So, for example, in order to supply our hospitals, we have reduced our incubation of the two bottles from 24 to 12 hours so that we can get product to the hospital with enough shelf life left on it that they can manage their inventories.  Again, there's no regulation or AABB standard that tells us how to do this.  So in the interregnum between now and whenever we have that sort of regulation, places are pretty much allowed to do what they want.

            Our biggest concern of some of us, we had, in a sense, funded our plans to mitigate TRALI based on the decreased outdate rate of 7-day platelets.  So, for example, at my center, we sent from seven to eight percent down toward one percent.  That means that I had in the range of 1500 apheresis platelets to play with if I'm going to start screening apheresis platelet donors for HLA antibodies or multi parity, or those sorts of things, if you look at the pathogenesis of TRALI.

            So we wanted to know what impact  the discontinuation of PASSPORT had on plans for TRALI mitigation.  And, as you can see, 11 of the 15 said that discontinuation was going to slow it down on average six months, a few for nine months or more.  And, again, some of the non-participants as well were going to have to delay TRALI because of the inability to get enough platelets to being deferring donors that might present a risk of TRALI.

            Okay.  So that's the ABC survey.  And I want to very quickly go through a risk assessment that has been put together by an AABB ad hoc subcommittee.  And let me just say up front that the heavy lifting in this has been done by Larry Dumont and Mark Brecher, and the rest of the people on the subcommittee have provided a lot of input regarding assumptions and whatnot, but most of the model was done by those two guys.

            You know this, that the study was discontinued based on culture positives, not clinical events.  And, in the best of all possible worlds, we wouldn't have been measuring microbiologic end points, we would have been measuring clinical end points.  We didn't think that was operationally feasible when the study was originally designed, so we used the Asurrogate@ of culture positivity.

            We have developed a sensitivity model to explore the risk reduction for clinical sepsis by limiting bacterially screened SDPs to a 5-day shelf life, and a second model looking at the potential impact of TRALI mitigation strategies.  These models, we all understand, are only as good as the assumptions upon which they're based and in many areas our assumptions are not supported by really hard data, so this is an example, perhaps, of GOBSAT, good old boys sitting around the table.

            We've looked at the literature; we've looked at the abstracts; we've looked at our experience in the centers who are participating and tried to come up with reasonable estimates, and this is in my handout so that you can go over these in detail and we can talk in the hallway if you want, but the basic assumption is the model is that whole blood platelets are more dangerous than apheresis platelets.

            So to the degree that you have to replace single donor platelets with whole blood platelets, you may, in fact, have an increased risk of clinical sepsis and bacterial contamination.  And the reason for that is a five unit pool of whole blood derived platelets has five skin sticks involved in it.  Okay.

            Plus, that with few exceptions, whole blood derived platelets are not tested with culture.  They are tested with surrogate tests that have a very high false negative rate and that's all in the assumptions.  So this is the model.

            And this is kind of complicated, so I'm going to show you on a table later.  But, basically, the horizontal axis is the proportion of day 6 and 7, apheresis platelets, that are replaced by platelets derived from whole blood.  And as that percentage goes up, the risk goes up, and then the three lines represent different proportions of whole blood derived tested with surrogate, whole blood derived tested with culture.  And, as you can see, if you get kind of between 20 and 80, which is where we think reality will land, the risk of the reversion to platelets derived from whole blood may actually represent an increased risk of clinical sepsis compared to 6- and 7-day platelets.

            So this is the table and I'll spend a little more time here because this is really where the meat is.  This is just some examples off the graph, okay.  So if you look at 7-day PASSPORT line, we think that the clinical risk based on the point estimate from the Red Cross passive surveillance and the upper bound of the 95 percent confidence interval for clinical sepsis, not microbiologic contamination, okay, those two risks are 7.4/M and 16/M.  That 16/M is the worst case upper 95 percent confidence interval.

            In the top line of the table, if you replace it entirely with cultured 5-day platelets, the risk falls to about 1/M.  So if we were able to completely revert to  5-day apheresis platelets, there is a decreased risk and that's the risk associated with blooming of contaminating organisms later in culture.  Okay.

            If you go down let's say to around here, maybe is a reasonable assumption from the ABC survey that we replaced 25 percent with cultured whole blood platelets, that may be too high, and 25 percent were surrogate tested, in fact, the risks are about four and ten and may actually represent an increased risk of clinical sepsis with reversion from day 6, 7 transfusions to 5-day outdate.

            The best estimates that we have from my center and from Peter Tomasulo Blood Systems is that right around 20 percent of 7-day labeled platelets get transfused on day 6 and 7.  Again, the denominators are not very robust compared to the entire size of the PASSPORT study, which is about 400,000 distributions per year, but Peter estimated I think 17 percent transfused on day 6 and 7, and we did a one month survey in our system hospitals and came up with 23 percent transfused on day 6 and 7.

            So the conclusions regarding septic transfusion risk, this not culture data, this is septic transfusion risk is replacing 7-day platelets entirely with 5-day will reduce the current risk avoiding about two septic transfusion reactions per year.  The worst case analysis using ARC's admittedly passive clinical surveillance suggests up to six may be avoided.

            If we replace with surrogate tested 5-day whole blood platelets, it's likely that the septic transfusion risk will increase, and replacing with cultured will not reduce the risk.  And, again, that's because of the problem of false negatives and the multiple sticks that are required to produce whole blood platelet, which increases the risk both of overall bacterial contamination and probably false negative.

            Now, TRALI was a different issue for the reasons that I told you.  We had, perhaps unwisely, essentially many of the PASSPORT centers had used 7-day platelets as an opportunity to increase inventories in anticipation of TRALI mitigation efforts, which are required by AABB November of this year is my recollection.

            The risk of TRALI from platelets is unknown and we looked at a variety of estimates.  Mayo, 1/1000 probably, perhaps higher than that in their ICU population; whereas, many as 1.7 percent of their ICU patients who are transfused have transfusion related acute lung injury, but that's not a hard estimate.

            Popvosky's original publication said 1/5000.  There's Canadian passive surveillance, 1/23000.  So we looked at three levels of risk, 1/100 to 1/10000 for the model.  The risk reduction from HLA or gender-screening of apheresis platelets we don't know.

            But if we look at the UK SHOT data, we thought that 40 to 80 percent probably covered it.  So if we take all the alloimmunized donors out of the apheresis population, we can make a 40 to 80 percent reduction in the risk of TRALI associated with this high plasma volume component.

            The third bullet point, we can talk about in the hall if we want.  The TRALI risk of a 5 unit pool was soon to be equivalent to that of single donor platelets, and that also is something that we might want to talk about.  It depends probably on the pathogenesis in the individual reaction.

            If it's a human neutrophil antibody, this may, in fact, be spot on.  If it's a relatively weak HLA antibody, maybe not.  And if it's a biologic response modifier of some point, we really don't know the answer.  And then we looked at six to 12 month delays in optimal TRALI mitigation.

            So this is that model and what you see here is baseline, that is with no TRALI mitigation and 10 percent efficacy at the three risk levels that we used in the estimate, 100/M, 200/M and 1000/M, or 1:10000.  And so you can see here that if you delay for six months, that this fall in cases of TRALI will not be realized.  So it's a little backwards to look at this.

            Let me show it to you this way, and just pay attention to that which is in yellow.  This is the cases not avoided from baseline with either a 40 percent or 80 percent risk reduction, and at the higher rates, which I frankly believe are probably more accurate.  We're looking at 80 to 160 TRALI cases that would have been avoided with mitigation that will not be avoided if we have to delay for some period of time and then stratified by months.

            It's pretty straightforward.  I think it's understandable.

            So our conclusions regarding TRALI is that if discontinuation delays TRALI mitigation measure, 8 to 160 potentially avoidable TRALI cases may be observed with six months and 16 to 320 with 12 months delay.  Delay in TRALI interventions due to PASSPORT discontinuation may result in more TRALI cases in six months than the anticipated maximum number of septic transfusion reactions avoided in one year.

            This is the transfusion fatality data reported to FDA and recently made available I think on the website.  And I just want to show you, we don't know the risk associated with apheresis platelets.  We have this passively reported mortality data.

            TRALI is the most commonly recognized and reported source of transfusion associated mortality, and that which may be attributable to apheresis platelets, six cases for sure and nine that received multiple products, and here we can see eight sepsis deaths attributed to apheresis platelets.  So the balance is interesting.

            We may avoid two to six septic reactions a year while seeing an increased number of TRALI cases, and I think our real conclusion is that the study's been suspended.  We're working on making a proposal.  The sponsors are working on making a proposal to FDA that might allow us to bring 7-day platelets back, but a comprehensive risk assessment prior to the decision to discontinue PASSPORT would have allowed for more informed debate about the impact and whether risk exceeded benefit.

            So that's it and I can take questions if anybody's interested.  Please, don't beat me up for all the assumptions.

            CHAIR SIEGAL:  Thanks, Louis.  There are questions?

            DR. KUEHNERT:  Thanks.  That was very nice, Dr. Katz.  I just wanted to ask if in the model you mentioned the effect of going from two bottles back to one bottle by discontinuing PASSPORT.  Did you include the decrease in sensitivity in the model?

            DR. KATZ:  The assumption in the model was that everybody would keep doing what they're doing, okay, two bottles.  And in our proposal that will -- I think it's already been sent to FDA, or at least an outline of it, will, in fact, maintain two bottles and double volume cultured to increase sensitivity.  So, no, this model assumes that everybody does what they did for PASSPORT.

            CHAIR SIEGAL:  Dr. Epstein?

            DR. EPSTEIN:  Just a question about the assumption on rate of TRALI.  We know that the vast majority of cases in the SHOT data, and I think the French hemovigilance data, are related to FFP and not platelets.  And I'm just wondering whether you adjusted those rates for association with platelets.

            DR. KATZ:  No.  We made our best bet about what the rate might be and it's admittedly something that needs to be --

            DR. EPSTEIN:  But the amount attributable to platelets might be no more than 20 or 30 percent of that figure, which would then have a proportionate impact on the estimated --

            DR. KATZ:  Yes.

            DR. EPSTEIN:  -- cases of TRALI.

            DR. KATZ:  We didn't have hard numbers, so we looked at this is a bag that has 250 cc of plasma in it, just like a bag of plasma does, and that the rate would be the same.  And as, Jay, we understand that our assumptions are very important in discussing this.

            CHAIR SIEGAL:  Dr. Szymanski?

            DR. SZYMANSKI:  What about the decreased viability of platelets between five and seven days?

            DR. KATZ:  That is not in the model, and when 7-day platelets were approved by FDA, it was based on data that suggested that these platelets circulate and do what platelets are supposed to do.  Clearly the number of active platelets declines over time and that's not arguable.  I think 7-day platelets are a balance between availability and efficacy and that given the efficacy, the availability allowed FDA to approve these kits.

            I don't think there's anybody in the room that's going to argue for hemostatic efficacy.  They'd rather have a 7-day than a 2-day platelet, but there are no 2-day platelets now because they have to be cultured for that period of time before released.  So that's a balance.

            Thank you.

            CHAIR SIEGAL:  Thank you, Louis.  We're now going to hear from Dr. Haddad.

            I'm sorry.  There was one other question.

            DR. FLEMING:  You mentioned that the outdate rates in your center will go from three percent to approximately seven percent.  Could you state that in terms of units and do you have a number on a national level?

            DR. KATZ:  Since the largest centers have just in the last week or two converted back to 5-day platelets, we don't have hard numbers yet.  We distribute about 17,000 doses a year.  So we're going from one percent would be 170, two percent 300, to above 1,000, well above 1,000.  That's based on one month's data.  So we're really looking for anything, and everybody is that had to revert, looking for ways to optimize inventory.

            CHAIR SIEGAL:  Dr. Haddad from FDA will give us the FDA's perspective on PASSPORT.

            DR. HADDAD:  Good morning.  I will be presenting this morning the course of action taken by FDA in evaluating the preliminary data of the PASSPORT study prior to its suspension.

            FDA for a number of years has been actively engaged in efforts to improve the storage of the platelets.  FDA has previously presented to this committee for its advisement the topics of pre-storage pooling of whole blood derived platelets, the extension of the shelf life of platelets from five to seven days, bacterial contamination of platelets, and most recently the rapid testing for detection of bacteria in platelet products.

            In 2002 FDA sponsored a workshop on pathogen reduction technologies to be used in cellular blood products.  And as we heard earlier, the PASSPORT study addressed the issue of bacterial contamination in 7-day platelets.  And prior to the initiation of the study, FDA had extensive discussions with the blood community both on a bilateral basis and as a member at that time of the AABB task force on bacterial contamination.

            Very briefly and perhaps with some overlap with Dr. Dumont's presentation, but just to substantiate FDA's decision and action, in March of 2005 FDA granted Gambro clearance to extend the shelf life of its apheresis platelets from five to seven days when the platelets were tested with the BacT/ALERT bacterial detection device early in the storage of the platelets.

            The users of the Gambro seven days had to commit to a Phase IV post marketing study, the PASSPORT study, whose objective was to confirm that 7-day platelets, when tested early in storage with the BacT/ALERT bacterial detection device, presented no greater risk for bacterial contamination than untested 5-day platelets.  And later that year Fenwal joined the study as a co-sponsor under a regulatory pathway identical to Gambro's.

            The study design of the study consisted of sampling the platelet product between 24 to 36 hours after collection with the BacT/ALERT device.  Units that turned positive were discarded, and negative units which were not transfused were retested at outdate after seven days of storage, again with the BacT/ALERT testing.

            And the primary hypothesis was that the upper confidence limit of the residual bacterial contamination rate for

7-day platelets was no greater than 1/5,000 with 95 percent confidence, 1/5,000 being the estimate of the contamination rate of the untested day 5 platelets.  The study sample size was determined to be 50,000 outdated units, and a successful outcome implied a detection of less than five positives at day 7.

            In January of this year FDA received a joint letter from Gambro and Fenwal raising safety concerns about the PASSPORT study based on the initial data.  And the data showed that on day 1, out of about 200,000 collections tested, there were 48 true positives for a true positive rate at day 1 of about 1/5,000, which is consistent with published data.

            At outdate there were two true positives out of about 2,500 units tested.  And in platelet transfusion recipients, out of five reported reactions, we estimated that there were three septic reactions confirmed to be resulting from transfusion of a contaminated platelet product yielding a septic transfusion rate of about 1/64,000 collections.

            This septic transfusion rate in the PASSPORT study was compared to a surveillance study being currently conducted by the Red Cross.  It was published last in Transfusion with the most recent update in two public meetings.  And one caveat is that the protocols of these two studies were not identical.

            The main similarities were that both studies used the BacT/ALERT as the bacterial detection device.  They both sampled the product at least 24 hours after collection, and the main similarities is that the BacT/ALERT testing in PASSPORT consisted of using two bottles, one aerobic, one anaerobic, four amount in each bottle.  Whereas, the Red Cross study used only the aerobic bottle with a sample in their revised protocol.

            Another difference is that the PASSPORT study was stored for up to seven days and we tested at outdate.  Whereas, the Red Cross studies were stored only to five days and they were not retested at outdate.

            So the comparison was not ideal, but it was the best comparison available.  And what it showed is that the septic reaction of PASSPORT was almost double that of the Red Cross.  However, the two rates were not statistically different.

            The main conclusion from the PASSPORT interim analysis, at least from our standpoint, was that the septic transfusion rate comparison while it did not conclusively demonstrate that the PASSPORT rates were higher than those of the Red Cross, it certainly raised a safety concern, and that the finding of two positive at outdate suggested that the probability of a successful outcome was low if the study was pursued to its completion, meaning 50,000 units.

            Many factors went into the decision-making process regarding the fate of the study.  There was divergence of opinion among the sponsors between insistence on an immediate suspension versus the pursuit of the study with the introduction of additional safeguards.

            There were no stopping rules established in the protocol, and the reason is that the high contamination and septic rates observed in the study were not anticipated.  And these high rates are related to the unexpectedly high force negative rate of the Day 1 testing with the BacT/ALERT.

            As mentioned earlier, the transfusion sepsis risk at day 6 and 7 could not be fully assessed because the study did not include reporting of the proportion of platelets transfused after day 5.  So if there was any incremental risk between day 7 and day 5 that risk would not be documented and could not be quantified.

            Also, the cessation of the PASSPORT study meant the suspension of the 7-day platelets and the return to storage with the potential for platelet shortages.

            So taking all those issues into consideration, FDA balanced the concerns for platelet safety and availability and opted for a four week phase-out period to allow the participating centers to adjust to a reversion to 5-day platelets.

            In addition to the potential for platelet shortage, there was also concern over the impact of the discontinuation on the TRALI mitigation strategy that the blood centers were instituting to comply with the AABB recommendations.

            And, also, there was a concern on the part of the blood establishment over meeting the good manufacturing practices if the transition period back to five days was short.  So the concern was over relabeling, retraining staff, rewriting SOPs.

            And then also, throughout that period, FDA maintained open channels with America's blood centers and with the AABB in order to deal with any unintended consequences of the discontinuation of the study.

            And Dr. Katz mentioned the ABC survey that was done at that time, and one important finding is that it showed there was a need for a 19 percent increase in platelet production to compensate for the anticipated platelet shortage.  And, again, Dr. Katz elaborated on the AABB assessment on overall platelet safety in the case of the discontinuation of the study.

            So based on those concerns, the sponsors requested an extension of the phase-out period from 28 to 90 days, and FDA did not object to the extension in order to allow the users to go back to five days safely and without too much disruption to the collection and distribution of the blood system.

            The next steps in terms of the PASSPORT endeavor, FDA, we will continue to monitor and evaluate the data generated as PASSPORT is phased out, such as the data that Dr. Dumont presented earlier.  And we are committed to working with the AABB task force and with the sponsors to introduce additional safeguards to ensure the safety of the day 6 and day 7 platelets and to make them available once again.

            And on that, thank you for your attention.

            CHAIR SIEGAL:  Thank you, Dr. Haddad.  Are there questions?  Dr. Szymanski?

            DR. SZYMANSKI:  I'm sorry to ask this because this probably was presented in a previous presentation, but I was unsure as to how severe the bacterial event was in these two donors.

            DR. HADDAD:  You're talking about the reactions?

            DR. SZYMANSKI:  Yes, because you discontinued the study because of two septic events, but the description of the septic events remains unclear to me.

            DR. HADDAD:  I think the two contaminations that you're mentioning, these occurred at day 7, so these were bacterial contamination detected at day 7, and according to the protocol, with the 50,000 outdated units as a sample size, and in order to satisfy the hypothesis, then no more than five positives are supposed to be detected --

            DR. SZYMANSKI:  I see.

            DR. HADDAD:  -- on day 7.

            DR. SZYMANSKI:  But were these units transfused or not?

            DR. HADDAD:  No, they were not transfused because the only units that were tested on day 7 are the ones that were negative on day 1 and that were not transfused.

            DR. SZYMANSKI:  Okay.  So that's  a question.

            CHAIR SIEGAL:  Other questions?

            DR. KUEHNERT:  It seems like there were a number of factors that conspired to reach these conclusions which were seen as alarming, but I'm just not sure that safety was compromised.  And, as you pointed out, there were no stopping rules for the study that caused the study.  There were some bad assumptions about what contamination rates were going to be in part because most blood centers use one bottle instead of two, and this one with PASSPORT manufacturer's instructions are being followed.  So that was another factor.

            The definitions I think were suboptimal.  I saw one case that was included where you had an organism that was identified, and then on confirmation another organism was found and that was called a case.

            And, also, the tools for confirmation don't seem to be present.  I don't see anything on matching staph epi isolets by molecular typing, which isn't necessary for all organisms, but I think for something common like staph epi you have to be able to tell whether it's the same organism.

            So I'm just wondering, you know, we could criticize a lot of things in retrospect, but what I'm concerned about is in the future, are all these factors going to be considered to try to ensure that the study can be performed in a way where we can get useful results?

            DR. HADDAD:  We agree with you.  When we reviewed the revised protocol, these are some of the items we're going to be addressing.  We have learned that we need to improve the safety of day 7.  We have learned that day 1 testing is not sensitive to pick up all the bacteria on day 7.

            And, also, we need to tighten up the protocol because, for example, the data that Dr. Dumont presented, we saw a lot of cases that were indeterminate, and, as you mentioned, there was a discordance between the organisms.  And it's unfortunate that you cannot determine whether there was causality or not.  And so this is an item that we need to address.

            And then, also, in terms of the classification that was used, again, in that instance, we need to probably tighten up the classification.

            DR. KUEHNERT:  I just want to add that I mean I think a lot of effort was put into this and that's why I think it's so important that something come from it as far as some sort of a continuation because it's very important.  Obviously, it has a real impact on platelet safety.  So it seems like it would be very important and it's very complicated, too.  So it's just very important I think to put as much thought as possible into it the next time around given what we've learned from this first attempt at it.

            DR. HADDAD:  Yes, absolutely.  Thank you for your suggestions.

            DR. FINNEGAN:  I'd like to support what was just said by Matthew.  I think that at 2:00 in the morning I'm more interested in platelets than I am in a fever and I can treat the fever.  I can't necessarily treat the problem that I need the platelets for.

            The other thing is there's good literature in the orthopaedic world on Propiobacter being attached to everything in the world, and it does not appear to be an actual pathogen, but it just seems to sit there.  So I think that that sort of data needs to be sorted out from what you have.

            I agree.  I think this study is really important.  I think we've heard earlier that keeping our blood supply as maxim as we can is important, and I think the fact that you can't tell whether these two staph were 5-day, 6-day, or 7-day means that you don't know that the 5-day protocol actually works.  So I think that this study needs to be encouraged to be rewritten and redone, but to be continued.

            DR. HADDAD:  Yes, absolutely.  We are determined and committed to doing that.

            CHAIR SIEGAL:  Okay.  If there are no more questions, we will take a brief break of only 15 minutes because we're running behind.  So please be back here by no later than quarter after.

            (Whereupon, the foregoing matter went off the record at 10:58 a.m. and resumed at 11:12 a.m.)

            DR. SIEGAL:  Hello, everybody.  Let's resume, please.  Let's start again.

            Now we're going to have informational reports from CBER safety teams related to blood and tissue.  The first report will be Dr. Jonathan Goldsmith at FDA.

            DR. GOLDSMITH:  Thank you for that.  Good morning to everyone.  I have the opportunity to talk to you about CBER's Blood Safety Team and I appreciate the BPAC giving us this opportunity.  My talk is really broken into two parts.  One is introductory in terms of the basis for creating a blood safety team, and then the second part is to talk about the blood safety team and it's activities over the last couple of calendar years.  I'll talk to you about the need for a blood safety team, the legal framework for blood regulation, the layers of blood safety that assure the provision of safe blood products, and then the blood safety team itself, the goals and objectives, the organizational structure and the long-term challenges that lie ahead.

            In terms of the basis for the blood safety team, you have to look at the annual U.S. blood donation and utilization figures as shown here.  There are 8 million unpaid volunteers who donate about 15 million units of whole blood each year.  4.5 million patients receive about 29 million units of blood components.

            There are appropriately 2.4 million units of recovered plasma from whole blood donation that are sold for further manufacturing, including fractionation in to plasma protein products.

            There are about 1 million paid apheresis donors who provide an additional 10 million liters of source plasma for fractionation into plasma derivatives.

            Blood is collected from approximately 1300 blood collection centers in the U.S.  90 percent of these are community-based, 8 percent are hospital-based, and 2 percent are military-based.  There are about 5000 transfusion services in the U.S., the vast majority of which restrict their activity to cross-matching and dispensing of blood.

            There are about 400 device manufacturers who make test kits to test blood from potential blood donors.  Blood grouping reagent manufacturers, and there are also those who make the bigger equipment, the apheresis machines that are used to collect blood and blood components, blood warmers, and other types of paraphernalia.

            Drug manufacturers also make anticoagulants, and there are about thirty of these in the U.S. that are regulated.

            In addition to the whole blood collection, there's also the collection of plasma for the manufacture, there are about 300 plasma pheresis centers in the U.S., and there are about 20 manufacturers of plasma derivatives, plasma protein products.  These include the coagulation factors such as Factor 8, Factor 9 and thrombin, immunoglobulin, antitoxins, albumen, alpha one proteinase inhibitor and anti-thrombin 3.

            Just to review for a moment the legal framework for FDA blood regulation.  U.S. blood and plasma are collected, processed and distributed by private industry.  It's regulated by the FDA under two national laws.  The first is the Public Health Service Act.  Section 351 is biologics regulation, and section 361 is the communicable disease control part of the Public Health Service Act.  Biologics regulation includes aspects of good manufacturing process and the actual manufacture of blood and blood products.

            The other broad act is the Food Drug and Cosmetic Act which addresses drugs and medical devices, and as you know, the Food Drug and Cosmetic Act was amended from the Congress in September of 2007, with the FDA amendment act, and this gave additional authorities to the FDA in the area of pediatric study requirements, public disclosure of trials, post-marketing commitment by sponsors, amongst other requirements.

            Blood organizations also keep in mind that they comply with the state laws and with voluntary standards from their organizations, such as the AABB and the Plasma Protein Therapeutics Association.

            The overlapping layers of blood safety provide assurance of the safety of blood and blood products, and it's actually composed of about six layers in this day and age.

            The first is donor eligibility.  Potential donors are provided educational materials to permit self-deferral.  Specific questions are asked about their health, medical history and other risk factors.

            Communicable disease testing is performed for diseases that we require this.  HIV-1, 2, HBV, hepatitis C virus, human T-lymphotropic virus and syphilis, and there's voluntary testing for communicable disease by those who collect blood for West Nile virus, for Trypanosoma cruzi, the agent of Chagas disease, and cytomegalo virus.

            General donor deferral registries must be kept current by blood establishments.  They have to have a list of individuals who have been deferred as blood or plasma donors, so that these people are not accidentally reentered into the blood supply, their donations.

            Fourth is quarantining of unsuitable blood.  Blood products are quarantined until the products have been thoroughly tested and the donation records have been verified.  Investigation of problems.  Blood establishments must investigate any breaches of these safeguards and correct all system deficiencies.  They must have control of their manufacturing.

            And last, sixth here is pathogen reduction.  Plasma derivatives undergo viral inactivation procedures and these may be applied to other types of blood and blood components in the future.

            The CBER initiative to start a blood safety team began in the summer of 2005 when a Blood Safety Working Group was put in place at the direction of the CBER Center director, to determine what our current practices were and what some of the problems might be in terms of how we were trying to do the business of blood safety.

            After about a year of review, we actually had the establishment of a blood safety team in July of 2006 and we have been meeting since that time on an every other week basis.

            The goals of the blood safety team are to formalize the center operating procedures, to make sure that we do things in a fairly uniform way, so that we do it in a better way, to establish roles and responsibilities in the management of blood safety issues, to be certain about whose job it is when something happens, so there are not errors of omission.

            And third is to enhance internal and external communications that is within CBER, within the FDA, within government and with those outside government.

            The major objectives of the blood safety team, which were drawn up by the working group and have been put into effect, are to improve the CBER response to blood safety issues, and this is done through defined cross-office collaboration, creating increased sensitivity to safety signals, so that things that occur in one hallway are quickly picked up and transferred to a central group that can then deal with these issues.

            Second is to improve the value of safety information and to broaden public and regulated industry access to the information.

            Not to be repetitive about this, but to make sure that information that we do collect is of use to the regulated industry as well as to those who regulate.

            Third is to improve the processing of blood safety information through establishment of a forum for review and evaluation, permitting discussions in a noncrisis mode, and facilitating anticipation of events.

            As we all know, preparation leads to a better response than what we do at the last minute or during a crisis.

            And fourth is to enhance external outreach evaluation and risk communication.

            This is a staffing type model of the Center For Biologics, it's highly simplified and just shows some course areas.

            What I've tried to highlight for you is where the membership of the blood safety team is drawn, which offices contribute members to the blood safety team.

            The Office of the Director, the Office of Biostatistics and Epidemiology Office of Communications, Training and Manufacturers Assistance, known as OCTMA.  The Office of Blood Research and Review, and the Office of Compliance and Biologic Quality, all contribute members to the blood safety team at CBER.

            Each office contributes between probably two to four individuals on an ongoing basis.  Individuals serve for about two years.

            What are the activities of the blood safety team?  I'm going to talk about several different areas where the blood safety team has been actively involved in dealing with safety issues.

            The first is coordination of investigations and potential shortages of blood and blood products.  Shortages can occur due to manufacturing changes, reports of adverse events, reports of reduced stability of a product.

            For manufacturing changes, manufacturers sometimes implement changes in their manufacturing process, and it's up to us sometimes to determine if there's been any impact on the safety, purity or potency of the product, and whether or not these changes will have a potential impact on the public health in terms of keeping products out of the market that have been manufactured in this new method.

            Shortages may also be due to reports of adverse events.  Adverse events can be of a clinical nature, as you're most familiar, or they can be of a technical nature, and they can lead to the same kinds of problems in terms of balancing supply with safety.

            And third, shortages that we've dealt with in the last couple of years have been due to reports of reduced stability and we've had to do investigation of how we could respond to this.

            Part of the job of the blood safety team is to help explore the regulatory pathways to avert shortages.

            There are things that can be done.  Can a product be given shorter dating?  Can a dose be redefined?  These kind of approaches.

            The blood safety team reviews the required annual fatality reports from whole blood and source plasma establishments.  The sites from the CFR are shown.  The blood safety team provides oversight for the annual report and reviews communication opportunities about the annual report on fatalities, and has been noted previously today, this is published on the CBER Web site and it's open for all to review.

            We also seek some potential etiologies, meaning what puts a donor at risk for dying, if they donate blood or plasma?  And what happens in terms of trying to increase our understanding about recipients and their adverse outcomes that end up as fatalities?

            We are trying to develop ways to think about mitigating strategies to reduce the number of deaths that are associated with transfusion medicine.  What could make it safer for a donor to donate?  For instance, are there other criteria that might need to be incorporated, to exclude people at risk?

            The blood safety team also reviews the biologic product deviation reports, known as BPDRs, and potential enhancements to reduce reporting burdens.  This is a required report also under 21 CFR 606.171.  We provide oversight for the annual report, to try and refine some of the focus, and we also review some of the potential benefits of continued implementation of some of the post-donation information requirements that are required of blood establishments and plasma establishments.

            In the last couple of years, we dealt with issues about tatoos and post-donation information, and donor history of cancer, and we've made some recommendations for consideration at the office and center level.

            We also evaluate manufacturing issues and potential safety impacts, including breaches in good manufacturing practices such as bioburden excursions, starting material that has more bacteria than are permitted, and what is the impact on the safety, purity and potency of the product?  Can these stay in the marketplace?

            We also investigate approaches to threats to the blood supply such as emerging infectious diseases.  We review some of the existing scientific information and try to support and participate in as possible, in public workshops that deal with these issues.

            We investigate the impact of outbreaks of transfusion-transmissible diseases on potential blood donors.  A recent event, I think we all know from the media, is the outbreak of endoscopy-associated hepatitis C virus transmission in the State of Nevada, in which medications that are used for preparation for these procedures resulted in contamination from one patient to the next.  And we did a fairly extensive amount of investigative work to learn about what the impact was on the donor supply in the community, what this adversely impacted.

            We also implement rapid responses to urgent safety events.  One of the most recent ones in terms of adulterated pharmaceutical ingredients is the hypersulfated chondroitin sulfate, that has ended up in Heparin products that have been used in the U.S.

            You don't think of Heparin, necessarily, as part of biologic products, but it may be used in terms of manufacture, and some of the plasma derivatives actually contain small amounts of Heparin in the final container.  We also thought about the issues of Heparin as it's used in our screening devices for tests for blood donors and those used to diagnose viral disease.

            We've had some very careful interactions with the regulated industry in terms of procedures they can take to reduce the risk of having any Heparin with these types of contaminants in their products.

            Our ongoing challenges are the development and the formalization of best cross-office approaches to key safety areas.

            We're going to focus, I think in the next year, at further examination of biologic product deviation reports.  We want to seek ways to increase the value to FDA and to regulate industry.  We realize that it is a substantial burden to file these reports, almost 40,000 a year.  Even though two-thirds are filed electronically, it's still a great burden, and to make sure that this information is the information that we need and results in the best possible products at the end of the day.

            Also in terms of emerging infectious disease, we want to explore improvements in informatics as a way to try and be alert to changes that are occurring around the world.

            Some of our members who have more of a statistical bent are interested in data mining and the use of advanced algorithms to detect safety signals.  There are huge health databases in the U.S. and these probably haven't been used in the most efficient way to be the most effective in terms of learning about safety signals.

            And then we also want to explore the need for denominators.  We just heard, in the previous study, about the lack of denominators and the difficulty that poses in terms of interpreting scientific information.

            Well, we would like denominators in terms of the number of units of red cells transfused each year.  That would be helpful for us in terms of interpreting the safety signals that come to us from around the country.

            One of our goals is to try and investigate further the role of the hospital-based transfusionist to improve databases, and are there ways to work together with some of our fellow governmental agencies to make this happen.

            So just in summary, then, CBER's blood safety team functions as a coordinated, agile, interoffice team that evaluates processes, investigates and responds to a variety of blood safety issues, and we believe that we play an important role in external outreach and risk communication as well.

            Thank you for your attention, and I think I saved a few minutes.

            DR. SIEGAL:  You certainly did and we thank you for that, and this is open for questions from the committee.

            MS. BAKER:  Thank you, Dr. Goldsmith, for that excellent presentation.

            Can you talk a little bit more about some of the external communications.

            DR. GOLDSMITH:  Yes.  I think what we try to do is to have a productive interaction with regulated industry, sometimes in a very formal way but a very confidential way, so things that are not obvious in the public domain.  We do a lot of work that way, to be honest.

            In addition, through the CBER Web site, I think we try to maintain a way for the public to have access to the kind of information that we're dealing with, whether it's something to do with a product withdrawal, which you could read about, or a product approval, sometimes, that has some safety aspects, and I think those are the two ways that we're doing this currently.

            We also have some outreach at national scientific meetings in terms of having booths there and some interaction with the public.

            But we'd be open to further ideas, if the Advisory Committee wants to suggest some. 

            MS. BAKER: I  was thinking about any formal communication, about your activities with the CDC or NHLBI, about your activities, or some of the patient advocacy groups.

            DR. GOLDSMITH:  Oh.  I see.  Well, thank you for that suggestion.

            DR. SIEGAL:  Is there any more discussion?

            DR. KATZ:  I have a quick question, Jonathan.  In the other governmental agencies that you interact with, is CMS at the table at this point?

            DR. GOLDSMITH:  It doesn't--it's not part of the blood safety team.  It's a CBER organization, but by having a blood safety team, we have a bit of a louder voice, and it will carry up the chain of command, and then ultimately across to interagency kind of communications.  So I think it's, I think we serve a useful function that way.  It gives us more of a voice.  That's why I talked about the transfusionist issue, that for that to happen will require many arms of government to work together, and I think that we can be part of the starting point for that kind of process.

            DR. SIEGAL:  Anyone else?

            DR. McCOMAS:  I was just curious: Do you engage with the media with your risk communication, or does that go through another office of FDA?

            DR. GOLDSMITH:  Well, risk communication, as you know, because you're an expert, and we've consulted with you in the past about these issues, this is something that reverberates up through the organization.  I mean, the blood safety team may put together what are the scientific facts about a recall, for instance, but the communication and the message will come, will be developed, actually, by other parts of the organization and the actual communication of that may come from somebody higher in the organization.

            DR. BALLOW:  Jonathan it seems like you have a very broad, very comprehensive charge of this committee.  I don't know you can possibly get it all done.  So when you identify an issue, do you actually triage it outside the committee to get some help, or--

            DR. GOLDSMITH:  Yes.  Sure.  Yes.

            DR. BALLOW:  --or further evaluation, cause I don't see how a group of five, six, seven individuals, can possibly do all this.

            DR. GOLDSMITH:  Okay.  Well, it's actually more like 10 or 15 individuals.  But it's the same problem that you present.  and what we do is we try to work with a subcommittee structure, that we try to have people who are part of the blood safety team, when there's an issue that needs more rapid exploration or deeper exploration as you suggest, to take them and set them aside as a subcommittee, and then they operate with the authority of the whole team, basically.  And they may be able to reach conclusions.  If there's a question about the safety, purity or potency of a product, you might have to reach some conclusions within a few hours.  So it's not--a bulky committee doesn't work very well for that but a small subcommittee can be highly effective if it's drawn from individuals from several of the CBER offices, so you have expertise in biostatistics or you have expertise on compliance, expertise on blood.  So it can be effective.

            DR. SZYMANSKI:  You mentioned about this Heparin catastrophe and you said you have some involvement, you know, by monitoring that, and I have a question.

            Could it have been avoided by any means?  You know, does that belong to your, you know, charge, at all?

            DR. GOLDSMITH:  If I understand your question, in the terms of the contamination of Heparin products with oversulfated chondroitin sulfate, was there a way that that could have been blocked in terms of occurring in the U.S.

            DR. SZYMANSKI:  Yes.

            DR. GOLDSMITH:  And I think it's the question of the day, right now, in terms of what could be done and how could it be done better, and I think the agency is making serious efforts to look into ways to avoid these kind of problems in the future, as well as deal with the ones now, in terms of making additional--in terms of validating testing that will exclude these kind of contaminants in the future for Heparin at least.

            DR. SZYMANSKI:  Thank you.

            DR. KULKARNI:  That's an excellent presentation, Jonathan.  I was just wondering about your shortages of blood and blood products.  Would you address in your safety team about emergency preparedness and shortages resulting--

            DR. GOLDSMITH:  It's really not our charge.  It's only a tangential issue to us.  So there would be other parts of CBER that are specifically dedicated to emergency preparedness.  But the person who is responsible for coordinating some of those efforts at the CBER level is a member of the blood safety team.  So there is some favorable interaction that way.

            We try to choose our membership in a way that we pick up all these pieces, and so I think it's a fairly effective strategy.

            DR. SIEGAL:  If there are no other comments or questions, let's proceed.

            Now we'll hear from Ruth Solomon about the CBER tissue safety team.

            Dr. Solomon.

            DR. SOLOMON:  Good morning.  This morning, I'm going to be talking about sort of a tangential issue, the tissue safety team, and I'd like to present to you, since some of you are new on the committee, a background about what do we consider human cells and tissues, how are they regulated, how do we define an adverse reaction for them, and which adverse reactions must be reported to FDA.

            Then I'll go on to talk about the tissue safety team and its challenges, and also to give you some statistics on what types of reports we've received over the past two years.

            Okay.  First, what are HCT/Ps?  That acronym stands for human cells tissues, or cellular or tissue-based products, and they are defined--they are articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion or transfer into a human recipient.

            And some examples are--well, first, I'd like to say these cells and tissues can come from cadaveric donors as well as living donors.  So those on the left-hand side are from cadaveric donors, musculoskeletal tissue such as bone, ligament, tendon, skin, cardiovascular tissues such as heart valves and blood vessels, and ocular tissues such as cornea and sclera.

            Then from living donors, we also regulate reproductive tissues such as semen, oocyte and embryos, hematopoietic stem cells derived from peripheral and cord blood, and other cellular therapies.

            It's important to know what is not an HCT/P.  This is also written into the definition.  First of all, organs.  Many people are under the conception that FDA regulates organ transplantation and we do not.  Organ transplantation is overseen by another federal agency, HRSA.  Also not included are whole blood or blood components or blood derivative products, secreted or extracted human products such as milk, collagen, or cell factors, and bone marrow is another type of cellular product that FDA does not regulate.  That also is overseen by HRSA, and particularly if the bone marrow is what we call minimally manipulated, or for homologous use, or not combined with another article. 

            In other words, your "run of the mill" bone marrow.

            Also, it does not include devices used in the manufacture of the HCT/Ps.  We're only focused on human HCT/PS, so cells, tissues and organs derived from other animals are not included.  It doesn't include in vitro diagnostics, and lastly, we recently added this because this was sort of a "gray area."  But blood vessels recovered with an organ and intended for use in organ transplantation, and labeled as such, are not regulated by FDA.  HRSA, since they regulate organs, or oversee organ transplantation, are going to take on blood vessels recovered with an organ.

            Okay.  So how are HCT/Ps regulated by FDA?  And we began regulating human tissues in 1993, but that was focused on the cadaveric tissue, and was very limited in scope to having requirements for donor eligibility, donor screening and testing.

            Then, in 1997, we got the idea to combine cellular products and tissues, and we issued a proposed approach to the regulation of human cells and tissues, and out of that came three proposed and then finalized rules.  They're all codified in Part 1271, and the three rules were establishment, registration and product listing, donor eligibility again, and also current good tissue practice, which is similar to current good manufacturing practice, and I'll mention that again.

            But these rules, you've got to realize are fairly new.  They all became effective May 25th, 2005, and the legal authority for the regulation of cells and tissues comes from Section 361 of the Public Health Service Act.

            That section says that the Secretary can make rules and regulations to prevent the introduction, transmission or spread of communicable disease.  So that's what our regulations focus on.

            We don't get our legal authority from Section 351, as Jonathan explained, and also, we do not have the Food Drug and Cosmetic Act at our disposal.  That is not part of our legal authority.  Okay.  So these products under the umbrella of HCT/Ps can be regulated in different ways.

            This approach we put out was called a tiered risk-based approach, and some of the HCT/Ps which are lower risk, because they're minimally manipulated, and used for the same use in the recipient as they had in the donor, so these type of HCT/Ps, which we have sort a nicknamed 361 HCT/Ps, they don't have premarket review.  They can go right on the market, and they do have to follow the regulations in Part 1271, but that is assessed on compliance, on inspection.  So no application comes into FDA for these types of products.

            But under the umbrella of HCT/Ps, some of these can be regulated as biologic products for medical devices, and as biologic products, they'd be like any other biologic product in that they'd have to follow Part 1271 because they are an HCT/P, but there'd also be the other applicable regulations like the 600s and the 200s, and those would need premark review and approval and licensure.

            And similarly, medical devices that contain human cells or tissues are another route for HCT/Ps.  They follow Part 1261 and the regulations in the 800 series, and they have premarket review and either clearance or approval.  Okay.

            So the third rule, called the current good tissue practices rule, contains a section regarding adverse reactions and their reporting to FDA.

            First, we define an adverse reaction as a noxious and unintended response to any HCT/P for which there is a reasonable possession that the HCT/P caused the response.

            That is somewhat different from the biologic products definition of an adverse experience, which means any adverse event associated with the use of a biologic product, whether or not product-related.

            Okay.  So first of all, tissue manufacturers, we call them manufacturers, they're the tissue and eye banks and cord blood banks, etcetera.  These manufacturers, when they hear about an adverse reaction from the hospital or health care center, they are required to first investigate it, but notice that only if the adverse reaction involves a communicable disease.

            In other words, that's where the authority comes from for regulating these 361 HCT/Ps, and so we can't go beyond that legal authority.

            Then they're not required to investigate other types of adverse reactions but they're encouraged to do so.

            Okay.  Then after the investigation what adverse reactions must manufacturers report?  They must report to FDA any adverse reaction involving a communicable disease, if it is fatal, so we have fatality reporting, life-threatening results in permanent impairment or damage or necessitates medical or surgical intervention, and remember that it's the tissue manufacturer that makes the decision about whether there's a reasonable possession that the tissue caused the adverse event and thus reports it to FDA.

            So some examples of adverse reactions that involve communicable diseases would be, for instance, if the recipient developed a bacterial infection, if there was a failure of the graft, that the surgeon believed was secondary to infection, any viral seroconversion in the recipient suspected to be allograft-related.

            However, types of reactions that would not be required to be reported would be something like a product defect, like, for instance, the package was labeled incorrectly, there was mechanical failure of the graft.  In other words, our regulations don't say anything about the efficacy of the graft, just about preventing communicable disease transmission. 

            If there were an allergic reaction or a donor-transmitted malignancy, again that's not required to be reported, or any sort of product damage, but again we recommend that those are reported also.

            So we use the same mechanism that any other--that CBER uses to report adverse reactions, and they're reported through what is called the Med Watch system, on a particular form.  There's a form for that manufacturer, 3500A.  They have to report within 15 days of receipt of the information by fax or mail and that's just the top part of the 3500A form.

            And it's been modified.  Originally, that form just had boxes for you to fill in.  It said device, suspected device, or suspected drug.  So the tissue people didn't know where to--what they were, what boxes to fill in.  That's now been changed and we have a section of boxes called suspected product.

            Okay.  Then any health care worker can also report an adverse reaction.  That's voluntary of course.  They use a slightly different form, and we recommend that they report to the tissue bank, where the tissue came from, that there's been an adverse reaction.

            Some health care workers might think that we forward their reports to the tissue manufacturer; but that's not the case.

            So what are some sources of these adverse reaction reports?  The majority, as I just mentioned, come through these Med Watch forms, and also voluntary reporting by the consumer or health care professional, or the tissue establishment is required to report.

            But we could also learn about a case from if CDC learns about it first, or CDRH sends some of the HCT/Ps, or on regulated medical devices.  And then there's another voluntary program that CDRH runs called MedSun, and we've tacked on to that.

            This is a mechanism by which individuals--it's a voluntary thing and hospitals agree to participate, and an individual in the hospital takes responsibility for reporting, making sure that adverse reactions get reported to FDA.

            There's also a MedWatch Web site, which makes it easy to obtain these forms.

            Okay.  Now on to the tissue safety team.  We have the distinction of being the first CBER safety team.  Next came the blood safety team as you've just heard about, and we also have a vaccine safety team.

            And the idea to form this team, again, came from the center director in anticipation that the rules were going to go into effect.

            So back in May 2004, we had our first meeting.  The main purpose of the tissue safety team is to provide a coordinated efficient approach to the receipt, routing, investigation, evaluation, documentation and trending of reported adverse reactions involving HCT/Ps across five offices in CBER, and also beyond CBER.

            So it includes multiple offices, which I'll show in you a minute.  A small working group of the team reviews all MedWatch reports, even if they're not related to the communicable disease.  We would still log them into our system but not do any follow-up on them.

            We would conduct follow-up on infectious adverse reactions, and that involves seeking additional information from the clinician and from the tissue manufacturer.

            These cases are then presented to the larger group, the tissue safety team, which meets monthly.  We also have an SOP that describes the responsibilities of each office for handling the adverse reaction.

            So our team, very much like the blood safety team, consists of five offices within CBER.  So we have the Product Office where I'm from, Office of Cellular Tissue and Gene Therapies, Office of Compliance, the Office of Biostatistics and Epidemiology.  We also have a representative from the Office of the Director, and we have a representative from  OCTMA for the person that asked the question about communication, because we feel it's important for some very serious adverse reactions, where we have to, for instance, in form the department or inform the public that we have a representative from that office who's familiar with the case.

            Okay.  Then we also have points of contact outside of CBER.  For instance, still within FDA, we have CDRH.  We have the Office of Regulatory Affairs.  They manage our field investigators.  The Office of Crisis Involvement, and we even involve the Office of Criminal Investigation because you may have heard recently about a recovery establishment where they were doing criminal activities.  Then outside of FDA, we involve CDC, and there's actually a person from CDC stationed at DA who helps with the communication there.

            We also involve HRSA because the same donor could be both an organ donor and a tissue donor, and so HRSA may learn of an infection spread to an organ recipient, that we'd be concerned that the tissues were also infected.

            CMS is also involved because, as you know, CMS has a contract with the Joint Commission, and we rely on the Joint Commission, which accredits health care organizations to handle the tissues once they get into the hospitals and health care facilities.  We don't really have jurisdiction over that.

            We also have a special government employee who we consult when we have unusual cases.  Okay.  Then the tracking and routing of the reports.  They are received by Office of Biostatistics and Epidemiology, determine if it's a 361 HCT/P, because right now, those are the only types of HCT/Ps that the tissue safety team is monitoring.

            Then we enter into a database and if it's an infectious adverse reaction, we determine if it's a high priority, which I'll show you in a minute, and would notify the entire tissue safety team, the working group and the entire team, and maybe even the center director's office.

            And if it's not a high priority--oh, and we definitely do follow-up on a high priority case.  For other reports, we determine if follow-up is needed.  So we consider high priority cases, any fatality, any infection with Clostridium species or Group A strep.  You may wonder why we selected those.  Because we've had extremely severe and even fatal recipient adverse reactions to those particular organisms.  any serious viral disease or seroconversion.  Any possession of a report that CJD was transmitted through a tissue.

            Also if two or more recipients of tissues or organs from the same donor develop an infection with the same organism, it's pretty convincing that that originated with the donor, the infection, and would require follow-up.

            Also, if we had the same unusual organism cultured from the recipient as was found in one of the cultures done on the donor tissue, or even environmental cultures in the tissue bank, if those matched, that would be considered a high-priority case.

            And so the Office of Biostatistics and Epidemiology does any clinical follow-up by contacting the health care person that signed the MedWatch form, and these are some of the questions that are asked of that person, if they're not already on the MedWatch form.

            Okay.  Some surgeons would take cultures of the tissues or the transport fluid when it arrived in the OR, prior to implantation, and so that would be important to us, and any cultures of the wound or explanted graft.  I won't go over the rest, in detail, to save some time.

            Often, devices are implanted along with the tissue, so those would also be suspect, and then the Center For Devices is brought in.

            We also ask the health care person, What is their general impression? Do they think the adverse reaction was related to the allograft?

            And so if we need more manufacturing information from the tissue bank, our Office of Compliance would contact them, and at this point the tissue bank, probably the processor of the tissue, probably has done an investigation, having heard that there was an adverse reaction, and so we request the paperwork on that and what conclusion did they come to.

            We would also request donor medical records, to review them again.  What processing methods did they use?  That would be reviewed.  Any deviations, environmental cultures that were suspicious, pre- and post-processing culture results, and whether or not there were complaints related to the same donor.  Okay.

            So some of the challenges of the tissue safety team are similar to the ones for the blood safety team.

            First of all, it's a passive surveillance system where we wait for someone to tell us that there's been an adverse reaction, and that has its biases and limitations, particularly underreporting, and then it's common, since these grafts are implanted during a surgical procedure, some post-op surgeries can develop wound infections.

            It's estimated about 2 to 5 percent of people who have surgery develop infection afterwards.  So trying to distinguish between whether it's just your post-op wound infection or attributable to the graft is extremely difficult, and it's also very labor-intensive to do the follow-up, as I explained, and often it's not a very satisfying feeling because usually we would close a case when we think there's no more information to be obtained.

            However, that doesn't mean that we reached a conclusion about whether the tissue caused the reaction.  In most cases, there's no evidence that we can get, that proves that the tissue caused the reaction.

            Okay.  This is just some summary data in 2006 and 2007, showing you approximately how many adverse reaction reports we received, 147 in 2006, and then 123, and mostly, as you would expect, they're from implants of musculoskeletal tissue because that is the most commonly transplanted graft.

            Also, when we people were first required to report, when the banks were first required, they didn't realize that they were only required to report the infectious adverse reaction, so many reported, for instance, corneal graft failure, primary graft failure in a cornea, which is usually not related to an infection.

            However, you'll see in 2007, that that number dropped, and sometimes, as I mentioned, product problems are reported, and where there's no adverse reaction in the recipient.

            Okay.  And this is just a summary of where we're getting the reports.  As you would suspect, most are coming from the manufacturer because they're required to report, but we do get many reports, they're called direct reports, from the health care professionals.

            Okay.  If you would like any further information about the regulation of tissues, the rules or guidance that we've published, here are some Web sites, and lastly, this is our small division of seven very dedicated and committed individuals, that are called the Tissue Program.

            So do we have any questions?

            DR. SIEGAL:  Are there questions for Dr. Solomon?

            DR. BALLOW:  I certainly understand that a long time ago, when this was set up, that the major adverse outcome that people were interested in was infection because of using cadaver tissues.

            But, you know, with your expanded list of, you know, stem cells and a variety of other tissues, I am surprised at your, you know, the breadth of the adverse events has not been broadened just beyond infectious.

            I mean, in medicine, you can never anticipate what's going to happen around the corner, and, you know, as we get into more use of, you know, stem cells or other cell types like neuro tissues to, you know, manipulate the host in some way, that you might come up with some unanticipated adverse events, that wouldn't come under your program, and perhaps it comes under another program.  I don't know.

            DR. SOLOMON:  Actually, the stem cells, the unrelated allogeneic stem cells, and the cellular therapies such as neurologic stem cells, right now there are no licensed products in those areas.

            We have many INDs and there are requirements under an IND to report to the IND any--they're called a safety report.  So there is another mechanism for those types of more-than-minimally manipulated types of products.

            If we were to expand our authority for over this, quote, 316 tissues, that would require a rule change, probably, and that would take quite a while.  But we feel we have these other mechanisms, at least for the more highly complex cells and tissue products, that under IND, and then once they become licensed, as I showed you, there's requirement for--they're called adverse experiences and there are requirements for reporting serious and unanticipated adverse experiences.

            DR. MANNO:  I'm interested in the establishment of 15 days for reporting adverse events.  Can you talk about that, please.

            DR. SOLOMON:  That's the standard length of time for not only these tissues but all products regulated by CBER.  We want to give the tissue manufacturer an opportunity to do an initial investigation, and have some facts under their belt before they have to report to us.

            DR. SIEGAL:  Then let's proceed to the open public meeting.

            Don, do you want to read the rules.

            DR. JEHN:  Yes.  We have three members of either industry or organizations that requested to speak.  What I request is that they stay behind the security barrier and they use the microphone behind there, when they come forward.

            The first person will be Dr. Corash from Cerus.

            DR. CORASH:  Mr. Chairman, members of the committee, I'm Laurence Corash, the chief medical officer of Cerus Corporation and professor of Laboratory Medicine at the University of California, and thank you for the opportunity to comment on bacterial contamination and pathogen and activation technology.

            May I have the next slide, please.  May we have the next slide.

            The risk of transfusion-transmitted disease from hepatitis C and HIV and hepatitis B viruses decrease markedly over the past 40 years due to innovations in donor screening and testing.  But testing is inherently a reactive technology and would offer little protection against emerging pathogens, and of course one of the things that you've heard today, and you see from this publication by Harvey Klein of the NIH, is that the risk of bacterial contamination and transfusion-transmitted bacteria remains unacceptably high.

            Can I have the next slide, please.  Thank you very much.

            In addition to the passport study that was presented today, there are other studies alluded to by Dr. Dumont, that have shown the same type of data, that basically with sensitive release and surveillance culture methods, where sufficient volumes are cultured and using sufficient technologies, there's a substantial risk of bacterial contamination of platelet components.

            You heard from Dr. Dumont today that these rates, the prevalence of contamination, if one looks at these large studies, are about one in a thousand components, particularly if you culture out to day seven.  There are other studies with similar numbers, and this means that somewhere around 2500 platelet components in the United States are contaminated on an annual basis.

            But if one looks at it from the patients's perspective, where patients may receive multiple exposures, for example, an acute leukemic patient during induction therapy may receive six platelet components, those risks become much higher, and there are some studies in the literature that show the risk might be as high as one in sixteen patients receiving a septic event, an actual clinical septic event from a contaminated component.

            The work by Dr. Yomtovian at the Case Western Reserve shows that surveillance, whether it be passive surveillance, is particularly poor in terms of identifying clinically relevant septic events.  Their experience over 14 years showed that 41 percent of contaminated platelet components were actually only associated with a septic event after the positive culture had been reported to the clinicians and the medical record had been re-reviewed.

            And this has also been confirmed by the recent work from Murphy and the Irish blood transfusion service.

            Now there is an alternative to bacterial detection and it has been used for plasma fractions for some time, Dr. Goldsmith alluded to that, and it is pathogen inactivation.  The system that you see here is one that we have developed, which is a photochemical system using synthetic psoralin, amotosalen and ultraviolet light.  It's nucleic-acid targeted, and it inhibits the replication of DNA and RNA, bacteria, viruses, protozoa and leukocytes.

            The commercial embodiment of this is a series of functionally closed plastic containers that are compatible with whole blood-derived platelets in Europe and single-donor platelets.  It does use an additive solution which lowers the plasma transfusion burden.  The same system can also be used for plasma.

            The spectrum of pathogen inactivation is very broad, I won't go through this in detail, but envelope viruses, a good spectrum of non-envelope viruses, including parvovirus B19, gram-negative bacteria, gram-positive bacteria, spirochetes, protozoans, leukocytes, particularly T-cells are well-inactivated, and many emerging pathogens, and these data are very well-described in a series of publications.

            Importantly, I should point out that picornaviruses and prions are not inactivated by this technology.  Bacteria are particularly well-inactivated, as I said, both low levels and high levels, gram-negatives and gram-positives, and the level of inactivation is manyfold greater than would be present in a newly collected platelet component.

            The logistics of this technology fit very well within blood center operations, and here you see a comparison of the logistics for testing with bacterial detection plus the typical viral serologic and nucleic acid tests, compared in the extreme right, with the use of the pathogen inactivation technology.

            With pathogen inactivation, there is no delay in release of the components, and so one gets the full benefit of the shelf life as opposed to the obligatory quarantine process, plus the potential for tracing and recall of the product with bacterial detection methodology.

            This product was introduced into Europe, it received a Class 3 drug device registration in the European Community.  The labeling is such that the platelets and the plasma can be used as conventional components with no population restrictions, and in certain countries it is registered for seven day platelet components.  The treated platelets have undergone secondary national registrations in both France and in Germany.

            The technology is in use in multiple blood centers in more than 20 countries.  To date, more than 120,000 doses have been transfused, and importantly, an active hemovigilence program has been put into place, in which 30,000 of these transfusions have been reported.

            This is a program that requires reporting of all transfusions with an electronic Internet-based system, and analysis of these data, to date, have shown a very favorable safety profile, and these data are currently published.

            So in conclusion, detection methods are insufficient to prevent transfusion-transmitted sepsis.  There is a technology that depends upon broad inactivation of pathogens and leukocytes.  It's been successfully implemented in routine use in multiple blood centers.

            An active hemovigilence program has demonstrated no cases of transfusion-transmitted sepsis, a reduction in acute transfusion reactions other than septic reactions, and there has been no adverse impact on platelet or red cell component utilization.

            This technology has replaced bacterial detection, CMV serology, and gamma irradiation in these centers that are using it, and we are involved in ongoing discussions with FDA to define a pathway for licensure in the United States.  Thank you for your attention.

            DR. SIEGAL:  Thank you very much.

            DR. JEHN:  Okay.  Next we have Scott Brubaker from AATB.

            DR. BRUBAKER:  Hi.  Thank you, and I'd like to thank Mr. Jehn for honoring our request for ten minutes to speak on this subject.  I'll be talking about West Nile assays and Chagas antibody testing for certain donors of HCT/Ps.  Dr. Solomon--would be referencing her slide, the left side of that one slide for deceased donors' tissues.  Next.

            Basically, I'll try to review some data at the end but I think I'll probably run out of time to go over that in detail.  If you have a handout, certainly that information is there.  But these four points I will make.

            Deceased donation of HCT/Ps is unique and certain facts must be considered.  Pitfalls of infectious disease test kits when using postmortem specimens, have a profound effect on many.  The vast majority of HCT/Ps from deceased donors are highly processed and safe, and the disease incidence and the disease donor population is rare.

            And then we should also consider an entire list of expectations of the public that you serve.  Next.

            And to begin also, consider this. There have been no reported cases of any transmission of West Nile virus of Chagas disease to recipients of tissues from deceased donors.

            This discussion includes possibly introducing a new test to prevent something that has not yet occurred, and because of the lack of science, we don't know if it would occur if we did nothing.

            But the ramifications of implementing these new tests are widespread and I'll describe those as we go on.  Next.

            I'm scripted to try to stay within ten minutes.  In our donation world, we cannot tolerate inadequate testing.  Upon death, this is the only chance for a human to donate these tissues, and the usual tissue donation event includes surgical removal of entire long bones, of the limbs, as well as soft tissues such as tendons and ligaments.

            Pelvic bones are included.  A person's whole heart and pericardium, the eyes, and sometime veins and arteries.  Most often these tissues are surgically recovered.  Then the infectious disease testing is performed.  Next.

            Now test kit labeling approval is obtained, and when testing postmortem specimens, test kits are flawed.  It is true that manufacturers can receive labeling approvals but these approval methods are not without problems.

            As you can see, true positive postmortem samples are not required for validation and the variety of postmortem sample quality issues are not being appropriately addressed.

            Total numbers of samples use din validations that have been reported on the package inserts are allowed to be very small.  I can just name a few.  Twenty, forty-five, fifty-one, and seventy-one.  These test procedures themselves do not contain steps to identify lab-caused errors.

            When a test has initial reactives, these show a high false-positive rate when using postmortem samples.

            And all those tissues you saw on the other slide, that were donated, are now deemed ineligible due to flawed testing and are needlessly wasted.  Next.

            So false-positive test results for postmortem samples.  The ramifications are widespread.  First, I know this has not been thought of, but the donor family can be confused, shocked, and fearful regarding what the result means to them.  They do know that their loved one was ineligible and not eligible due to infectious disease testing.

            Also we found out that some, and possibly many state departments of health don't follow up on reports of positive tests on deceased members of the public because they don't have systems in place to investigate such an odd report.

            In a survey the AATB performed in 2006, another point to be made is that one-third of all organ donors were tissue donors.

            If tissue donors must be screened for Chagas disease or West Nile virus, and organ donors are not, what happens when a tissue donor's test is positive and that report is received by an OPR transplant center?  How will the transplant surgeons react?  Will they begin to treat recipients with medications that may not be necessary or desirable?

            One OPO actually insisted that a tissue processor not test for West Nile virus on shared donors from their OPO.

            When a false-positive test occurs an the donor's an infant, which did happen with West Nile virus in that testing, and I'll show you that later, this negates the use of a life-saving tissue that's also in short supply, and that's namely cryo-preserved pediatric allograft heart valves.  Next.

            So public expectations.  This committee must consider the expectations of the public heavily relying on flawed testing to protect them, and that discarding useful tissues is harmful.  There are many layers of safety employed but one should not be flawed testing.  Only a few very of the total number of eligible tissue donors actually become a donor, so discarding tissues needlessly can affect supply of transplantable tissues.

            Donors and donor families expect us, as stewards of their gift, to do the right thing.  Is adding these tests the right thing?  It will add to the cost of allografts and costs associated with reporting of positive test results, depending on how that's investigated or handled.  Next.

            Now FDA has instituted a tiered risk-based approach and we have concerns about that because it's not being applied to HCT/Ps from deceased donors very well.

            As I showed this committee a year ago, a vast majority of tissue distributed in the U.S. is highly processed, devoid of marrow elements such as blood and lipids, treated with chemicals and freeze-dried.

            Why are processed blood products, such as source plasma and plasma derivatives allowed an exemption to West Nile virus NAT and processed tissue from deceased donors is not?  Next.

            By data to follow, our profession can expect to identify a few true positive tissue donors and a year for each disease, but in contrast, there will be a few hundred false-positive tests.  We're also interested in the role of the advisory committee for blood safety and availability in regard to review of new tests.

            Since their new charter, it started, I believe it was changed last December, includes not only transfusion safety and availability, but also transplantation safety and availability.

            Will these tests be on their agenda soon?  And I don't have it listed there, but what about the advisory committee for organ transplantation?  Are they aware of what's happening with this committee?

            And there's also a committee that's actually our committee, and I don't think they've discussed this yet on their agenda, and that's the Advisory Committee for Cells, Tissues and Gene Therapies.  Next.

            So what happens when there is a positive NAT on a deceased donor?  Should that be reported, then, to the local blood center, and that would then trigger them to start ID NAT testing?  So that's a good question there.

            I'll show you on a later slide, that we have had a positive test on a tissue donor, a deceased tissue donor in Oregon this year.  Next.

            One of the things you may not realize is that blood samples for donors of HCT/Ps must be qualified.  In other words, we can't use a sample that is diluted and  might cause a false-negative test.

            Sampling is hard to find after infusions and transfusions.  Samples of different types are needed for different tests.  Different volumes are needed, and that's very difficult to actually have a qualified sample for a donor-screened acceptable donor.  So we need to keep these in mind as we add new tests.  They may be too difficult to actually--that we may lose some donors because we cannot test them.  We have no sample.

            And also if there's retesting that needs to be done, that takes up more sample.  Next.

            So the AATB urges the CDC to study various human tissues to verify or disprove that either T. cruzi or West Nile virus can be present, and be infectious in tissue type donated by deceased donors.

            Now this is irregardless of processing methods, we urge this to be done.  Any recommendations being made and future decisions about testing should be based on science and facts, and I will try to show you that test kits are not optimized for testing blood collected after death.

            These should be improved and it should be a priority.  Next.

            West Nile testing by tissue banks.  Here's some data for you that we have.  This particular bank tested 4000 tissue donors over three and a half years.  There were 24 positive tests, and by their analysis of those donors' histories, one was considered a true positive based on test- sample-to-cutoff values, and identification of West Nile virus in the blood donors, in the region of the tissue donor.  This was a tissue bank and a blood establishment as well.

            Now some of the positives were also organ donors, which was problematic for the OPOs when told of these results.

            This 0.6 percent positive rate may be acceptable to you, but to us, this is not acceptable.  Also note that the Oregon case this year, and today it was reported that there have not been any reports of human or even West Nile virus in Oregon to date.

            Also look at the two month old donor in Ohio, in March 2006.  West Nile virus was not found in humans during that time period, in that state, when that occurred.  Next.

            The other tissue bank who's been voluntarily testing for West Nile virus NAT.  You can see their information.  They tested over 7000 samples and none of the 29 positive tests were shown to be by retesting, or antibody testing, to be true positives.

            They experienced a .04 percent false-positive rate overall.  Next.

            Basically, both tissue processors now have made decisions to stop this testing due to these high false-positive rates.  Next.

      Here's an independent lab's results.  It's for the most recent 12 months.  They found three reactives but only on postmortem samples that they tested.  Next.  Hit it again.  And again.  Okay.  Yes.  We're over?  Okay.  If you can just review the information, we do have a problem with testing.  It's shown there again.  We have a lot of false-positives and we'd just like the committee to definitely look at al the aspects involved with making a decision on testing.  Thank you.

            DR. JEHN:  Okay.  Next we have Susan Stramer.

            MS. STRAMER:  Hello.  I'm Susan Stramer and I'm representing the AABB West Nile Virus Task Force.  The committee should have a copy of my statement as well as the AABB association bulletin number 0803, which I will reference.

            In 2007, and now again, in 2008, the AABB provided recommendations to its membership regarding uniform triggering and detriggering criteria for West Nile virus.  That is, uniform criteria for the conversion from minipool NAT to the more sensitive ID-NAT, and then the resumption of minipool NAT, as appropriate.  In so doing, we recognized the importance of communication of West Nile reactive donors across blood establishments that collect in the same or adjacent geographic regions, and therefore recommended the use of communication plans, so that multisites triggering could occur.