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-r