The biggest issue that has come up repeatedly is suicidal tendencies.

Follow up. Testing in the home leaves the decision to seek confirmatory testing and medical care up to the individual, rather than facilitate it through a counselor. Also critical is the need to notify partners so that they can be tested as well.

There is the issue of coercive testing. Concerns have been expressed about testing people against their will, for example, by insurance companies or employers. Also, forced testing by abusive spouses or family members could potentially lead to violent back lashes.

Another issue is testing by minors. This is not testing of minors, but testing by minors, the ability of a minor to go out and purchase a test, and the question is whether a minor is able to handle the test result, or properly interpret the test result when it is achieved.

A few additional issues, obtaining a test result without a supplemental test. The false positive rate is very significant in low prevalence populations or when there is little risk present.

The availability for those who need the test the most, and a potential conflict with state and/or federal health reporting requirements.

As I close my introductory remarks, I would like to set the stage for you, so that you will know what you are about to hear.

What we have done is arrange for speakers to address issues that FDA feels are key to considering HIV test kits for home use.

You will first hear a proposal by OraSure Technologies for an over-the-counter claim for its OraQuick Advance Rapid HIV-1, 2 Antibody Test, for use with oral fluid specimens, including proposed studies to validate adequate performance in the hands of intended users.

What will also be addresses is the populations that would be studied, and will they be reflecting intended users of the tests, as well as the ability of informational materials to provide counseling and other information in a comprehensible manner by intended users, addressing such issues as accuracy of testing, correct test interpretation, management of psychological and social issues, and medical referral.

You will be hearing a discussion of changes in HIV testing practices and counseling recommendations from Dr. Bernard Branson from CDC.

You will be hearing from Dr. Devery Howerton, also from CDC, who will speak to the role of quality systems for diagnostic tests.

You will be hearing from Dr. Joseph Inungu from Central Michigan University, who will address psychological and social issues associated with HIV testing and HIV home use tests.

You will be hearing an overview of the over-the-counter review process and human factors consideration by Arleen Pinkos from our sister center, the Center for Devices and Radiological Health, and the Office of In Vitro Diagnostics.

Finally, you will be hearing from the public. You will, no doubt, hear passionate arguments on all sides of these issues.

I ask that, while considering all of the information that you will be presented with today, you do so keeping in mind the need to address the following questions:

Number one: Are FDA's previously established criteria for sensitivity and specificity for rapid HIV tests also appropriate to support OTC use for home use HIV test kits.

Number two: Please comment on the design of clinical studies necessary to validate the safety and effectiveness of an over-the-counter home use HIV test kit.

Finally, number three: Please comment on the proposed content of the informational materials and the steps that should be taken to validate the adequacy of the informational materials to communicate or provide pathways to adequately address issues including: accuracy of testing; correct test interpretation; the importance of supplemental testing for confirmation of positive results; management of psychological and social issues; the availability of counseling; and medical referral.

I am going to be returning to these questions, of course, later -- it may be much later -- to assist you in addressing these questions, which the heart of these questions is, what is needed for the validation of these systems. Thank you very much in advance for your input.

DR. DI MICHELE: Thank you, Dr. Cowan. Do the committee members have questions? I actually have one. In reading the Federal Register document from 1995, regarding the licensing of collection HIV test kits for home use, there was a recommendation that the manufacturers follow up with post-marketing surveillance on the psychological and social impact of home collection kits.

Is that some of what we will be hearing later? I guess, did that ever happen, and is that some of what we will be hearing later?

DR. COWAN: I am not aware of any formal studies that have been done. However, the speaker who will address the psychological social issues will cite various references in the literature, at which these sorts of things were examined.

As far as formalized studies to address the psychological and social issues, in a phase IV type study, I am not aware of any results that came out of those.

DR. QUINN: Although it is very different, there are parallels to what the FDA probably went through with OTC pregnancy testing being used by young people, the counseling that is inherent with knowing one is pregnant or not, and so forth.

Will we hear, or would it be appropriate, to hear the steps that the FDA had to go through in those considerations and how they were dealt with, and the type of information and so forth? I don't know how far back that actually goes, as to when that was approved.

There is a big long track record and, if there are some parallels, at least -- different, but parallels -- we might be able to learn from some of those experiences.

DR. COWAN: I believe that Arleen Pinkos will be addressing some of those issues in her talk, and it is her center which was actually involved in those studies, and there are other folks here from CDRH who could help address some of those, if questions remain, after her talk as well.

DR. SCHREIBER: One of the things that we continue to see are these sensitivity specificity issues. We all know that, in blood testing anyway, the EIA is not particularly accurate in terms of the number of repeat reactives that confirm.

In fact, the rate is probably somewhere around 10 percent or so, so that 10 percent of the repeat reactives confirm positive.

Whatever we look at in sensitivity and specificity is a function of the population that it was tested on. If you look at only the high risk populations, you are probably going to get a much higher sensitivity and specificity.

The sensitivity is only a function of the number of positives that are picked up, true positives, not a function of the false positives.

If you look through the information that we have, it appears that there is still the chance for a fairly substantial false positive rate, probably in the literature that we saw, somewhere on the order of 10 percent, and we have a letter here that indicates a 50 percent false positive rate.

I think that, when we review these presentations, I think we really have to keep in -- at least I have to keep in mind how many people are tested repeat reactive, that would never confirm, and those people probably wouldn't go back and seek a confirmatory test, I am afraid.

DR. COWAN: I think it is also important to keep in mind -- to separate the ideas of sensitivity and specificity from positive predictive value and negative predictive value.

These are concepts that I alluded to a bit, where I referred to the fact that someone who has few risk factors -- a low risk person, a low risk group of people -- who are going to be taking this test are most likely going to have a false positive result, again, in the absence of any risk factors.

These are statistical epidemiological considerations that need to be taken into account. Sensitivity and specificity are more absolute numbers, whereas positive predictive value and negative predictive value take into account the group of people that are being tested at the time.

MS. BAKER: Thank you for your presentation. In the course of today's hearings, will we learn about the experience of other countries with infectious disease testing, over the counter?

DR. COWAN: That is not on the agenda at this time. We had considered that briefly, but -- I take that back. You will be hearing some data, I believe, from Dr. Inungu, on some studies that were done abroad as far as psychological testing goes, and there is a variety of experience around the world with over-the-counter testing.

At the same time, there are cultural differences from country to country, what our society is willing to accept versus what other societies are willing to accept.

We felt that it was most relevant to restrict our discussions to what we would expect to find in the American public.

DR. KULKARNI: I just also wanted to know if there is any data available on the impact of these home use test kits that are currently available on adolescents and minors. That is one of the issues that was raised with this particular kit.

DR. COWAN: Dr. Branson may be able to better address issues like that, and I believe you will be hearing something to that effect from him when he speaks.

DR. DUFFELL: I noted that your second point that you want the committee to consider deals with the design of clinical studies.

Can you tell me right now whether or not there are any such studies that have already been undertaken by a manufacturer and, if the answer is yes, are they going to speak to us about the design that they chose and the logic behind it?

DR. COWAN: I will speak to you as an FDA person and say that any questions regarding what a manufacturer is doing should be addressed to the manufacturer. The information is considered confidential and proprietary.

I am not being cagey. I believe that the OraSure people will be able to address issues like that, and you should certainly feel free to question them on any concerns that you have regarding what they are presenting as far as the clinical trial data goes, or as far as anything goes. That is really the point of our questions.

DR. DI MICHELE: Are there any further questions? Okay, I would then like to thank you, Dr. Cowan, for a very, very clear presentation. I think we understand what we are about to hear and the decisions we will be faced with.

I would like to invite Sue Sutton-Jones to the podium. She will speak on the proposal for an OTC home use HIV test kit, on behalf of OraSure Technologies.

Agenda Item: Proposal for an OTC Home-Use HIV Test Kit.

MS. SUTTON-JONES: Hi, good morning. On behalf of OraSure Technologies, I want to express our appreciation just to be here.

We have been very pleased with the adoption of our product in the market since 2002 by public health and other agencies, and we are very encouraged by the results and the feedback we have gotten from that.

To be able to be here and participate in the meeting, listen and learn from all the discussions today, is just a great opportunity for us. So, we are really excited to be here with you today. Hopefully, we will answer all your questions.

Briefly, I just want to go over the agenda. During the talk, what I will do is just elaborate on some of the key points that we feel are important, the intended use of the device as an OTC.

I just want to show you the device very briefly. We have a slide that shows you how easy the sample is to collect, we will talk about the test system itself as it exists now, and how it supports the validation of an over-the-counter application.

Then, what OraSure would propose is needed for studies to further validate an over-the-counter application for this product, our consumer labeling, messaging and packaging, and then a very brief conclusion and recap at the end.

I won't go over all the information on the slides. So, if you have any questions about a specific slide, feel free to stop me. Otherwise, I will just keep moving through them. There is a lot of information on them.

Our proposed intended use statement is very straightforward. It focuses a target or an intended user on the following, which is, it is a single-use device. It is a qualitative test.

The user won't have to worry about calculations or number ranges, as you do with some other tests. It is also a test that will detect antibodies to both HIV-1 and 2, which is important, and it is an oral fluid test.

So, there is no finger sticking, no blood collection that is going to be required by the user in their own home.

Now, this is the collection device. As you see in the picture here, it is very easy to use. You simply go around the gum line once, around the region of the gum, and then it is going to be inserted into a developer bottle, and that is it.

What it does here is, this is the flat pad, and there are no parts or anything that can harm someone with that. Then the results are simply ready to read in 20 minutes.

Now, materials in our test kit for a consumer will be especially configured for use by a consumer and not a laboratory person.

So, we are going to have pre-test and post-test counseling information in the package. We will also have a risk assessment pamphlet. We will have other printed materials in there as well.

We are also going to have pictorial based collection testing and interpretation materials in there. So, even if they don't read everything, they will be able to see it graphically.

Then they will encounter the single use device. They are going to see the developer vial, and then the test stand, which we propose will be built into the package itself.

It is also important to note that there are no hazardous components in this kit. So, disposal is simply household waste or trash. There is no special handling that will be required either with this test for the user to deal with.

Now, the device contains an internal control. It is easy to interpret. What it will do is let the consumer know that the test is functioning properly.

They will know if the sample has flowed through -- well, they will know if the sample has been collected, and then they will know whether it has flowed through the device after they have put it into the developer vial, because of this C triangle, where there is a line that appears here. That will indicate to the user that it is a valid test. So, they will see that.

The technology behind that is basically the antibody conjugate complex is captured on an immobilized protein line that is on that pad. All the consumer will have to know is simply to look for the C triangle here.

Using the same view, once the user has actually performed the test, what they will do is interpret it after 20 minutes.

For a negative, there is only going to be that single line. So, a line will appear here, they will know it is a valid test, at that C or control triangle.

If it is a preliminary positive, what the user will see is two lines. They will see, again, the control line that is going to tell them that it is valid, and then they will see a line here at the T.

This may indicate the presence of antibodies to HIV. The negative result indicates that there are no antibodies to HIV-1 or 2 in the sample tested. So, it is just a very simple two step process that an individual would go through.

Next, I would like to briefly describe some of the clinical studies that have already been performed with oral fluid.

There is a question raised today about the specificity and sensitivity, lower confidence boundaries of 98 percent, and whether that is appropriate or not but, as you saw, we do meet and exceed, with greater than 99 percent, the recommendations by FDA for rapid tests at this point.

So, our sensitivity, specificity and ease of use have been demonstrated through many of these CLIA studies that we have done here.

These studies were also conducted with sufficient statistical power and followed the recommendations of FDA for the population demographics and size.

So, we generated our claims for sensitivity and specificity based on the negative, positive and high risk populations that you see here on the slide.

We based the specificity of the test on all the negative samples that were determined from all three population groups and, of course, their sensitivity was calculated using positives we found within our high risk population, as well as known positive populations that we sourced from known infected individuals.

Now, here in this study, all of these samples were collected, self collected by the subject, and the test performed by them.

Here, again, it shows, one, it is able to be used very easily, and the results of all these studies are well within, again, the sensitivity and specificity claims so far in place for rapid HIV tests.

This is our CLIA waiver study. It was granted based on demographics in a population from a lot of different areas in our target users.

This slide here demonstrates that we had male and female, we had varying ages, as well as a fairly diverse population.

In the next slide, we also considered their educational backgrounds and experience, as well as their professional experience.

You will notice, down here on the bottom of the slide, actually none of them -- 99 percent, not none -- but 99 percent of them had no experience with our device or with rapid tests prior to participating in the study.

In this study, users were actually given a panel to use. There were negative, low positive, and high positive samples that they were to test and interpret.

This study validated the safety and efficacy of our device in those untrained user hands, as well as the accuracy of that test interpretation by an untrained user.

Now, here we also performed studies to just determine the impact of common household substances on performance of our test.

What we found was, there was actually no influence there at all, no effect. We also realized that this is going to be performed under varying environmental conditions, and so, to evaluate that, what we did was focus on these changing environments, perform the testing there, and we found no effect on performance of the test as well.

All of these results, as here on the bottom of this slide, were accurate, and they were concordant with the true serostatus of the specimen that was tested.

Now, in these slides, what we have shown you are studies that have already been done. So, we feel that the technical performance of the test actually does validate this application as an OTC.

However, what we would like to do now is go through slides where we are going to propose some of the studies that we would like to do in order to fully validate it as an OTC application.

This is just a summary slide here. What we have proposed to do is, we want to demonstrate that, with the instructions for use, the messaging, the labeling of the device, that an individual that is untrained is able to perform the test correctly, and that they are also able to interpret the test correctly and accurately.

We want to validate that the labeling and printed materials provided communicate effectively the importance of linkage to care and counseling to the user, and also communicate the options that are out there and available to them for those.

Lastly, we see a need to perform post-market surveillance studies, which were mentioned earlier, to estimate the number of individuals that are taking the test, and then also which options did those individuals actually choose from those available to them.

So, the first study here, the objective is simply, the study will be designed to test the ability of the untrained user to actually collect the sample correctly which, again, is just very simple, one time around the gum line, and then into the developer vial.

They will do this after they read the instructions for themselves, and then also interpret the results. Again, can they do it accurately based on the labeling and instructions for use that we provide to them.

Now, as expected in any study, the population will reflect the demographics of the expected or intended users. We will have untrained users, again, as I said, collect these samples themselves, read the instructions, and perform the test.

The devices will be interpreted by them. They will look for that C or control triangle which, to us, will indicate that it was a valid test and performed properly.

We will develop design or acceptance criteria prior to the study, in order to assure verification of the efficacy of the collection of the sample by the untrained user.

The size of the study population will be sufficient enough to supply statistical verification of these results.

We propose to perform another study, to validate the ability of an untrained or lay person to interpret the results accurately after reading the instructions and performing the test.

It is very similar to the previous study that I just talked about. The difference here is, these individuals will be given a positive and negative specimen panel that they will use to test and interpret.

We will have parallel interpretation of the devices by a trained reader, so that we will have a comparison between trained and untrained users, and then the size and the statistical validity of the study will be established, just as it was in the previous studies, and the ones we have done in the past.

Now, understanding the importance of counseling referral to care, or show or validate the ability of the labeling and printed material to ensure that important linkage to care.

The same rationale will apply for sample size, population demographics, and for statistical validity, as it did in the other studies.

The key objectives that I want to point out in this study is that, the ability of a user to understand will be evaluated.

What we want to know is, they understand the options for pre and post-counseling based on the labeling and instructions for use in the product.

We also want to look at key messaging. That would be messaging such as risk factors, risk behaviors, the potential for false positive and negative results, and then also the important window period where the disease may not be detected if they are tested too soon.

Now, we have not developed fully our labeling that we would use within these clinical studies. That is one of the reasons we are here today, is to hear from the audience, as well as from the advisory committee, what we should include in there.

So, this is just an example of the information or the type of information we would expect to include in our labeling and packaging material. So, it is not intended to be all inclusive, but it is one of the approaches and one aspect of it.

The linkage to care and counseling is very important. With this in mind, we are keenly aware that the clarity of the printed materials, as well as the messaging, is essential to this process.

Because of the criticality of this information, though, we are very eager to partner with other organizations that have experience within this area.

We also will solicit input and recommendations from FDA and Public Health Service during our development process as well.

Now, continuing on with labeling, our general approach again would be to provide pre and post-counseling options that are very clearly defined, so that the consumer can understand them very easily, as well as act upon them.

By establishing a comprehensive support network, the consumer will be enabled to make decisions they are comfortable with and, therefore, reduce their risk of HIV.

Our emphasis is going to be on the numerous choices an individual may make in order to reduce the risk of HIV in the general population.

Now, the post-marketing studies, the last piece of the keystone. Everyone recognizes that an over-the-counter HIV self test kit can play a very vital role in testing where both positive and negative individuals are actually linked to appropriate care, and also to risk reduction counseling.

We intend to partner with public health authorities in order to disseminate and capture some of this information.

By collecting and sharing this information, we can assess which options are the most successful in linking an individual to the multiple resources that are out there now for their use.

In this context, our packaging is a key and critical component to it. So, we have talked a little bit about the labeling and the concepts that we have about what belongs in that.

We actually want to go into now the physical package itself. We have come up with a prototype design based on the following.

We recognized early on that the packaging is an important opportunity for us to communicate key concepts and understanding to the user of the product.

So, we focused on the items here. We want to take the user through a step by step, very methodical procedure on how to use the kit, as well as introduce them to the packaging and printed material within, and the labeling and instructions for use.

We also wanted to enable multiple visual cues. So, again, if they don't read everything, they will see how to collect the sample and how to process it.

Important, it is to minimize missteps, as well as go through procedure sequencing by the user. So, the following is just one concept of how that might be accomplished.

There is our package. It is a prototype. So, it is not a fancy one here. What you are seeing is that the package will be opened by the user.

The lid will come off and then multiple layers, where we have an opportunity to message how to use the kit, message about risk factors, pre and post counseling options with it.

So, as the layers come out, it is intended to be provision of educational materials. There will be graphical representations, as we just spoke about. They are pictorial based, and will provide an individual with visual cues as to how to perform the test and interpret it.

So, now it is revealed here. What you are seeing is that you are now going to see the package. The smaller one is the developer vial.

What they will do is, they will take it out. They will open it up, and they will place it in the test stand. They will open it up. So, that is the developer vial opened.

This is actually this collection device. They will open it, once around, and then insert it immediately into that developer vial, and that is it.

So, it is just a two step process, very simple, and in 20 minutes they will be able to read their results as well.

So, in conclusion, the technical performance of our approach for an over-the-counter HIV-1, 2, oral fluid antibody test, we believe, has already been proven through studies that we have done in the past and have submitted.

The sensitivity and specificity are well above 99 percent, which is well within the FDA guidelines that have been established already for rapid tests, and are under consideration today.

Then, the validation of the test system itself, which includes the labeling and the packaging, for use by a lay consumer, will be further studied, through other studies that will go on, and that will validate that.

Then lastly, we propose to demonstrate the effectiveness of that very important link to counseling and care through post-market surveillance studies that we want to partner with public health to perform.

So, at this time, I would be glad to answer any questions you have. I do have other individuals from OraSure here, that can help out with questions as well.

DR. DI MICHELE: Thank you very much. Perfect timing. Congratulations. The committee has questions. We will start with Dr. Nelson.

DR. NELSON: I wonder if you have done any studies to document the timing of the control spot, or band.

MS. SUTTON-JONES: The line?

DR. NELSON: Yes. In a person who is positive, does that precede, or is it in parallel with somebody who is positive for the HIV band?

In other words, if somebody at the home, instead of letting the device stay in the fluid for 20 minutes, they allowed it to stay 10 minutes or five minutes or eight-and-a-half minutes, is there any possibility that they would have a control band showing that it was a valid test, but that the HIV band had not yet developed?

I wondered if you had done any studies on HIV positives to look at this sequence. We have had some experience with injection drug users using bleach to disinfect injection equipment.

What we find is that, when the drug is there, ready to use, and it requires one minute to disinfect the syringe, oftentimes they do it for 15 minutes, and we found that this disinfection is not very effective in practice.

There is a difference between what a lab would do and what a person would do. I just wondered if this has been studied in any detail.

MS. SUTTON-JONES: It has been looked at, and that is how we established the window for read. The window actually goes from 20 minutes to no longer than 40 minutes to read for the test.

There are studies that have been done. I don't know that any of them have been performed specifically -- unless one of the members of my team do -- that actually addressed an HIV positive individual, and how fast that line developed versus the control line.

It all flows together. It is a lateral flow device. So, in theory, they both come out at the same time and develop.

DR. NELSON: Are any of your studies on seroconverters, that is, within people who have been known to be infected, let's say, a month or two months, as opposed to established infection.

MS. SUTTON-JONES: Yes, there are seroconversion studies that we have done. This is an antibody test and, as long as there are antibodies to HIV, I think we have -- our claims are 400 copies are great. Then, it will most certainly detect it. We will address the window period in the labeling and following the CDC guidelines, of course, for re-test.

DR. DOPPELT: You mentioned that you put the developer in this stand. I assume it has to stay upright during the full 20 minutes. What happens if the cat knocks it over and you find it and stick it back up.

MS. SUTTON-JONES: Actually, it doesn't sit straight up. It is at a slight angle, once it is in there. What the packaging is intended to be -- and that is why we propose to build into the package -- is so that, once it is inserted, it is securely seated there.

So, you would have to turn over the whole test stand to actually turn over the developer vial. So, it is not going to be set on a flat surface.

DR. DOPPELT: If it does fall over, is the test still valid or not valid, and you put it back up.

MS. SUTTON-JONES: We haven't really considered that.

DR. DOPPELT: Does it alter the flow. I mean, it falls over, you put it back up. This is not done in a laboratory.

MS. SUTTON-JONES: That would be one of the -- we call it bash testing, but we would do some consumer testing to actually look at how they perform the test and what possible mistakes they could make with it, and label for it.

DR. KULKARNI: Even though I know that this is for oral fluid only, have you tested other body fluids? I am sure, if I know my patients, they will probably dip it in every little thing that they can think about. Would you label it that way? Do you have data on other body fluids?

MS. SUTTON-JONES: We have data on blood and plasma, whole blood and plasma.

DR. KULKARNI: I am talking about breast milk, vaginal fluid, seminal fluid, things like that.

MS. SUTTON-JONES: We have done testing where it is just common substances, and that is one of the questions, obviously, that we have to address.

Again, this is an OTC application and previously we were working, as you said, with a laboratory. So, it is all part of the consumer testing that we will have to go back and look at, those common substances.

DR. QUINN: On your slide about the untrained user study validation, I mean you did negative samples, low positives, high positives and so forth, and you give sensitivities, how well they did compared, but I wasn't quite sure, what is the gold standard.

Is that a negative sample on OraSure, compared to a western blot? In other words, how well did the untrained people do compared to, say, a trained technology on OraSure? That would be one way of looking at the data, and your potential studies, I hope, will address it.

The other is, compared to a gold standard of EIA western blot, how well do these untrained use individuals compare to that golden standard?

MS. SUTTON-JONES: That is typically the characterization we do of our specimens. Before we actually use them, we know, in general -- it depends on the study, but we will do western blot as well as EIAs.

DR. QUINN: So, for these, the low positives, high positives, that is like western blot confirmed, and that is how well they compared to that.

MS. SUTTON-JONES: Right.

DR. QUINN: Another study will be, how well does an untrained individual compare to a technician. I think lots and lots of data on that would be useful.

The follow up question is, although you have addressed many of the issues that have been raised, the two that I don't know if your future studies are going to get into, one if these reporting requirements by state. The other is no follow up, or partner notification issues. That is a little bit beyond your control. I didn't know if you had any thoughts about that, for future studies, how you might want to look at that down the road.

MS. SUTTON-JONES: Certainly, through post-market surveillance, we would want to look at it, and you bring up a good point about reporting.

We obviously are not going to distribute or work within an area where it is not allowed. So, if a state, for instance, has specific reporting regulations, then we would be precluded from selling over the counter there.

We are going to work, though, with public health services to do that, and establish that, and find out what the impact might be, if any, on them.

DR. SZYMANSKI: I wonder, to which kind of population you are intending this test. Is your purpose to meet some need that is not met right now?

MS. SUTTON-JONES: Right now what we have talked about is just the general population. What we need to do is a market study, where actually we look at who would be the most typical consumer of this product.

Right now we are guessing general population, because of the venue it would be sold in. So, we do need to do further market studies to actually pinpoint who would do it.

The unmet need is actually -- much of what was up there is the benefits for an HIV home use test. That need is not met, because there are individuals that don't get tested, or won't come back for results to a health clinic.

DR. KUEHNERT: I saw that the sensitivity and specificity is very high, but you do have some false positives and false negatives.

I was just wondering if we are going to hear today about the reasons for those false positives and false negatives, both in terms of those that are thought to be operator dependent and those operator independent, along the line of what Dr. Quinn was saying.

That would give us some insight into what the pitfalls might be. So, I didn't know if you were going to be presenting that data today. That would be very useful.

MS. SUTTON-JONES: No, but basically it is just based on the specificity and sensitivity of the assay. We have a very nice balance where they are very close to each other. That is the reason, obviously, that they occur.

There are also certain preexisting disease states, for instance, that would cause a false negative to occur. Certainly, if you are on any kind of immunosuppressive therapy, for instance, for AIDS, your antibody level plummets on some of those, and we wouldn't pick that up, but no one would.

So, it is just that has an antibody based test. So, that primarily is why you are going to see a false negative.

The other is, it is going to based on obviously also the predictive positive calculation. Therefore, we are going to have to identify exactly who might use it or, if it is general population, what the demographics of the United States are, as far as prevalence of AIDS infection.

DR. KUEHNERT: So, for the false positives, that also, you said, was based on some underlying condition and not based on, as Dr. Doppelt said, something of the cat knocking over the test.

So, it basically was some underlying condition in the patient. Is that what was thought to account for false positives?

MS. SUTTON-JONES: That, and there are just false positives that occur. It picks up something within the specimen.

I can't say that they are all related to disease states, no. There are false positives, and that is in the literature.

DR. KUEHNERT: Just one more thing. On a false positive or a false negative, there will also be data on whether, on a repeat test, whether that happened again? Will there be any data on that, whether it was associated with the test episode or, again, just with the patient being repeatedly positive on the test? Will that be sort of looked at?

MR. SUTTON-JONES: That is part of the clinical studies we do now, yes. We will look at that.

DR. DI MICHELE: Just relating to Dr. Kuehnert's question, if you read the brochure and your untrained individual for the OraSure validation studies you did for CLIA, it appeared that the errors really did segregate to one or two individuals performing the test. Is that not correct? I mean, that is what the brochure says.

MS. SUTTON-JONES: It does. I am not sure if they were the same individuals in each instance, though. Do you guys know?

DR. DI MICHELE: We can come back to that.

DR. MANNO: I have two questions about the package information. The first is, how likely do you think it is that people will go to a web site to find a local provider for care for HIV infection? Do we know how often that works?

MS. SUTTON-JONES: Well, there are generalized research studies. We would have to establish that ourselves.

DR. MANNO: It just concerns me that some of the people at risk might not be the sort of part of our population that uses on line resources.

MS. SUTTON-JONES: No, but there is a toll free number, and there will be 24/7 access for individuals to call, if they want to call and talk to someone rather than use a web site.

DR. MANNO: Would you recommend other local public health recommendations for care?

MS. SUTTON-JONES: Oh, yes. Both will be there. We will have geographic specific.

DR. MANNO: The other question I have is about packaging, and I am sure your packaging people gave you recommendations about how people open packages.

It seems to me that someone would want to see the information about the requirement for counseling as well as the testing standards prior to purchasing the product.

It might be a good idea, rather than depending on them opening these two pieces of cardboard, which I can assure you they would toss, that some of this information be on the label.

MS. SUTTON-JONES: Actually, those pieces that flip up would have printing and figures on them.

DR. MANNO: Once they get the product, I think they are going to want to use it.

MS. SUTTON-JONES: Okay, we will do that.

DR. LAAL: I wonder what the sensitivity of your test is in non-clade B infections, in the other clades of HIV.

MS. SUTTON-JONES: Actually, I don't know. Keith, do you know? Keith is from OraSure.

MR. CARDOS: For the non-clade B, we did run the worldwide panel, and that is reported within the package insert. So, we did look at the kind of full diversity. I can't quote that right now without a slide, but it is in the labeling.

The other question that was brought up on the user study, the reason it was delineated to the two users, when that test was done, it was a batch mode of randomized samples.

So, in any case where there could be a potential sample mix, that would count against us, but that was one thing in that study that we would correct in a following study, is that samples would not be given together. You would be giving them together. So, there is no chance of that.

DR. SIEGAL: A couple of questions. The negative sample is obviously prescreened for HIV negativity and, therefore, screens out false positives.

What about the characteristics of your low positive sample? Is the N actually just 200, and what were the demographic characteristics of that sample?

MS. SUTTON-JONES: Actually, the negatives are any negative, even if it comes from the high risk population. So, negatives weren't screened prior to -- we did include those in specificity. Now, to your next question, I think Keith is coming back up to actually answer that one.

DR. SIEGAL: I just wanted to know a little bit more about what you guys considered a low positive sample. What was the N. Where did they come from. Where was the geography of that population and so on?

MR. CARDOS: The low positive -- for the CLIA study, we actually had a panel that was evaluated in a larger user study, and we picked samples on the low end from really the color of the line.

You saw in the presentation there was a dark line. There can be a somewhat fainter line, and we made sure we covered both ends of the spectrum to make sure we accounted for that in the study. So, the low positive really is the reaction within the test, is the way we have delineated it.

DR. SIEGAL: My question really has to do, in part, with whether you are looking at populations of people from low risk areas, or low prevalence areas for HIV, to find out what the false positive rate is there.

MR. CARDOS: Within the population that we have, we did have the low risk population, which was a substantial set of the clinical data, and also the negatives that came from the high risk. So, there was a good mix of both of those populations in the study.

DR. SIEGAL: And what was the N?

MR. CARDOS: The N I couldn't quote off hand. I would have to look that up in the insert.

DR. SIEGAL: But it is larger than 200?

MR. CARDOS: It was larger than 200, yes.

MS. SUTTON-JONES: It is thousands.

MS. BAKER: