UNITED STATES OF AMERICA

P-R-O-C-E-E-D-I-N-G-S

8:05 a.m.

DR. SMALLWOOD: On the record. Good morning. Welcome to the 81st meeting of the Blood Products Advisory Committee. I am Linda Smallwood, the Executive Secretary. At this time, I will read the Conflict of Interest Statement that applies to the proceedings for this meeting over two days.

This announcement is part of the public record for the Blood Products Advisory Committee Meeting on October 21, 22, 2004. Pursuant to the authority granted under the Committee charter, the Director of FDA Center for Biologic Evaluation and Research has appointed the following individuals as temporary voting members: Drs. Charlotte Cunningham-Rundles, Jonathan Goldsmith, Liana Harvath, Blaine Hollinger, Matthew Kuehnert, Kenrad Nelson, Keith Quirolo and George Schreiber.

To determine if any conflicts of interests existed, the Agency reviewed the agenda and all relevant financial interests reported by the meeting participants. The Food and Drug Administration has prepared general matter waivers for the special government employees participating in this meeting who required a waiver under Title 18, United States Code 208.

Because general topics impact on so many entities, it is not prudent to recite all potential conflicts of interests as they apply to each member. FDA acknowledges that there may be potential conflicts of interests but because of the general nature of the discussions before the Committee, these potential conflicts are mitigated.

We would like to note for the record that Dr. Michael Strong is participating in this meeting as the Non-voting Industry Representative acting on behalf of regulated industry. Dr. Strong's appointment is not subject to Title 18, United States Code 208. He is employed by the Puget-Sound Blood Center and Program and thus has a financial interest in his employer.

He also is a researcher and a speaker for a firm that could be effected by the Committee discussions. In addition in the interest of fairness, FDA is disclosing that his employer, Puget-Sound Blood Center has associations with regional hospitals and medical centers.

With regard to FDA's invited guest speakers, the Agency has determined that the services of these guest speakers are essential. There are interests that are being made public to allow meeting participants to objectively evaluate any presentation and/or comments made by the guest.

For the discussions of Topic 1 related to Reentry of Donors Previously Deferred for Anti-Hepatitis B Core Reactivity, Dr. Susan Stramer is employed by the American Red Cross.

For the discussions of Topic 2 related to The Simian Foamy Virus, Drs. James Brooks and Peter Gantz are both employed by the Biologic and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada. Dr. Walid Heneine is employed by the Division of AIDS Research at the Center for Disease Control. Dr. Nicholas Lerche is employed by the California National Primate Research Center, University of California.

For discussions of Topic 3 on Deferral on Donors with Possible West Nile Virus, Dr. Michael Busch is employed by the Blood Centers of the Pacific. He has contracts and is a researcher, speaker and advisor for firms that could be effected by the discussions. Dr. Theresa Smith is employed by the National Center for Infectious Diseases, Center for Disease Control in Fort Collins, Colorado. Dr. Susan Stramer is employed by the American Red Cross.

In addition, there are regulated industry and other outside organization speakers making presentations. These speakers have financial interest associated with their employer and with other regulated firms. They were not screened for these conflicts of interests.

FDA members are aware of the need to exclude themselves from the discussions involving in specific products or firms for which they have not been screened for conflicts of interests. Their exclusion will be noted for the public record.

With respect to all other meeting participants, we ask in the interest of fairness that you state your name, affiliation and address and any current or previous financial involvement with any firm whose products you wish to comment upon. Waivers are available by written request under the Freedom of Information Act. At this time if there are any additional declarations to be made by anyone involved, please do so.

Hearing none, I will move to my next series of announcements. First, I would like to announce that Dr. Jay Epstein, the Director of the Office of Research for Blood, is delayed because of an accident on his way in. So we will proceed with the meeting. However once he arrives, we will make adjustments with respect to acknowledgment of our outgoing members.

So at this time, I would just like to make a few announcements and I will then turn the meeting over to our chairman. On the table outside, there was an announcement of a notice of the Second Annual Stakeholder Meeting on the Implementation of the Medical Device Userfee and Modernization Act. That meeting is to take place on November 18, 2004. So if you would please be advised of that and there is this copy that is out on the table.

Secondly, I would like to give you the tentative meeting dates for the Blood Products Advisory Committee for 2005. They are as follows: March 17 and 18, July 21 and 22, December 1 and 2. Again these are tentative and you will be advised in the appropriate fashion.

At this time, I would like to introduce to you the members of the Blood Products Advisory Committee. As I call your name, would you please raise your hand. For this meeting, the Acting Chairman is Dr. James Allen. Seated next to him is Dr. Liana Harvath, Dr. Kenrad Nelson, Dr. Matthew Kuehnert, Dr. Keith Quirolo, Dr. Blaine Hollinger, Dr. Jonathan Goldsmith, Dr. George Schreiber, Dr. Michael Strong, Dr. Judy Lew, Dr. Harvey Klein, Dr. Samuel Doppelt and Dr. Kenneth Davis. Dr. Allen.

ACTING CHAIRMAN ALLEN: Good morning. I would like to welcome you all to the Blood Products Advisory Committee Meeting. We have, I think, a very important agenda before us over the next two days. We'll start out with some Committee updates. I would like to remind all of the speakers please that it is important to keep to the time limits that have been assigned to you during the presentations.

Also I just would like to remind speakers that you have a diversity of backgrounds of people on the Committee. I think everybody here is expert. Together we make a remarkable committee. We do not all have expertise in all the jargon of each of the fields that are necessarily being presented. So to assist in our fully understanding what you're saying, it would be helpful as you first begin talking about a topic if you're using jargon or abbreviations or acronyms and so on, please provide explication for the Committee about that term.

We'll move forward. The first update is a summary from the meeting last week of the Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC) to the FDA. Dr. Asher.

DR. ASHER: Thank you. Good morning. I'm going to present my own informal summary of part of last week's TSE Advisory Committee's meeting. With the exception of one statement that will be obvious, the rest of the talk is my own informal summary. There's a formal summary out on the table kindly prepared by Bill Freas, the Executive of the Committee. And within two weeks, we should have posted on the web the transcripts, all the Government presentation slide sets and most of the non-government presentation sets for your use.

The Committee heard five informational presentations that I won't summarize and then the sixth issues was decisional and that is one of periodic reviews of our FDA/CJD, vCJD Blood Safety Policy. The Committee was asked to reappraise the adequacy of current policies. We began with a history of FDA actions, then the recent events of concern which I'll go over in just a minute and then we had a full scientific program addressing the blood policies and then questions for the Committee. Next please.

The Committee, the formal charge was to provide advice on whether recent information regarding Variant Creutzfeld-Jakob Disease (vCJD) warrants consideration of additional safeguards for FDA regulated human blood and blood products. Next please.

Actually the history of FDA policy goes back to 1983 which was the first time that the FDA announced policy based on the assumption that human blood was likely to be similar to animal blood in that it would be infectious during both the incubation period and clinical disease of Spongiform Encephalopathies.

The first geographic based deferral policy was recommended in 1999, deferral of donors who had spent six months in the United Kingdom between the beginning of 1980, the presumptive start of the BSE outbreak there and then end of the 1996 when the U.K. had implemented a full set of strict food chain protections. Current policy was announced in January of 2002.

In December of 2003, U.K. authorities reported the first case of vCJD occurring in a small cohort of recipients of labile blood components, one of the 50 such recipients in only 15 to survive underlying disease for more than three years. In July of this year, the United Kingdom reported a second transfusion associated case.

In the same month from the U.K. came a survey of appendicle tissues from an anonymous operating room specimens and it found this as I'll show you in a few minutes a surprising high number of those tissues contained abnormal protease resistant prion protein thought to be a finding years before the onset of neurological disease.

Then finally, an issue of concern to many people in September of this year, the United Kingdom authorities notified certain recipients of plasma derivatives that they were at increased risk for variant Creutzfeld-Jakob disease.

In conjunction with that although referred to indirectly at the TSE Advisory Committee, I'd like to read to this Committee a statement from CBER. "U.K. authorities recently notified some recipients of plasma derivatives that they might be at increased risk of vCJD. These products included Coagulation Factors 8, 9 and 11 as well as Anti-Thrombin 3 and intravenous immunoglobulins. The derivatives of concern were manufactured from plasma of U.K. donors between 1980 and late in 1999 when consistent with a decision announced in 1998, U.K. manufacturers stopped using U.K. plasma. The last expiry date for any of the U.K. products was in 2001.

Some Factor 11 made from U.K. plasma was used between 1989 and 1997 to treat a relatively small number of patients participating in several investigational new drug studies in the United States. No Factor 11 product used in the United States was manufactured from a pool containing plasma from any donor known to have become ill with Variant Creutzfeld-Jakob Disease. That is there were no known implicated lots. The FDA and CDC are discussing the Factor 11 importations and assessing the risk to recipients. This assessment will be the basis for any further recommendations."

I think it's fair to say that this issue which was not on the agenda of the TSE Advisory Committee is of sufficient significance that one can expect that it will be addressed more fully in subsequent meetings of the TSE Advisory Committee. Next slide please.

I summarize in the handout current U.S. blood donor policies and there are policies regarding both donor at increased risk for conventional forms of Creutzfeld-Jakob Disease and Variant Creutzfeld-Jakob Disease. Next slide please and move on to the next slide.

There's a greater concern about Variant Creutzfeld-Jakob Disease because it's so very different from other forms of Creutzfeld-Jakob Disease, both in its neuro-pathology and in other pathology. There are accumulations of abnormal prion protein in lymphoid tissues that are not seen in other forms of Creutzfeld-Jakob Disease. Next slide please.

For that reason, we were concerned that because of this unusual involvement of lymphoid tissues there was a greater likelihood that there might be infectivity in blood. In a general way because the disease was so different in clinical presentation and in pathology, there was uncertainty about how predictive the relatively reassuring epidemiological information that suggested that if actual transmissions of conventional CJD had occurred through blood, we wondered whether we could rely on that evidence to predict the behavior of vCJD. For that reason, more strict policies were recommended. Then of course, when the U.K. authorities announced their own lack of confidence serum of U.K. origin, it had to increase our own concern. Next slide please.

There is some good news. Throughout the world, the 23 known BSE countries, the recognized cases of the disease are decreasing in most of those countries with the exception of Spain and the possibility of one other country. Next slide please.

In the U.K. where the disease peaked at tens of thousands of cases in cattle, in 1992 only 600 cases were recognized last year. Also good news, over 80,000 cows in risk groups have been tested since June by the U.S. Department of Agriculture and although the surveyance program may not be perfect, it has to be reassuring that not a single true positive brain has been detected in that survey nor have any brains been detected in a smaller survey conducted in Canada. Next slide please.

The number of cases of vCJD worldwide is smaller than some had feared at the beginning of the outbreak. One hundred and sixty cases have been recognized as of earlier this month. One hundred and forty-nine of them have been in the U.K. and three in long time residents who moved to other countries. However, seven cases in France and one case in Italy occurred in people who had never visited the United Kingdom. Next slide please.

There is also good news from the United Kingdom in that new cases of vCJD appeared to have peaked in 1999 and deaths in 2000. Next slide please.

The cases of vCJD in U.K. residents have permitted some projection about what the minimum incubation period of the disease might be. A minimum of nine to 11 years incubation is concluded from the U.S. and Canadian case.

The Irish case had a history that traveled back and forth. So it's hard to draw any conclusion from that case. The blood borne cases that I'm going to present now suggest that there's an incubation period of six years in one case and greater than five years in a second case who had not developed symptomatic disease. Next slide please.

Not such good news is a finding of an appendicle survey that was published in July of this year. This is based on the recognition at autopsy that most patient with vCJD had detectable prion protein in lymphoid tissue and then fortuitously, two of the cases had had operations on tonsils and appendix done several years before they died which demonstrated that the abnormal protein was detectable in tonsils and appendix for at least two years before death, but not ten years before death.

That was the basis of a survey of normal tonsils and appendix that I just referred to. The tonsular survey didn't turn up anything, but the appendix based survey found three positive appendices out of 12,674 adequate specimens which predicted a probable rate in the population of more than 100. Two hundred thirty-seven was their actual predication cases of incubating vCJD per million population which is somewhat discordant from the mathematically-based projections, but it certainly is of concern and shows you the uncertainty surrounding the whole situation. Next slide please.

As most of you know, the first probable transfusion transmitted case of vCJD in the U.K. was recognized last year. A clinically healthy blood donor became ill with vCJD three years after the donation and a recipient became demented and died with vCJD three years after that. Next slide please.

The second case was reported in July of this year. The donor became ill 18 months after donating whole blood in 1999. Both these recipients by the way received non-leukoreduced red blood cell concentrates. The recipient died of a ruptured aortic aneurism without any history of dementia. It's interesting that the tonsils and appendix of that recipient were normal but abnormal prion protein was present in several areas of the spleen and in cervical lymph node. There was really very little doubt that the recipient was incubating Creutzfeld-Jakob Disease and judging from the behavior of these infections in animals, one would think that within a couple of years the patient would probably have come down, the infection would have entered the central nervous system, the patient would have come down with Creutzfeld-Jakob Disease.

One unfortunate interesting observation of this patient, this is the first patient studied found to be heterozygous for methionine and valine at Codon 129 of the prion protein and coding gene. The heterozygous genotype is known to be somewhat but not completely protective against other forms of Creutzfeld-Jakob Disease, Sporadaica Creutzfeld-Jakob Disease, Iatrogenic Creutzfeld-Jakob Disease and some had hoped that it would be completely protective against Variant Creutzfeld-Jakob Disease. Clearly, that is not the case. Next slide please.

So the implications for public health of these findings I've listed here. CJD was transmitted by transfusion. I think the only logical, the chances that these are two fortuitous dietary acquired cases occurring in a cohort of 15 people who survived for more than three years is less than one in a billion. So I think the only logical conclusion is that these were transfusion transmitted cases. Although there's nothing like genotyping that one can do to establish the connection at a molecular level.

The prion protein, methioline and valine 129 genotype did not convey absolute resistance to infection at least after adaptation to humans and intravenous exposure. A second wave of vCJD cases in heterozygous individuals is possible, possibly smaller than the first wave and of unknown magnitude. That's because 50 percent of the U.K. population is heterozygous for that gene, for methioline and valine at that gene.

A recent survey of prion protein in appendix predicted a rate of 237 infected people per million in the U.K. That has to be considered a minimum rate if it's confirmed. A number of persons in the U.K. and other BSE countries potentially have vCJD in their blood and that can be present for at least three years prior to the onset of clinical disease. For that reason, we continue to believe that BSE geographic-based blood donor deferral policies have been prudent and remain justifiable. Next slide please.

We put to the Committee no specific options although Peter Gantz who I think will be here this afternoon laid out the three options that Canada is addressing, one of which is through keep current policies and the other two we'll discuss now. There are really only a limited number of ways in which risk can be reduced further.

The policies are based on reducing the risk that a donor has been exposed to the BSE agent either in food or through pharmaceuticals. We've had to take residence in a BSE country as a surrogate for food exposure because dietary histories are considered quite unreliable.

The only other exposure of concern has been bovine insulin. That's already part of the deferral policy. There's no comparable bovine product that was made either in the U.K. or in any other BSE country that we're aware of. So that one approach would be to reduce the time that an acceptable donor might have spent in a BSE country or to add new lower risk BSE countries to the list of countries for which there is deferral.

The second strategy would be to reduce the risk that the donor had been exposed to vCJD agent from a human exposure and in 2002, we recommended deferral for anyone who had been transfused in the United Kingdom after 1980. One might consider deferrals for transfusions received in other countries. The Committee itself suggested that we might consider similar deferrals for people who had surgery in BSE country although that remains a theoretical risk whereas the transfusion transmission is now a demonstrated risk. Next slide please.

To help the Committee in their deliberations, there were a number of very useful talks. Robert Will summarized the situation that I just summarized for you. Steve Anderson compared the risk of classic and vCJD. Peter Page, I think, is here this morning presented the American Red Cross Lookback Study of recipients of labile components here in the United States, one hundred and sixteen recipients living more than five years without a single case of Creutzfeld-Jakob Disease.

Steve Anderson did a Fisher Exact Test and it's a highly significant difference. The pathogenesis of the two diseases in regard to their transmissibility by blood appears to significantly different. Louisa Gregori from Bob Roars' lab in Baltimore presented very interesting results of their studies with one leukoreduction filter and found that although about 40 percent of hamster blood infectivity was removed by the filter about 60 percent of it remained in the plasma.

The good news is that although there has been some fear that filtration might fragment cells and release infectivity into plasma, that didn't seem to happen. The other good news is that there is still no evidence to suggest that there is intrinsic infectivity of either red cells or platelets. The infectivity found there appears to be attributable to contamination with plasma which suggests the possibility of technical solutions to reduce the risk more.

Peter Gantz presented recent Canadian policy actions and discussed possible future actions. I've mentioned those. Dob Scott presented the summary of the current policies and then Alan Williams addressed what it would do in reducing risk and what the cost might be if additional policies or enhancement to the current policies were adopted. Next slide please.

This is a crude reduction of some of the information that Alan presented. First, let me remind you that the deferral policies are risk reduction policies. It's not possible to eliminate all risk by deferral policies for the following reason.

If we attempted to defer any donor who had ever been in a BSE country after the beginning of 1980, we found the following projections. If we attempted to defer anybody who had been to the United Kingdom, 23 percent of current blood donors would be deferred. If we tried to defer anybody who had been to any one of the 23 BSE countries, well 22 BSE countries, we won't even mention Canada, 36 percent of current donors would be deferred. It's simply not within the realm of the feasible.

Now let's look at what enhancing current policies might be predicted to do and these are very rough estimates based on certain assumptions. If we attempted to reduce the acceptable time, the time that a suitable donor might have spent in the U.K. during the time period mentioned from three months to one month, we would expect to reduce the risk by an additional four percent over the current 91 percent total estimated risk reduction achieved by the deferral policy and a cost in donors of about three percent which is a very large increase in the number of deferred donors.

If we deferred for transfusion in France, the amount of risk reduction is not quantifiable. But it would be very small. However the loss of donors would also be very small. Alan estimated about a loss of about 1.4 donors per 10,000 and for history of transfusion in Western Europe including France outside the U.K., also an uncertain very small reduction in risk but at a cost of only a total of three donors lost per total of 10,000. Next slide please.

So we put the three questions to the Committee. Are the measures currently recommended by FDA to reduce the risk of transmitting CJD and vCJD by blood products still justified? Do the recent scientific data on vCJD warrant consideration by FDA of any additional potentially risk reducing measures for blood and blood products? If so, comment on the additional risk reducing measures that FDA should consider at this time? Next slide please.

The Committee voted unanimously, 14 to zero, that the current measures remain justified. However, they voted 13 to 1 that the recent new scientific data do not warrant consideration of any additional potentially risk reducing measures for blood and blood products. The one holdout felt that we really needed more information about the seven European cases whether they might have had blood exposure and clearly, that member felt uncomfortable about not deferring donors transfused in non-U.K. BSE countries. After the vote, that concern seemed to be met with some sympathy by other members of the Committee as well, I must say, by FDA staff. Thank you very much. I don't know if there's time for questions, but if there is, I would be happy to answer any that I can.

ACTING CHAIRMAN ALLEN: Thank you for that very complete summary. I will comment with regard to Question No. 2. I think everybody on the Committee who voted no did so with the understanding that they did not believe there was sufficient data or information available at the present time to warrant consideration of specific measures, but clearly there was an expectation that the FDA would continue to monitor the situation as would be blood collection centers and transfusion medicine specialists and that as new information became available, the FDA would bring it to the Committee for consideration. Other questions or comments?

DR. ASHER: I might say in regard to that. We are committed to reevaluating the situation every six months regardless and bringing the issue to, and of course we watch it all the time, the Committee whenever new information as it did in this meeting warrant formal consideration.

DR. HOLLINGER: Dr. Asher, did you say that they are deferring persons who have had transfusions after 1980 from the U.K.? I'm not sure I understood that. In the U.K. but not here.

DR. ASHER: No, people who have received any transfusion in the United Kingdom after 1980 to the present deferral of such people is currently recommended.

DR. HOLLINGER: In this country.

DR. ASHER: In this country.

DR. HOLLINGER: As policy.

DR. ASHER: As policy recommendation.

ACTING CHAIRMAN ALLEN: Okay. Thank you very much. We'll move on to our second committee update which is a statement on Supplemental Testing for HIV and HCV. Dr. Ruta.

DR. RUTA: Good morning, Dr. Allen, Members of the Committee. Thanks for the opportunity to update you on HIV and HCV Supplemental Testing. I'm Martin Ruta. I work in the Office of Blood and if you go to the next slide.

I wanted to update the Committee on supplemental testing and I hope it's helpful, but I wanted to step back a bit and talk about the testing schemes and this is FDA's current policy considerations on donor screening for example for HCV. So one way in which one can view the testing scheme is for blood establishment and the requirement for testing falls with the blood establishment. It's a test donation with a license owner screening test that detects the antibodies of HCV. Then hopefully, all those donations are negative.

As the committee remembers over the past ten years, we've encouraged the development of NAT to capture window period cases. So if the donation is negative, one can view it as sequentially although in blood establishments, it occurs contemporaneously. And one goes on and runs the NAT test and that captures the window period units. So hopefully both tests are nonreactive and donation is used.

Now if one runs the HCV antibody test and the test is reactive, then one can go straight to perform the HCV supplement test. In fact, that's what occurs in the source plasma setting for applicant donors. So I wanted first to have the Committee understand that there are different practices that occur in the blood-for-transfusion setting with regard to NAT testing versus the source plasma setting. In the source plasma setting at least for the applicant donors, if the donation is reactive on the HCV test, they go straight to the supplemental test. So we can go to the next slide.

The next slide says essentially the same thing, but it's now for HIV. So as the Committee remembers, we put a rule into place that says blood establishments have to test for HIV and HCV, they have to use one or more donation as needed to ensure the blood is safe, but we've currently recommended that donations be tested for antibodies to HIV and we have a draft guidance document that's recommended that donations also be tested for NAT.

And again if one runs through this scheme, if one tests the donation using the test to detect antibodies to HIV and that's negative, then one goes on to the licensed NAT test and that's intended to capture the window period units. All right. That's what pretty much happens in the volunteer blood-for-transfusion setting. In fact, my understanding is that they are both run essentially contemporaneously.

In the source plasma setting again for at least the applicant donors and these are the first time donors or people who have not donated in six months, that the HIV antibody test is run and if it's reactive, they go straight to the supplemental test. Now as I mentioned, we've issued a draft guidance recommending the use of NAT and it's my understanding that the final guidance will be coming out very, very soon and possibly may be posted today on our website. So I would encourage you to start looking for it.

Okay. I hope that's helpful to try and explain that there may be different testing schemes that occur within the blood collection setting. Now I want to move on to supplemental testing and this was an issue that we brought to the Committee last March. We asked for the Committee's advice on supplemental testing.

So the current requirements that are in the Reg are up here and I won't read it to you except to say that what we require is that if a donation test reactive on one of the screening of the test, that the blood establishment must go on to further test the donation with the license supplemental test if such a test has been approved.

So the reason that we put in supplemental testing requirements into the Regs is first to clarify for the donor their status whether they are really infected or not. It also places a role in donor reentry. As part of their report that the GAO wrote in 1998, they were finding that not everyone was doing supplemental testing and in fact, that there was inconsistency in notification messages and not everyone was being notified. So we put in requirements of both, that supplemental tests be performed and that the donors be notified when they are deferred and of their test results. The next slide and the next slide.

All right. So we brought the issue of supplemental testing to the Committee last March for your consideration and we thank you for your thoughtful discussion. Actually we tried to bring it a year ago September, but we were rained out and we had the discussion last March on supplemental testing for HIV and HCV. At that point, the Committee, I think what you advised us to do is review the existing algorithms and to look at additional data.

What we've done since then is to establish a public health service working group to try and look at all the data that was collected and try and make some sense out of it. I think where we were last March was that we saw presentations from several people which showed a correlation between EIA reactive samples that were also NAT positive showing that these were truly infected individuals.

A number of the members of the Committee thought that if both the EIA and the NAT were positive that in fact the license supplemental test would not be needed. But the data that we saw last March or the Committee saw last March primarily involved only one of the license NAT tests and in fact there are three FDA approved NAT tests and they are in order of approval, the National Genetics Institute UltraQual HIV I and HCV Test, the Procleix HIV I/HCV Multiplex test and the Roche COBAS HIV I and HCV test.

So we established a PHS working group. If I can go to the next slide. We tried to address a number of scientific questions and these are limited to the blood bank setting. We started off with what we were hoping would be the simple questions and that is if donation is reactive/positive on a license HCV NAT on a single donation and the same donation is also HCV antibody reactive, can those results be used to confirm infection in lieu of the HCV supplemental test? The answer that we came up with was yes, you could.

We asked a similar question for the HIV testing and the reactive/positive results of a license HIV NAT performed on a single donation that is also HIV antibody reactive. We used to confirm infection in lieu of the HIV supplemental test and again the answer we came up with was yes, it could. So let me explain here for, I said, reactive or positive results. In the case of the multiplex test, we actually mean that it's discriminatory reactive. It's reactive with a specific primary for either HIV I or HCV. Okay. If I can move onto the next slide.

I've told you the answer already but where the Committee came out and where the working group is that if the donation is reactive on the HCV EIA screening test to detect antibodies of HCV and the donation is reactive or positive on an individual sample using a license HCV NAT meaning discriminatory reactive for the multiplex test, then as a scientific matter, the license HCV supplemental test would not be needed to confirm infection. This is a scientific statement and as a regulatory requirement, the supplemental test is still required and I'll get to that at the end.

So moving on to the next slide, we come to this, and I've given you the answer for this already for HIV. For HIV supplemental testing where both the EIA is repeatedly reactive and the NAT is positive, we've said that as a scientific matter, the license HIV supplemental test would not be needed to confirm infection. All right.

So now we deal with the more complicated issues in the next slides and that is what happens when the tests don't agree. I think this is sort of where the Committee was left to consider some of the data that was presented and wasn't quite so sure. Where we ended up that if a donation is reactive on a license HCV EIA donor screening test to detect antibodies for HCV and the donation is nonreactive or negative using an appropriate license HCV NAT, negative or nondiscriminated on an individual sample, then as a regulatory requirement, the license HCV supplemental test would still be needed to provide information about the donor's infection status. So these are the ones that are EIA reactive NAT negative. So the RIBA is still needed.

If we go onto the similar consideration for HIV in the next slide, again if the donation is reactive on the license HIV donor screening test to detect antibodies to HIV and the donation is not reactive or negative on the appropriate license HIV NAT or not discriminated on the individual sample, then as a regulatory requirement the license HIV supplemental test would still be needed to provide information about the infection status of the donor.

Let me correct what I said before. Here's where there was a bit of a debate about the science involving alternative schemes to try and resolve HIV infections. So we recognize that there's still a scientific debate involving the use of alternative tests to resolve HIV status.

And if I could go to the next slide. So what have we done? We actually have received a variance request from a blood establishment and we've issued a variance under 641.20 to allow a blood standard to not perform the HCV supplemental test which is a required test under 610.40(e) our testing requirements when the donation was reactive on a license HCV EIA for antibodies and also was positive on the license HCV NAT on an individual donation. If I can go on to the next slide.

There are possible other courses that we could use to address this issue. One would be we could consider whether to relabel the HIV and HCV NAT test, the supplement test, when the NAT is positive. That would require manufacturers actually to come in and seek such changes and we would entertain those requests. In addition, we may need to relook at the regulations requiring supplemental testing and consider changes to those in the future.

Finally, well, almost finally, other issues. Okay. So now we deal with the more complicated issues that I think the Committee was pondering last March. If you remember there were a number of data sets presented and I think what the Committee was struggling with is that there were discordant results on the same sample. So we had donations that were EIA reactive NAT negative or positive on the Western blot but then had been tested on other EIAs and were discordant on some of the EIAs. The Committee was sort of pondering what does this mean and how do we sort this out.

Where I think a step further into the datasets and at this point, we have a lot of questions, just to give you an idea for the type of things that we are looking is some of the discordants actually had very high signal to the cutoffs and were negative on one EIA and positive on another and we had some questions about those. There's been a limited amount of retesting and there may be some testing issues with those particular samples.

There were additional samples that I was hoping that our laboratories could obtain and test for us that have not been retested yet. We run into a phenomenon of the Federal Government where we came to the end of the fiscal year and basically they told me we didn't have any money. So I'm hoping now with the continuing resolution that our laboratories will be able to do some of these studies that I was hoping that they could do.

I think the, I see my time is signaling. So I'll try and wrap up quickly. There are a number of other questions that we're facing with the datasets that were presented and that is how do you know, a number of the presenters were suggesting that the blots were actually false/positive blots and that some were actually real infections.

One of the first questions that we asked was how do you know which ones are real and which ones are not real. We've asked for additional data to sort out which ones are real and which ones are not real. We're waiting for some of those datasets to arrive.

Some of the other issues that we are struggling with are minor things like there were band patterns that were presented which included molecular weights that are not described in any of the current inserts so I presume were errors in transcription. We're dealing with issues that the datasets again involved only one of the NAT tests and only involved the whole blood sector.

We actually didn't see any data from the source plasma sector and whether we would need these additional datasets. So we're wading deeper into the data now and in an interactive dialogue with the presenters and trying to figure out what data is needed. Finally, I'd like to thank the members of the PHS working group who are up here on the slide. So I'll stop and see if there are any questions from the Committee.

ACTING CHAIRMAN ALLEN: Thank you, Dr. Any comments or questions? Yes, Dr. Lew.

DR. LEW: I just wanted to know what percentage of patients who are donors have actually been EIA Western blot positive but NAT negative.

DR. RUTA: Right. Well, this would come from the datasets that were presented and I think in those cases that datasets that we saw ran around five percent of the donors were Blot positive, EIA Blot reactive positive but NAT negative. Now some of those were said to be real infections and other were asserted to be not real infections. So we're trying to sort through those.

ACTING CHAIRMAN ALLEN: Other comments or questions? This is obviously a very important area and we look forward to further discussion about that in learning how the FDA intends to resolve it. We will actually deviate a little bit from our published agenda at this time and move to an open hearing if you will and allow Dr. Kleinman to make a combined statement on HIV and HCV supplemental testing. This is a combined statement from the AABB, ABC and ARC. Yes, if you would like to come up here, that would be fine.

Now I need to read a statement first because this is an open public hearing. So bear with me. Open Public Hearing Announcement for General Matters Meetings. Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision-making. To ensure such transparency, at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual's presentation.

For this reason, FDA encourages you the open public hearing speaker at the beginning of your written or oral statement to advise the Committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting. For example, the financial information may include the company's or group's payment of your travel, lodging or other expenses in connection with your attendance at the meeting.

Likewise, FDA encourages you at the beginning of your statement to advise the Committee if you do not have any such financial relationships. If you chose to not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking. Dr. Kleinman.

DR. KLEINMAN: Good morning. I'm Dr. Steven Kleinman, Chair of the AABB Transfusion Transmitted Disease Committee. With regard to conflict of interest, I do have and have had some consulting arrangements with companies that manufacture NAT assays.

I'm reading this statement today. It's a joint statement endorsed by AABB, American Bloods Centers and American Red Cross. Our statement today is similar to that presented to the Committee in March 2004 when supplemental testing for HIV and HCV was last discussed. The purpose of today's statement is to emphasize the importance of this issue and the urgency to make rapid progress especially with regard to HIV.

AABB, ABC and ARC strongly endorse the revision of supplemental testing algorithms for donors testing EIA, Repeat Reactive for HIV and HCV antibody as previously presented to the Committee during the March 18 meeting. These algorithms were subsequently summarized in a letter from AABB to Dr. Epstein on August 10 of this year.

We acknowledge the FDA for moving forward with the integration of nucleic acid tests into supplemental testing algorithms. The extensive amount of data presented at the March BPAC meeting clearly established the scientific validity of using reactive NAT to determine the existence of HIV I or HCV infection in EIA repeat reactive donors. In such circumstances, HIV I Western Blot and HCV RIBA add no useful information to the evaluation of the donor's status.

So this is good that we heard today that FDA and the PHS Committee are scientifically in support of this. However the inclusion of NAT in the HIV supplemental testing algorithm will not prevent the classification of many donors as HIV Western Blot indeterminant since only three percent of HIV I/II repeat reactive donor samples are positive leaving 97 percent of such specimens to be tested by Western Blot. In cases with non-reactive HIV I NAT and alternate HIV I/II negative alternative HIV I/II EIA results, the data indicate that the Western Blot has no usefulness.

It's not surprising that in alternate HIV I/II EIA is superior to a Western Blot for confirmation of HIV I infection. This is a direct consequence of the continued improvements in the sensitivity of HIV I/II EIAs.

In contrast, no similar improvements have occurred since the first use in the licensure of HIV Western Blot. We now and have for some time been in the paradoxical situation in which the Western Blot originally licensed as the HIV I supplemental assay is less sensitive than is screening EIAs and is certainly the least specific test used in the blood donor setting.

While the scientific validity of using NAT or an alternate EIA in supplementing testing algorithms is a necessary prerequisite for making a change, there is a much more compelling reasons for such a revision. Indeterminant test results create confusion and anxiety for the donor. This is well documented by REV's investigators who surveyed donors about their perception of and reaction to the notification process.

Responses were received from 203 donors with indeterminant results for HIV antibody or P-24 antigen, HCV and HTLV. These data published in "Transfusion" and presented at the March BPAC indicate that the vast majority of such donors were both upset and confused when initially notified of their test results and remained upset and confused six to 12 months later. This is not surprising when donor have been told based on their indeterminant Western Blot results that there is some possibility that they are infected with HIV I.

Unfortunately, such notifications are not confined to only a handful of donors. According to American Red Cross data, approximately half of all HIV EIA repeat reactive donors have an indeterminant Western Blot result. When the ARC data are projected nationally, we estimate that over 5,000 donors receive this message annually in the U.S.

This translates to anxious donors contacting blood centers each day confused and frustrated about their HIV indeterminant result or occasionally and even worse, their false positive HIV Western Blot results. This situation has not changed since 1987 so we've been living with this now for 17 years.

Instructions for carrying out the HIV I/II EIA screening assay state, it is recommended that repeatedly reactive specimens be investigated by an additional more specific or supplemental test. Since the majority of donors with indeterminant Blot results are not infected with HIV I, it is apparent that the Western Blot assay is not achieving the enhanced specificity expected of a supplemental assay.

Until recently, this situation was a necessary but unfortunate outcome of the notification process given that there were no alternate means of assessing the donor's infection status. However, such disservice to the donor community cannot be justified when we have the tools available to do better. Testing technology has advanced to the point where donors would be more accurately apprised of the meaning of their test results if FDA were to permit blood centers to use the AABB proposed testing algorithms.

The Committee has agreed that revised supplemental testing algorithms is the correct course of action that this Committee, the BPAC, based on scientific and ethical considerations. However there still appear to be hurtles to cross. As Dr. Ruta told us, 21 CFR 610.40(e) states that you must further test each donation including autologous donations found to be reactive by a screening test whenever a supplemental, that is an additional more specific test, has been approved for such use by FDA.

Now NAT assays or licensed HIV I/II EIAs do not currently carry these supplemental testing claims. However these assays have undergone rigorous review by FDA for donor screening claims and as such they meet all CGMP requirements including those for clinical and analytical sensitivity, specificity and reproducibility.

Furthermore, over five years of data establish the usefulness of NAT to confirm HIV I and HCV infection status supplemented by HCV RIBA or HIV I/II alternate EIA in circumstances in which many pool (PH) NAT is nonreactive. The use of an alternate HIV I/II EIA coupled with IV NAT, individual donation NAT, as included in the AABB proposed algorithm will serve to reduce substantially the number of HIV I Western Blots that will need to be performed.

Considering these facts, we urge BPAC to recommend to FDA that it find a way to allow both NAT and the HIV I/II alternative EIA approach to be a major approach of HIV and HCV supplemental testing algorithms without requiring new clinical trials to establish this claim. To this end, we also encourage the manufacturers of NAT and the HIV EIAs to work with blood centers to submit the required supplemental claim data to FDA for expedited review.

Lastly, and I think very importantly, use of the proposed supplemental testing algorithms has no impact on blood safety since all EIA repeat reactive units are discarded and the donors are deferred. Furthermore, these algorithms, the use of these other supplemental tests like an alternate EIA, is not being proposed for the purpose of donor reentry.

So to restate this is a tool by which to give donors better notification methods, not a tool that at all affects whether the unit will be transfused or whether the donor will be eligible in the future. Therefore, supplemental testing algorithms should be adopted based on their ability to provide a timely and accurate result to a blood donor who is taking the time to make a generous gift. The AABB proposed algorithm is well suited for the purpose of accurately informing a donor of test results. Thank you.

ACTING CHAIRMAN ALLEN: Thank you, Dr. Kleinman. Any questions or comments for Dr. Kleinman? Thank you. At this point in the meeting, we will go back to our opening since Dr. Epstein is here. We will go ahead and proceed with the Topic 1 which is FDA's current thinking on reentry of donors previously deferred for anti-HBc reactivity. We have a series of four presentations in this segment. The first introduction and background by Dr. Kaplan. I'll be pleased when wireless technology simplifies the transfer of computers.

DR. KAPLAN: Good morning. I'm Geraldo Kaplan. I will introduce for you the reentry for donors that were deferred for repeat reactivity with anti-core tests results. So this is a current thinking session and the FDA would like to present to the Committee a proposed algorithm that will allow reentry of donors deferred for testing repeat reactive for antibodies to hepatitis B surface antigen on more than one occasion.

This guidance dated September 10, 1991 for the screens of anti-HBC it says that donations for transfusion should be tested for HBsAG and anti-HBc. Only reactive units should be transfused. The donors should be indefinitely deferred when they test repeat reactive more than once and that donor reentry algorithms were not recommended at that time because there was no supplemental test, basically a more additional more specific test for anti-HBc.

The consequences of this anti-HBc screening were that although anti-HBc donor screening contributed to blood safety, many donors were indefinitely deferred because of potentially false positives anti-HBc results. In the BPAC meeting in December 1998, FDA and AABB presented to BPAC similar reentry algorithms based on negative test results for hepatitis B surface antigen, anti-HBc and anti-HBsAG.

The Committee did not recommend reentry because the American Red Cross data showed that some HBsAG and anti-core negative samples were HBV reactive using an experimental NAT. As you stressed that in some tests the anti-HBV were also positive so some samples where one was positive with one test and negative with another one.

We have had recent developments basically that hepatitis B in NATs have been developed for screen donations in meaningful format. They can be used to test individual donations. It does enhance its sensitivity. The FDA is considering testing algorithms to permit reentry of donors that will include use of this sensitive HBV NAT and I will talk about that proposed algorithm in a few minutes.

Some of the considerations is that will permit reentry only on the premises that (1) historical test for anti-HBc were false positives and (2) that there is no evidence for past or present hepatitis B virus infection. Also reentry base on testing of hepatitis B surface antigen, anti-core and hepatitis V DNA by the NAT that antibodies to HBsAG is not part of this reentry or algorithm because extensive hepatitis B vaccination programs have been in place for a number of years and many individuals are antibody positive so this is not a good marker of hepatitis B infection at this point.

So what's our current thinking? A donor that has been indefinitely deferred because of having tested repeated reactive for anti-HBc on more than one occasion may be reentered if after a meeting of eight weeks subsequent to the last repeated reactive anti-hepatitis B core test a new sample is collected from the donor and this sample tests negative for surface antigen, anti-HBc and hepatitis B NAT and the sensitivity that we're looking for is 95 percent detection at less than 10 copies per mil. However, we are at this point flexible on that limit and this test should be FDA license assays.

Also that whenever a donor presents at a blood center to the NAT subsequent to the negative test for surface and anti-core and HBV NAT, all donors with that criteria for donors of whole blood and components are fulfilled. So basically that's what I would like to present to you. The data of the full evaluated algorithm is being collected at the present time and basically the part missing is using a more specific test for anti-core. So we will hear a presentation by Dr. Susan Stramer regarding her data on NAT testing of repeat reactive samples. At this point, I would like to introduce Dr. Blaine Hollinger that will give us an introduction on serology.

ACTING CHAIRMAN ALLEN: Can we take just a second first? Are there any questions first of all for Dr. Kaplan's setting of the stage? I've have just one quick question with regard to the sensitivity of the HBV NAT. You talked about a sensitivity of 95 percent detection at 10 or fewer copies per MIL. What is the range there that you actually find in the FDA license assays?

DR. KAPLAN: Well, there is no license assay. The FDA last week presented a set of possible license in the near future of HBV NAT. That is a meaningful assay so the sensitivity of that meaningful assay that it's lower than the ID NAT in donation. Unfortunately, I think that Rush (PH) had given a presentation, the last presentation of the session. I haven't seen him in the room. They are here. Good. So they will probably talk about the sensitivity of their assay that would meet this 10 copies requirement and I understand that other assays could reach that limit though we are flexible at this point on that requirement. So restating what I'm saying is that the future license test are meaningful and this is probably pushing a little bit the envelope because it will be done on ID NATs single units.

ACTING CHAIRMAN ALLEN: All right. Thank you. Dr. Hollinger.

DR. HOLLINGER: Thank you, Dr. Allen. I'm going to try to give again a brief overview of serology to those of you who may not be quite so familiar with the hepatitis B virus. I think any time that you start with serology you need to understand something about the mechanisms briefly of viral multiplication.

With any viral infection usually initially specific cells are targeted for infection and of course where hepatitis B virus this is the hepatacytes. The genetic material then from that virus is introduced in some fashion into the cell. Following this, genes are expressed and viral genomes are replicated and following this replication there are both non structural proteins which are important for the viral replication as well as structural proteins which are important for the assembly and release of virions. In most cases following this but not always cells are destroyed and disease develops.

This shows these particles that are found in hepatitis B virus infections. It's really interesting because initially we were all expecting to find really virions present and in this virus, you found a very large number of these non-infectious particles. Indeed the plasma derived vaccine initially was made from this small particle here. These long tubular forms, the tubulars you can see coming off of the surface of the virion itself is the surface antigen is composed of these small particles here.

There is no infectious nucleic acid in these particles. So you have surface antigen here and on the surface of the virion itself, there is probably 10,000 or more non-infectious particles per each infectious virion that's present. Then of course inside this virion is a nucleocapsid that protects the nucleic acid which is inside of this particle. Next slide please.

The nucleic acid for hepatitis B virus has four open reading frames. Two of them are important for the discussion here today and that is the open reading frame which is important for the surface antigen and of course it has its own antibody, the anti-HBs and then there is the open reading frame that produces the core antigen important for the nucleocapsid. Part of this core antigen also is important for the production of the HBe antigen. The e antigen is not part of the structural protein of the hepatitis B virion but does circulate free in the circulation indicative of an active replication of virus. Next slide please.

This just again shows the life cycle of the hepatavirus. It enters the cell. The coating is taken off. The nucleocapsid gets into the nucleus from which there is transcription of the genome with translation. It is then packaged into the nucleocapsid where there is synthesis, minus strand and plus strand synthesis. It's then budded. It goes through a budding phase in which the envelope is found in the virions which is then exported out the cell. Next slide please.

It is interesting. If you look in this cell, this is a freeze fracture EM if you will of a cell and what's very interesting in these cells is that there are nucleur pores. We wondered how these nucleocapsids could get inside the nucleus as well as being present in the cytoplasm. So this slide shows these nuclear pores and the next slide please.

This shows an infected cell with hepatitis B virus in which the nucleus is loaded with these small nucleocapsid some of which or most of which contain the virion. There are also nucleocapsid here in the cytoplasm. Indeed in the very early phases of infection, nucleocapsid is probably excreted free into the blood stream. In fact even as long ago as 1975, we reported the presence of free nucleocapsid in the blood of patients in the early phases of their infection which was found at that time with DNA polymerase but it preceded the development anti-core or anti-HBc. Next slide please.

Now what about the course of HBV infection in general. Next slide.

Before you understand anything about the course of infection, you have to have some grasp of the sensitivity of the assays which are available today. This slide goes from micrograms down to attograms here. Picograms, fentograms and attograms and so on getting down the HBV genome. The hepatitis B virus has one picogram of the HBV virus which is equivalent to about 280,000 genomes in there. So that's about at that level.

The hepatitis B surface antigen test which are currently available, I mean the unlicensed test. Some of the unlicensed test can get teched down one tenth of a nanogram or less in this range here which is approximately 100 picograms. You also then see that as you get into radioautography, hybridization assays maybe that could detect in this level here, some of the very first assays might detect only 750,000 genomic equivalents and then as the tests were developed and you got into PCR and then into nested PCR and into some of the amplification assays, you began to move down toward this range here where you're almost testing or evaluating one HBV genome circulating per ML of blood.

So all of these tests are important because it tells us something about some of the studies that were done previously when, look at the next slide and you can see this on the next slide. Let me go on with this first. HBV DNA in the blood is detected about two to five weeks after infection and up to 40 days before the hepatitis B surface antigen is detected with a mean of only six to 15 days. It rises slowly. It's distinct from hepatitis C virus infections and it's at a relatively low level perhaps maybe only 10,000 genomes per ML or 100,000 or less during the seronegative period. Next slide.

HBsAG appears one to three week before the ALT becomes abnormal or three to five weeks before the onset of symptoms or jaundice. It reaches the peak during the acute stage of the disease and then it declines to undetectable levels within four to six months in most of the individuals who resolve their infection as is true for probably 97 to 99 percent of immunocompetent individuals, adults. Next slide.

This slide I think points out again the relationship between HBsAG and HBV detection as we get more sensitive. The earlier tests maybe could only have a limit of detection of about 1,000. When you look at HBV DNA and those only about 66 percent of them were positive for HBV DNA.

As the tests became more and more sensitive and we are now down to 20 or 10 or 1.3 IUS per ML of detection, you can see that virtually all or at least most of the HBsAG positive material contains HBV DNA. This also just throws in here at these levels here some of the positivity in samples that are anti-HBc positive only, about 13 percent with this particular report and nine percent here. Next slide.

The third product is IgM anti-HBc. IgM of course is one of those early acute phase products which occurred. It's indicative of on-going viral replication when present. It appears acutely at the onset of an ALT abnormality. It's primarily in the acute phase a 19S component. It's present but undetectable in some chronic infections.

Some people would say most chronic infections at a level that you usually don't detect it because a current IgM assay starts at an evolution of one to 1,000. This was initially set up to avoid a prozone (PH) which occurs at one to 100 levels or higher.

It is a 7S IgM fraction. That's kind of interesting because some of the new reductant assays that are available that use reductants like cysteine e or diathiathriatol (PH) usually break down the 19S component to a 7S component and often are more sensitive because of that when you add specific antibody present. So you don't lose the sensitivity of the assay in most cases. The IgM anti-HBc may reappear during reactivation of HBV. Next slide.

Now the total anti-HBc test and we say total just like we do for the total anti-HAV test is because it can detect both IgM and IgG. It is not just an IgG assay. It is detected in past or present HBV infections. It does not result from the hepatitis B vaccination which uses only HBsAG and therefore the antibody response is only anti-HBs. Next slide.

And finally you have anti-HBs which comes later. It is the neutralizing antibody which occurs during recovery and after vaccination. It may become undetectable in up to 20 percent of patients after several years of follow-up. The next slides shows this.

If you can see here, here's an acute infection here and after many years, what happens is the anti-HBs is not a very strong immunogen as compared to the anti-HBc and so the antibody levels that circulate in the blood stream are much lower. So over time, the anti-HBs may disappear. It's very unusual for the anti-core antibody to disappear. So out here many years later, all you'll have is anti-HBc only.

If you take these individuals and vaccinate them or give them the regular vaccine within two to four weeks they will generate an anamnestic response which is one way you can try to determine whether or not this is anti-HBc only from a remote infection as distinct from something else. Next slide.

This slide then looks at the serology of the disease and again as we pointed out what happens is HBV DNA occurring early followed by the HBsAG and the e antigen present here in the bloodstream. IgM anti-HBc occurring early, switching over, not switching over but really switching very early with some IgG here as well and then both circulating. The IgM disappearing. The IgG continuing.

So what you have from this kind of slide here is you show that if you want to evaluate the relative infectivity of the blood, then HBV DNA and HBeAG is the most important thing to look at. e Antigen positive specimen in most cases is indicative of a very active infection with lots of virus in the bloodstream. There are exceptions to everything we talk about here but in general that's a very good rule.

The second rule is that the presence of IgM anti-HBc helps you differentiate in most cases acute from chronic infection. And a third rule is that the presence of anti-HBs and anti-HBc is indicative of immunity. Next slide.

This then shows the progression to chronic hepatitis B. Of course in very young infants born to mothers who are e Antigen positive perhaps 90 percent of these infants will become chronically infected. But for the immunocompetent adult, it's probably one to three percent that will become chronically infected. We used to think it was 10 percent, but we know now that many of those patients had reactivation of chronic and not really acute hepatitis B which is why that initial level of 10 percent was felt to be the resolution of disease.

So in this case what happens is the patient becomes positive. Their HBs antigen remains elevated for more than six months. That's an arbitrary level to establish chronicity from nonchronicity. As you get more sensitive tests, of course I'm sure those arbitrary levels might have to change a little bit, but basically these patients remain HBsAG positive with a total anti-core.

There is no antibody that's usually developed that you can detect in most cases. They are e antigen initially and as years and years go by, about five to 15 percent a year will go from HBeAG positive to anti-HBe positive. Usually it occurs with reactivation of their disease. Enzymes go up. They may even get jaundice and look like acute hepatitis B.

This limited detection is very important because some patients can circulate virus at very low levels below the detection limit of your assay and therefore they will be negative but there may be anti-core present only and that may indicative of that disease. Next slide please.

Now this sort of summarizes a couple of things which I've said and it goes through the factors that we just talked about. These are HBV DNA column, HBsAG, anti-HBc and anti-HBs. The first new HBC DNA positive is usually in the presero-conversion window period.

Next, if they develop HBsAG but are still negative for anti-core and anti-HBs this is usually in the early acute infection. Anti-core is then developed which is then indicative of an HBV infection either acute or chronic. You can't tell at this stage unless you do IgM anti-core.

As I mentioned, a few patients will have IgM anti-core who have chronic disease. The difference is is that IgM anti-core is at very low level, usually below three times the cutoff level as compared with an active acute infection which is very high. So that's a good way of determining whether this is an acute reactivation of a chronic disease versus acute disease.

Then you have patients who are anti-HBc and anti-HBs positive but have no DNA or surface antigen. This is usually indicative of a previous infection with immunity. Next slide.

The thing we're going to talk about a lot today has to do with this group here which may or may not have HBV DNA in the blood. They are negative for surface antigen but they are positive for anti-core. The total anti-core, I'm talking about here and they are negative for anti-HBs. This could indicate either a low level carrier as we talked about where the antigen cannot be detected.

It could be an early convalescent period in which case the IgM anti-HBc will be positive and these patients will also be anti-HBe or HBeAG positive as well in that window period. It could be HBV infection in the remote pass as I discussed a minute ago or it could be a false positive or nonspecific reaction. A fifth one would be passive transfer of anti-HBc as say from a mother to her infant or through some blood products.

Finally, the other ones. This is a patient for all of these markers here but positive for anti-HBs. This is the kind of response you would expect after receiving the vaccine. Then of course if they are all negative, it usually excludes HBV infection. Next slide.

I want to just dwell just a little bit on the anti-core positive only group, the isolated group or the solitary anti-HBc group. This just looks at the prevalence of isolated anti-HBc of blood donors and HBV DNA in those samples. It's a large group of patients, about eight studies here with a large group of patients and you can see that the anti-HBc only population, that's without anti-HBs, but anti-HBc only, no HBsAG, no anti-HBs, that it goes from a 0.07 percent up to 4.8 percent depending on the region of the world with sort of a median of somewhere around 0.3 percent.

The HBV DNA levels in these studies again you have to remember that there are different degrees of sensitivity when these assays were done, but they ranged here from zero up to 3.9 percent positive in those particular individuals. Next slide.

This slide shows the HBV DNA detection in anti-core positive only blood donor samples. Depending on the prevalence of chronic HBV infection in a population in this group the HBV DNA detection was 3.7 percent. In a population where there was a lot of virus around in that endemically, it was up to 24 percent in this study. Next slide.

Now finally the last thing I want to talk about is just a little bit about HBV transmission from HBsAG negative donors. Next slide.

I'll start just briefly with a study that we did many years ago and again you have to understand that the sensitivities of the assays change and that's why I want to bring up this study because it points out the difficulties with looking back 10, 15, 20 years ago or even looking at assays that were done 10 years or so. In that study, we found HBV infection occurring in about one percent of the recipients of blood transfusions that were anti-core positive, but HBsAG negative and the untransfused control was less than ten percent.

There were five recipients who were co-infected with HCV in this study. I'm not talking about those. There were ten that had 12 implicated donors with HBV alone. Next slide.

Six of these donors, now this was done as I told, these were all HBsAG negative by the initial test that we did, but with a more sensitive test about ten years ago, three of them were actually found to have HBsAG in their bloodstream. It may be possible with even the more sensitive assays today that some of the other assays, some of the other donors, may also have HBsAG if you looked at them with the newer test. But there were six individuals here that were positive for anti-core, negative for HBsAG and HBV DNA. The same thing I said about HBsAG can be said about HBV DNA. Next slide.

In this particular study of the individuals that were anti-core positive only that had no anti-HBs, 17 percent of those donors were associated with a hepatitis B case. Of the individuals that were anti-HBc positive that had anti-HBs in their blood up to 9.9 MIUs per MIL or International Units per liter, ten percent were associated with the case and most importantly, none of the donors that were anti-core positive only that had a high level of anti-HBs were associated with the case.

I must say that going through the literature I have yet to find a case of hepatitis B that has been transmitted from an individual who had anti-HBs and anti-HBc with a level that was at least above 10 or certainly above 100 regardless of their HBV DNA status. Next slide please.

So in looking at the risk of hepatitis B following receipt of anti-core positive products from blood or organ donors, 17 percent in our study here showed this. Allain showed three at ten percent.

Among organ donors, it's much higher. These are now organs that were given, not transfusions, but organs that were given from patients who were anti-core positive and they may have anti-HBs and you can see a very percentage of those showed the development of hepatitis B. Immunosuppressed individuals. Next slide and the last slide.

This also shows anti-HBc transmission from pregnant females to their infants. There were 66 mothers with anti-HBc reactivity only. Three of the infants had high ALT levels. Two had HBsAG and one HBV DNA without HBsAG. The HBV DNA was found in the leukocytes of two carrier mothers and in the cord blood of leukocyte samples, the infants became carriers with elevated ALT levels.

So I hope that this gives you some idea now as we're going to start talking about these issues about anti-core gives you a background of the serology of this disease. Thank you very much.

ACTING CHAIRMAN ALLEN: Thank you. A quick question. You showed data about the 12 donors that were implicated in transmission and then tested with later or more recent assays. I assume the testing was done on old stored samples of serum.

DR. HOLLINGER: It was done on stored samples, stored minus 70.

ACTING CHAIRMAN ALLEN: Thank you. Questions for Dr. Hollinger. Yes, Jay.

DR. EPSTEIN: Blaine, can you comment on the sensitivity of the DNA assays that were used in these retests?

DR. HOLLINGER: On the retests?

DR. EPSTEIN: Yes.

DR. HOLLINGER: They were certainly more than, I would say probably in most cases more than 100 in there, but I don't know specifically. These were done in 1993 I believe. So it wasn't the assays done with PCR. Well, there was PCR but it wasn't done with the more sensitive assays that we have today. I can't tell you exactly, Jay. I don't know.

ACTING CHAIRMAN ALLEN: Any other questions or comments? Yes.

DR. GOLDSMITH: Has the sensitivity of the anti-core changed over time, the tests that are being used?

DR. HOLLINGER: The tests that are currently being used, the licensed tests, probably have not had a great deal of change in sensitivity. I mean if you go back 30 years or 20 years, yes, but the more recent ones not very much.

ACTING CHAIRMAN ALLEN: Did it change as the antigen in the test, wasn't it initially derived from an infected chimp or nonhuman primate lever and then became the recombinant test? I assume that the sensitivity probably changed with that. Okay. Other questions or comments? Yes.

DR. HARVATH: I was wondering in the last slide you showed where the transmission from mother to newborn, do you know whether in those studies those were from Asian countries or do you know the ethnicity of that? And would we have a different concern in a population, let's say, an Asian country where there would be higher incidence overall of HBV infection?

DR. HOLLINGER: Liana, I can't remember if those were from Asian populations or not. I have to go back and look it up again. Sorry.

ACTING CHAIRMAN ALLEN: All right. Any other questions? Our next speaker is Dr. Susan Stramer from the American Red Cross, studies of deferred donors.

DR. STRAMER: Thank you very much. For those of you who have a handout, I've updated my slides so please bear with me. But the Committee should have the new and improved version. Hopefully, it's improved. It's certainly new. Can we go to the next slide?

This is what I hope to cover today. The current situation with anti-core testing, to show you reactive rates and the efficacy of the 2X deferral policy that Dr. Kaplan outlined, the history of the reentry algorithm development, what happened at prior BPACs which was already highlighted and then what successes we've had as a AABB task force is looked at the issue of anti-core reentry.

I'll review data of a pre-IND pilot study that we did with NGI, the current status of an IND that we have for testing anti-core repeat reactive donors for DNA which is also with NGI. Preliminary data was presented by Dr. Richard Smith at the June BPAC and then I will conclude. Next slide please.

This is during my life with the Red Cross the reactive rates of anti-core. So that's what the beginning of the X axis represents. But what you see of the initial reactive rates and the repeat reactive rates are both a linear decrease over time. So we are calling out anti-core repeat reactive donors as we lose true positives and false positives. This was 9/11 but also you see that the pattern of IR and RR rates parallel one another indicating that it's probably related to a characteristic of the test. Our mean repeat reactive rate is 0.44 percent and it's over the last fiscal year. Next please.

We know that no confirmatory test exists for anti-core. Neither does a standardized confirmatory strategy and also there's high non-specificity of tests currently in use. The historical and present repeat reactive rates I showed you ours at 0.44 percent have ranged from about 0.4 to 1.6 percent.

The estimated majority of these are false positives and from some email exchanges that we've had over the last couple of days with some blood centers, I've put together the low and high reported for blood centers of false positivity based on in-house algorithms such as anti-HBs, repeat anti-core with a second ELISA, etc. So we have this range of false positivity. It's obviously dependent on the specificity of the test used.

The policy for anti-core repeat reactivity is that if you're core reactive for the first time you may donate again. But there may be a negative impact of a repeat reactive notification on a donor returning to donate. They may not understand what we're trying to tell them. But if you're anti-core repeat reactive twice, you're deferred.

Now in trying to determine how many deferred donors we have who lack other deferrals, that is their anti-core repeat reactive only and otherwise would be suitable for donation, the Red Cross has put together data since we have been tracking this at greater than 200,000 donors over this time period. However, the number is probably considerably higher because we and most blood centers implemented core screening in 1987 and then this doesn't include 2004. So perhaps the number nationwide if we represent about half may be close to one million donors. Next please.

What is the success of having a 2X anti-core deferral option? That may tell us a little bit about what the likelihood of donors who will come back if we did have a reentry algorithm. These data will be presented by Chang Fang and co-workers at this year's AABB meeting, but I will highlight the findings.

I'm going to present data for 3.9 million donors representing 6.5 million donations from the year 2000. They were the anti-core repeat reactive donation and continued donation history was examined from 2000, that's the index year, plus three additional years to look at their return history. We excluded autologous and donors with other deferrals.

The ortho anti-core LIs (PH) was used for the entire period of time and for this period of time, I showed you why repeat reactive rates have been decreasing, but for this period of time, our repeat reactive rate was 0.64 percent and for control population those were anti-core nonreactive. We selected first time and repeat donors at 500 selected at random per month for the one year period of time. So we had about 6,000 for each group. Next please.

The total number of first time donors, 36 percent of the 3.9 million was 1.4 million. 1.4 percent of the first time donors tested core repeat reactive. Looking now over the next three years, 81.5 percent never came back.

In comparison to first time donors where our control was 54 percent came back. Of those who did return, that is the remainder which is about 20 percent, 88 percent were core repeat reactive at their donation. Of the remaining 12 percent who remained eligible which is 428 total donors, 14 percent became anti-core repeat reactive in the next three years. From this 14 percent, 98 had subsequent anti-core nonreactive donations from 60 donors ranging from one to seven donations per donor. The remaining 86 percent had 809 subsequent anti-core nonreactive donations and this was from 368 donors with a range of one to 13 donations per donors.

So the overall yield for first time donors who were core reactive for the first time was 0.016 donation per donor per year. I don't know if that equals to your pinky or your big toe but it's certainly not a lot of success. Relative to controls, we have 0.74 donations per donor per year from the control group. Next please.

Now looking at repeat donors, 2.5 million or 64 percent of the total, 0.24 percent were repeat donors who tested anti-core repeat reactive. Similarly to the first time donors, 80 percent did not return in three years versus 26 percent of the controls. Of those who did return, 38 percent were anti-core repeat reactive for the second time on the subsequent donation.

Of the remaining 62 percent who remained eligible, that's 752 donors, 12.5 percent were anti-core repeat reactive in the next three years. From 12.5 percent, we had 224 subsequent anti-core repeat reactive donations from 94 donors with this range, one to 23 donations per donor and for the remaining 87 percent who were not deferred in the next three years, we had 3,000 subsequent anti-core nonreactive donations from 658 donors with a range of one to 57 donations per donor. The overall yield was 0.18 donation per donor per year which relative to the controls is lower. Controls was 1.36 donations per donor per year. Next please.

You can skip this slide and skip the next slide. These were provided to the Committee to let you see how the data were derived. Next please.

So of the total 3.9 million donors in 2000, the donor return rate is low. Three hundred sixty-eight of 1952 anti-core repeat reactive donors who were first time donors, their return rate was 1.9 percent. Six hundred and fifty-eight of 549 (SIC) repeat donors successfully donated for donation over the next three years or 11 percent.

Of those who did return, high rates of 2X anti-core reactivity that was 88 percent of first time, 38 percent in repeat. The total successful donation yield per year is low and these were the numbers that I quoted, 0.16 for first time, 0.18 for repeat and 0.74 for first time controls versus 1.36 for the repeat controls or 46 and 8 times higher for the control group. That is their yield of successful donations. Next please.

So the 2X deferral policy is of limited yield. The impact is greater on repeat donors who we lose 80 percent for core reactivity on the first time donation versus 26 percent who will come back. The anti-core reentry algorithms are projected to have higher yields if a different test is introduced. That is the blood system converts to a different method. We have two hurdles here. One is that the donors don't return and secondly, the donors continue to be repeat reactive when the same tests are used. Next please.

So where do we stand? At the December `98 BPAC, this was reviewed by Dr. Kaplan, but it was our data that caused some concern. We were involved in the PRISM clinical data and as Blaine discussed, there were some discordant samples or at least Blaine discussed this category of samples where you may have DNA positivity and isolated core reactivity. Here we had core discrepant reactivity. Our test record was negative, but the PRISM test and anti-core test was positive.

Upon further testing, two our of three of these samples did have weak anti-HBs so they likely were from infected donors. Converse, we had one DNA positive sample that was PRISM negative and ortho positive and that sample was negative for all HBV serologic markers. So we know we had some discrepancies and one explanation for discrepancy other than true HBV infection is false positivity of the DNA test perhaps due to carryover or sample contamination.

So we faced a reentry algorithm proposed such that we would have a follow-up or a clean sample and that sample would have to test negative for HBsAG, anti-core using a second licensed test. We included anti-HBs and an investigational or research HBV DNA assay. Subsequently at the BPAC discussion, the use of anti-HBs was discouraged. Next please.

So we formed the AABB TTD Task Force. We collected preliminary data that I will review from the Red Cross and sent it to FDA DETTD to request that the data that we collected were adequate to qualify a reentry algorithm. The FDA questioned the sensitivity of the DNA protocol and the study has yet to be completed because of the availability of PRISM reagents.

On May, 2003, we again met with FDA to propose a reentry algorithm which is comparable to the one today and I'll highlight the difference. Based on an eight week follow-up sample that test anti-core nonreactive preferably using a different test with comparable sensitivity but improved specificity and -- Next please.

The sample must test DNA negative and an assay that has a sensitivity of less than or equal to 10 copies per MIL. At that time we requested that IND tests could be used and that the next donation then could be used for transfusion if it tested nonreactive by all FDA required tests and the donor was otherwise suitable. We know now that the FDA requires the licensed DNA test for reentry and the qualification of that DNA test must use a licensed anti-core assay. Next please.

So the prepilot study that we did involved 3,000 anti-core repeat reactive unlike donations that were selected in 2001. The surplus NAT samples were contained in our NAT tube to limit contamination. The criterion for inclusion was nonreactive by all other test methods so we would have an anti-core only reactive.

There was no preselection of first time or two time anti-core repeat reactive donors. So we chose 3,000 to allow it to be robust enough so that we would include both one time and more importantly, two time repeat reactive donors. At the time of the study, our 2X anti-core repeat reactive rate was about 24 percent of Red Cross donors. So we could project how many were 2X anti-core reactive of the 3,000 to be 708. Next please.

The samples were tested individually with the NIG UltraQual 8-rxn test that has a 0.2 ml input. The definition of positive, that is the test is run in eight replicates. If any test is positive, the interpretation of the sample is positive. The sensitivity was 9 IU/ml and using NGI's conversion factor of an IU to a copy, it comes out to 31 copies per mil. Next.

So of the 3,000 tested, we had 0.63 percent samples reactive or 19. Eleven had less than 100 copies per mil low level as we know anti-core onlys have and of the eight reactions run, there was an average of only 1.7 reactions that were positive. We have another eight of the 19 with viral loads above 100 but not exceeding 500 with a mean of 287.5 copies per mil and here there was an average of 4.75 reactions of the eight that were reactive.

Data was provided to the FDA as I mentioned. FDA requested additional testing on the residual sample which has not yet been completed and the FDA stated that 31 copies per mil is an adequate sensitivity for anti-core donor reentry which is how we get to the 10 copies per mil or that is they want it sensitivity better than 31 knowing that commercial tests were available to achieve this. So "since higher sensitivity DNA tests are available, it would be preferable to use such an assay instead." Next please.

So as I mentioned, the goal is to complete the study by looking at a second core test so that we could project the number of core nonreactives that would be eligible for reentry using this algorithm. The anti-core reactives would be investigated for anti-HBs and the assumption is that our 19 DNA positives would be PRISM anti-core reactive and we're in the process of getting this going. Next please.

If you put the study that I just described in context with other studies that have looked at similar types of data, we have 0.63 percent rate of anti-core positivity. The Roche clinical trials that were presented at the last BPAC had a 0.35 percent rate of anti-core only that were DNA positive and a study done by REDS had a little bit lower, a 0.24 percent. So this study still yields at the highest number of DNA positivity or one in 37,000. Next please.

Next, please.

So where are we now? We are under IND with NGI. The purpose of the IND is so that we can use the DNA test as a counseling tool for anti-core repeat reactive donors. I mentioned there was no standardized confirmatory algorithm, so this would be one purpose of the study.

We would continue our survey of anti-core repeat reactive donations for HBV DNA reactivity, and, lastly, to limit viral loads and plasma pools for further manufacture, since anti-core reactives are included in frac plasma.

We rolled out the program earlier this year.

Next, please.

We used the eight-reaction test that I described for primer pairs used, each tested in duplicate, and, again, a reactive in an EVAY test is positive. Here we test in pools of 16. Positive pools resolve to the individual positive donation, and all positive samples are quantified.

Samples without adequate volume for pooling or resolution are tested individually. So we have a mixture of pool tests and individual tests.

The sensitivity of the pool test is the eight-reaction test with a 2 mL input ‑‑ this .9 IU per mL, or 3.1 copies per mL. However, when we have requalified with NGI, we have now found a three-fold increase in sensitivity. So it's probably closer to one copy per mL sensitivity.

But in a pool, using the original validation data, it's about 50 copies per mL. When we do resolution testing, the resolution tests is about five copies per mL. And if we test a single unit, it's back to the 31 copies per mL that I mentioned for the qualification ‑‑ the pre-pilot qualification study. The quant assay has 100-copy per mL sensitivity.

Next, please.

All donors in this IND are notified of their test results, and they're deferred if they're even one-time or two-time core reactive and DNA positive. They're deferred if they're DNA negative but two times anti-core repeat active. And deferred donors are eligible for a followup study that we've just initiated, and donors will come back and be tested for all markers of DNA, but we won't do ‑‑ I shouldn't say "all." We won't do E and anti-E, at least at this point.

Next, please.

So how many donations have we tested to date? We've tested 6,006. This is now twice as large as the 3,000 pilot study I mentioned. .44 percent anti-core is our reactive rate, but not all donations were available for PCR testing.

These are the outcome. About 60 percent were negative in pools. About another third of the donations were negative from positive pools. And of those that we were able to get one-time or two-time core data for, about 23 percent were two times anti-core repeat reactive donors.

Now, positives, we have 304, or 5 percent from positive pools, with another six samples that were positive and samples that were never pooled but tested individually. So we have a total of 310 positives of the 6,006, and this translates to about a 2.4 percent pool reactive rate.

Next?

If we separate out the 6,006 into HBsAg positive versus HBsAg negative, first, I'll go through the HBsAg positive. 179 of the 310, or just over half, were HBsAg positive. 99.2 percent was their mean HBsAg percent neutralization result, and they were all very high.

Viral loads ranged from below the limit of detection to five billion copies per mL. The median was 5,500 copies per mL. Eleven, or 6 percent, of the 179 had less than 100 copies per mL, but were qualitatively positive.

Now, if we look at the data a little bit differently, if we just look at HBsAg positive samples from our database, about 97 percent, 96.7 percent, are anti-core repeat reactive. And of those, 96.4 percent of these HBsAg positive anti-core reactives were HBV DNA positive. So the data seem to all fit together as expected.

Next, please.

Now, with the HBsAg negatives ‑‑ and these would be the ones who potentially would qualify for reentry, we had 131 of 310. The viral loads were lower than the HBsAg positives, as you would expect, less than 100 to 6,400 copies per mL, and the median was lower than the limit of detection by the quantitative assay. 57 percent ‑‑ again, very similar to the pre-pilot data ‑‑ had less than 100 copies per mL but were qual positive.

Next, please.

So this graph shows you the distribution of the HBsAg positives by viral load, the HBsAg negatives by viral load ‑‑ again, these are all anti-core repeat reactive. The same data, just showing you the lower distribution of virus in the anti-core in the HBsAg non-reactive samples.

Next, please.

So, in total, 131 of 6,006 samples, or 2.18 percent, were anti-core repeat reactive only samples that were DNA positive. This is three and a half times higher than the pilot study which I showed you at .63 percent, and these two numbers are significantly different.

Why would we come up with a higher number now when the sensitivity, actually, by the original qualification data was actually less than the pilot study? I've listed some thoughts.

There has been no change, at least to the assay sensitivity. We have not changed the assay. However, upon revalidation of the assay, it did produce a three-fold increase in sensitivity the way the assay is run today at NGI. There were no changes to donor selection criteria. I mean, perhaps there's contamination in some of these samples. But from the way the data fit together with HBsAg, I don't think that's a high number. But our followup study will resolve the discrepancy.

And my last slide, please.

So, in conclusion, poor assay specificity and the lack of confirmatory test has led to the use of a two times anti-core repeat reactive algorithm prior to deferral. But we know that donor return rate is low. Of those who return, two X anti-core reactivity is high, and the total successful donation yield then per year is low.

Anti-core reentry algorithms are projected to have higher yields if we switch to a new test with improved specificity. That should allow the validation or use of reentry algorithms with anti-core tests of improved specificity. A mass of anti-core repeat reactive donors demonstrates that .63 percent to 2.2 percent have HBV DNA, although the level of viremia is low.

So anti-core testing does have value, but mechanisms should exist to capture those donors that are lost.

Thank you.

ACTING CHAIRMAN ALLEN: Thank you very much, Dr. Stramer.

Quick question with regard to how these donors are handled the first time that they're found to be repeat reactive. What are they actually told?

DR. STRAMER: They're provided with a donor letter and a fact sheet that thanks them for their donation. We found repeat reactive on a test for anti-core ‑‑ you know, we explained the ‑‑ if you tested abnormal on a test for hepatitis B virus, this does not mean that you're infected. And because of the high false positive rates of tests, you're encouraged to come in again and donate.

And then, we give them a little bit of a fact sheet that gives them risk factors and what you should do if you think you're infected with hepatitis B.

ACTING CHAIRMAN ALLEN: So they're told they can come back in eight weeks or ‑‑

DR. STRAMER: Correct.

ACTING CHAIRMAN ALLEN: ‑‑ or ‑‑ and when they come back in, it's not just for testing. They're coming back in to go through the donation process again.

DR. STRAMER: Correct. As any other routine whole blood donor.

ACTING CHAIRMAN ALLEN: So their testing process would be exactly the same in the mini pool as if they had never had an abnormal test.

DR. STRAMER: Correct. If their anti-core repeat reactive again, their donation will go to NGI. Correct.

ACTING CHAIRMAN ALLEN: Thank you.

Other questions for Dr. Stramer? This is certainly a very important database. Yes?

DR. GOLDSMITH: I just wanted to ask two things. On the ‑‑ I thought I heard you say that the plasma from the units that were core reactive was used for further manufacture. Did you say that?

DR. STRAMER: Yes. Anti-core repeat reactive donations can be used for fractionated products, yes.

DR. GOLDSMITH: So the donor units that you collect are split. The cellular components are discarded.

DR. STRAMER: Correct.

DR. GOLDSMITH: And the plasma is used for further manufacture.

DR. STRAMER: Correct. And that's to maintain anti-HBS levels and factor ‑‑ you know, fractionated products.

DR. GOLDSMITH: And I just have kind of a philosophical question about the practice of medicine. When these donors present and have a reactive test, if I understand what you said correctly, they get a letter indicating that they should come back to the donor center to donate again. Are they referred to physicians for medical follow up or ‑‑

DR. STRAMER: Well, we ‑‑

DR. GOLDSMITH: ‑‑ care or individual testing, to try and sort out what their status is?

DR. STRAMER: Well, we ‑‑ firstly, the letter is pretty generic. And it says, "You've tested with ‑‑ you have an inconsistent test result. If you'd like more information, please call the Blood Center." But we explain what test they were used and ‑‑ what test they were found reactive. And because of the high rate of false positivity in this particular test, you're eligible to donate again.

But if you have risk factors, you know, we encourage you not to donate ‑‑ and those are listed on the attached fact sheet. So we go through, you know, typical information about hepatitis B, who is at risk, what to do if you're at risk, if you believe at risk or you're unclear about the meaning of these test results, please see your physician.

So they are referred to the medical system, but they are ‑‑ they are told that they can come back and donate. And if found non-reactive, their donation will be used.

ACTING CHAIRMAN ALLEN: Dr. Hollinger.

DR. HOLLINGER: Susan, a couple of questions, and you may not know the answer to these.

DR. STRAMER: More questions than you've sent me on e-mail?

DR. HOLLINGER: Huh?

DR. STRAMER: More questions than you've sent me on e-mail?

(Laughter.)

DR. HOLLINGER: Yes. Sorry about that.

DR. STRAMER: That's okay.

DR. HOLLINGER: Just one question about ‑‑ you mentioned that there were 97 percent of the HBsAg positives or anti-HBC repeat reactive. So there's 3 percent that were not anti-HBC reactive, repeat reactive. Were HBV DNAs done on those three? I mean, on that 3 percent? And how positive were those HBS antigens on those 3 percent in terms of ratios?

DR. STRAMER: You'll have to come to my AABB presentation where I discuss those data. The 3 percent are not part of the IND. The IND specifies only anti-core repeat reactive donors who tested.

The HBsAg's confirmed positives ‑‑ now we have switched back from the Ortho test to the Abbott test ‑‑ they split into two groups. Clearly, there are false positive neutralizations that have low signal to cutoff ratios, and lower percent neutralization values. Although about 60 percent still have greater than 80 percent neut vales, they're a large proportion of this half that we believe are false positive have low percent neuts.

So it's really mix ‑‑ a mixture of both positive and negatives. If we were to do DNA testing on this, this would obviously resolve this, or if we were to do donor followup. But we have not pursued that for these 3 percent.

DR. HOLLINGER: The other thing ‑‑ again, you may not have the data. But, again, of those that are anti-HBC positive but, say, PRISM negative, what's the HBV DNA in those? That were ‑‑ the previous tests that are repeat reactive anti-HBC positive that turned out to be negative by another test ‑‑ let's say PRISM test ‑‑ what ‑‑ were those looked at for HBV DNA?

DR. STRAMER: The only one ‑‑ well, the only time we had that discrepant population was in the PRISM clinical trial. And I said we had one of those that was Ortho test of record reactive and PRISM non-reactive. But it turns out that that donor was not HBV infected. We did get donor follow up for that particular donor.

DR. KUEHNERT: First, just a clarification on the sensitivity. So with the pooled method you get a sensitivity that's significantly higher than with the single unit detection method. Is that right?

DR. STRAMER: Significantly lower.

DR. KUEHNERT: I mean, it's ‑‑

DR. STRAMER: It's less sensitivity.

DR. KUEHNERT: Yes. So the ‑‑ so, for instance, for single unit you said it was 31 copies per mL sensitivity versus pools of 16, 3.1 copies per mL?

DR. STRAMER: No. No. That's ‑‑ 3.1 is the test sensitivity. But then, when applied to a pool of 16, I said the pool sensitivity in copies per mL was about 49.5 copies.

DR. KUEHNERT: Oh, okay. Okay. Thanks for that. And then ‑‑

DR. STRAMER: But that 49.5 ‑‑ you know, it depends if you look at ‑‑ NGI filed an IND. And in that IND, they have the .9 or 9 IU per mL, which I reported. But then, before we did the study and the way that we all operate, I wanted to revalidate their test and look at even a more sensitive test. So instead of doing an eight-reaction test, I wanted to use a formula input and use a 16-reaction test.

So we, then, had to requalify tests of record. And at that time we got a three-fold increase in sensitivity of the NGI method. So it may be 50 divided by 3 is the operating sensitivity of the assay.

DR. KUEHNERT: Susan, it confused me, because then it became more sensitive than the single units. That was ‑‑ okay. That clarifies that.

DR. STRAMER: Yes.

DR. KUEHNERT: The second question I had was about the 75 samples that were less than 100 copies per mL but qualitatively positive. And maybe I missed this, but what ‑‑ are you able to quantitate what those are in any way?

DR. STRAMER: Well, linearity of the NGI quant assay, or their standards only go down to 100 copies per mL. So the qual assay, which runs at much more sensitive, you can have a qual positive sample that you can't quantify, because the viral load is too low.

Now, I haven't pushed NGI with more standards, but certainly, as one of their largest customers, that could be done. And it's an issue, because many times, not only for HBV but HIV/HCV/West Nile, we can't get quants less than 100.

DR. KUEHNERT: That would be useful.

DR. STRAMER: Yes. I agree.

DR. KUEHNERT: Thanks.

DR. EPSTEIN: I have two questions, Sue. You noted that among first-time donors with a one-time reactivity anti-HBC their rate of a second reactive anti-HBC was 88 percent, whereas for repeat donors, or previously repeat donors, in a comparable situation there was only 38 percent. That tends to suggest that the true positive rate is higher for the first-time donors. Was that borne out with the DNA data? Did you stratify that? I may have missed it.

DR. STRAMER: No. I haven't done that yet, but it's certainly interesting.

DR. EPSTEIN: So it's an interesting question.

DR. STRAMER: That's right.

DR. EPSTEIN: Okay.

DR. STRAMER: That's right.

DR. EPSTEIN: And then, the second question that I have ‑‑ I've noted that in your histogram, where you showed the viral loads for ‑‑

DR. STRAMER: Yes.

DR. EPSTEIN: ‑‑ the HBsAg negative population and the HBsAg positive population, the histogram is bimodal for ‑‑

DR. STRAMER: Yes.

DR. EPSTEIN: ‑‑ viral load and antigen positives. And can you comment on whether there's an explanation for that?

DR. STRAMER: No. I haven't delved into ‑‑ into that yet, but I noticed the same thing. And there has to be some explanation for that. I just haven't had time to ‑‑ to determine --

DR. EPSTEIN: I was wondering whether that distinguished maybe acute versus chronic infections, but ‑‑

DR. STRAMER: Right. Right, right. I ‑‑ yes. But ‑‑

DR. EPSTEIN: Okay. Thank you.

DR. STRAMER: ‑‑ early acute when they're anti-core reactive versus lower level carriers. Yes, we haven't ‑‑ well, we haven't gotten there yet.

DR. EPSTEIN: I was just curious.

DR. STRAMER: Yes.

DR. EPSTEIN: Okay. Thank you.

ACTING CHAIRMAN ALLEN: Dr. Strong.

DR. STRONG: Just a comment. Most of this data has been presented with the Ortho anti-core assay, although, as Sue has said, they have now shifted back to Abbott for other reasons. But in the clinical trial with Roche, the repeat reactive rate with the Abbott assay was about double Ortho's. So I think their false positive rate is quite a bit higher, and there is still a lot of centers using the Abbott anti-core. Everybody is waiting for PRISM to be approved.

The question I have, Sue, do you have any cases in which you have a surface antigen positive that is negative for core and DNA?

DR. STRAMER: Because we haven't tested the HBsAg only for DNA, I can't answer that question. We know the HBsAg confirmed positives do distribute into two clearly definable groups ‑‑ those that have high ST ‑‑ just like HIV, those with high STCOs that confirm strongly in confirmatory tests, and those that are weakly reactive on EIA screen and don't neutralize to the same extent as this high EIA population does.

So what we would ‑‑ what would be interesting is to know how DNA segregates in those populations.

ACTING CHAIRMAN ALLEN: Okay. From the floor microphone, would you please introduce yourself for the Recorder?

DR. TABOR: I'm Ed Tabor from FDA. I think it's important ‑‑ by the way, Sue, I'm always impressed by the scope of your research.

I think it's important at this point to say that the anti-core test was originally developed in the Bureau of Biologics, the forerunner of CBER, by Drs. Lewellis, Barker, and Dr. Robert Garrity, as a result of basic untargeted research. And it came out of this serendipitous observations resulting from an attempt to see what would happen if you gave cytoxan to a chronically infected chimpanzee.

Now, I state this because in the previous discussion one of the panel members said something about the reagents coming from chimpanzees in the older tests. There's no question that the original research tests used chimpanzee reagents, but I'm ‑‑ I couldn't be wrong, but I don't recall that any of the licensed assays use chimpanzee reagents.

And I think there have been changes in this test configuration over the years, but basically most of the tests have been competitive inhibition assays, and that's been one of the problems with this test and particularly with regard to its specificity.

DR. STRAMER: May I add something to Dr. Tabor's comment? The two tests used ‑‑ one is a competitive inhibition test, and the other is a direct anti-globulin test. And the anti-globulin test is the test with the improved specificity.

ACTING CHAIRMAN ALLEN: Thank you for that historical perspective. I think too often we don't spend enough time looking back at the history of some of these issues, and that was important.

Yes, Dr. Kleinman.

DR. KLEINMAN: Steve Kleinman. I just wanted to comment on one of the issues raised by the panel member about what are the deferral policies currently for anti-core positive donors. And we heard the ARC deferral policy, which is to follow the FDA guidelines and defer after two times and notify the donor after one time. But there's great variability in what other blood centers do.

Many blood centers will defer the donor, or have up until now, deferred the donor after a first time anti-core, basically because they haven't thought that it was worthwhile to allow people to come back a second time.

Secondly, some blood centers have actually on their own decided to, in addition to doing the anti-core assay test of record, they would do a second manufacturers' anti-core assay and/or an anti-HBS assay, and the notify donors based on several different results and stratify their notification message to say there's a greater probability that you may have been infected, that this is a real result, or there's a greater possibility that you're a false positive.

So we don't have uniformity of practice in terms of how we implement donor deferral for anti-core or how we actually go about notifying persons.

DR. HOLLINGER: I like what Sue does when she ‑‑ on some of her slides will show a quotation around anti-core only, just to make it clear that many of these have not been tested for anti-HBS, anti-HBE, or other hepatitis B markers. And I think that's a good way of doing it, so that we're not thinking that anti-core only means just nothing else there.

DR. BUSCH: Hi, Sue. Just a question. The increasing rate of DNA in ‑‑

ACTING CHAIRMAN ALLEN: Would you introduce yourself, please?

DR. BUSCH: Sorry. Mike Busch from Blood Systems. In your recent data compared to the earlier, could that relate to the anti-core test that was employed? Was your earlier work with the Abbott in the more recent drive for ‑‑

DR. STRAMER: No. The entire data set, as I showed, since 1995 we have been using the anti-core Ortho test, actually since earlier than that. So the second or third slide I showed with the anti-core rate shows over nine years of anti-core Ortho repeat reactivity. And the entire data set also includes Abbott HBsAg. It was post our conversion from Ortho 3.

ACTING CHAIRMAN ALLEN: Dr. Strong.

DR. STRONG: I might just add to the complexity of what Dr. Kleinman just mentioned that there is also some centers that are doing DNA. So it really goes all over the map.

DR. STRAMER: Right. That's why I mention there's no standardized confirmatory algorithm. And you seconded it and thirded it.

ACTING CHAIRMAN ALLEN: Dr. Schreiber.

DR. SCHREIBER: Sue, have you made any estimate of what the capture would be of reentry of donors, deferred donors? I did just a back-of-the envelope and it doesn't seem to me that it would be very big based on the million donors that seem to be deferred over a 17-year period. It seems to me that you'd only get somewhere around 100,000 units a year maximum from ‑‑ if you reinstate donors, or less.

DR. STRAMER: Well, I think you have to look at reentry, generically, really has two purposes ‑‑ one, to allow donors who truly believe that they want to give to have that ability to give; and, secondly, but of more frequently less consequence, is an increase to the blood supply, because we're reentering donors.

The yield of reentry for any marker is not high, and certainly is ‑‑ if we went back to 1986, to those donors we initially deferred because of corzine, you know, one, would we even be able to contact them? And after 18 years, you know, they'd look at us cross-eyed. You've finally done something about our anti-core false positivity? That's not a very good message from the blood centers.

So it really is proportionate to the amount of time, or inversely proportionate to the amount of time that the donor has been deferred. So we likely would start, as we have with other reentry protocols with the most recent deferrals and work our way backwards.

But you're right, George. Any ‑‑ you know, one of these reentry have huge yields, but just the ability to do it for those donors. And if any marker we do reentry for, certainly anti-core has the greatest catchment.

Okay. Thank you.

DR. STRONG: I'd like to say "only 100,000 donors." For a blood center, that's a lot of donors.

DR. SCHREIBER: But then you have to divide by three, because her rate was for three years.

DR. STRONG: But you'll also notice that in her data set she has some donors that donated 57 times. Those are the ones ‑‑ those dedicated donors are the ones we'd like to have back.

DR. STRAMER: Well, it's an emotional issue more than anything. I mean, probably more than anything else.

ACTING CHAIRMAN ALLEN: Thank you.

We'll move on to our next presentation in this section, which is studies of deferred donors. Thomas Clement from Roche Diagnostics.

DR. HERMAN: Okay. I'm Steve Herman. I'm not Tom Clement. And I'm going to speak about a small study we did to look at the potential application of the COBAS AmpliScreen HBV assay, which is currently under review, and the reentry algorithm for donors deferred for anti-core reactivity. And this study was conducted by Guy Tegmeier at the Community Blood Center of Greater Kansas City, with Yungfin Yang and Jim Glarda from Roche.

So Dr. Kaplan reviewed the history, so I'll just go through it very quickly. The anti-core antibody test was introduced in the United States in 1987, and, in 1991, the test was licensed for blood screening. And over the past 16 years it's estimated that the components from up to one and a half to two million donations have been discarded due to anti-core reactivity. And testing ‑‑ testing with the second license test has shown that a large fraction of them are likely to be false positive.

So what are the ‑‑ there's a reservoir of donors that exist that could be reentered if there was an algorithm. And with the licensed assay of greater specificity, and the availability of sensitive nucleic acid amplification tests, the tools for reentry algorithm may now be available, or may soon be available I should say.

So here's the current algorithm for how donor and product management decisions are made with regards to anti-core reactivity. Donations tested for anti-core antibody, and if the donation is repeatedly reactive ‑‑ and it's the first time that that has been observed ‑‑ the products are discarded, but the donor remains eligible for repeat donation.

If the donor comes back and is again repeat reactive for anti-core antibody, the products are discarded and the donor is deferred. And the challenge is to identify a reentry algorithm that maximizes the recovery of those donors without posing any risk.

So this is the same reentry algorithm that has been described already today. The idea is to obtain a followup sample and test it with either the same or an alternate anti-core assay. If the sample is again repeat reactive, then the donor remains indefinitely deferred.

But if the followup sample is not reactive with the alternate or anti-core assay, then that followup sample would also be subjected to HBV DNA testing with the sensitive NAT assay. And if the NAT test is reactive, the donor would be ‑‑ remain deferred. If the NAT test is non-reactive, the donor could be reentered.

And the required sensitivity that has been proposed is less than 10 copies per mL. So now I want to talk about the COBAS AmpliScreen HBV test, which is currently under review. The test has two sample preparation methods ‑‑ a standard method which is used for individual samples and has a 200-microliter sample input, and that has a sensitivity that is a 95 percent limit of detection at 16 international units per mL, which is about 80 copies.

And then, the MultiPrep method, which is used for pooled samples, which has a larger sample input of one mL, and uses a high-speed centrifugation step, to concentrate the virus. And then, after that, the steps are essentially the same as the standard specimen preparation method. And that has a more sensitive limit of detection at 4.4 international units per mL, which is about 22 copies, which is still not as sensitive as the proposed requirement for using that in a reentry algorithm.

So what we tried to do is identify a method to lower the 95 percent limit of detection to under 10 copies per mL, with minimal procedural changes.

So at such low titers, the sensitivity of a test is significantly affected by the limitations of sampling. So if you take a one mL sample that might have three detectable DNA molecules in it, and apply the MultiPrep procedure, so centrifuge it and then eventually recover the sample in 200 microliters, the PCR test is done on 50 microliters of this material.

So the 50 microliter sample that is tested may not contain any of the targets. So a non-reactive result might be observed, even though there were some targets in the sample. So low titer samples can appear negative, just due to sampling error.

And you can increase the odds of detecting that just by testing more samples. So if we start with the same sample that's recovered in 200 microliters, but then use three aliquots of it into three separate PCR reactions, it's likely that at least one of the three aliquots will contain one of the targets.

So in this cartoon, two of the three aliquots contained the target and were reactive, and the interpretation of the result is that if at least ‑‑ if one or more of the tests are reactive, the sample is positive. And if all tests are negative, then the sample is considered negative.

So we can do some calculations. As I stated, the limit of detection of the test is 4.4 international units per mL. That's the concentration that's detected 95 percent of the time. So using Poisson distribution, one can calculate what the hit rate would be for lower concentrations.

So a 65 percent hit rate, for example, would be observed on a concentration of 2.4 international units per mL, which is about 12 copies per mL. So just looking at the statistics, if one had samples of 12 copies per mL, and did ‑‑ and analyzed one sample and conducted three PCR reactions on it, and considered the result to be positive if at least one of the three were reactive, then the sensitivity would improve from 65 percent to almost 96 percent.

And this just illustrates that the probability of getting a reactive result at 12 copies per mL with the test is 65 percent. So if you just do one test, you can pick it up 65 percent of the time. But if you do two more replicates, then you have a much greater chance.

You have eight possible outcomes. Seven of them are reactive. And if you add up all of the probabilities, you have a 96 percent chance of picking it up, and only a 4 percent chance of missing it.

So we tested these calculations out with the study, and the experimental design was to take the HBV international standard and make dilutions to 30, 10, 3, and 1 copies per mL, and then to do 40 ‑‑ to analyze 40 replicates of each of those levels. And on each replicate one one mL aliquot was extracted, and three PCR reactions were conducted.

So I don't expect you to read this, just look at the colors. These ‑‑ this table shows all ‑‑ the results on all 40 samples at 30 copies per mL, and there's two columns for each replicate. One shows the target result, and one shows the internal control result. But what you should look for is where the red is, so the red indicates a non-reactive result.

So out of the three replicate tests done on the 40 samples there were a few non-reactive results, but all 40 samples had at least one positive result. So the overall cumulative detection rate was 100 percent.

And then, at 10 copies per mL, again, all 40 samples had at least one of the three replicates detected. So the cumulative detection rate at 10 copies per mL was also 100 percent.

At three copies per mL, we're starting to see, again, that the sampling issue prevents many samples from being detected. But 29 out of the 40 still had at least one of the three replicates positive for a cumulative detection rate of 72-1/2 percent.

And at one copy per mL, 10 of the 40 samples had at least one test result positive for an overall detection rate of 25 percent.

So if you take this data and use Probit statistics to determine the 95 percent limit of detection, it would be six copies per mL.

So the conclusion is that using the MultiPrep specimen preparation method on one aliquot per sample, and doing three PCR reactions on each aliquot, and calling a sample positive if one or more of the reactions are reactive, then the cumulative 95 percent limit of detection for the COBA sample screen test is under 10 copies per mL calculated to be six copies per mL.

So if a followup sample from a deferred donor was non-reactive with an alternate anti-HB core test, coupled with a negative test result with a highly sensitive NAT test, this should provide sufficient data to safely reenter donors who were previously deferred.

And I'll be happy to take questions.

ACTING CHAIRMAN ALLEN: Thank you.

Dr. Hollinger.

DR. HOLLINGER: Yes. I'm just a little confused. Is there ‑‑ why is it that it doesn't work with the 200 microliters? Why don't you just test the 200 microliters which has all the particles in it, instead of doing three replicates? What am I missing here?

DR. HERMAN: The reaction can't accommodate that large a volume. So I can't take the 200 microliters of the extracted sample and put it all into the PCR reaction. The PCR reaction is designed ‑‑ that would be developing a whole new assay.

DR. HOLLINGER: I thought initially you showed that you had looked at 200 microliter samples, though, in the very first slides. And you looked at ‑‑

DR. HERMAN: Oh, no. Let me go back to the ‑‑ we have two different sample preparation methods ‑‑ one that uses one mL plasma, and it's a more sensitive method but it's less convenient because it requires this high-speed centrifugation step. And when you do the high-speed centrifugation step, and then extract the pallet, the pallet ‑‑ the recovered ‑‑ DNA is eventually recovered in 200 microliters of an assay reagent with specimen diluent.

And then, 50 microliters of this material can be brought into PCR reaction. Regardless ‑‑ and with the standard sample preparation method, one starts with 200 microliters of sample, skips the centrifugation step, and just extracts that whole volume. But that still gets recovered in 200 microliters of specimen diluent.

With both methods you end up with a recovered DNA in 200 microliters, and only one-fourth of it ‑‑ 50 microliters ‑‑ can get into the PCR reaction.

Does that clear it up? Maybe ‑‑

DR. HOLLINGER: Thank you.

DR. HERMAN: We have things that we've thought about to do large volume PCR reactions. With infectious disease testing, the ‑‑ one of the main limitations is, how much sample can you get into a test? And one way of doing that is to make better sample processing methods that can concentrate big plasma samples into very small volumes, and there are many factors that limit that.

And the other is to make a really giant PCR reaction, and there are factors that limit that also.

DR. HOLLINGER: Just for information, how fast are you spinning this down?

DR. HERMAN: It's 23-1/2 thousand G's, I believe.

DR. HOLLINGER: For just an hour?

DR. HERMAN: For an hour.

DR. HOLLINGER: And that's in serum?

DR. HERMAN: That's in plasma.

DR. HOLLINGER: I mean, plasma.

DR. HERMAN: It doesn't pallet 100 percent of all the virus particles.

ACTING CHAIRMAN ALLEN: Other questions or comments?

Okay. Thank you very much, Dr. Herman.

The schedule now has us moving to our open session. We're going to actually modify our agenda very slightly. Earlier this morning we did not have the presentation of plaques and recognition of the BPAC members who are ‑‑ for whom this is the last formal meeting, let me put it that way, and we will do that now.

We will then have a break of 15 minutes and come back and move into our open hearing.

So, Dr. Epstein.

DR. EPSTEIN: Well, this is always a bittersweet moment at our Advisory Committee meetings. On the one hand, it's a very special privilege to be able to thank our BPAC members for their service to the committee and to the FDA, but, obviously, it's a sad moment when we have to ask those people to step down because they've completed a term of service.

We value greatly the advice that we receive from the Blood Products Advisory Committee, and we're fully aware that it requires a very special effort to digest the materials that we send to you and to pay close attention during the course of our very detail-oriented meetings.

And so it's my pleasure, my privilege, and with sadness, to thank these specific persons. Dr. Kenrad Nelson, who completed not just a term of service at the last meeting but also his tour as Chairperson; Dr. Jonathan Goldsmith, committee member; Dr. Michael Strong, who has been our member as a ‑‑ the industry representative; and Dr. Charlotte Cunningham-Rundles, also a voting member.

So if each of these people would come up in turn, I'll be happy to award a certificate and a plaque as a token of our appreciation for all your effort on our behalf.

Okay. First, Dr. Nelson.

(Applause.)

And did you have the photographer ready? Okay. Notice this spontaneous setting.

Okay. Next, we'd like to thank Dr. Charlotte Cunningham-Rundles.

(Applause.)

Okay. Next, we'd like to thank Dr. Jonathan Goldsmith.

(Applause.)

Now, Dr. Michael Strong, thank you.

(Applause.)

So perhaps one round of applause for everyone together.

(Applause.)

So, Jim, do we get our break now?

ACTING CHAIRMAN ALLEN: Yes. We'll take a 20-minute break. Please be back here at, well, 10 minutes after ‑‑ 10 minutes after 11:00.

(Whereupon, the proceedings in the foregoing matter went off the record at 10:50 a.m. and went back on the record at 11:14 a.m.)

DR. SMALLWOOD: We're in countdown mode.

Dr. Allen?

ACTING CHAIRMAN ALLEN: Thank you. We will now move into the open public hearing. Just got new stuff put on my papers here, so I ‑‑ I've got two speakers who want to speak at the ‑‑ on the reentry of anti-HBC donors, Dr. Andrew Heaton and Dr. Steven Kleinman. I need to, first of all, read the open public hearing statement.

Both the Food and Drug Administration and the public believe in a transparent process for information-gathering and decision-making. To ensure such transparency at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual's presentation.

For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement, to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting.

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

If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

Okay. Dr. Kleinman, may I call on you first, please, to present a combined statement from AABB, ABC, and ARC.

DR. KLEINMAN: Hi, and good morning again. The AABB and other blood banking organizations have been working with FDA over the last several years to develop an algorithm for reentry of donors who have been deferred due to reactive anti-HBC results.

Blood banking organizations believe that the proposed anti-HBC reentry algorithm will be a major benefit to deferred donors, will increase the number of donated units, thereby improving blood availability, and will not compromise blood safety.

AABB, ABC, and ARC support the FDA proposed algorithm and urge BPAC to endorse its use. Approval of this algorithm is only the first step in moving anti-core donor reentry forward. The next step is for manufacturers of HBV NAT assays to work with the transfusion medicine community to design and carry out the necessary studies to establish that their testing system can be used for anti-HBC reentry.

The blood banking organizations are committed to this project and will provide the needed donor specimens. We urge the manufacturers to promptly meet with FDA, so as to devise the appropriate studies to obtain an anti-core reentry claim. Furthermore, we urge the FDA, under its critical path initiative, to encourage HBV NAT assay manufacturers to participate in pursuing this reentry claim.

Another necessary element for anti-core reentry is the availability of an FDA-licensed more specific anti-core assay for routine donor screening. Compared to the non-specific assays used at the end of the 1980s and in the early 1990s, one such assay currently exists, and the data suggest that another core assay currently under FDA review may have even greater specificity, thus potentially increasing the yield of donors who could be reentered.

It is the goal of the majority of blood collection agencies to move forward with anti-core donor reentry soon after licensure the implementation of the PRISM anti-core assay, provided that one or more HBV NAT tests are approve for this purpose.

AABB, ABC, and ARC believe that there is widespread consensus that anti-core reentry will be beneficial to deferred donors and to the blood system and urge that all involved parties find a way to expedite its approval and use.

Thank you.

ACTING CHAIRMAN ALLEN: Thank you, Dr. Kleinman.

Any questions or comments pertinent to Dr. Kleinman's presentation?

Okay. Dr. Heaton.

DR. HEATON: GEMProbe, Incorporated and Karon Corporation have submitted a biologics license application for the procleics ultria blood screening assay to the U.S. FDA on September 29th. Both Karon and GEMProbe do support the FDA request for BPAC advice on a reentry algorithm for the application of HBV nucleic acid testing to allow reentry of donors previously deferred for HB core antibody serology tests.

Specifically, and in addition, Karon and GEMProbe also support the AABB proposal for a validation study of 3,000 recalled anti-HB core deferred donors as a means to establish HPB NAT as a required component in an anti-HPC deferred donor reentry algorithm. The companies fully support the transfusion medicine community in their desire to pursue HB core reentry.

Thank you.

ACTING CHAIRMAN ALLEN: Questions for Dr. Heaton?

Okay. Thank you.

Are there any other comments that anybody wants to make during the open public hearing?

Okay. We will close the open public hearing and move to the committee discussion. This was stated to be ‑‑ or the next presentation was the FDA perspective and questions for the committee. I understand that, in fact, there will not be formal questions for us to discuss. But Dr. Kaplan will present the FDA perspective at this point.

DR. KAPLAN: Okay. So what you have heard is that we have a ‑‑ we're proposing an algorithm, or the Blood Committee is proposing an algorithm to reentry repeat reactive anti-core donors. This algorithm, at the current time, cannot be validated because two big elements ‑‑ mainly one big element is missing, is that the testing with a more specific anti-core test of ‑‑ it's not available.

Sue Stramer mentioned that she is conducting a trial, and that she ‑‑ she's in the process of collecting that data. So basically we don't have formal ‑‑ as the Chairman said, we don't have formal questions for the committee. However, we would like the committee to ‑‑ if they have any comments on the proposed algorithm, if they can do so.

ACTING CHAIRMAN ALLEN: Okay. I guess we don't have a slide or a piece of paper that shows the formal algorithm. Well, we've got lots of paper. We don't have a ‑‑

(Laughter.)

‑‑ slide that shows the formal algorithm.

DR. KAPLAN: Yes. Let me see if I can pull it forward.

ACTING CHAIRMAN ALLEN: Okay. You know, we certainly heard a lot of data presented by blood collection organizations. We have statements from the organizations themselves in terms of the way in which they would like to see this proceed. I think we've got lots that we can discuss and provide guidance to the FDA in terms of its moving forward on this process, even in the absence of specific questions.

So with that as background, let me open the floor to discussions, questions, comments, or whatever, on the issue before us of reentry of donors that test repeatedly reactive for anti-core.

Jonathan. Dr. Goldsmith.

DR. GOLDSMITH: I was just trying to figure out about the impact of this whole system. Have any of the blood collectors surveyed these donors who were deferred to learn if they would actually come back as donors again if they were reentered through some kind of algorithm?

Do we have any information about that? Or are these people who have had a test, it came back negative from their point of view, and, therefore, they are going to drop out of the blood donor pool from that point forward? Do we have any information about these people? Have they been surveyed?

ACTING CHAIRMAN ALLEN: And I would add to that, I would be interested, in particular, from, you know, the Red Cross' perspective what has been ‑‑ I mean, certainly, in looking at the data that Dr. Stramer presented we see a much lower return rate by those donors that received that letter. Even though they're invited to come back in eight weeks, we I think saw a much lower return rate than was true for donors who didn't get any letter of notification.

And I will just throw it open. Are there any representatives from blood collection agencies that would like to address the question that Dr. Goldsmith raised?

Dr. Kleinman.

DR. KLEINMAN: Yes. I don't have a good answer to your question. I don't think that that specific type of survey has been done for anti-core positive donors. I was going to relate a similar phenomena, though, and that is for ATL deferrals that occurred prior to the change of criteria.

Centers have tried to access donors who were deferred for ALT and reinstate them, since there is no longer a deferral criteria. And I think the yield has been ‑‑ and I don't have any numbers, but I think anecdotally the yield has been reasonably satisfactory, whatever that means.

I mean, the centers who do it say that they find it a worthwhile process, but we don't have the actual numbers to help you there.

DR. STRAMER: Regarding a survey for anti-core, we don't have that. And for ALT, for reinstatement, I don't have the numbers off the top of my head. But we did see higher rates for those donors that were more recently deferred. The numbers that I do have are for P24 antigen in which we did do reinstatement, and about 30 percent of the repeat reactive donors who were eligible for reinstatement did return and were successfully reinstated. So for P24 antigen it was about 30 percent.

But those ‑‑ that was automatic or more proactive reinstatement closer to the time of their next donation. So the question is these long-term deferred anti-core donors, what would be our success of getting those back?

But, again, as I said, if we don't do this for anti-core, then we might as well not do reentry for other ‑‑ any other marker, because this is clearly the highest marker of why we defer donors for test results. And we hear from donors ‑‑ I alone hear from donors every single day about, how can they be reentered for HIV, HCV, HBV? So it's definitely something that the community or these committed donors want.

ACTING CHAIRMAN ALLEN: Dr. Nelson.

DR. NELSON: Yes. It seems to me that beyond the numbers of donors that could be captured or reentered, the benefit ‑‑ there would be a benefit to an individual person to know that, in fact, the test was false positive, the initial screening test, and that he doesn't have a chronic infection ‑‑ an infection with a chronic infection, viral infection. So I would think there would be some benefit to that.

And probably if the blood bank didn't do it, if a person is asymptomatic, probably nobody else would. I doubt his physician would do that. So I can see some benefit to the individual person who was repeated reactive on the core antibody alone. And it seems to me there would be some individual donor benefit from that.

ACTING CHAIRMAN ALLEN: I certainly agree. And, in fact, the availability of more specific tests probably could allow a total reexamination of the testing scheme, which tests are used, and in what sequence, quite apart from the reentry issue.

Dr. Fitzpatrick, do you want to introduce yourself formally, please?

DR. FITZPATRICK: Mike Fitzpatrick from America's Blood Centers. Two things. One is it's very hard to measure the impact of reentry of anything. And it's hard to measure the impact of the deferred donors on other donors who have been deferred for some reason.

But the thing that I would suggest is that this would be the first step toward the next step, which is a supplemental algorithm to core testing that would allow us to use a battery of tests, whether it's NAT or a more specific ‑‑ more sensitive core, to evaluate those initial repeat reactive tests and not have that initial deferral.

And so if we don't have the initial deferral on a new donor, we don't have to worry about reentry, and we're not deferring donors who are eligible to donate. So I would see this as a first step in the progression toward accumulating more information about the tests available and the results available, so that we can come up with an algorithm for supplemental testing that will allow us to not defer those individuals who shouldn't be deferred.

ACTING CHAIRMAN ALLEN: Thank you.

Any questions or comments on that?

DR. SAYERS: My name is Merlin Sayers, and I'm CEO at Carter Bloodcare, which is the community independent blood program for Dallas/Ft. Worth.

Dr. Allen, this will be an acronym-free statement.

(Laughter.)

I'd like to applaud the FDA for taking this approach to donor reentry. And without wanting to downplay the importance of the question that prompted these comments from the floor, it's not just the yield of a reentry program that's important.

One of the issues that we are dealing with is increasing incredulity on the part of donors who perceive that their donor deferral flies in the face of their own self-assessment of good health. And this is particularly true with regards to core antibody deferral.

These donors who dispute why they might have been deferred, if we cannot confirm to them that the reason they are deferred is because there is genuine risk to their health, these individuals essentially have become disincentives to others in the community when the deferred donors, particularly these core antibody deferred donors relate their experience to friends, family members, and neighbors, saying that they have indeed been deferred.

But during the deferral process, we do not have anything really beyond the precautionary principle to invoke to explain to them what the dual core deferral might mean to their good health. Reentry of these individuals, even individuals who might have been deferred 10 or 15 years ago, is going, to a significant extent, enable us to restore credibility in the minds of deferred donors, and I hope reduce the likelihood that their experience is going to act as a disincentive to other would-be donors.

So we do applaud the possibility of reentry for this particular group of deferred individuals.

ACTING CHAIRMAN ALLEN: Thank you. I think the point that you make is extremely important, and along with that ‑‑ with the comment from Dr. Fitzpatrick, about perhaps with the right evaluation, with new tests, we may never need to send out that letter of deferral initially, or the letter of ‑‑ "There is something that's not quite right in your testing mechanism. Please come back and donate again, so we can retest you."

You know, the point being that if you take healthy people with tests that have less than 100 percent sensitivity, and less than 100 percent specificity, you are going to have some inaccurate test results. The specificity being ‑‑ for a perfectly health donor being the most important measure there.

And our donors are supposed to be a totally healthy population. So it ‑‑ it really is an important issue in terms of the message that is given to them about their health.

Dr. Kleinman.

DR. KLEINMAN: Yes. One other aspect moving forward ‑‑ and that follows up on these comments ‑‑ is that when we do go to a new anti-core test, hopefully it will be more specific and the people that we defer really will have anti-core. But we still may have some false positives, even on a new test. So I think if we have a reentry algorithm in place, it permits our donor notification message to make more sense.

We can say to people, "We don't know" ‑‑ you have these results, and if you want to check them out further, if you're concerned, you can come back and potentially" ‑‑ and this is for the newly-identified people, you can potentially be reentered.

Now, we may not be able to reenter many of those, but we could get a bad lot of reagent, for example, and wind up deferring persons for an anti-core test result that doesn't reproduce in the future. So I think just moving forward it gives us the ability to notify donors, and that issue that always comes up, "Well, if I'm okay, why can't I donate?"

And we never have an answer for it, and it creates cognitive dissidence in people's minds. "They are telling me I'm okay, but they're telling me I can't donate. That means they don't really think I'm okay. They just sort of think I'm kind of okay."

And by at least offering people reentry you can say, "We have a way of knowing ‑‑ we have a way of coming back to you and giving you further information." And I think that's valuable in the notification message also, psychologically valuable for donors, that we've gone the extra step.

ACTING CHAIRMAN ALLEN: Yes.

DR. SCHREIBER: I guess I'm a little bit confused, because when we're talking about reentry, we're only talking about reentry of the people who were deferred, and, therefore, had two subsequent repeat reactive tests and different donations.

80 percent of those, as Sue indicated, will ‑‑ that have the first repeat reactive will never show up again in the door. So they will never be deferred for hepatitis B tests. So whatever you put out, they will never get a message letting them know what their true status of infectivity is, because they will never come back to the blood center, unless you go through some process to rerecruit those.

Sue's data showed that of those 20 percent of first-time donors that came in, 88 percent were ‑‑ were repeatedly reactive a second time. So those are the people who are deferred. And then ‑‑

DR. KLEINMAN: And that's with the current test, because you had ‑‑

DR. SCHREIBER: Right, right. But still ‑‑ you're still going to have a significant number of people, unless you really drive that false positivity rate way down that are not going to be told to come back and be retested.

I guess the other question I had is that when we talk about this reentry algorithm, and it seems that it's been deferred because there is not a more sensitive core antibody test, what about all of those people that are still out there?

And if we really are talking about a reentry algorithm, why wouldn't we institute it now, because that test is really dependent on the subsequent NAT and other test followup. And the chance that they would get a second or a third ‑‑ a third core antibody test would probably be really, really small at this point.

ACTING CHAIRMAN ALLEN: Dr. Kleinman, are you responding to ‑‑

DR. KLEINMAN: Yes. I just wanted to clarify that. Maybe we didn't state it strongly enough. For reentry to really work, you have to have a licensed, more specific test that the blood center switches to. And without trying to promote or detract from any companies, we do believe that the Abbott PRISM assay is that more specific test, we do think that most Abbott users will switch to that test once it's licensed. And we do believe that the false positivity rate will go down.

But, I mean if you had a reentry algorithm and you're using the same test you used before, it's quite ‑‑ I mean, it wouldn't make sense, because you're still going to be repeatedly reactive on that non-specific test. Most people who are repeatedly reactive are repeatedly reactive to that test over time. They don't ‑‑ it doesn't go away. It's not a one-time thing.

So, really, we need that new test, and, you know, it's been under consideration at FDA for quite a while, and hopefully it will be licensed at some point. And then, at that point, once test centers are using it, then reentry hopefully, if we validated the NAT assays and have the claims, then it might be a practical thing to do. But without that new assay, it's unlikely that reentry would have as good a yield as we would hope.

I don't know if that clarifies it a little bit.

ACTING CHAIRMAN ALLEN: Dr. Epstein.

DR. EPSTEIN: Yes. You know, I think what would be helpful to the FDA is if the committee members would comment specifically on the elements of the proposed algorithm and their scientific validity. And they are posted here on the slide that Dr. Kaplan put up, but just to highlight it it's the idea of an eight-week delay. That's to allow, you know, full-blown development of markers.

It's the idea of an offline test. In other words, you don't collect a unit that might be at risk before you've resolved the status. It's the idea of hepatitis B done on the individual sample ‑‑ in other words, ID NAT ‑‑ but with a sensitivity of at least 10 copies per mL. And I think you've heard that that's hard to reach, but it is feasible.

And that, you know, some data appeared to have been ‑‑ generated less sensitive assays that, you know, could be debated. And that we have dropped the idea of looking at an anti-HBS as part of the reentry algorithm on account of the vaccine issue, and retaining the concept that you must demonstrate at least some negative anti-core test, whether it's the same assay or a different assay.

It's been explained that it's highly desirable to switch the assay, because if you simply use the same assay over again the likelihood it will be reactive again is very, very high.

So I think it would help us if, you know, there were specific comments on the elements of the algorithm.

ACTING CHAIRMAN ALLEN: Thank you. We will get to that.

Dr. Kuehnert.

DR. KUEHNERT: Yes. I just had a question about how this would work practically. So someone comes in, they're repeat reactive the first time, under this algorithm they would not get any kind of a letter or indication that they have a positive test. Is that right? Or are they going to have some indication that they have a positive test the first time but can donate?

ACTING CHAIRMAN ALLEN: Dr. Kaplan, do you want to address that question?

DR. KAPLAN: Yes. So, basically, a person will be repeat reactive on any test, and then it will be deferred about eight weeks, and then it will be asked to ‑‑ a new sample will be collected. And so it will be again tested for surface anti-core and NAT.

DR. KUEHNERT: So they would be asked to come ‑‑ I guess I'm a little confused. So they'd be ‑‑ they'd get a letter saying that they have a positive test, and they need to come back for testing, or it would be when they come back to donate?

DR. KAPLAN: Well, this would have to be a testing at eight weeks, because they were reactive twice and ‑‑

DR. NELSON: The person has already been tested twice and found to be anti-core positive. So under the current algorithm, they are permanently deferred.

DR. KUEHNERT: Right.

DR. NELSON: And I guess what this is, it's a ‑‑ it's to try to reenter those people are permanently deferred because the feeling is that a lot of permanently deferred ‑‑

DR. KUEHNERT: I understand that. I'm just saying, subsequent now to this, not thinking about people who have already been deferred, but people who in the future then are repeat reactive to anti-hep B core ‑‑

DR. KAPLAN: Okay. Basically, we are not right now talking about in the future, what will happen with a future license test. And that's something we are developing and we are thinking about it. However ‑‑

DR. KUEHNERT: But that will apply. If you change this algorithm, that will apply to them as well, won't it? What am I not understanding?

DR. KAPLAN: Yes. Robin wants to comment on this.

DR. BISWAS: Robin Biswas, FDA. This after somebody is repeat reactive on the initial ‑‑ initially. They wouldn't be deferred at that point. You know, the unit, of course, would not be used. The person could return and donate. I think that the blood organizations said that they do get a letter, in fact.

ACTING CHAIRMAN ALLEN: The Red Cross does send out a letter ‑‑

DR. BISWAS: Right.

ACTING CHAIRMAN ALLEN: ‑‑ after the first repeat reactive that invites the donor to come back in.

Dr. Stramer, do you want to clarify that?

DR. STRAMER: First-time core reactives are not deferred. It's up to the blood center ‑‑ well, clearly, the policies of two times deferral are up to the blood center. As Steve mentioned earlier, some blood centers will defer after the first time core reactive, because the yield on the second time is so low.

Some blood centers do the two times deferral policy and don't notify after the first time core deferral ‑‑ I mean, the first time core reactive and just let the donors come back and only notify them based on the second deferral.

We do notify after the first-time deferral for the reasons that these donors truly could be hepatitis B, in fact, and we believe it's the right thing to do. But they still can come back a second time.

So did I help clarify that?

DR. KUEHNERT: Sort of. I mean, what I'm asking, if this gets put into place now ‑‑

DR. STRAMER: Would that change?

DR. KUEHNERT: Yes, right. That's what I'm asking.

DR. STRAMER: Okay. I don't think the question on the table is whether the two-time core deferral policy will change. I think the question just is for those donors who have been core reactive two times, can they be reentered using the algorithm that the FDA proposes.

DR. KUEHNERT: That is correct. I know other people ‑‑ it will just be explained to them that this was a false positive test, and that now they can donate?

DR. KAPLAN: Well, the following slide ‑‑ it's basically at this point people will be told that they can donate, come back, they're negative, and then they will be tested again on the donation. And if it's negative, everything is fine. They can donate if everything is negative.

So I don't know if you can put the next slide ‑‑

DR. NELSON: Do you have an estimate of what proportion of the people who were twice positive will qualify under this?

DR. KAPLAN: No. Because we don't have to ‑‑ we haven't seen the data yet with the PRISM, and that's what Sue Stramer's data was ‑‑ would fill that blank, and then let us know how ‑‑ fully validate this algorithm.

ACTING CHAIRMAN ALLEN: We've got several hands up. Dr. Strong, and then Dr. Doppelt.

DR. STRONG: We don't have good data on that. However, if you go back to the ‑‑ several years ago when the PRISM clinical trials were being done, comparing current license tests with the clinical trial results, there was about a 10-fold improvement in specificity. So it could ‑‑ that's what got everybody excited about the possibility that these donors could be recovered.

ACTING CHAIRMAN ALLEN: Mr. Doppelt.

DR. DOPPELT: I was just going to say I ‑‑ I thought I had it straight. Now I'm ‑‑ perhaps I'm confused. But in terms of fairness to the potential donor, it seems to be there's a difference between whether you say come back a third time and we're going to retest you, to see if you can be a donor, versus come back a third time and we're going to do some different tests and try and sort out whether or not you really have an ‑‑ you're really infectious or not.

So I'm a little bit confused as to what information is going to be specifically relayed to the potential donors.

ACTING CHAIRMAN ALLEN: I think that's an important question to answer. And my guess is based on what we've already heard from different blood collection centers today that since there isn't any single way of handling that first time, that this is an issue that needs to either be clarified by the FDA or to allow the marketplace to sort it out on its own as currently has happened.

DR. DOPPELT: I mean, it just seems to me that you are far more likely to get patients to return if you tell them there is some additional testing that may be done to help sort this out versus come on back and try it again and let's see what happens.

DR. KLEIN: In the proposed FDA algorithm, they are going to do a NAT test that's quite sensitive. So they are, in fact, going to be doing something different.

ACTING CHAIRMAN ALLEN: Right. And one might, you know, raise the question ‑‑ and I'm sure there aren't data there to answer that today, but one might raise the question, if you've got a donor who is repeatedly reactive the first time, if you want to give them the best possible information, maybe you ought to take, you know ‑‑ take the samples from that first donation and subject them to these additional tests instead of asking them to come back in eight weeks.

And I understand the reason for ‑‑ you know, for the eight-week or longer delay in terms of trying to find out if there's progression of markers over time that might indicate real infection, but if you want ‑‑ you know, if you want to give the most reassuring message back to the donor the first time, you would do that before you contact them the first time.

So, you know, I think there's a lot of permutations here that aren't really on the table and haven't been discussed.

Dr. Klein.

DR. KLEIN: Yes, I ‑‑ just to move this a little forward I hope, I'd like to support the concepts of the FDA algorithm. I think it's a good one, and I certainly support reentry for those people who have been deferred because of a two-time causative core antibody test.

At the same time, I'd also certainly like to encourage you to do whatever is possible to get a more specific core antibody test available, and also keep an open mind to the possibility of having an algorithm that will prevent us having to defer such donors in the first place.

ACTING CHAIRMAN ALLEN: Thank you for that statement.

Dr. Strong.

DR. STRONG: Actually, I was going to support his proposal. I think we ‑‑ we have lots of ‑‑ we have lots of donors who get that message by letter. The letters are constructed in different ways, so the recipient may get a different message than was intended. But many of them at least will be told that they should see a physician, and they go to a physician and they get tested and it's negative, because they're using different tests.

So I think also to accelerate the discussion that we've probably heard enough, and I would certainly support it.

ACTING CHAIRMAN ALLEN: Yes. Dr. Hollinger.

DR. HOLLINGER: Again, I support this statement. I think it's a good statement. You might ask the question, you know, even when you look up, there will ‑‑ why even have to do ‑‑ I mean, if you have a test, a new test, let's say, that's licensed, that is completely specific, then why do you even have to do HBV NAT in these patients?

And it goes back to the other issue is ‑‑ what has been taught by the blood bank a lot, and others here, is that it's important to tell those donors who do not have an infection, or do not have any evidence of exposure, that they're clear of this disease. I mean, there's nothing really there.

But I ‑‑ I also want to say that the blood bank does the clinicians a great service in this regard, because it also tells those who may be infected that this is an issue. So we've talked so much about the ones who may be falsely positive, and what it's going to do by telling them and talking to them about this issue.

It's just as equally important to talk to those who have a positive result of whether they might be infected, and that's where the HBV NAT comes in. And by looking at all of the things ‑‑ one of the things I like about getting information from the blood bank is that they are willing to send to clinicians all the information ‑‑ the cutoff levels, which I like to look at, the ALT levels, which are often ‑‑ when they were doing them, which is also ‑‑ can be elevated, and yet the patient ‑‑ the donor can contribute. It could be a variety of things.

But all of that information is really helpful when you then can sit down with a person, and certainly by looking at this, then I could say to that person, "Look, I see no evidence that you have an active infection here. Even if it's a very specific positive anti-HBC test that's highly ‑‑ that has a high titer, or high concentration of the antibody," and the HBV NAT is negative.

Then I might be able to tell them that and reassure them that I see nothing in these studies that would have me concerned. I don't mind telling them that they're not infected. It's not a real issue at that point. And if they're positive, then one can deal with that issue also and reassure them about their risks, and so on, for transmission and other things which are usually very small.

ACTING CHAIRMAN ALLEN: Thank you.

Dr. Bianco, first of all, if you'll introduce yourself, and then Dr. Biswas.

DR. BIANCO: Celso Bianco, America's Blood Centers. I want to make two quick comments. One is the reason why only old people remember that plain ‑‑ the reason why we do it twice in terms of only deferring on the second time is from day one we recognized that this is a lousy test, in terms of specificity. And we were hoping that we could recover some donors. Hopefully, a new test, more specific, we will be able to do it only once and make a conclusion about that. We don't need to wait for two.

The second point that I'd like to make is addressing one of the questions that Dr. Kaplan has asked us, and Dr. Epstein, is the question of offline testing. I think I'd like very much to discuss that. It appears that it's a note of caution that you will call back the donor, collect only a sample, and then, after getting the results on that sample, you will allow the collecting of blood units.

Donors, unless they are very angry with us, and they come together with a bill from their doctor for all the tests that they did because of our core positive doctor, and they want the blood center to reimburse them for that, they don't come back just for a test. They come back for a blood donation. That's what attracts them is their sense of altruism, sense of trying to help.

And so the chances, I believe, of releasing a unit inappropriately because of a test result are very small. Usually units are released inappropriately when it happens. Because of other issues, they are not so much dependent on the interaction, direct interface between testing machines, computers, and the computers that release the unit of blood.

So I would ask that these requirements be dropped.

Thank you.

ACTING CHAIRMAN ALLEN: Dr. Epstein first.

DR. EPSTEIN: Well, I think the other side of that argument needs to be heard, which is that there is a finite risk of inadvertent/inappropriate release of a unit, and the risk of consequences goes up if that is, in fact, an at-risk unit.

So that's why in our reentry algorithms we have always wanted to requalify the donor offline, because otherwise you've drawn an at-risk unit, you don't know its status yet, it might turn out to be true positive, and there's a finite risk unrelated to the testing that it might get out.

ACTING CHAIRMAN ALLEN: Dr. Klein.

DR. KLEIN: I'm not sure that those data are correct, Dr. Bianco. We've never had any difficulty getting people back for our studies just to be tested. And, in fact, we've found that people are more reluctant to give a unit that they think might be discarded, so I don't know of any data to say that they won't come back to be tested. Our experience is exactly the opposite.

ACTING CHAIRMAN ALLEN: Dr. Kuehnert, and then Dr. Biswas.

DR. KUEHNERT: I just wanted to say that I'm supportive of the statement. I think, you know, this is probably going to apply to a very small number of people, at least the way the tests are currently applied. And I do have concerns about sort of donor counseling and health, but that's not at issue here.

I think it could be a good topic for another government committee, but, you know, just with that in mind I think donor health is important. And I think there is some work to be done here. There's probably going to be more confusion when the new algorithm is applied initially concerning counseling, but overall I think this is a good statement.

ACTING CHAIRMAN ALLEN: Dr. Biswas.

DR. BISWAS: I just wanted to say, you know, there's been a lot of talk, which I agree with you, about the specificity, lack of it, and, you know, the importance of having a specific anti-core test. But remember that the reason we are bringing this issue to you at this time is because of the improvement or the development of NAT technology, and that really was the driving force here. I just wanted to say that.

ACTING CHAIRMAN ALLEN: Dr. Busch.

DR. BUSCH: Yes, I want to address the issue of the NAT sensitivity requirement. The only donors who will be reinstatable will have to be negative on test of records ‑‑ surface antigen anti-core assays. In fact, these donors, if they came in for the first time today, they wouldn't be screened out at all. They were the historical false positive anti-cores.

We know in true anti-core positives that are persistently anti-core reactive on all the assays, if you progressively increase the sensitivity of your NAT test, you will cull in a little bit more, you'll detect a smaller incremental fraction of very low viremic donors.

So the studies that we've done and Sue described where if you go from 100 copy to 50 copy to 10 copy sensitivity, you pick up a small fraction of additional low viremic carriage, but this is in people who are fully seroreactive and would be reactive on any anti-core test.

And, you know, the requirement for 10 copy, 95 percent hit rate is making all the companies have to do multiple replicates ‑‑ would make the NAT screening cumbersome for the blood centers even if these tests can achieve that level of sensitivity.

And I just don't understand where that number came from and why FDA is pushing such an extremely stringent low sensitivity threshold when, again, these donors would be eligible today. And in the absence of any NAT screening right now, and certainly once NAT is in place, it will be likely done on small pools, and certainly not with assays that have this level of sensitivity.

ACTING CHAIRMAN ALLEN: Would anybody like to respond to Dr. Busch's comment?

DR. BISWAS: Mike, I think you were asking ‑‑ I didn't hear everything you said, but your questioning the ‑‑ the requirement for 10 copies and less, that was it. I should say that ‑‑ actually, Dr. Kaplan did say it earlier ‑‑ that we are sort of flexible on that point. It will depend on some of the results ‑‑ on the results that we get back using the less sensitive test that Sue Stramer is doing with NGI.

And it ‑‑ but I should say that although it is stringent, it does seem to be as though it is possible. But as I said, we would be flexible and will take into account the clinical trials ‑‑ the results of the trials that are being done under IND, and that we are flexible on that.

ACTING CHAIRMAN ALLEN: Dr. Kaplan, did you want to respond?

DR. KAPLAN: Yes. You know, someone was deferred ‑‑ gave twice anti-core, it was repeat reactive anti-core, so this ‑‑ there's some flag there. It could be ‑‑ you know, it could be a false positive measurement, but there's a flag there. So there's some rationale there to try to increase the sensitivity of the NAT. And as we heard from Roche, that's achievable.

And then, so what ‑‑ what you don't want to do is someone that's ‑‑ you know, has a very low core and a very ‑‑ a very low DNA, but it could be an infectious unit to ‑‑ to reenter it. So there's some rationale for asking the state-of-the-art sensitivity, maximum sensitivity achievable.

ACTING CHAIRMAN ALLEN: Dr. Lew.

DR. LEW: I think I heard pretty well that, you know, for those who are ‑‑ and someone can correct me ‑‑ anti-core antibody positive alone, but if you keep on going down, you know, might detect real, real low levels, and for our immunocompetent patient it's quite possible these patients will not become infected.

But since a lot of our blood products go to immunocompromised patients, and they get a lot of blood products, I'm not hearing that potentially, you know, these ‑‑ if these patients do get it, that they will become positive. They will get infection. So I'm a little concerned about those patients and how this algorithm works.

ACTING CHAIRMAN ALLEN: I think that's a very important and interesting comment.

Dr. Hollinger.

DR. HOLLINGER: I think part of it comes back to we need to know how many of the ‑‑ these new licensed tests might be negative when the other test is positive, and that we need to know the false negative rate, if any, of the ‑‑ of HBV DNA in those samples.

If not, then it ‑‑ then I don't think that's ‑‑ if it's not there, and I suspect it may not be, then they're not at risk. I don't think they would be at risk in a ‑‑ with a good assay that's very specific. And if it's given to an immunocompromised individual, if there's no virus in the blood, or detectable virus, then those patients are not going to get ‑‑

DR. KAPLAN: Can I add something? It's that this algorithm that you have the donor tested at least three times, you know, it was ‑‑ all markers negative, but it was repeat reactive, then you bring it ‑‑ bring them back at eight weeks, and then you test them with all the battery again. And then, if they are negative, they are ‑‑ then you have a donation.

So, you know, if it's low levels, you should ‑‑ you should be able to detect it at that time. I think that's a pretty well functional algorithm.

ACTING CHAIRMAN ALLEN: Dr. Lew, and then Dr. Strong.

DR. LEW: No, I don't really have a problem with this algorithm. I'm just talking ‑‑ hearing the conversation of other methods of how to decide. And as far as I'm aware, I don't know if there's any lab test that I know of that's 100 percent sensitive-specific. You know, I'd keel over if there ever was one.

(Laughter.)

So ‑‑

DR. STRONG: But I think the point is that it won't be worse than it is now, because the new tests are actually both more specific and more sensitive. So, if anything, we're going to catch more.

ACTING CHAIRMAN ALLEN: Dr. Kleinman.

DR. KLEINMAN: Yes. I just wanted to emphasize, I think the issue of reentering somebody is dependent on the sensitivity of the tests you use to reenter. And remember, the reentry scheme includes two tests, three tests actually ‑‑ surface antigen as well. But it includes another anti-core test.

So if you are positive on that anti-core test by a second manufacturer, you're out. It doesn't matter what your HBV NAT test shows. So if that's an equally sensitive test, I mean, if you ‑‑ you're negative on that anti-core test, and that anti-core test is equally or more sensitive than the one you're using, you don't really have anti-core. And, therefore, you wouldn't need any NAT testing.

I mean, it would just be the same as if that person came in today and had never been deferred in the past, and was screened with the new test. They'd be anti-core negative, and you could say, "Well, gee, we might be missing somebody. Maybe we should do HPB NAT testing at 10 copies per mL on every donor in order to increase the safety of the blood supply."

Well, obviously, you're not going to do that. So I think we need to see the clinical trial data that validates the reentry algorithm, and then we'll know if there are discrepancies between ‑‑ if somebody is negative on the new test, and actually has HBV DNA in their serum. If we find somebody like that, how sensitive in that test did we need to do to find that person? Did we need to do a 10 copy mL test? Or was a 50 copy mL test enough? And then we would be able to test ‑‑ to maybe set our sensitivity levels.

Now, I don't know if we could do a big enough clinical trial, because I don't expect we'll have many people who are NAT positive failing the second reentry test. So it does become kind of arbitrary. But I think maybe that's why the FDA is saying there is some flexibility; we just don't have the data to know yet.

But I think, really, to answer the question that's on the floor we ‑‑ we do have protections in place with this algorithm, and even if we were to increase the ‑‑ or I guess decrease the sensitivity of the NAT, increase the copy number of detection, even if we were to do that, I think our patients would be protected from getting unsafe units because of the second core test.

ACTING CHAIRMAN ALLEN: Dr. Stramer.

DR. STRAMER: Yes. Two points, commenting along the same lines that Dr. Strong brought up. As Blaine mentioned in his presentation with the use of reductant in this new, more specific test, it's the use of this chemical treatment that eliminates the false positive non-specific early IGM antibodies that cause interferences or false positivity in the test.

But because of this concern, the test before the FDA has gone through extremely robust validation. And as has been pointed out before by Mike, the test is not only more specific but is actually more sensitive because of the disassembly of all these false positive, non-specific antibodies, so that it's more specific for low-level true antibodies.

So the test is more sensitive, it's more specific, and what FDA is proposing is actually a very robust reentry algorithm. You would use the more sensitive and more specific anti-core test. The donor would not only have to be negative on followup, but then again negative at donation.

And we're kind of quibbling ‑‑ is 10 copy, 50 copy ‑‑ certainly, if you want to increase the catchment, a more sensitive test is what you should do, or to really identify those people who are circulating DNA, from a public health perspective and from a reentry perspective, and there are tests that are ‑‑ you know, that can be achieved.

Whether it's 10 copies or 30 copies, I don't think that makes a difference. I mean, we were ‑‑ when Red Cross presented data to FDA, FDA actually said 30 copies was inadequate. So we moved it down to 10 copies quite arbitrarily, just because if we thought 30 wasn't enough, well, what would be sensitive enough? So we just chose 10 as something that we thought even the FDA wouldn't reject.

So that's kind of the derivation of the 10 copies per mL. But robustness has ben built in the algorithm, and robustness has been built into the tests that are before the FDA for licensure.

ACTING CHAIRMAN ALLEN: I would like ‑‑ okay. Dr. Lew.

DR. LEW: If I could just say that ‑‑ just for ‑‑ I think everyone agrees it's a given, but for clarification, that this statement seems suitable for most people ‑‑ given the caveat, we're talking about a more sensitive hepatitis C core antibody test. I mean, just for that clarification.

ACTING CHAIRMAN ALLEN: Dr. Epstein.

DR. EPSTEIN: I just want to comment on what we know and what we don't. What we know, and these are Sue Stramer's data from the histogram that you showed of viral load, there are indeed samples that have a viral load of 10 copies per mL or less in individuals who have a repeatedly reactive anti-core test, and who ‑‑ 65 percent of whom have a negative HBsAg test.

What we don't know is whether those same samples would be found if a third independent test were negative for anti-core. And we couldn't show you those data because we don't have those data. But no one should think that there are no samples with low-level viremia in individuals with so-called anti-core only by current testing. There are such people.

So the problem here is, you know, can we really place our faith that there won't be any such low-level viremias in those in whom another EIA is negative. We just don't know until we have those data.

So I just don't see ‑‑ but the, you know, proposal that we use assays as sensitive, that is based on the observation that some of the true positives do have DNA at that low level. What we don't know is whether the ones with the further negative EIA would have DNA at that level.

ACTING CHAIRMAN ALLEN: Thank you.

Let me come back to the proposed FDA statement here and just ‑‑ we've heard some ‑‑ actually, all of the committee members that have spoken have spoken in favor of the basic algorithm. What I'd like to do is just ask the committee for any additional comments that anyone might have about the FDA proposed algorithm and issues directly related to that.

DR. QUIROLO: Well, it would seem to me that if this is such a sensitive core test that you wouldn't really need to come back twice to have two ‑‑ a repeat reactive and then a third test, it sounds like, before you did the NAT and the surface antigen again before donation.

The other thing is if this is such a sensitive test, what's the possibility that somebody would come back for their second core test, being reactive the first time, and being negative the second time? And if you're using the same core over and over again, isn't that the same dilemma you're in now where you're ‑‑ if you're reactive once, you're more likely to be reactive over and over again?

DR. KAPLAN: Well, this algorithm basically solves a present problem. And so, you know, Mrs. Stramer ‑‑ through the number of a million people that they could be ‑‑ reenter with this.

I think that the ‑‑ the other issue that you are raising is: what is the performance of this new test that has not been approved? And how will that fill into the ‑‑ this algorithm or the deferral ‑‑ deferred algorithms for repeat reactives in core? It's something we have to see at the moment of approval of that new test. I think that's on the table at this point.

However, we are ‑‑ we agree with ‑‑ I personally agree with what you said is that, yes, that's a very important point that we have to retain ‑‑ or reevaluate when we have this more specific, more sensitive test available. Yes.

ACTING CHAIRMAN ALLEN: In actual fact, if the belief is that most of these people are not truly infected but are false reactives, then, in fact, the issue is not ‑‑ it really doesn't matter how much more sensitive the test is. The question really is needing a test of increased specificity, and the new generation tests coming on the market should meet that.

DR. QUIROLO: Will those be the initial tests, though, for the new donors once the test is available? Will that be ‑‑ will the more sensitive test be the initial test? Or will there be two tests, a less specific and then another second test after you fail the first one?

DR. KAPLAN: We don't know how many people will adopt that. We don't even know when this will be licensed at this point. And I think that's a market force ‑‑ speculation at this moment.

ACTING CHAIRMAN ALLEN: Yes. As you were asking your question, I saw heads nodding around the room from blood collection people.

Dr. Strong, do you want to comment on ‑‑

DR. STRONG: Yes. Once we have a new test that has greater sensitivity and specificity, the old test goes away. We'll only be using one test. And the donor is likely to be deferred, because we fully expect that we're going to be doing DNA as well.

ACTING CHAIRMAN ALLEN: Other specific comments from the committee members on the FDA proposed reentry algorithm? Anybody have major heartburn over it? We basically heard comments in support with a few questions on technical details.

Okay. I would like to add my support to the basic proposal, and, you know, would encourage, based on all that I've heard today, I would encourage the FDA to continue working to get this completed as rapidly as possible.

Does the committee ‑‑ and this is a straw vote ‑‑ does the committee believe that this needs to come back to the committee again once as a formal question, or have we given sufficient direction to the FDA and would like to encourage them to move forward as rapidly as possible to implement?

DR. EPSTEIN: Jim, if I could just clarify, that, you know, the committee serves to advise us on the science. You know, FDA takes unto itself the responsibility of determining the policy. So in phrasing your question, really, is ‑‑ the question is: are there other scientific issues that need to be brought back to the committee?

ACTING CHAIRMAN ALLEN: Thank you. Yes, that was what I meant.

Dr. Kuehnert.

DR. KUEHNERT: I just wanted to ask if there ‑‑ there was some discussion about the sensitivity level required, if that's a ‑‑ still an open question, or has FDA gotten enough guidance on that issue?

DR. EPSTEIN: Well, our position is that we want to see the data that emerge from combining historic, you know, twice anti-core repeat reactives with negative results of a more sensitive and specific screen, and then see: a) if there are any DNA positives, and b) what their levels are. But we think that those studies need to be done with the most sensitive available assay, otherwise we'll never get a meaningful answer.

So I can't answer the question on point. I can only answer it by saying this is why we want to see the studies that we describe.

DR. KUEHNERT: And I think, you know, the discussions we've had in previous meetings about mini-pool NAT screening in general, you know, the consensus was for more sensitive screening. So I think this all works towards that.

ACTING CHAIRMAN ALLEN: All right. Any other comments or questions? Does the FDA want further discussion from the committee, or have you achieved what ‑‑ okay.

It's approximately 12:15. The official game clock here says it's 12:21. That's a little faster than my watch, which tends to be one or two minutes fast most of the time. We will adjourn for lunch. Let's plan to have ‑‑ have people back ‑‑ we will reconvene at 1:20 by the game clock here.

(Whereupon, at 12:15 p.m., the proceedings in the foregoing matter recessed for lunch.)

DR. SMALLWOOD: We're ready to reconvene. May I ask all Committee members present to please take your seats, and may I have the attention of the audience?

Before we start, I just wanted to make an announcement. Dr. Martin Ruta this morning mentioned a draft guidance that was expected to be published, and I just wanted to announce publicly that on the FDA web site guidance for industry, use of nucleic acid tests on pooled and individual samples from donors of whole blood and blood components, including source plasma and source leukocytes to adequately and appropriately reduce the risk of transmission of HIV I and HCV has been posted as of this morning. So it is on the FDA web site. Dr. Allen, were you ready? We're ready to reconvene.

ACTING CHAIRMAN ALLEN: Good afternoon. We're ready to continue our discussion with Topic 2, the potential risk of Simian Foamy Virus transmission by blood transfusion. Our first presentation will be the introduction and background by Dr. Tabor.

DR. TABOR: Good afternoon. I'd like to begin by thanking the other speakers who will be participating in this session. Dr. Kahn from Sieber but also people who came from a great distance ‑‑ Dr. Heneine, Dr. Brooks, Dr. Peter Gantz and Dr. Lerka ‑‑ all of whom you'll be hearing from soon.

The potential risk of transmission of Simian Foamy Virus by blood transfusion is being brought to be BPAC at this time because of a report in the Lancet that this retrovirus is being transmitted under so-called natural conditions from non-human primates to the human population in Cameroon. This not only places a renewed focus on Simian Foamy Virus transmission but also represents a mechanism by which Simian Foamy Virus and other non-human primate retroviruses might enter the human population and ultimately the blood supply.

This issue is made more urgent by recent research developments related to the possible transmission of Simian Foamy Virus to non-human primates by blood transfusion, and this information will be presented by the other speakers at this Advisory Committee meeting today. Can I have the next slide, please?

Transmission of Simian Foamy Virus to humans due to occupational exposure to infected non-human primates has been reported to occur in two to five percent of persons working with non-human primates in research institutions and zoos. Most of the infected persons had histories of scratch or bite injuries caused by the non-human primates.

Because of these reports, the topic of Simian Foamy Virus was discussed at the December 13, 2001 BPAC and the consensus of BPAC in 2001 was that more data were needed to determine whether Simian Foamy Virus presented any risk to the safety of blood transfusions. Next slide, please.

This year, in the March 20, 2004 issue of the Lancet, transmission of Simian Foamy Virus to humans by so-called non-occupational contact with non-human primates was reported by Wolfe et al. and was accompanied by a commentary by Peters et al. In fact, the exposure was only somewhat non-occupational in the generally accepted use of the term, "occupational," since the authors felt that the transmission probably occurred as a result of a hunting preparation and consumption of food made from tissues of non-human primates, sometimes referred to as bush meat. Next slide, please.

Wolfe et al. studied 1,099 residents of the tropical forest area of Cameroon who had regular contact with blood or body fluids of non-human primates. Antibodies to Simian Foamy Virus were found in ten persons. Among these ten, Simian Foamy Virus itself was found by RTPCR in the peripheral blood lymphocytes of three. These three apparently had acquired Simian Foamy Virus in three distinctly separate transmissions from non-human primates. The individuals were each from different villages and the nucleotide sequence of each isolate of Simian Foamy Virus showed that the Simian Foamy Virus in each person was from a different primate species, each consistent with that person's individual hunting and food preparation history, enveloping gorilla, mandrill and cercopithecus species, respectively. These observations are consistent with the known fact that the different Simian Foamy Virus strains are each highly specific for their host species. Next slide, please.

Simian Foamy Virus is quite prevalent in the non-human primate populations, ranging from 31 to 61 percent among non-human primates in the wild and from 70 to 90 percent among those in captivity. In contrast, the prevalence of Simian Immunodeficiency Virus among non-human primates in the wild, in the same geographic areas, is about 16 percent, and the prevalence of Simian T-Lymphotropic Virus is about 11 percent.

What is the risk of Simian Foamy Virus becoming widespread among humans once it has entered the human populations. Recent reports by Heneine et al. and Switzer et al. provide strong evidence of persistent Simian Foamy Virus infections in humans, with infections lasting as long as 19 and 26 years or longer. However, human-to-human spread of Simian Foamy Virus has not yet been shown to occur. We do know that the study of a small number of wives evaluated in studies of persons with occupationally acquired Simian Foamy Virus infection has not revealed any instances of spousal transmission. And the low percentage of infected persons working in primate facilities suggests that human-to-human transmission, if it ever occurs, must be very inefficient.

Nevertheless, there is clearly primate-to-primate transmission among non-human primates in the wild. Transmission between primates is believed to occur by means of saliva since Simian Foamy Virus can be isolated easily from the saliva of infected non-human primates. Transmission by bites theoretically could be one mechanism of transmission from captive, non-human primates to their handlers.

In support of this theory, a gorilla strain of Simian Foamy Virus was detected in two Cameroonian hunters who had had multiple bite injuries during separate fights with gorillas. As we evaluate additional human cases, particularly those occurring in areas where careful observation is possible, we may have to revisit the issues of human-to-human transmission and the potential infectivity of human saliva if any evidence is found contrary to the concept that human-to-human spread does not occur. Next slide, please.

There are few clinical studies to evaluate the transmission of Simian Foamy Virus by blood transfusion. In one small lookback study, reported by Boneva et al., summarized in this slide, no evidence of transmission of Simian Foamy Virus by human-to-human blood transfusion was found. Although this study may provide a basis for optimism, its small size and the absence of information about viral load in the blood donor preclude any firm conclusions. And, in addition, no ideologic association between Simian Foamy Virus and any human disease has been established so far. Next slide, please.

Our concerns today are twofold. We wish to discuss the possibility that Simian Foamy Virus could be transmitted by blood transfusion, and we wish to discuss the risks suggested by Simian Foamy Virus as a model of cross-species transmission of a retrovirus. We know that two Simian Immunodeficiency Virus strains emerged to form HIV Types I and II. And two strains of another Simian retrovirus, Simian T-Lymphotropic Virus, emerged to form HTLV times one and two.

Human diseases associated with infections with these emerging retroviruses were not recognized for many years, and in the case of HTLV I this delay was due in part to the fact that fewer than five percent of persons infected with the virus develop a disease. Even though no human disease has been linked to Simian Foamy Virus infection, these theoretical concerns I've just described may leave many people to urge taking precautionary measures. However, such precautionary regulatory measures require careful consideration of risk level and of the impact on the availability of needed blood products.

Handlers of non-human primates in the laboratory setting are not the only people with close contact with non-human primates. Other groups include zoo workers, people who have non-human primates as pets ‑‑ there are about 15,000 households with such pets in the United States ‑‑ and bench laboratory scientists and technicians who conduct testing of primate serum and tissues. Any of these people could be at various levels of risk for acquiring Simian Foamy Virus infection. The risk for scientists conducting behavioral studies on non-human primates theoretically could be lower than that for scientists conducting other types of studies. It would be a challenge to define precisely which individuals would pose a risk as blood donors.

And now I'd like to show the questions we have for the Committee. Next slide, please. The first question: "In the absence of any known disease association, should FDA be concerned about the potential for transfusion transmission of Simian Foamy Virus?" Next slide.

The second question is, "Do the recent evidence of Simian Foamy Virus infections in humans and the evidence of transmissibility of Simian Foamy Virus by blood in animal studies heighten concern that known and unknown pathogenic viruses of non-human primates could enter the human blood supply?" Next slide.

And the third question, "Do the available scientific data warrant possible consideration of donor exclusion criteria for exposure to non-human primates?" And we would like the Committee to please discuss the factors that we should consider if you recommend this.

Thank you. I'll now take any questions and after that we'll move on to the other presentations. Are there any questions? Dr. Lew.

DR. LEW: Can you just remind me, did you tell us if it causes any disease in the monkeys?

DR. TABOR: I believe it does not, but the next speaker is a sufficient expert that I'll defer to him. And with that, I'll introduce Dr. Walid Heneine from the Centers for Disease Control and Prevention.

DR. NELSON: I was a visitor on one of the other FDA committees a few years ago, namely the ‑‑ I forgot the name of the committee but it dealt with transplanted organs and tissues. And my recollection of that meeting is that currently tissues from non-human primates are not acceptable or permitted by FDA to be transplanted into humans. Is that correct or am I wrong on that?

DR. TABOR: I'd like to defer that question to Dr. Epstein, if I may.

DR. EPSTEIN: The FDA doesn't regulate organ transplantation.

DR. NELSON: Oh. Well, somehow that committee was discussing it and it was an FDA committee. Maybe I was in the wrong room.

(Laughter.)

DR. NELSON: Xenotransplants.

DR. EPSTEIN: Oh, xenotransplants. Oh, okay. Sorry. Well, there was a moratorium on xenotransplantation from non-human primates on account of various viruses and primates. But I believe the moratorium is now lifted, and I can't comment on the current status.

DR. HOLLINGER: This may be discussed later and if it is, Ed, just let me know. When we talk about donors who have been infected from like '81 to 2000, this is a Boneva study, what do we mean by infected from ‑‑ were there bloods available then in which they found nucleic acid and so on?

DR. TABOR: Well, let me first ask, is Dr. Boneva in the audience by any chance? No. Okay. I've read the paper and I can describe it to you, but perhaps I can ask Dr. Heneine to answer that one too since he's from CDC. The question was how the blood donor samples were collected after the donor was identified in the Dr. Boneva study.

DR. HENEINE: I'll get to it probably in my talk, but let me follow up on the answer of Dr. Epstein regarding the xenotransplantation guidelines. I think the moratorium on using non-human primates as sources of tissues and organs is still in place, and the only species now we think is useful is pigs as sources of xenographs because of the issues of xenogeneic infections and xenogeneic viruses.

DR. EPSTEIN: I just wanted to clarify, I thought what Dr. Nelson was asking was whether there's a policy to exclude human organ donation from humans exposed to primates, and that would not be something that's FDA regulated.

ACTING CHAIRMAN ALLEN: We will have a chance for discussion later, so what I would suggest is that we get through our presentations, asking questions just of the presenters just for clarification, and then we'll get into the broader discussion later. And I suspect most of the ‑‑ or all of the presenters will still be here and can answer at any time. Dr. Heneine?

DR. HENEINE: Thank you again for giving me the opportunity to present our data. I begin with the first slide. I'll be giving a summary of our data thus far. How can I move the ‑‑ move it for me. Next slide, please.

But I'd like to reiterate the fact about our experiences or the lessons we've learned from pathogenic retroviruses we're aware of that have resulted from cross-species transmission. And of course like you've heard from Dr. Tabor, HIV-1, HIV-2 are primary examples that originated from transmission of Simian Immunodeficiency Viruses from chimpanzees and sutimangabees, respectively. But we have also additional examples, human T-Lymphotropic Virus Type 1 or HTLV-1 that resulted from STLV-1; Gibbon Ape Leukemia Virus resulted from a strain of Murine Leukemia Virus and Feline Leukemia Virus that also resulted from transmission from Murine Leukemia Viruses. So these are not dead end zoonotic transmissions, but very successful cross-species infections that have become established and endemic in the new host end-cause disease. So this really highlights the ability of retroviruses to cross species that persist and then spread into the new host and cause disease in many instances. So next.

So what about transmission of Simian retroviruses, what are the mechanisms that could be in fold in this transmission? Or course, hunting non-human primates in the wild, butchering, preparation consumption, keeping non-human primates as pets and of course occupational exposures in zoos and primate centers. Next.

So although we know that HIV-1 and HIV-2 as well as HTLV-1 resulted from these cross-species infections, we still don't know if SIV or other Simian retroviruses continue to cross species to human and what are the public health sequences of these events. We were aware almost ten years ago of isolated cases of transmission of SIV, something our lab has done, and Germans reported a couple of cases of Simian Foamy Virus transmission in occupationally exposed person. And, of course, these reports have raised concerns about the magnitude of these events. So back in 1995 we decided to establish a link study for volunteer testing for simian retroviruses in exposed laboratory workers and primate handlers. Next.

So what today I will do is summarize the data that we have generated from these studies. I will be talking about the prevalence of Simian retroviruses among North American primate handlers, prevalence of the Simian Foamy Viruses in Central Africa, what we have learned from these studies about human-to-human transmissibility and disease and also comment on the risks from other Simian retroviruses, the topic that Dr. Tabor highlighted earlier. Next.

So a little bit of background about those viruses. SIV, we know it's prevalent in African non-human primates, shows a lot of diversity, at least nine different lineages have been described, and the list keeps growing as more studies are done. They're generally benign and natural hosts and only cause disease when they sometimes spread to different hosts. The Simian T-Cell Lymphotropic Viruses, again, they're prevalent in African and Asian primates, there are three different viral species here and can cause disease. Simian Retrovirus Type D or D Type retroviruses are prevalent in Asian Macaques, can cause a pathogenic international host and cause AIDS-like illnesses. And, finally, the Simian Lymphoma viruses, they're ubiquitous in almost all primate species, show species-specific clades and like SIV they appear to be benign in their natural hosts. Next.

So what is the study design on the surveillance in North America that we've been doing? We have a protocol where we invite primate research centers who wish to participate on a voluntary basis in a linked study for testing for these viruses. Participants fill out the questionnaire and provide a serum sample that gets tested serologically first for all those viruses, and we've developed assays that are not commercially available. The active samples are then identified, and those persons are contacted again to provide an additional sample where serology is repeated and DNA is obtained from peripheral blood lymphocytes to do PCR sequence analysis and in many case virus isolation. And we've developed diagnostics to do those tests. And once the individual is found to be infected, the participant will be interviewed closely. Next.

So this is an update of the results we have so far. We have 20 institutions that have joined the study, a total of 3,000 samples collected. Institutions have two choices: To only get tested for SIV or get tested for all four retroviruses. But 441 persons so far have elected to be tested for the four retroviruses. They're from 13 research institutions and four zoos. And here are the results. We saw only two cases were positive for SIV, and these are older cases that we've reported in the past. No STLV infections have been identified. Two cases were seropositive for Simian retroviruses, and I will comment on this later. However, the big surprise was with the prevalence with the Simian Foamy Virus where 15 cases have been identified so far, giving a prevalence of 3.4 percent. One of the SRV-positive cases is also Simian Foamy seropositive. Next.

This gives you an idea about the distribution in research centers versus zoos; again, 3.2 percent in centers versus 4.5 percent. And here are the papers. Just to clarify, the first four cases were published back in 1998, ten additional cases were published or reported earlier this year, and the 15th is a recently identified case from a new institution that enrolled. Next.

Again, we saw similar results from a unlinked survey of zoo workers that was led by Paul Sandstrom and he was with us at CDC where the prevalence of Simian Foamy Virus was found to be about three percent as well in this population versus zero percent rise in workers that had no contact with non-human primates. Next.

Again, as I mentioned, these viruses have cross-speciated with their natural host and therefore follow genetic trees that are similar to the hosts, so, therefore, when we see virus and analyzed it and we can look with which viral species or cluster, you can identify the species origin of these infections. Here, for example, is the ape group, here's the monkey group from baboon, African Queen monkey, macaque and so forth. The samples we were able to evaluate thus far show us that there are eight cases that have chimp-like SIV, four that have baboon-like, one macaque and one African Queen monkey-like. So large variety of different SIV clades that have been identified. And this makes sense because these are the species that are usually commonly used in primate centers and in zoos. Next.

From the interviews, we collect a lot of case histories and histories of exposures, and we also obtain archive samples in these institutions which gives us an idea about the duration of seropositivity in these individuals. In general, all the cases usually report working with the primate species that was responsible for the infection, and many but not all report receiving bites or injuries from that species. The duration of seropositivity, again, shows recent as well as long-standing infections. Next.

So what about the key issues here, about disease and human-to-human transmissibility. Here's some basic background on those cases. Thirteen cases were males and two were females; in fact, they were from the zoos, the females. Seropositivity is a mean of 17 ‑‑ or, no, I think it's 19 years, six to 28 years documented from archive samples. Now, what about disease cessation? Those cases report being in generally good health, but, again, this is ‑‑ I'd like to stop at this point because we receive a lot of questions on this issue. This is a limitation of surveying health persons. We enroll full-time employees that are health, and we identify some of them to be infected, and then we ask them, "How do you feel," and the result is, "We feel fine." So in fact this is not the best design to identify disease cessation. So keep that in mind, that limitation of the study in mind as we discuss the implications of the data.

However, we can tell something about sexual transmission. So six wives of men that reported regular sexual activity, unprotected sexual activity, remain uninfected despite mean documented exposure of 14.5 years, suggesting that probably male-to-female transmission, sexual transmission is not very easy. But, again, we don't have a lot of power in these numbers, and we cannot exclude transmission after longer exposures, similar to the case scenario with HTLV-1 or HTLV-2. We require longer times for sexual transmission.

However, we have a second protocol where we invite infected cases to participate for a long-term follow-up study where we can follow them up clinically and immunologically and virologically for five years, and seven cases have opted to participate in this study. Next.

Of course, the main issue here is transmissibility by donated blood. This is important because we document persistent peripheral blood lymphocyte associated viremia in all cases. We can easily amplify the viral sequences from lymphocytes and also isolate virus from those cases. We're a bit surprised that 11 of the workers we identified were blood donors and six were confirmed to be positive. This is confirmation retrospectively at the time of donation. So if I understood the question earlier about the case from the lookback study which is here, this is a case that was identified retrospectively to have donated blood, and the lookback study here that we worked with with Dr. Boneva really targeted the recipients of that components from this case, in particular two recipients of red cells, one of filter red cells and one of platelets and all tested negative. Again, very little data, not a lot, but we need additional data to have conclusive information. Next.

So the bigger question now is what about transmission in the natural setting? Are these infections only get transmitted to humans in special type of occupational exposures or they also occur in the natural setting? As I mentioned, hunting, butchering and keeping pets is a primary mechanism for this transmission and keeping in fact the estimates about the bush meat trade mainly in Central Africa, central and deforested areas in West Africa. But one to five million tons annually has been estimated to be traded. So there's a lot of contact that occurs in that region. Next.

So we collaborated with Rubin Hopkins to answer the question of prevalence of SFV in samples that were collected from rural villages and persons that reported direct contact with non-human primates. The progress we saw was 0.9 percent. They were all in lowland forests. This is the forested areas where hunting takes place, is prevalent. There were seven men, three women from different villages, and three were PCR-positive. Next.

These are the sites of data collection and these were the areas where the seropositive cases were identified, and the ones in red were those that were also PCR-positive. Again, this area where prevalent practice of hunting and butchering takes place. Next.

Analysis indicated that we have one case infected with a gorilla, one with mandrill and one with a cercopithecus species, more precisely dubrozakeenan. Next.

These are the examples, the pictures of these non-human primates. Next.

And, again, more recent better to confirm our findings from the Pasteur Institute in Paris where the lab reported those in the fourth international Foamy Virus meeting in July in Germany where he screened also southern Cameroonian villagers for Foamy and found 11 out of 720 to be positive, three were PCR-positive and two were hunters, 60 and 67 years old, that have gorilla-type SIV and reported injuries, like you've heard earlier, from gorillas. There was a third person who was a woman that did not ‑‑ has no history of ‑‑ did not report hunting but contact with bush meat. And she has a chimpanzee-type Simian Foamy Virus infection. Next.

So the bigger question right now is what is the scope of these infections? Is it an infection that is only limited to people that have direct contact with primates or are we dealing with a global dissemination of this infection that has gone so far unrecognized? And this is one scenario, how can a global dissemination or emergence of this virus can happen, first, from exposed injured individuals that some of them do get infected but not associated with secondary transmission. However, very few can lead to secondary human-to-human transmission for maybe one or two generations, but then maybe this local epidemic can die out or it can have ‑‑ one of those can really adapt this virus and be able to disseminate and spread among humans. So we really do not know where we are in the scheme of things. Are we here or are we already here? However, only expanded screening would probably tell us where we are. Next.

So how widespread is SIV? Is it ‑‑ first, you can think of it in West Central African countries. What about the situation in Congo, Gabon, Equatorial Guinea, Central Africa public, DRC or Nigeria where all practices of non-human primates hunting and consumption and butchering takes place? Do we have a situation where endemicity has already occurred, and this is sustained by human-to-human spread? We are very interested in looking at this scenario.

We started in fact looking at samples that are collected from different groups, different populations. This is unpublished data that we have recently generated by looking at recently collected Cameroonian blood donors from Yaounde, the capital of Cameroon. We have screened 180 samples and one found SIV-positive individual, giving a prevalence of 0.5 percent. The virus has a mandrill-type SIV, which is consistent with the common hunting of mandrills in Cameroon. More interestingly is that this blood donor was also HIV-1 infected, so we are now dealing with a co-infection situation with HIV-1.

The second population of samples which were already available to us at CDC was a collection of samples from sex workers from the Democratic Republic of Congo, from Kinshasa. Those were collected back in 1985 and we screened those, and one was positive, giving a prevalence of 0.72 percent. Again, the sex workers was also HIV-1 co-infected.