according to your study, what percent of the total units of blood would be--are being used today?  Of all the units of blood that are being transfused today, what percent of them would be from processes that would not meet your--the current criteria?  Does that make sense?

            In other words, how big a problem is this?

            DR. DUMONT:  I think I understand your question.  I'm not sure I know the exact answer.  More of the red cell products that have been approved recently have been automated methods, like red cell collection with different machines.  There's been some red cell collection and leukoreduction with different types of leukoreduction filters.

            But some of the products that were approved back in the nineties, like the AS-1 and a PBC bag, I mean those products are the same, and there is not universal leukoreduction, and it's really hard to put a number on it.  Maybe some of the marketing people would know better than I do.

            I think there's a substantial number of platelets that are--or excuse me--red cells that are made from whole blood collections, not from machines, and not from apheresis.  So I'd say it's probably a big number.

            DR. SIEGAL:  Okay.  Anyone else for now, before the break?

            (No response.)

            DR. SIEGAL:  Then let's break for ten minutes.

            (Whereupon, the above-entitled matter went off the record at 5:13 p.m. and resumed at 5:22 p.m.)

            DR. SIEGAL:  All right.  At this time we are scheduled to have an open public hearing.  It happens that, at least so far, we don't have anyone on the list to speak from the public sector.

            Is there anyone who wishes to comment during the open public hearing?

            Well, if not--oh, there is.  Okay.

            DR. DUMONT:  I just wanted to make one more comment, something that we brought out in our manuscript, that we didn't talk about today, is if the performance criteria is set so high, that it can be difficult for people to innovate, then what that means is innovations won't come.  And there's a lot of reasons, not only just the numbers, but also the costs and the time.  So that it might actually drive a stasis in where we are with our current performance.  So that's another aspect to consider, I think, in your deliberations.

            DR. SIEGAL:  Okay.  With that in mind, is there any discussion before we specifically address the questions for the committee, based on what we've heard?

            DR. MCCOMAS:  Well, I've been thinking about this innovation, and I'm questioning how does a lower standard spark innovation, and I'm using an analogy of, for instance, how the U.S. is responding to its fossil fuel reduction, and how wonderful lower standards have begun to spark technological innovation compared to other counterparts who have adopted more stringent standards.

            So it seems to me that the lower standards argument suggests more that we accept the status quo rather than we spark innovation.  So that's all I would just comment.

            DR. ZIMRIN:  Can I make a comment.  I mean, there are other things besides red--oh, there's someone else talking?  No.  There are other things besides red cell life span I guess that you'd be interested in, and one is, as was mentioned earlier in the morning, I guess, was pathogen reduction.  So that would be something else that one would be looking for it.  It's not that innovation might achieve a slightly different goal.

            DR. SIEGAL:  Okay.  Anybody else?

            Dr. Szymanski.

            DR. SZYMANSKI:  I think it's laudable to have very high and stringent standards.  Another thing is: Are they possible to achieve, in reality?  I've done a lot of these survival studies in my life, and right now, if somebody would come to me and say, okay, I need the survival studies because of this and that, I would not do them, because if I can have only three failures in 24 cases, I think this is extremely difficult in vivo survival, red cell survival.  Very, very difficult.

            And as I said in one of my comments, that sometimes these might not really be even failures, because some patients release the red cells later.  They just keep them longer, and this 24 hour survival might not mean, actually, as bad as it sounds.

            So I think for this reason, I think I might be sort of similar to many other people who are in this field, that they would not really start going into these studies because it's so much work, it's a really tremendous effort, and you are faced with a failure, in the end.  That's my only comment.

            DR. SIEGAL:  Okay. 

            DR. TROXEL: I just want to reiterate a few things that have already been stated, probably, in various ways this afternoon.  But it seems to me that the purpose of the standard, in this context, is to try to maintain some reasonable likelihood of achieving some level of quality that's deemed important.

            And I specifically say that in kind of general terms because I think we can get "hung up" very easily on 70 percent versus 73 percent and, you know, all of these particularities, and there is some inherent arbitrariness to them because they're cutoffs.  And so, you know, we can always argue that you should go from 75 to 74, or 74 to 73, and you can usually, you know, deal with the slight changes in probability of success and failure and risk, and so forth, that are attached to those changes because they're small changes.

            But at some point you have to make a decision, yes, it's approved, or no, it's not approved.  And so, you know, that arbitrariness is sort of built into the system at a certain level.

            So one reasonable rationale for relaxing a standard might be to maintain the same level of quality and yet still allow more products to be approved.

            And I think the proposal that's been put forth today addresses the approval rate of that, part of that equation, without really saying anything at all about the maintenance of the quality standard part of that equation.  And so I think that's something that we really should keep in mind.

            Having said that, if you look at recent history, where "recent" again can be fairly generously defined, as Tom said earlier, by the last decade, the likelihood of products getting approved is actually, you know, overwhelmingly--the vast majority of products have in fact been approved with the current standard. 

            so there's not a proposal to increase the stringency of the standard.  It's simply a question of maintaining the current standard until we have such evidence that allows us to say whether or not we're going to in fact sacrifice any of the safety in terms of the patient outcomes.  That is in fact the bottom line, ultimately.

            So I think it also has a little bit of a flavor of trying to fix something that isn't really broken at this point.

            DR. SIEGAL:  Further discussion?

            (No response.)

            DR. SIEGAL:  All right.  Then let's address the questions.  We have a slide.  All right.  So question number one.

            Does the Committee agree with FDA's proposal to maintain the current criteria?  And we've heard the current criteria stated about 15 times this afternoon, so I won't read that part.

            And if we vote "yes" on this as a committee, then the further votes aren't indicated, and if we vote "no," then there are two other questions.

            So shall we start talking, first of all, about this first question.  We sort of have done this a little but we ought to do it some more, because remember that we can't really state our opinions after the vote.  So we want to come to some kind of conclusion.  Yes; we can't change our vote but we can certainly state our opinions.

            DR. MCCOMAS:  I have a point of clarification, being new to this.  So when you say does the committee agree, are you going by--and then if it does, then there's no further votes.  Would that be based upon a majority of people, or a consensus of the people here?  If one more voted yes, than no, then we wouldn't continue on?  Okay.  Thanks.

            DR. SIEGAL:  Okay.  So who wants to talk to this?  Shall we just go around the room?

            You want to just call the question?

            All in favor of calling the question?

            (Chorus of ayes.)

            DR. SIEGAL:  The question has been called.  Let's vote.  Do you want to do that, Don.

            DR. JEHN:  Okay.  And remember, we want to keep--we're going to start with "yeas" but we want to keep our hands raised until your name is called off, and I have your vote.  Okay.

            Who's in favor of this question?  Yea?

            (Showing of hands.)

            DR. JEHN:  Okay.  Dr. Macik.  Dr. Fleming.  Dr. Kulkarni.  Dr. Manno.  Dr. McComas.  Dr. Rentas.  Dr. Troxel.  Ms. Baker.  Dr. Bello.  Dr. Cryer.  Dr. Di Bisceglie.  Dr. Edwards.  Dr. Finnegan.  Dr. Kuehnert.  And Dr. Siegal.  Okay.

            And "nays"?

            (Showing of hands.)

            DR. JEHN:  Dr. Szymanski.  Dr. Zimrin.  Okay.  So it's one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen--fifteen years and two nays.

            DR. SIEGAL:  Do we want to have any further discussion on how we voted or why?

            DR. JEHN:  Dr. Katz, do you have an opinion?  You can't vote; but do you have an opinion?

            DR. KATZ:  Of course not.

            Yes. I feel very strongly, both was, and I'm not sure I'm speaking for the industry when I say this.  I think the critical issue here is it's a bad time for me to go to my heart programs, for example, and say, well, we've got this bag a buck cheaper but the survival's 3 percent less than the current standard because we changed the standard.  I really don't want to be in a position to do that.  I don't think that's sound judgment on my part, given all this retrospective data that has got us concerned about the storage lesion.

            So from that standpoint, I think the current standard's fine, with the caveat that when, as an example, pathogen reduction is approvable except for one percent too low survival, or one extra failure in the survival study, that that has to be a very careful discussion about risk and benefit, so that we don't lose the opportunity to do pathogen reduction or take certain plasticizers out of the sets used for neonates.  Those sorts of things can move along and not get "hung up" for a one percent survival miss, or an extra, a fourth failure in a study of twenty-four.

            DR. SIEGAL:  All right.  Well, if there's no further discussion--yes, please.


            DR. BALLOW:  I mean, another point of view is, Are we stringent enough?  Should we make the criteria even more difficult?  I mean, we've heard some clinical studies, and although they have be retrospective, I think we do need some better-controlled prospective studies to really look at this issue about, you know, about the age of the product, age of the red cells and whether they do have an effect on clinical outcomes such as cardiovascular surgery.  So it'd be nice to get some additional data over the next several years, to be able to come back and perhaps reexamine the criteria, and make some educated decisions at that time, based on clinical efficacy and not just mathematics or statistics.

            DR. SIEGAL:  Somebody else?

            Dr. Cryer?

            All right.

            DR. DI BISCEGLIE:  Apparently my microphone doesn't work.  So I voted yes, but I would like to express some dismay.  I wrote some notes here about what I called "a primitive biomarker of questionable relevance."  You know, this is a surrogate red cell survival.  The Agency normally doesn't like surrogates.  When a sponsor comes to the Agency looking for approval of a product, they don't like to hear about surrogates.  So I guess I would challenge the Agency, and the blood banking community to--I'm not sure it's--somebody pointed out the difficulties of doing studies based on clinical end points, but this needs to be examined.

            Are there better surrogates, perhaps, more modern surrogates?  Or maybe some studies that match up the clinical relevance with the surrogate.

            DR. SIEGAL:  I actually ought to second that by pointing out, as I think I sort of did before, that the study that we're debating the significance of is done on 42-day-old red cells, and it's already been strongly called into question, that 42-day-old red cells may be really adverse, and maybe we ought to be really thinking about a major study, possibly funded by an HLBI.

            I just can't help but wonder whether we couldn't, in fact, get data from a previous prospective study that was done a long time ago, the transfusion safety study, and perhaps there are data there that can be mined, that could be looked at retrospectively, but were collected prospectively, and that could give us some information about these sorts of things.

            Dr. Epstein, is there any possession of that?

            DR. EPSTEIN:  GSS is a very old study, and, you know, products have evolved.  On the other hand, there is now an RFA to look at issues related to red cell preparations and clinical outcomes.  Dr. Glynn had to leave early and could have addressed, with more precision, what's in the RFA.  I really can't do that.  I don't work for the NHLBI.

            But I think that there's a growing awareness that the whole question of the rue safety and efficacy of not just red cell therapies but transfusion therapies needs a modern reexamination in the era of prospective randomized controlled trials, and it's my fond hope that this will be the recommendation that comes out of the forthcoming meeting of the Secretary's Advisory Committee for Blood Safety and Availability, which will be taking up specifically the question of toxicity, or potential toxicity of older red cells at the next meeting, which is May 29-30.  The subject will be on May 30.

            So, you know, certainly I think it'd be a good thing if some of the experts here attended that meeting, and, you know, I agree fully.  I think that we do need a scientific examination of these issues with modern tools.

            DR. SIEGAL:  Thank you, Dr. Epstein.  Anyone else want to comment?

            All right.  Dr. Fleming.

            DR. FLEMING:  Thanks.  I'd like to actually reinforce what some of my colleagues have been saying.  I think Dr. Dumont, in his presentation on the slide that I went back to, did hit two key questions, "hit the nail on the head."

            The second of his two key questions is: What's the availability of current RBC products?  Well, given the totality of the data that we've seen, the capability is very high, to be able to achieve success based on the current state of the art.

            The first of his questions is what's the clinical evidence, and the best case that was made to weaken the standard was that the evidence that we have for why percent recovery is important is not from highly-reliable studies, and then the other argument that was made is there's a level of arbitrariness.

            Well, those two arguments together don't justify weakening the standard.  The congressional mandate to FDA is you need substantial evidence of efficacy, and so as I've already mentioned, those arguments are more sounding like absence of evidence is evidence of absence, as I mentioned earlier.  What we really need, or what my colleagues are saying, we really need more studies that will allow us to improve the surrogate.

            So if it's viewed that this bar is too high, and in part because there's some arbitrariness to the surrogate, the answer isn't weaken the surrogate.  The answer is let's continue to probe as to whether or not this surrogate can be improved upon without having to ultimately go to a clinical end point, which would in fact be something I would love to see in terms of reliability, but I acknowledge would be very huge trials.

            So a bottom line to this is how do we go about pursuing much more enlightenment about what biomarker would be reliably screening in effective therapies, and screening out ineffective therapies, if one wants to move beyond the current standard that FDA is using.

            DR. SIEGAL:  We really should have more discussion on this.  However, since there don't seem to be any takers--okay. 

            Dr. Szymanski.

            DR. SZYMANSKI:  Well, I would be very interested in actually doing a survival study in a patient who receives a unit of two red cells that are of different age.  Then you would really hit the proper population, to know what happens when you give these units to patients, how much recovery you have, and this could be done, not so terribly, in a cumbersome way, because you can measure their red cell volume with the chromium and you can measure their survival with different techniques, which gives you actual survival, not the chromium survival.

            It would be very interesting to compare that to the so-called surrogate that we have in normal volunteers, giving a 10 milliliter, 20 milliliter volume, a blood sample.

            And that I think would open our eyes, to see what really happens with patients when you give them these cells, young or old.  But I doubt anybody's going to do it.

            DR. CRYER:  I will comment on that because I think, first of all, it is the crux of the matter.  We somehow have to be able to figure out whether or not there's something about old blood cells, or even new blood cells, that's doing something to our patients.

            The problem is, is that, you know, I was a little concerned about the cardiac study where one or two blood cell transfusions didn't make any difference.  It's not until you get a whole bunch.

            Well, in cardiac patients, that's going to be long pump runs, there's going to be other things that are damaging to the micro circulation of the patient's organs, and so forth, than just the red cells.  and the same holds in my patient population, the trauma patient, where even--we have a couple prospective studies that have demonstrated a very nice correlation with the more blood transfusion you get, that the higher incidence of organ failure, and then you still are stuck with the problem that the more blood you get, is directly proportional to the more blood you need, which is directly proportional to how badly you're hurt.

            So you can never separate out those factors in any clinical study and I don't know how we're ever going to get around that.  I'd love to do it if any of you have some good ideas, and work with you, but that's the conundrum.

            DR. SIEGAL:  I have a question, actually, for people who know this, because I don't, and that is whether studies have been done that look at people who are in less catastrophic circumstances than cardiac surgery, and whether the age of the red cell matters in people who just need routine blood transfusions, because it might affect how we handle supply.

            And the other thing is, I want to mention, which has been mentioned before by others, that what we call red cells aren't red cells.  They're an interesting mixture of red blood cells and packets of cytokine-producing lymphocytes and granulocytes and what have you.  And those cells are there, and unless we do leukocyte depletion studies, and figure out what their contribution is, it may very well be that they are the prime offenders in some of the toxicity that we see.

            DR. ZIMRIN:  The problem with looking at patients that are not so sick is that you can't look at survival as an end point.  Otherwise, you'd need, you know, a tremendous number of patients.  So you would have to look at much fuzzier end points, which is why I don't think the studies exist.  I certainly don't know of any.

            DR. SIEGAL:  You know, tat's a good point.

            DR. MACIK:  I would just kind of make a couple of points, since I haven't spoken all day, but I would agree, number one, if a person needs a blood transfusion, they're almost never well.  You don't need a blood transfusion if you're well.  There are sicker people.

            The other is when we talk about surrogates--and I am not a blood banker, so I don't know exactly how these studies are done--but when you look at some of the earlier studies, and there's a far off-scale outlier, do we know the red cells are normal?  If we pick, quote, normal people, how do you define it's a normal person for your surrogate study?  Do we really know they don't have a mild red cell membrane defect?  Therefore, their recovery isn't as great, even though they are in normal control.

            A comment was made earlier, well, maybe industry wouldn't pick that person again because they know they didn't have good recovery before.  I would say that wold be a valid point to make, that you wouldn't want to pick somebody unless you did a full workup of that person and show it wasn't their own red cells that were bad.

            And there are many, many red cell membrane disorders of varying intensity, they're fairly common, that, you know, any individual may not be a good model, even though they are normal as far as more criteria used.  To my knowledge, I don't think with any of these studies, that they go through a minute workup of the normal controls, red cell membranes and enzyme systems.  So you have to be careful with some of these surrogates from that standpoint also.

            DR. SIEGAL:  More commentary?

            (No response.)

            DR. SIEGAL:  Well, all right.  Then I call this meeting adjourned.

            (Whereupon, at 5:47 p.m., the meeting was adjourned.)