Blood Safety Transcripts

DEPARTMENT OF HEALTH AND HUMAN SERVICES
ADVISORY COMMITTEE ON
BLOOD SAFETY AND AVAILABILITY

13th Meeting

HOW SHOULD THE GOVERNMENT RESPOND TO
THE CURRENT PUBLIC DEBATE OVER LEUKOREDUCTION?

Volume II

8:14 a.m.

Friday, January 26, 2001

Hyatt Regency Capitol Hill Hotel

400 New Jersey Avenue, N.W.

Washington, D.C. 20001

P A R T I C I P A N T S

Arthur Caplan, Ph.D.

Larry Allen
Michael P. Busch, M.D., Ph.D.
Rajen K. Dalal
Richard J. Davey, M.D.
Jay Epstein, M.D.
G. Michael Fitzpatrick
Ronald Gilcher, M.D.
Edward D. Gomperts, M.D.
Paul F. Haas, Ph.D.
William Hoots, M.D.
Karen Shoos Lipton, J.D.
Lola Lopes, Ph.D
Gargi Pahuja
John Penner, M.D.
Jane A. Piliavin, Ph.D.
John Walsh

Paul R. McCurdy, M.D.
Stephen D. Nightingale, M.D.
Mary E. Chamberland, M.D.
David Snyder, Rph, D.D.S.
CAPT Lawrence C. McMurtry

C O N T E N T S

AGENDA ITEM

Approach to Leukoreduction
by the Food and Drug Administration
Jong-Hoon Lee, M.D.
Food and Drug Administration

Committee Discussion and Recommendations

STATUS OF CURRENT EFFORTS TO MONITOR
THE UNITED STATES BLOOD SUPPLY

Committee Discussion --

Old Business --

New Business

ADJOURN

P R O C E E D I N G S

DR. NIGHTINGALE: Good morning. My name is Dr. Stephen Nightingale. I'm the executive secretary of the Advisory Committee on Blood Safety and Availability, and this is the second day of our thirteenth meeting. Dr. Caplan will chair the meeting. I wish to note for the record that after the roll was taken yesterday, Dr. Caplan and Mr. Allen arrived. We did have a quorum for the meeting.

Dr. Caplan?

CHAIRMAN CAPLAN: One way to get us underway this morning, as we start to deliberate a recommendation, whether we want to make one or not, is I was going to ask Dr. Penner if he would summarize a bit, briefly, what took place yesterday for some of us who weren't here.

DR. NIGHTINGALE: And may the executive secretary suggest that we do that after Dr. Lee's presentation.

CHAIRMAN CAPLAN: Oh, you mean put Dr. Lee on first. All right.

DR. NIGHTINGALE: Dr. Lee is on first.

CHAIRMAN CAPLAN: Okay.

DR. NIGHTINGALE: And no joke was intended by that.

[Laughter.]

DR. LEE: Thank you, Dr. Caplan and Dr. Nightingale.

This morning I'm going to try to rapidly outline for you the FDA's approach to leukocyte reduction, and this is a product of many years of intensive deliberation and sort of stands as an interim final product. However, this is only a starting point on which the public may now formally engage to alter or modify according to the wishes of those interested.

And this just goes to show you the number of specifically FDA-initiated public meetings about leukocyte reduction. We started way back in 1995, and almost every year we've had a major meeting about that. This is not to include other industry-initiated meetings that also discuss leukocyte reduction in depth, but only those initiated by the FDA. And we are writing one more chapter today, in January 2001, where we are discussing the cost of universal leukocyte reduction by this committee.

And I'm going to take a similar approach that I took last year when I spoke about the Blood Products Advisory Committee meeting on leukocyte reduction. At that point, a formal guidance document had not been drafted. Today it's out on the Internet. It's accessible to the public. We have a written document on which to base our discussion. The approach that I'll take is the same. I'll briefly discuss the manufacturing aspect, the quality monitoring aspect, to be specific, and then I'll talk about the licensing aspect and then make a brief general comment about product use, as I did in 1999--in 2000.

We might as well start with the definition of product manufacturing from the standpoint of quality monitoring. What do we mean by pre-storage leukocyte reduction? And the text that you see on the screen are in two colors. The white is the same text that I used in 2000 June BPAC, and the orange indicates that alterations that have been made since then based on internal discussion and also external input on which to base the internal discussions. And it reads, the pre-storage leukocyte reduction definition reads, "As the reduction in the content of leukocytes in a blood unit to 1.0 times 10 to the 6th cells or fewer per unit, while retaining at least 85 percent of the original therapeutic product and meeting additional product specifications..." to be discussed in the following slide "...within..." and this is a point of contention, and at present it reads in the current draft guidance document it reads, "...a time frame specified in the filter product insert, but not to exceed 72 hours..." originally, it was proposed 24 hours, "...of blood collection using a method which assures at 95-percent confidence level that more than 95 percent of the units meet prior specifications."

And this definition attempts to address product purity most of all, in addition to potency, safety and efficacy. It keeps in mind the cell degradation and cytokine release problems associated with filtration after storage and also keeps in mind operational feasibility, in deciding the time frames of when it should be leukocyte reduced, and it therefore outlines specific processes and product specifications.

So what are these process and product specifications and what is the testing plan going to be that uses these specifications? As for the filtration or leukocyte-reduction process specification, the number of units that should meet a defined set of product criteria specifications should be more than 95 percent, should be, in terms of actual number, it should be far more than that, but in terms of demonstrating at the number of percentage, demonstration level begins at greater than 95 percent.

Once you've demonstrated something, with what confidence level can you demonstrate that? And that confidence level should be also 95 percent.

Now, these are process specifications. Now, what are the specific product specifications? Of course, the residual leukocyte content should be 1.0 times 10 to the 6th residual donor leukocytes per unit, and this is for a product derived from an apheresis product or whole blood red cells or packed red cells. But in the case of a random donor, platelets derived from manual phlebotomy, it would be approximately one-sixth that. And that's further clarified in tables that follow.

In terms of product recovery, as was stated last year, at least 85 percent of the product should be recovered. In addition to this, there are more specific product criteria. For red blood cells and whole blood, there should be at least 160 milliliters of red blood cells--of red cell mass in the unit. For apheresis platelets, there should be at least 3.0 times 10 to the 11th platelets per unit. And platelets derived from whole blood is one-sixth of this or 5.5 times 10 to the 10th platelets.

At this point, I should point out that the additional criteria that arose since last year, as indicated in orange there, are product specifications that apply to every specific unit and will be verified through routine quality monitoring. And if a product were to not meet these product specifications, labeling has to be altered to be able to release that unit under appropriate labeling.

The product recovery of 85 percent is slightly different in that, although this applies to the quality monitoring process, if a unit fails 85 percent recovery, but still meets the other specific product specifications, as outlined in orange text, then that unit can still be released without further altering the product labeling. So the 85 percent is more of a process parameter, in that respect.

About the testing plan. These process specifications should be validated initially and should be continued to be demonstrated as being valid through periodic monitoring. And in order to demonstrate the meeting of these product specifications, in more than 95 percent of the units at 95 percent confidence, the sample size that should be tested is 60 units per facility, per process, per product. So this is specific for each facility using a particular leukocyte-reduction process for a particular process. So each process is very specific, and for each process 60 units should be tested, and this is based on strictly a nonparametric approach of demonstrating 95-percent confidence level.

Now, you can readily see that 60 units is an absolute number that is independent from the manufacturing scope. A large blood center will make 60 units in a short period of time. A small blood center will make 60 units in a much longer period of time. So, therefore, it is also necessary to define the manufacturing period. So these 60 units have to be demonstrated within a three-month period, and a modification of that arose since last June BPAC is that these three months should be followed on a floating basis; that is, it is not hard blocks of three months that follow one another, but a sliding three-month block that follows the monitoring process.

These 60 units, however, need not be tested in one lump sum. They really should be tested as frequently as possible, so that any process that interferes with proper leukocyte reduction, any variable that interferes with that process, can be identified and corrected as early as possible so that a minimum number of products are affected by that variable.

So the sampling frequency is recommended, at this point, to be at least weekly or more frequent. In other words, the number of 60 units on a floating three-month should be divided so that approximately five units or so are tested weekly.

All of this is assuming that every unit that you test, all of the 60 units, pass quality control testing. Then, after you have validated your initial process and through periodic monitoring, the initial process of validation will involve 60 consecutive units, per process, per product, per facility. And then as you continue to monitor that, you are doing another 60 over each floating time block of three months. Now, if everything is according to the product specifications, then there is no need, obviously, for repeat process validation. You simply continue to monitor.

If you were to encounter one or more product that fails quality control testing, then you have lost the ability to assure, at 95- confidence level, that more than 95 percent of the units meet product specifications. So it may be that everything is still fine, but you have simply lost the ability to assure, from a statistical base, to state that more than 95 percent meet product specifications at that high degree of confidence.

So what should you do? And, of course, you would look into the process to make sure that anything correctable is corrected. And if you encounter no problems at all, you may simply resort to re-establishing the fact that this is according to the initial process specifications by testing another 60 units consecutively, per process, per product, per facility.

Now, you might wonder that you might have to do this quite frequently, even when there is nothing wrong with what you are doing. That would be true if you are operating right at the margin of the process criteria that was just shown. In other words, if you are operating at 96 percent, for instance, very close to 95, the criteria calls for more than 95 percent and let's say you were at 96 percent, at that level you may, from time to time, encounter a need to revalidate solely from a statistical reason.

However, if more than, let's say, 99.9 or maybe 99, something high, much higher than 95, at that level, the need for you to revalidate because of a product failure that arose just on a statistical basis becomes smaller, and that's intuitive for everyone, I hope. In other words, in terms of demonstrating, we call for 95 percent, more than 95 percent. However, it is understood, in the way that demonstration based on statistics works out, that the further above you are of that process specification, the less likely it will be for you to have to revalidate based on statistical reasons.

Having said that much about the quality monitoring approach, now this is sort of a continuum, starting at the top and moving through the bottom, the different things that have been considered over the past five years. We started out saying test four units per month or 1 percent of units per month, and that was just an arbitrary approach to monitoring that was not based on any level of statistical assurance, and it was recognized that this is insufficient.

An alternative to that is to simply increase the number to ten. Whereas, that is very simple and appealing, for that reason, it also gives you no more assurance that you are any better off, in terms of knowing where you are, in terms of quality assurance.

It has been also suggested that the entire QC testing be switched to devices or leukocyte reduction equipment, as it is referred to in the guidance document--basically, apheresis machines and filters. Now, this is a major switch in the way we think about quality control testing, but it's good to keep in mind as a potential alternative in the future. But, at present, the way things have evolved, it is too drastic a change to consider.

Therefore, we have the next line, which is the Quality Monitoring Proposal and Draft Guidance that we are discussing today. Here, the QC burden is relatively high. It's at least higher than what it used to be. However, it gives us the single confidence in product quality assurance, and it is superior in that respect.

Now, I'm sure we will continue to receive comments that are listed down below. These comments have already been received and have already received extensive internal attention. And some of the comments that were received about how to alter the existing guidance are as follows:

Since we have product specifications already outlined, it may not be necessary to have additional 85-percent product retention requirement. Now, one would expect that if you are able to meet the product specifications, you will, in all likelihood, also meet the 85-percent product retention requirement. Therefore, it is not really all that important to remove it because you will be readily meeting that. While that is true, the whole point of quality assurance is demonstrating what you already know or what you suspect to be true. And in order to demonstrate 85-percent product retention, the burden is on the blood centers to test all products, pre and post, for cell counts, for red cells and whole blood, the measurement of the hematocrit, and for platelets, the platelet count, as well as weighing the product pre and post.

So if you consider the testing burden that accompanies this demonstration requirement, it may be worthwhile to consider removing that requirement or we might find that it's okay as a belt-and-suspender approach to making sure that our processes are robust.

The next comment that might be considered is potentially decreasing the minimum product potency specifications. And the current product specifications that you saw earlier, 160 mls of red cell mass, 3 times 10 to the 11th platelets per each platelet dose are fairly stringent. And if you were to have a unit of leukocyte-reduced red cells that are 150 ml, is that violative? Or 2.8 times 10 to the 11th platelets, is that violative?

And many have suggested perhaps relaxing that minimum floor.

The next comment to consider might be increase the leukocyte threshold to 5.0 times 10 to the 6th. Right now we have harmonized with the European standard, for the sake of harmonization. And because this is moving towards increasing the product quality, we have decreased our '96 recommendation or 5.0 times 10 to the 6th to 1.0 times 10 to the 6th. However, the question remains, for a product that is 3.0 times 10 to the 6th, you would be compliant by the old recommendation; you would be noncompliant with the newly-proposed leukocyte threshold. Is that product leukocyte reduced or not? And there hasn't been clear reason, other than harmonizing with the European standard, that it should be 1.0.

And it also creates some potential problems in demonstration of the actual leukocyte content. If you were to do it manually, there is really no concern. If you were to use an automated method, however, only if you use the less widely-accepted flow cytometers, it'll be of no concern. At least one automated instrument has had problems detecting down to the--it's not possible to detect to 1.0 times 10 to the 6th level. Whereas, it can down to the 5.0 times 10 to the 6th level.

And the idea is should we allow as many automated alternatives as possible to the labor-intensive manual cell counting process? At this point, it's really kind of moot because that particular automated instrument is no longer on the market. However, the question and the principles still remain.

The next comment to consider would be to decrease the minimum process quality standard of the 95 percent. And this is a major point to consider. Right now we are recommending the demonstration of meeting product specifications at the 95-percent confidence level, that more than 95 percent of the units meet product specifications. And whether or not 95 percent is used or 90 percent is used or even 80 percent is used is really arbitrary, and it is based on how the public feels about not meeting a particular product. It ties back in with a product defect, as being whether or not it is critical or not. I'll talk a little bit more about that later.

So it may be possible to downgrade or lower that threshold of 95 percent, which obviously results in decreased quality monitoring burden and validation burden, the number that was proposed, that 60, rapidly, well, I wouldn't say rapidly, but does go down to something lower than 60, perhaps 40.

Another way to get at this, to decrease their quality control monitoring burden, which all translates into operational cost, and eventually product cost, I would think, is to increase the length of manufacturing period. Right now what is suggested is three months, what's recommended is three months on a floating basis. That could be extended to six months. That will immediately decrease by one-half, resulting in a twofold reduction in the quality control demonstration burden.

The last point that you might consider is consider whole blood and red blood cell filtration as a single process. In other words, we have defined that leukocyte-reduction processes be demonstrated on a per facility, per product, per process. Now, if you were to combine similar processes and look at them as a single process, that obviously results in a lowering of the overall quality control monitoring burden. Now, these are only points to consider and after extensive deliberation, the end product use you see in the current draft guidance, which is only for comment and not effective, has evolved.

Now, all of this does not exclude the possibility that individual blood centers may propose alternate proposals that are drastically different from what's proposed in the FDA guidance document. The FDA guidance document has taken a nonparametric approach. Many of the models have been applied that actually assumes specific distribution of the leukocyte reduction product specifications. And from such a statistical modeling, if you take that approach, it's also possible to somewhat lower the overall quality control demonstration burden.

What you get by assuming, obviously when you assume you're not as rigorous, but the benefit of making a correct assumption is that your demonstration burden is, to some degree, alleviated. And these alternate proposals, if well put together, will and can be considered by the FDA for individual blood centers.

That's about all I will say. I know that questions about CMV testing is out there, and I didn't specifically address it in a slide. But one of the major differences in this guidance from the 1996 guidance is that for a leukocyte-reduced product to be used in lieu of a CMV seronegative product, it calls for specific demonstration on that product, not just on the quality monitoring overall, but specifically for every product in lieu of a CMV seronegative product that the leukocyte threshold and product specifications be demonstrated. And I'm sure many people have comments about that.

Now, let me, at this point, turn attention to the licensing aspect. And one of the ways that the FDA tries to encourage the use of leukocyte reduction in lieu of a nonleukocyte-reduced product is to make the product more widely available and more readily licensed. And in addition to serving as FDA's manufacturing recommendations, it will also serve as licensing criteria when blood centers seek to supplement their license to include leukocyte reduction.

In the first column, I briefly outlined the requirements as called for in the 1996 memorandum. And it required for a cover form, some product specifications, standard operating procedures, product labeling, statistical plan, quality control data and manufacturing records. The brackets around the X's beside product specs, statistical plan and QC data are shown to indicate that, although the call for that review element was there, that the content of those review elements differs extensively from the similar elements called for in the current draft leukocyte reduction guidance.

The current draft leukocyte reduction guidance takes on a more complicated approach, but hopefully it's not so complicated to be not useful. In fact, we hope to be very useful. And it calls for three different approaches. For apheresis products or any approach to leukocyte reduction that differs from what's recommended in the parent draft guidance, then the submission should be made as a prior approval supplement; that is, FDA approval should be received before proceeding with implementation, and it calls for all of the elements. Whenever a prior approval supplement is called for, we expect all of those elements to be an important review element and all should be submitted.

Now, let me skip over to the last column, to the CBE 30. If, on the other hand, the product is manual product, not apheresis, but manual products derived from whole blood on manual phlebotomy, and in addition to being manual it also follows all recommendations as outlined in Sections D and E of the current draft guidance, then many of the elements need not be submitted, and it is assumed to be modeled to the contents of the current draft guidance.

Of course, there should be a cover Form 35OH to be submitted, but product specifications and the standard operating procedures need not be submitted. Labeling should be included as a matter of routine. Statistical plan need not be specified because it will followed what's specified in the guidance. Quality control data to demonstrate that you are indeed meeting the specifications should be submitted and records of manufacturing should be submitted. So the submission becomes substantially briefer and simpler, and it's briefer and simpler for the industry and it's briefer and simpler for the FDA to review.

In addition to that, the whole submission is made as a CBE 34, changes being effected in 30 days. And that means that submission is made. And if you hear nothing from the Agency, if you hear back nothing from the Agency within 30 days, then you may go ahead and implement that. Although it is not specifically approved by the FDA, it is not violative to initiate implementation without specific FDA approval. FDA reserves the right, of course, to respond at any period, to say whether or not that particular submission is approved or not approved.

Let me now turn my attention to the two middle columns, the comparability protocol. These columns were created in recognition of the fact that many blood centers make repetitive similar submissions, and there can be a lot of efficiency gained if some of these repetitive submissions can be lumped together. And this is one way to do it, through a comparability protocol.

Now, this will apply whether or not you follow their guidance or not. The fact that you're applying under a comparability protocol for multiple facilities is already substantially different enough. It is considered an alternative, and therefore should be made as a prior approval supplement.

The protocol itself is submitted as a prior approval supplement. And in that protocol you will be listing the elements that are indicated there, which basically outlines how all of the facilities, how an index facility and all facilities that will be added on after the initial facility approval, it outlines the criteria that they will follow, and of course it will indicate that this applies to multiple facilities to be reported later on. And that protocol itself should be made as a prior approval supplement, which means that implementation can begin only after Agency review and approval.

However, additional facilities that follow the index facility can submit abbreviated submissions, and that submission can now be made as a CBE 30, much in the fashion of the CBE 30 that I discussed earlier; that is, you simply report certain elements, and you can implement that within 30 days, if FDA responds to you in the affirmative, or, if you don't get a response, you may still proceed. If you get a negative response at any point, we'll have to deal with that separately. But assuming that things are okay, it allows you to implement much earlier.

In the data portion that I've submitted as CBE 30, under a comparability protocol, you will submit a Form 356H as a cover letter. You will include labeling, but you will only include as the substantive portion of a submission, you will only include QC data and manufacturing records as demonstration or proof of the fact that the protocol that you proposed in the original PAS submission, under comparability protocol, is being met as expected.

CHAIRMAN CAPLAN: Dr. Lee, I'm just going to interrupt you to say I want you to think about moving along a little bit faster. I understand some of the issues, in terms of going through the reg, but why don't you let the key points get out there, at this point, and then let some of the Advisory Committee follow up with questions on the areas that they might want to go into detail.

DR. LEE: Excuse me. I'll move right along here. Next slide. I'm almost at the end anyway.

The use of leukocyte-reduced product, which has been discussed in great depth yesterday, I'm sure, in the 1996 memorandum we talked about the medical decision as being the key as to whether or not one product should be used over the other. And both products are on the market, and that remains true. The current draft guidance still uses that model. However, it, by proposing these alternative licensing mechanisms and by direct statements, it recommends a higher level of use for leukocyte-reduced product in lieu of the nonleukocyte-reduced product. The benefits of prestorage leukocyte reduction are specifically outlined towards the aim of wider product availability and increased preference by the users.

So, in summary then, what does the draft guidance do and what does it not do? The guidance will not function, at this point, as a regulatory requirement; it will not be effective until reissued under the good guidance practice. The current draft is only for comments.

It does define prestorage leukocyte reduction. It discourages the use of bedside filtration. It does use statistical approach to quality monitoring. And this increases product quality assurance, and it, at the same time, quantifies a level of product quality assurance, the confidence level. It may increase product demand supply and its use. And one way to encourage this increased use is by facilitating licensing and product availability, but it may also increase costs associated with quality control burden, and this is a point that the public is open to comment on.

So what are some final remaining concerns and some potential strategies to address these concerns? Well, obviously, cost is a big issue. That remains the focus of yesterday's and today's discussion. And you have to probably keep in mind both the quality assurance aspect, but also costs on a global sense of operational cost, not just cost of adding on a filter, but also having to use that filter to demonstrate proper filter use. All of that translates to cost, operational cost, and eventually product costs. So those two factors have to be kept in mind at all times.

But most importantly, one has to keep in mind you can demonstrate anything to any degree you want, but it only comes at the appropriate cost of effort, time and money. And to justify all of that, you have to consider the clinical consequences of a product defect. If the product defect is a critical one, which will readily result in significant patient morbidity or even mortality, then appropriate costs of spending the necessary time, effort and money are justified. However, if the product is--prior defect, of course, is not desirable, but not critical, that's also something to keep in mind in demonstrating the level of assurance.

The next point to consider is, of course, to find ways to decrease or offset the filtration costs. And we've been talking about this for many years now. And whether or not we can find the appropriate mechanism for a timely and adequate reimbursement of the additional cost that may be incurred when we move towards universal leukocyte reduction, that additional increment, it may be only a minimal increment or it may be a great increment over the current level of cost. Whatever it is, there should be mechanisms for adequate and timely reimbursement.

And so, with that, I will conclude my remarks. Thank you.

CHAIRMAN CAPLAN: Thank you. Let's have questions for Dr. Lee, if he wants to stand up there for a second.

DR. DAVEY: Dr. Lee, Rick Davey.

Could you maybe elaborate a little bit on your comments about the requirements that each product or process must ensure that CMV transmission or testing is done. I missed that point a little bit.

DR. LEE: Yes.

DR. DAVEY: It sounds like a very important one.

DR. LEE: Yes. Right now one of the ways to offset the cost of filtration is to not do CMV testing. If you have a leukocyte-reduced product, use it as if it is CMV "safe." The current draft guidance calls for allowing that use, but only if each and every product is tested directly. So, in other words, rather than qualifying the whole process and therefore accepting all products manufactured under that process as being okay for CMV-negative use, the current guidance calls for specific testing of every unit. If it were to be used for a CMV indication, that product should be tested specifically outside of the overall quality assurance monitoring framework.

CHAIRMAN CAPLAN: Mike?

DR. BUSCH: A follow-up on that point. What is the approximate cost today of a quality control determination for residual leukocyte content?

DR. LEE: The actual dollar cost?

DR. BUSCH: Yes, what would be your estimate?

DR. LEE: I haven't a clue, quite frankly. I could use some help.

DR. BUSCH: My understanding, at least the flow cytometric or the prior previously available imaging system, you are talking I believe in the range of $10 to $12 per determination. And a manual nageotte count, you know, is a lot of labor, et cetera, so I suspect it's at that level or even higher. Whereas, the cost of a CMV antibody test is, I believe, only like 70 cents. So, de facto, I think your policy would result in people serologically screening, as in the past, for CMV antibody rather than spending a much greater amount of money to quality control each unit.

DR. LEE: Yes.

DR. BUSCH: A major question, though, relates to the standard of 1 times to the 10 to the 6th or 5 times 10 to the 6th, and whether you actually have data as to what percentage of current leuko-reduced products would meet that criteria. In the VAT study, we quality controlled every unit by a quantitative PCR assay. As I recall, in general, the results were quite good over time between centers, fairly consistent performance.

But .8 percent of the units failed to meet the 5 times 10 to the 6th standard, and 8.6 percent failed to meet 1 times 10 to the 6th. And if you even dropped it further, as some of the European countries are proposing, to 5 times 10 to the 5th, I think it was like 17 percent. So we're kind of right on the edge of meeting these quality standards. And to my knowledge, there's very little clinical evidence of benefit period, let alone benefit at a particular residual leukocyte content.

So, clearly, it looks like, as in the past, we're seeing international regulatory bodies constantly raising a threshold of, if you will, safety, but without any significant clinical data to support it. And the consequences, in terms of your proposed quality control requirements, would be extensive systems going out of control, and it's also not clear to me what is triggered at the point where you break quality control, process control.

What level of retesting, what do you do with those products? When do you get to the point where you actually say our process has been out of control to the point where we can't release blood or we have to release blood as not meeting specifications? And once there's a standard that says it has to meet specifications, what do we do as an industry to supply blood when a particular program or a filter is failing to perform or a center's QC is failing to perform?

DR. LEE: Those are excellent comments. I thank you for bringing those out, and I think Dr. Epstein has a prepared response here.

DR. EPSTEIN: Not a prepared response.

[Laughter.]

DR. LEE: We certainly talked about this.

DR. EPSTEIN: I think that the issues you raised, Mike, and you raised, Rick, are related. We recognize that there is some rate of filter failure. We don't fully understand what the causes are. They seem to be largely intrinsic to the donor, rather than the filter. And so the argument is that knowing that that happens, if you don't CMV screen, is there or isn't there a burden to check that unit because you can check that unit? It's different than the case of antibody. You've got your result. That's the best you can do. In the case of the filtered unit, there's belt-and-suspenders. You've filtered it to try to remove leukocytes and reduce CMV risk, but you could also check if the white cells are there.

Now, it has occurred to me that one way of going about it would be to release, as you call them, CMV-safe units, only units from donors who have previously had their blood filtered and the filtration tested because the likelihood that that same donor would fail on a future filtration is, in fact, low, from what we know. And there may be a need for more studies, and there may be others who know a little bit better.

Also, Mike, I'd like to challenge whether 8.6 percent of filtered units fail at the 1 times 10 to the 6th level. Perhaps, if some of the filter manufacturers are here they could comment. Because the data that were examined in-house at FDA suggested that filters are, in fact, one to two logs better than the standard proposed; in other words, that many filters routinely now are achieving something like 5 times 10 to the 4. Now, of course, there's a distribution, but the figure of 8.6-percent failures at 1 times 6 to the 6th strikes me as not conforming to what we currently are hearing about products, although it may have been true some number of years in the past.

So I just would ask, if there are filter manufacturer representatives still present, if they'd be willing to comment on the distribution of residual counts.

DR. GILCHER: Dr. Epstein, I can comment on that based on the processes used within our own institution, which is using universal leukoreduction.

We are able to achieve with our apheresis platelets, greater than 97 percent of the time less than 1.0 times 10 to the 6th and 100 percent of the time less than 5 times 10 to the 6th. So there is actually about 2.3 to 2.4 percent that are between 1 and 5. This is platelets by apheresis. I can give you no data on whole blood-derived platelets.

With respect to red cells, I told you the process yesterday that we use, by taking the platelets off on the front end, we're reducing the lymphocyte load into the filter. And so, again, we can achieve essentially 97 percent of the time a red cell, in fact, greater than 97 percent of the time, a red cell that is less than 1.0 times 10 to the 6th.

Now, there's a caveat there that's very important, and that was alluded to, and that is that you must define what the outliers are and know what are our outliers and know this up front. And we have been looking at outliers. And we've defined this through the process control and the process of leukocyte reduction. And we found three points that are important.

One was discussed yesterday, and that's clearly that any red cell containing a sickle hemoglobin, either will not filter or if it does filter, the product will not meet specifications. And there we use the process control is any red cell, Dr. Lee and Dr. Epstein, that takes longer than one hour will have 100-percent QC done on that. And we have actually found unusual situations with respect to hemoglobins.

The second outlier turns out, interestingly, to be something that we're not very happy about within our system. If we have inadequate mixing of a whole blood unit, there will be micro clotting that occurs, and those can impede the channels within the filter. And so we've had to actually improve the quality of our mixing of units to prevent the micro clotting because those units will also impede flow, and they will not meet product specification. And we've had one instance, on an experimental basis, where we looked at an individual with hereditary spherocytosis. Knowing that up front, the individual had a splenectomy, would have met criteria for donation, having had a splenectomy as a child, but knowing that up front we drew a unit, ran it through the filter, and it failed totally. There was very, very poor extraction of the white cells.

So knowing the outliers up front requires 100-percent QC of those units. And when we remove those, then we can meet, Dr. Epstein, the criteria of much greater than 8 percent. Our failure rate is really less than 3 percent.

CHAIRMAN CAPLAN: All right. Here's what I'd like to do on this. I want to maybe take five or six more questions/comments, some from the panel, some will go out to the floor mike, and then I think we can come back to particularly the fiscal implication of trying to attain either an outcome or a particular safety standard as part of the general discussion about whether we want to make a recommendation about leukocyte reduction overall, which leads me to a question.

I know you don't know necessarily what the dollar amount is to achieve certain QC procedures here, but I'm curious, if one were to follow the European standard or our standard, could you give the committee just a rough guess that 5 percent of the cost of leukocyte reduction is going to be involved in quality control. What sort of percentages are we talking about to get to a European standard, some of the more liberal ones, as opposed to the tighter standard? I'm looking for not a dollar amount, but are we talking about percentage points of difference in attaining outcomes or are we talking about major differences in cost?

DR. LEE: I think we're talking about percentage points. But what it translates to is that those few will trigger the need of having to revalidate. The actual percentage is not so much a problem, but the few little products that fail, one criteria meet the other, will have to be addressed if you use the more stringent criteria, and it will trigger the need to retest 60 units consecutively, and that becomes a burden.

CHAIRMAN CAPLAN: Jim?

MR. ALLEN: Dr. Lee, a couple of things here.

First of all, you mentioned earlier that the FDA has done many years of formal study on this issue.

DR. LEE: I didn't say we did studies. We talked about merits of various approaches.

MR. ALLEN: One of my issues is that it seems like the industry has been kind of gearing up for this issue for a number of years based on some of the talks that have been had in the past. And I believe that somewhere in the area of maybe 50 to 60 percent are producing leuko-reduced blood throughout their inventory. And as you know, this committee will probably be asked to make some type of recommendation based on universal leukoreduction.

And in a way, to me, it appears as if it's almost too late for us to make a recommendation because the industry has already started gearing up to go in that direction. So one of the questions I have for the FDA, in particular, is, whether or not we make a recommendation here, it seems to me that the FDA is going to go ahead with leukoreduction. Whether or not it becomes universal or not I think is maybe one of the main points here. Essentially, I guess we've been down this road before, where I've been kind of confused as to why we're asked to make a recommendation based on something that the FDA has already basically made a decision on. So that's one of the issues I have.

The other is has there been any discussion about some type of policy regarding the scientific advancements in blood safety, so that when something new comes down the pike, the issue of cost and reimbursement, all of these things are dealt with so that we don't have this constant debate each and every time there is some new technology down the road?

DR. LEE: As for the FDA already having made a decision, I don't think that's quite true. As I said, the current guidance is only a draft guidance, and even at that it doesn't call for leukocyte reduction as a universal requirement. It definitely and clearly explicitly states that it does not. It only forces formal recommendations of how to arrive at the leukocyte-reduced product if that is a product to be used. And it does go on to say some additional statements about the FDA's preference, from a product purity standpoint, of that being a superior product than a nonleukocyte product. Then we're back to the initial argument about--scientific argument--about whether or not the benefits are justified by the cost.

So I don't think we've really made any decision about that. We have decided clearly to support the switch to leukocyte reduction, but have definitely not decided anything in the way of any formal regulatory mandate.

As for the scientific information and the time of the regulatory approach to the available scientific information, the problem is that we don't have--the amount of science that's behind leukocyte reduction has been extensively discussed for years--and the correct projection of the appropriate cost and the cost implication towards overall transfusion safety and overall health care delivery, public health benefit, that kind of analysis has not been done in any detailed way, but it's an immense task, and it's difficult to do so.

So, in the absence of specific information, FDA is only recommending the wider use and have fallen short of actual requirement. If we had a scientific data, I think the rule would be already out there.

MR. ALLEN: Would you be comfortable, considering the shortages that we've had from time to time in blood in general, with expecting the blood banks to carry two types of inventory?

DR. LEE: Would I be comfortable with that? Well, the guidance certainly calls for the ability to have both types of inventories and to be used as prescribed by the physician. It specifically states that, and I think the Agency will be quite comfortable with that. Now, we will have to see how it plays out in terms of continuing evolving science about leukocyte reduction. And as the use level increases, the cost factor may also become open to further discussion. It may not cost as much as we all think when the use increases from 20 percent to 60 percent, from 60 to 80 percent. The higher the use, probably the lower the overall cost. There is certain overhead for carrying a separate inventory.

So, as those things evolve, I think the level of comfort may switch within the Agency. But right now we are entirely comfortable with a dual inventory.

CHAIRMAN CAPLAN: Jim, it's okay. You can go.

DR. NIGHTINGALE: It's not intentional, Dr. AuBuchon.

DR. Au BUCHON: I appreciate having a very clearly-stated FDA guidance to know what is expected of a producer of leukocyte-reduced components and a transfuser, and I will be submitting written comments to the FDA regarding my concerns about specific points on this document. However, I would like to point out to the committee certain features of this draft guidance that have an impact, may have an impact, on your decision as to how to handle leukocyte reduction in the future.

First of all, I'd just like to point out the obvious, and that is if leukocyte reduction becomes a universal criterion, then these requirements that are being discussed today apply to every unit. First, the requirement that there be 95-percent competence and 95-percent conformance far exceeds the medically-supportable requirement for the content of these units.

As I stated yesterday, we're not dealing with HIV here. And, in fact, there are no similar requirements for HIV testing. So leukocyte reduction quality control would have a higher standard of conformity and assurance than is required for any infectious disease testing currently performed in the United States. That, to me, seems out of balance and can have some unintended consequences.

For example, you just heard Dr. Gilcher say that about 3 percent of his red cell units would fail to meet the 1 times 10 to the 6th standard after removing those that he knows are coming from donors who have some specific problems, like previous splenectomy or hemoglobin S presence. This implies that there will be a loss of red cells in the supply chain in the United States. While it may not be 3 percent, it will probably be a percent or two, at least. This will be on top of the U.K. geographic deferral, which has cost us several percent in the last year, and who knows what other deferrals may come along in the future.

As we continually apply more and more reasons not to transfuse particular units of blood, the shortage may become more and more severe. This committee has seen data from the National Blood Data Resource Center showing how precarious the situation is. And I'm concerned that as we move to universal leukoreduction and more and more stringent controls, we will have difficulty achieving a safe supply.

Second, with respect to CMV requirements; that is, testing every unit that is used as CMV safe, this will pose huge logistic concerns not only for the blood centers, but for hospitals. Currently, I believe many hospitals do what we do, and that is once a unit is regarded as leukocyte reduced by whatever method has been shown to perform appropriately, we then no longer concern ourselves with whether or not a particular patient needs a CMV-safe product.

So, for example, all of our patients in the Neonatal Intensive Care Unit and all of our patients on Hematology and Oncology receive leukocyte-reduced blood, so we don't have to worry about CMV testing. This draft guidance would require us, essentially, to go back and, as Dr. Busch said, either begin testing for CMV seronegative status or do quality control on all of these units. If we're getting our units from the blood supplier, we're now going to have to ask for QC'd units, which will probably come at an even higher price tag, or we in the hospital will have to do quality control testing.

I have great concerns what to do when a unit is found to exceed the QC limit and what a blood supplier will do then. It sounds like the production process will stop cold until it is revalidated, which means 60 quality control determinations. Now, for those of you who don't work in a laboratory and do nageotte counting, which is the way that a blood center will probably have to approach this, that will take a technologist about two work days to complete.

You can say, well, put more technologists on it, train more technologists in the technique, but most blood centers don't have a plethora of microscopes to use. The may sound stupid, but that's the way that the world works, and it will slow down the release of leukocyte-reduced components until the blood center can gear up, revalidate its process and move ahead.

One other point on CMV, just note that the Bowden study, which most of us would point to as showing equivalency of leuko-reduced and CMV seronegative units for CMV safety had up to six protocol violations, whereby a patient who had been randomized to receive leukocyte-reduced blood did not receive either tested or leukocyte-reduced blood, and yet that study still showed the equivalence of those two technologies. So having not only a 95 and 95 requirement, but a requirement of 100-percent testing for CMV safety, is indeed overkill.

And I will not carry this out too much farther, but I would just point out, in response to Mr. Allen's question about gearing up, and that is that blood centers are indeed gearing up for converting toward universal leukoreduction, but they are not doing so, generally, at the request of the people who are transfusing the blood.

And if the FDA were not to push for universal leukoreduction, if this committee were not to feel that universal leukoreduction were the appropriate way to go, perhaps blood centers would be able to stop where they are or supply what is being requested by hospitals, and we would not have to approach some of these issues, particularly what to do with those units that fail quality control.

Thank you.

DR. MOORE: Breanndan Moore, Rochester, Minnesota.

I would like to reiterate the comments that Jim AuBuchon made relative to, in fact, all of the issues, but also come back to the question of CMV and the regulation, the proposed regulation regarding the testing of each and every unit that is sent out as CMV safe.

Today, in any institution that sees any number of patients who happen to be immuno compromised or who might be, and that includes most institutions, I would suspect, this particular stipulation would require that each and every unit coming into the blood bank to be used in the inventory be tested, each and every one. The only method available to us is nageotte counting. It's totally impractical. We transfuse in just our institution probably 200 units a day that are going out as CMV safe to patients who require it. And I'm not saying we shouldn't do that, we do it for a good medical reason. It's impractical to test each and every one of them.

If we say it's impractical and we have an alternative method, which is antibody testing, the old tried and true method, fine. Let's put antibody testing in place for all of these units. In our institution, in the "clean Midwest," 50 percent of our blood would then become unusable for a vast quantity of our patients. And in other parts of the country where CMV positivity is 80 or 90 percent, 80 or 90 percent of the blood supply would be unusable for patients who are acquiring "CMV-safe" blood. This is a huge issue in terms of availability of blood for patients who desperately need it with certain characteristics.

So I would advise the FDA or suggest to the FDA that they be very careful about this particular stipulation, because while it appears to be improving the quality and "purity" of the supply and ensuring it with greater statistical reliability, it's also choking the supply to the very patients who need it.

CHAIRMAN CAPLAN: Mike?

COL. FITZPATRICK: I just have two things for Dr. Lee; one in support of Dr. Moore and Dr. Au Buchon. The CMV requirement seems to be a giant leap backwards. I did a quick literature search last night, and CMV antibody-negative units are well known to transmit CMV because we know that we are not detecting the agent with the antibody, but exposure to the agent. And those levels of transmission ranged in that literature anywhere from 3 to 8 percent.

I don't think the filter failure that is being estimated equals either the 3 or the 8 percent figure. So I think that the requirement for 100-percent antibody testing of something that is probably a safer product than the antibody-negative units goes far beyond what we do, and, as Dr. Moore has said, limits availability of those units to the patients that require them. And we'll respond to that in writing too.

The other comment I had was on the 1 times 10 to the 5th versus the 5. That's a figure that seems to be becoming in the literature or in the regulatory guidance because it is achievable, not because we know the clinical significance. And as Dr. Klein said, we don't have any studies to tell us the clinically-significant level of white cell contamination in a unit. And I would suggest that the guidance documents should be more aligned to what is clinically significant as opposed to what manufacturers tell us is achievable. And we'll reply to that also.

DR. BLAJCHMAN: I'd like to point out what I think is a gross inconsistency in the FDA guidance document. And the inconsistency is such: You have created very stringent criteria for quality control of leuko-reduced blood products, which is fine, but it's not based on solid evidence. On the other hand, you are not proposing universal leukoreduction.

Therefore, there's going to be a supply of blood out there that doesn't fall into those guidelines at all. So a given patient may get leuko-reduced blood products that are reduced to a specified limit, but when the center runs out of that product, the product then given to that person is nonleuko reduced.

We had that situation in Canada a few years back. The universal leukoreduction implementation took place over two stages. In the first instance, the powers that be decided that it was cost-effective to do leukocyte reduction of platelets. So the powers that be provided funding for leukoreduction of platelets, but no funding for leukoreduction of red cells. So we had the situations that patients who required both red cells and platelets and even who needed leuko-reduced products received leuko-reduced platelets, but nonleuko-reduced red cells, an untenable situation which was corrected a year later.

So I would point out, in the absence of universal leukoreduction, I think the criteria and the stringency of the criteria to me don't make sense and represent an inconsistency which is clinically very important.

CHAIRMAN CAPLAN: Last comment on this?

DR. SANDLER: I'm Jerry Sandler from Georgetown Medical Center here in Washington, and I'd like to make a comment related to the impact on supply. My mom used to remind me not to bite off more than I could chew. Last night I signed off on six emergency releases of blood from the American Red Cross supply to my hospital at Georgetown; the situation being that the process of NAT testing could not get everything out to meet the requirements of NAT testing before the blood was needed.

We haven't digested NAT yet. We have not digested NAT testing to the point where supply is coming through on that testing. We must be very careful if we're going to add more things in the pipeline that we don't bite off more than we can chew.

CHAIRMAN CAPLAN: Mike?

DR. BUSCH: I just wanted to add the point that in the VAT data, for example, and Jay is right, we also had a median residual count in the range of I think it was close to 5 times 10 to the 4th. These are distributions. And when we say that 1 percent or 5 percent of products fail to meet a particular standard, those units that fail to meet the standard are just over that standard. They are not complete filter failures. They are still extraordinarily leuko-reduced products. So I would hope that FDA, even if they attempt to enforce a high-level quality process control program, that that not result in failure to be able to label products as leuko reduced or that the system doesn't stop because all of a sudden that distribution is shifted slightly up.

CHAIRMAN CAPLAN: Let me suggest we do this: John, did you want to offer some comment about where we got in terms of discussion? I think you wrote down some summary points.

DR. PENNER: Yes.

DR. NIGHTINGALE: Excuse me. This is the last time I will interrupt Dr. Penner. I think it is the third. I promise it will be the last.

There was a conversation between myself and Dr. Gomperts last night, which I feel needs to be put on the public record. The reason it needs to be put on the public record is that we do pay very serious attention to the conflict-of-interest statutes here, and we will perhaps have to pay even more interest to them than we did in the past as the focus of this committee shifts from very general questions to questions that can be perceived as more specific.

Yesterday, I read for I believe the twelfth time the story of the chemist who was employed by a manufacturer and nevertheless sits on an advisory committee panel. I anticipated that by reading that story 12 times it would get into your consciousness. But we have a very tangible evidence of the application of that standard before us.

Dr. Baxter reminded me, as I had been aware when I prepared for this meeting, that he is an employee of Baxter Corporation. Baxter Corporation is one of the manufacturers who spoke at the meeting yesterday. It was my prior determination, and confirmed by speaking to our counsel, Mr. Reisburg, who was in the audience yesterday, that the analogy that I made between the chemist and Dr. Gomperts was, in fact, valid. But I think that an additional note in the public record is important here.

The specific language of 5 CFR 2630.402 that draws the line for participation in the public meeting reads as follows:

"An employee..." we mean a special government employee, which all of you are in this case "...is prohibited from participating personally and substantially in an official capacity..." such as participation in a meeting "...in any particular matter which, to his knowledge, he or any persons whose interests are attributed to him, under Section 208, has a financial interest if the particular matter will have a direct and predictable effect on that interest."

That has been the guidance under which I have proceeded.

Finally, there is a catch-all section that I wish to be in the public consciousness, and not just the record, which is 2635.502(a)(2):

"An employee concerned that circumstances, other than those described in 2635.502(a), would raise a question regarding his impartiality should refer to Step 2 above..." which I'm about to read "...to determine whether he should or should not participate in a particular matter."

Step 2 reads as follows:

"Would the circumstances cause a reasonable person with knowledge of the relevant facts to question the employee's impartiality? Yes; do not participate in the matter without authorization. No; go ahead and participate."

I would invite any comment from the members or the public either on this matter or on this specific interpretation.

I see none. I thank you very much. I assure you that these matters will come before us repeatedly. I realize that we've had a long meeting, and we'll have a longer one, but this perhaps as important as anything else we do here. I thank you for your indulgence.

Dr. Penner, I promise not to interrupt you again.

DR. PENNER: Well, since you brought it up, I will admit to making my coffee using a filter each morning.

[Laughter.]

DR. PENNER: Beyond that point, I don't think any have any relationship with the blood program.

After all of the discussions yesterday, I tried to bring together at least a few perhaps consensus statements regarding leukocyte reduction by filter methodology. And essentially I think we might agree with these or perhaps disagree, as you wish. And I've put them together. It's four statements. Dr. Hoots and I discussed some of these earlier, and I think come together with the fact that these are probably representative.

First, we'd have to state, from our discussions thus far, that there is no evidence to indicate that leukocyte-reduced blood is dangerous to the recipient, perhaps with a caveat that filter failures may occur and perhaps infection might get in, which was mentioned.

The second statement is that there is an agreement that leukocyte reduction is beneficial for some patients, mainly by reducing febrile events, by reducing infectivity with cytomegalic virus, by reducing alloantigenicity and by reducing malignancy that is caused in individuals who have immune-suppressed situations.

Third statement is suggestive, and Dr. Hoots said compelling evidence, that products benefit patients with reduced morbidity from, one, postoperative infection; two, malignancy in unknown immune-suppressed patients; and, three, effects from reduced leukocyte degradation products.

The fourth statement represents the areas of contention, relate to, one, cost, which may or may not be significant, as presented by Dr. Gilcher and by the Yale group that the costs may not be that great, although offset by the discussion with Dr. AuBuchon and others, which was pretty well identified in some of the material that you received; secondly, it may affect supply. There is some loss by filter in red cells as well as platelets; there is a loss of sickle cell-containing blood, which has not been attended to as yet; and, lastly, there may be an effect on donation.

And the last area of contention, as Dr. Sandler had mentioned, it may eliminate future investigation to determine whether there are benefits or no benefits.

Those four statements, I would submit, summarize pretty much what we had discussed yesterday, although you may wish to add or detract from them.

CHAIRMAN CAPLAN: I think it would be useful to at least start off with some discussion of that effort in terms of key points that maybe others--that people want to put on the table. What I'd like to do is spend a little bit of time doing that. Then we'll take our break. Then we'll move, and see if we want to say something in the way of a recommendation. But let's open the floor just for areas of--

DR. HOOTS: I just wanted to clarify. I wanted to make sure. I didn't hear the word "no" before "compelling", and I just wanted to make sure that it was just my hearing and not everybody's hearing, because I--the part where we had said "no compelling evidence about post infection and recurrence of cancer", that was supposed to be in there, "no compelling evidence."

DR. PENNER: So you don't agree that there was compelling evidence that there was reduction in post infection?

DR. HOOTS: Well, I think, again, when you and I were discussing, I guess the reason I put in the word, I was arguing that you wouldn't say there was no evidence. You would say "definitive" or "compelling." And so we just used the word "compelling."

DR. PENNER: Can we say "suggestive" as I originally--

DR. HOOTS: Yeah. I mean that's fine. I mean, I just wanted to make sure that you and I were on the same wavelength about what we were saying, because I think what we--there was no scientifically definitive evidence proving that infections are reduced or that cancer recurrences are ameliorated by universal leukoreduction, is the way I interpreted the data at least.

CHAIRMAN CAPLAN: Karen.

MS. LIPTON: The only other thing I would like to add to that, under "areas of contention" is really whether we know that selective leukoreduction really does get the leuko-reduced patients to the patients who need it under our current system.

CHAIRMAN CAPLAN: We also--you could put on your evidence list too, John, that we did not hear any compelling evidence about the elimination of agents believed to be responsible for Jakob-Creutzfeldt or non-variant or Mad Cow, which came up.

DR. PENNER: Yes, as a negative, we didn't find.

The one other issue was the priorities and the cost factor that--the reasons for concern over the cost factors, that there were other priorities that might be more beneficial for the community as a whole, i.e., reduction in error, transfusion errors.

CHAIRMAN CAPLAN: Yeah, Mike.

DR. BUSCH: I'll just start with the first point, with respect to there being absolutely--the implication was that there is absolutely no risk of leukoreduction for recipients. And I think we have seen, annually, major problems with leuko-reduced blood. There was the red eye syndrome two or three years ago. There were well-documented cases of hypotension associated with negatively-charged filters, particularly in patients on ACE inhibitors, some of these very serious hypotensive episodes that were clearly documented to be linked to the use of filtered blood products.

In the past six months, the concern over potentially cracked filters or broken filters and bacterial contamination had a major impact on the ability of many blood centers to support the limited leukoreduction requirements that we've committed to. The products were simply--there was a period what FDA actually had to come out formally and say that the concern did not justify not supplying these products.

So in addition, you know, as you put it in a different bin, but I think the potential loss of 85 percent, up to 85 percent of each red cell component through filter trapping, the consequences of quality control, failures on inability to release blood from both selective donors, such as the sickle trait donors, or potentially donors who just happen to fall in the high-end distribution of a normal white count, and that we're going to be, what, deferring donors with high white count who have persistent failures? You know, how do we manage these ethical concerns?

So I think both on the availability of blood as well as specific incidences that I think are going to happen the more we implement massive leukoreduction, the more these incidents are going to occur. And I am concerned about the impact on--there is a, I think, a real impact on recipient safety that is potentially out there. So I would be uncomfortable agreeing with point one.

DR. PENNER: Maybe I could ask Dr. Gilcher to comment on--since he has universal reduction, and that--has that been a concern? Should we be bringing this in to a great extent?

DR. GILCHER: There's been no evidence of any problems at all within our system. When you talk about the patients on ACE inhibitors, angiotensin-converting enzyme inhibitors, I think that most of those were patients who were on inhibitors who were receiving blood being filtered at the bedside. And that is the setup. We're really talking about pre-storage leukoreduction, and we've seen absolutely zero incidents, and we've transfused essentially over 100,000 units within our system.

DR. DAVEY: I would certainly agree with what Ron said in his experience, but Mike's data are on the record. There are documented problems with some patients getting leukocyte-reduced blood, and Mike outlined them. So whether they've occurred at an individual center or not, I think is not too germane. We know they occur. They're in the literature. And I think we can't therefore say there is no evidence. We can modify it, say there is minimal evidence.

CHAIRMAN CAPLAN: Mike, are those bedside filter cases or not?

DR. DAVEY: No, pre-storage.

CHAIRMAN CAPLAN: Pre-storage cases.

DR. GILCHER: I think it's important, Dr. Davey, to look at those incidents, and specifically the red-eye syndrome that occurred, was clearly a specific filter at a specific point in time. To my knowledge, that problem has been corrected; that no longer exists.

The hypotensive events, again, to a particular situation, namely, bedside filtration in patients on angiotensin-converting enzyme inhibitors, if you take that out, I think there are really very few incidents.

DR. DAVEY: Well, maybe we can say there are very few incidences then, but there is not--we can't say there is no evidence.

CHAIRMAN CAPLAN: So, John, just in terms of areas of agreement, can we say that with few exceptions?

DR. PENNER: I think that would be reasonable, because, obviously, these are occurrences that have been documented, although one might say they've been corrected or they represent a minor element, but still could be worthwhile.

DR. EPSTEIN: I would just like to comment that I think we have also heard, although it was rarely stated, that leukocytes in a non-leukocyte product are of no known benefit. I didn't hear a single person argue that we want the leukocytes in the red cell or we want the leukocytes in the platelet.

DR. PENNER: We also represented that as "some of the degradation products from leukocyte reduction may be of benefit."

DR. EPSTEIN: I think it belongs in point one, that "Available evidence suggests that leukocyte-reduced blood presents minimal risks to patient, and that leukocytes in a non-leukocyte product are of no known benefit." See, I think both pieces belong there.

CHAIRMAN CAPLAN: Steve, I know you're working down at the bottom there, but come back up to one first, come up to the first one. What we're moving toward is to say, with--let's see--what did you just say, Jay? "With few exceptions."

DR. NIGHTINGALE: "There was no evidence with few exceptions." No evidence with few exceptions?

CHAIRMAN CAPLAN: Yes, I'm trying for a little better--

DR. NIGHTINGALE: Do you really want me to type that in?

CHAIRMAN CAPLAN: Let's try, "With few exceptions, there is no"--

DR. NIGHTINGALE: You're going to want to change this, I know.

CHAIRMAN CAPLAN: Get rid of "no evidence." Take out "no evidence."

DR. LEE: Dr. Caplan, could I make a comment about that? With respect to the red eye, as Dr. Gilcher pointed out, was related to a specific lot of a specific manufacturing defect, and that can exist with any equipment that we use, so it really should not apply to leukocyte reduction as a generally process.

As for the hypotensive episodes, actually not a very rare event. Actually, you might describe that as infrequent but not rare. It happens. We see it quite a bit.

CHAIRMAN CAPLAN: You can--

DR. LEE: However--however, it's limited to bedside, and the entire discussion here is focused on pre-storage leukocyte reduction.

CHAIRMAN CAPLAN: Right.

DR. LEE: And in fact, if you are to pre-storage, it will limit or even abolish the use of bedside, which will then abrogate that.

So I think we should produce "pre-storage leukocyte reduction" there, rather than just "leukocyte reduction", to differentiate the two processes. And the argument about the hypotensive episodes melts away.

CHAIRMAN CAPLAN: The phrasing that we're hunting for here, I think, is something like, "With few exceptions, LR-blood is not dangerous to the recipient." We can get rid of our "(sic)" and "evidence" and per anon.

CAPT. SNYDER: I have a problem with what Dr. Lee just said. Correct me, are bedside filters still on the market?

DR. LEE: Yes, they are, sir.

CAPT. SNYDER: Well, then you can't say the there's no evidence, because there is evidence that if a bedside filter is used--you know, if those were not allowed to be on the market, then I could understand limiting the statement, but the way you've got it right now gives a false sense--

DR. LEE: Yeah, I understand your point. But I think I'm suggesting rephrasing--there you go--"pre-storage leukocyte reduction." Focus our attention on pre-storage. Then there is no evidence.

CHAIRMAN CAPLAN: Happy? Mike?

DR. BUSCH: I just wanted to reply to Jay's comment with respect to there being no evidence of value to leukocytes. This is not a reason to transfuse leukocytes, but I think we obviously had the early experience with leukocyte-containing blood having a beneficial immunomodulatory or tolerizing effect with renal transplants. In the VATS study, there was a significant better survival in the recipients who got leukocyte-containing, than leukocyte-reduced blood. That was in a predefined analysis that controlled for baseline CD4 and HIV viral load, and the overall intention-to-treat analysis. I think the P-value was .06, indicating better survival in the patients who got non-leuko-reduced blood. Now, that's not a reason why you're going to transfuse leuko-reduced blood or non-leuko-reduced blood to VATS patients, per se, but you could investigate that and understand the mechanism of allogeneic enhancement. But, you know, I think in that context, the evidence is that there was better survival.

DR. EPSTEIN: You know, Mike, I'm aware of that, and that's of course, correct. But the issue is whether there should be a leukocyte therapeutic that's not your intent when you give the red cell, not our intent when you give the platelet. I mean, there may be a need for some leukocyte-based immune therapy. But I think ultimately we would recognize that as a different product with a different indication. Even if it's a red-cell product, it would still have a different name and a different indication.

I just think it muddies the waters. What we're really saying is that if what you want to give is red cells, there's no particular advantage to also giving white cells.

CHAIRMAN CAPLAN: Now, remember, as we look back on the computer overhead, we're not stumbling yet toward the task of doing a state-of-the-art review. What I'm trying to drive us toward is if we're going to move--or someone wants to move a recommendation about universal leukocyte reduction, pre-storage leukocyte reduction, when we come back from the break, I want to make sure that we have some consensus on key facts or things that might bear on this to get us going in that direction.

DR. NIGHTINGALE: I'd like to ask both Dr. Epstein and Dr. AuBuchon if they would agree with the following emendation to the first sentence there. Drop "with few exceptions", and say "Pre-storage leukocyte-reduced blood is not inherently dangerous to the patient." That would recognize Dr. AuBuchon's--what I believe Dr. Aubuchon's objection, which is that there are circumstances under which any product or any procedure could pose a danger to a patient. The question for Dr. AuBuchon is, does insertion of the word "inherent" incorporate the "minimal dangers that cannot be reduced for any product?"

MS. LIPTON: Do you mean Dr. Busch or Dr. AuBuchon?

DR. NIGHTINGALE: I'm trying to be fair here.

DR. AuBUCHON: I must admit befuddlement. I'm not sure what the presence of lack of the word "inherent" does in here, and I'm not an English major.

All I know is that there have been reports of other symptomatology associated with leukocyte reduction. I'm not sure to what extent I can talk about them because I received that information in confidence, but I am aware of some other problems that are not life threatening, but are nonetheless unusual situations after receipt of pre-storage leukocyte-reduced blood. It's not of the magnitude or the frequency that anyone is going to be really concerned about other than the patient and the physician caring for them. And I think with the way it was stated, "with few exceptions, leukocyte-reduced blood is not dangerous", but there are some exceptions, and I would not want the committee to think that if leukocytes are removed, everything is just fine all the time.

DR. EPSTEIN: I really think we're mixing up two things, okay? One is whether you need white cells in a red-cell product or a platelet product or a plasma product. I think the point of agreement is you don't.

What we're confusing is that current processes aren't perfect, and there's some risk when you do absolutely anything to blood. So nobody's prepared to say that with current technologies for making leukocyte-reduced products, that they are totally safe to the patient.

Personally, I'm happy with either formulation of the statement. I think the formulation that "leukocyte-reduced blood is not inherently dangerous" gets closer to the notion that I've been trying to advocate, which is the agreement that you don't need the leukocytes in the product.

CHAIRMAN CAPLAN: We could try--if you want, you could try "properly processed pre-storage leukocyte blood is not inherently dangerous", if we want to go there, because everything else--everything that's been talked about is an anecdote that I've heard about seems to be related to manufacture failure, not the blood, per se.

But let me make a suggestion about this. I know we love word nuance, but it doesn't matter. All we're doing here is getting a rough consensus about thoughts on risk and benefit, and all that's happening here, it's not a recommendation. So, generally speaking, I'd be willing to live with what's sitting up there because it gives us a pretty good idea that it's not inherently very dangerous. That's all we're fishing around for.

Let's jump ahead. Let's look at number two. Beneficial for some patients? Is that the main groups that seem right now to benefit for sure, with certainty, with some solid evidence? Anybody else belong up there?

CAPT. SNYDER: Yeah, I have one problem. I understand what we're doing with the first one. I can live it. Not happy with the "inherently." But I think we're doing a disservice if we don't say some type of a statement about the post storage leukoreduction. In other words, bedside leukoreduction. If we don't say something about that, I--

CHAIRMAN CAPLAN: That practice.

CAPT. SNYDER: I'm sorry?

CHAIRMAN CAPLAN: Just note that that practice is out there.

CAPT. SNYDER: Well, not only that it's out there, but there are--

CHAIRMAN CAPLAN: Dangers.

CAPT. SNYDER: --more inherent risks with it.

DR. PENNER: So it does not pertain to that, you put in, "and does not pertain to."

CHAIRMAN CAPLAN: Okay.

CAPT. SNYDER: Well, it's just the idea that that process is out there, it is being used. It does have a little bit more risks than this one, so we should identify that.

CHAIRMAN CAPLAN: I understand. Again, I don't think you have to wordsmith that one, Steve. Just got the general idea. I think the panel's got the fact that there are two ways to get leuko-reduced blood. One is more risky, for sure, than the other, and the latter, pre-storage, isn't very risky, whatever it is, for the recipient.

What about benefits? Benefit group? Anybody else missing there that we at least want to ponder as having some evidence those are the right indications? And how about in the suggestive or problematic category under 3?

DR. DAVEY: Mr. Chairman, I have a little problem with that. I think we, as a committee, have not had the opportunity to review the data in detail, but others have. And I am struck with the UHC review, which was very careful, used a very systematic approach for reviewing this literature, and others also have looked at it carefully, and I think the correct statement would be that "evidence is inconclusive that leukocyte reduction may have a benefit in those three", rather than a positive statement.

DR. HOOTS: I would concur with that. I think that's what we want to say. Because saying there's some evidence--when you don't say that there's some evidence to the contrary, I don't think is a really fair way to say it. I think you should just say that it's either inconclusive or it's yet to be determined or something to that nuance.

DR. PENNER: Could you say there may be benefit?

DR. LOPES: Or how about "suggestive but inconclusive." There does seem to the suggestion there.

DR. BUSCH: I don't think you can ignore the data that's out there. I mean, I think there's enormous amounts of data out there, and that data is inconclusive. It's not like these issues have not been extensively studied in large-scale trials. There is--you know, I think "suggestive" to me implies that there's a hypothesis that hasn't been studied in a rigorous context, and I think there's an enormous amount of data, and it is inconclusive.

CHAIRMAN CAPLAN: Well, how about, "The evidence is not conclusive." Let's just try that as a declarative. It seems like I'm getting that much. And then we can weigh that, so to speak, about what people think about benefits when the evidence is not conclusive. That's okay. We're okay with that. "The evidence is not conclusive." I think we can stand with there.

Areas of contention came up under number 4. I think--

DR. BUSCH: One other issue, number C, I don't know of any--one is it's not a clinical implication. You know, the leukocyte degradation products, clearly, they are responsible--the products in play listed are not pre-storage leuko-reduced or responsible for some of the febrile reactions, but I think that plays into number 2 there. I don't understand what's meant by number 3C.

DR. PENNER: Would you put it in 2, Mike?

DR. BUSCH: Again, I don't think--it's really a mechanistic thing. What is the clinical consequence of leukocyte degradation products? As I understand it, it's febrile reactions. I think we're talking here about clinical consequences, not about a mechanism of degradation products or intact leukocytes underlying the clinical event.

DR. PENNER: I'll agree we haven't identified, although it's a concern.

DR. BUSCH: I think I can agree with striking.

CHAIRMAN CAPLAN: Jay?

DR. EPSTEIN: Yeah. I suggest we strike 3. Also, I'm rather confused by B, because the evidence is also not conclusive where there's recognized malignancy, and you know, there's also an unresolved scientific debate whether all malignancy is due to some degree of immune deficiency or tumor surveillance. I would just stop the phrase at "reducing malignant recurrence."

DR. PENNER: I think it is recognized that malignancy can occur in immunosuppressed patients who receive blood products with white cells. I've taken care of patients like that. So I don't think this is something that can be disregarded.

CHAIRMAN CAPLAN: Yeah. Actually, I'm going to ask that we hold there for now too, given the way the presentations went that I heard yesterday. I think that was at least a claim that was made, both for originally recurring and recurrence. I think the evidence isn't conclusive, is accurate, but I think I heard claims of that nature.

What I wanted to do was make sure that we captured--there were two other points that I want us to be thinking about as we go into the break. One was--and I don't have a phrasing for it yet, but it's that question of, do the right patients receive leuko-reduced blood, given the current distribution system? That is, that was the--to put another terminology on it, it was the issue of effectiveness. So I think Karen or someone brought up some of the testimony we heard about if we recognize indications under the current system or lack thereof of American health care, do the right people, who should get leuko-reduced blood, get it?

DR. PILIAVIN: Are you talking about essentially administrative process problems?

CHAIRMAN CAPLAN: No. The question here is literally practice problems, that community people are treating pediatric oncology cases. They may transfuse before they figure out what's going on. The patient needed leukoreduction, and they don't do it. The expertise isn't there. All sorts of people sort of transfused with inappropriate things. If we had a total supply--

DR. PILIAVIN: Organizational problems then.

CHAIRMAN CAPLAN: Yeah, yeah.

DR. PILIAVIN: I would like to see something about the term "organizational" getting there.

CHAIRMAN CAPLAN: So we're looking for something that says it may have a benefit under C, 3C. "Organizational problems limit or interfere with access to leuko-reduced blood." That may be a sentence. Is that a sentence? I think it is.

And then, obviously, under 4 we've got some areas of contention, cost, what the effect would be of going to more leukoreduction on total supply of blood, what it would mean to accumulation of evidence in studies to answer questions about evidence for any of these claims of benefit.

I'm not sure who, if anyone, wants to come back after the break with a proposed recommendation. I mean, no one has actually come to me on this one and said, "I really would like to push a motion or make a motion with respect to universal leukocyte reduction." It may be we come back here and there isn't one on the table. It may be we come back here and something else is on the table to say we'd like to hold off on this, or we want to wait for a while, or something. But whatever the committee is inclined to do, they should be thinking about it during the break. There's a sort of factual background or summary as far as we can drive it, so a few other comments, and then we'll go to the break.

MS. LIPTON: I just want to change that sense in 3C. I don't care if you put it there or someplace else, but it really isn't administration of incorrect blood products. It's misidentification of patients or the failure to identify patients who actually need these products, which is a slightly different--it wasn't a system that's in place that there's an error. It's that we don't have a system in place to capture these people necessarily.

COL. FITZPATRICK: And on the opposite end of the--I mean, if we go to ULR, you obviously will eliminate that error from happening.

MS. LIPTON: Yes.

CHAIRMAN CAPLAN: Right.

COL. FITZPATRICK: So the evidence is conclusive that if you do ULR, you will eliminate that.

MS. LIPTON: You will eliminate that error, if you want to call it an error.

CHAIRMAN CAPLAN: Right. Some of it may not be errors. Some of it may be undetected need that just doesn't come up until you're further out in the system, so you'll pick up some people just earlier.

MS. LIPTON: But that's what I was just trying to capture in there.

DR. HOOTS: So as Mike was saying, in that case it is conclusive, so it shouldn't belong under there. It should go up one.

CHAIRMAN CAPLAN: Oh, that's true. It's more--you're right, you're right.

DR. PENDER: It should be in 2.

CHAIRMAN CAPLAN: In 2. After we get a phrasing that's satisfying, we'll make sure we move that up to 2. Jane?

DR. PILIAVIN: You can't really put it in 2, because there you're talking about the fact that it's beneficial, and this would be putting in something that's a completely different issue. It's an issue having to do with the blockage of that benefit because of organizational problems. It perhaps belongs somewhere between 2 and 3, but it doesn't belong in 2.

CHAIRMAN CAPLAN: All right. I actually don't care where it belongs. As long as we have it phrased correctly, I'm happy. I want it up there just for our talking and discussion, that this is one of the things that came up. Keith?

DR. HOOTS: I think there's one other point that--maybe under 4--maybe it's not in contention, and Paul raised--reminded me what we just discussed, which is regulatory--the impact of regulatory quality control issues on all these issues, needs to be very carefully thought out and refined.

CHAIRMAN CAPLAN: We could put that into D, I guess, 4D. You could just write under 4D, Steve, "Regulatory burden", something like that, not to bias anything about our fabulous agencies. Jay?

DR. EPSTEIN: Well, I think there's a problem of context, in that we haven't really framed pros and cons of "universal leukoreduction", as opposed to "leukoreduction." I mean, I think what we're really reaching for is that "universal leukoreduction" would prevent the problem of patients with indications not receiving leukocyte-reduced blood.

CHAIRMAN CAPLAN: Right.

DR. EPSTEIN: And likewise, there may be some cons about "universal leukoreduction", such as likely increased cost.

CHAIRMAN CAPLAN: So, given some areas where we've heard what benefits there can be for certain people under--who have access to leuko-reduced blood, given dispute about possible benefits, suggested benefits without conclusive evidence, thinking about some of what we've heard about cost, some of what we've heard about different ways that regulations could be imposed, given what the state of the science is in terms of pending studies, the question then we want to talk about when we come back is do we want to move toward a recommendation for universal leukocyte reduction or any other recommendation that bears on generalizing the practice.

So with that, why don't we come back in 15 minutes.

[Recess from 10:00 a.m. to 10:23 a.m.]

CHAIRMAN CAPLAN: Can we please take our seats? Can I get the committee to come back?

One of the things I think it's very important to understand about this committee, in terms of whether we do or don't make a recommendation to mandate universal leukocyte reduction in this point in time is that--and I'm reminded of this by our able executive secretary, but we've said it before, have to say it again--if we are not strong and assertive, our policy impact will be muted. There are many voices that speak to HHS. The new Secretary will be busy, and so I suspect we want to be thinking about not just what do we want to say, but how do we want to say it if it's going to have impact. If we don't want to go toward universal leukocyte reduction at this time, we want to say that pretty assertively too, just in terms of getting impact into the policy process.

I took away from our struggles at the computer that we do agree that there is a population for which leuko-reduced blood--and I have to say with deference perhaps not made by bedside filters, but by pre-storage--is appropriate for some category of persons. We're looking at three groups up there under 2A, B, C, and that seems to be a group of people that are indicated to get this product. We don't want to do anything then to make that more difficult for them is what I'm saying. There's a group that needs to have pre-stored leuko-reduced blood, so there they are. And I think just for the record, we want to make sure that nothing interferes with what's medically appropriate for them.

So the floor is open, with those cautions, to motions or proposals or comments at this time.

DR. EPSTEIN: I think that 3 needs to be broken into two parts. I think that Parts A and B are statements about leukoreduction and Part C and D are statements about universal leukoreduction. Likewise, I think that item 4 are areas of contention concerning universal leukoreduction. I just think we have to be a little bit more precise in our thinking of pros and cons when we're talking about selective leukoreduction versus universal leukoreduction. So again, the practical suggestion is--

CHAIRMAN CAPLAN: Mac, if you put under B, after "patients", just almost like a little subhead, the word "universal", we'll know--I understand what Jay's getting at.

DR. EPSTEIN: I'm saying 3A and B can stand, and then C and D should be under a heading, "The evidence is not conclusive that universal leukoreduction." But I have to say that I still find--

CHAIRMAN CAPLAN: Paragraph right there, and then write the word "universal" right there. We'll know what it--we'll get back to phrase that right.

DR. EPSTEIN: But I also find it--I don't understand C and D as not conclusive. I would have argued it the other way around, that among the likely benefits of universal leukocyte reduction are C and D, you know, averting the consequences and reducing the likelihood. I don't understand why they're packaged under "inconclusive" since those are likely benefits, in fact.

CHAIRMAN CAPLAN: I think that's right.

DR. EPSTEIN: So I think C and D--

CHAIRMAN CAPLAN: That's a category of possible benefit of universal.

DR. EPSTEIN: Right. I think what we're really doing is in 4 and 5, we're talking about potential benefits of universal leukoreduction, and then potential problems with universal leukoreduction.

CHAIRMAN CAPLAN: Likely.

DR. EPSTEIN: Likely, yeah.

CHAIRMAN CAPLAN: John, did you want to do your poll question? You asked if you could do that. I don't mind.

DR. PENDER: Since we've had some really very marvelous polling demonstrated to us earlier yesterday, we thought we could rephrase the polling, a very simple question, for members of the panel. If you were to go into the emergency room today and required a blood transfusion, would you request filtered blood, or would you accept unfiltered blood? Those who would request filtered blood, raise your hands.

DR. DAVEY: I have trouble voting on this, John.

DR. PENDER: Okay. And those who would not request filtered blood?

DR. PILIAVIN: That was not your second alternative. Your second alternative was that you would accept.

DR. PENDER: You would accept. I'm sorry. You would accept unfiltered blood. I just want to know where you stand when you get in the emergency room, that's all. No, no. You've got to have blood. You're bleeding out. Do you want filtered, do you want unfiltered?

DR. DAVEY: John, I think this is a problem. If I had a headache and I went to the ER, I'd like to have an MRI of my brain. That would be nice, to make sure. But that's not possible. So I don't--I put that in the same category, so I'm not comfortable at all answering this question one way or the other. But this is comparable. I mean, this is not that much different. If you want a CT scan or an MRI, might be a better way of looking at it, as opposed to the aspirin. I think the context is too separate. Or if you want Tylenol versus an aspirin; how's that?

CHAIRMAN CAPLAN: Aside from my lack of confidence renewed again in polls, let me ask this. Is there anyone who would like to offer a motion at this time about universal leukocyte reduction? Jane?

DR. PILIAVIN: Just to get us started, I would like to offer a motion that we reconsider the issue of universal leukoreduction in another year, and I will justify that in a variety of ways if you wish, but I think you all already know all those ways because you've listened to all of the testimony that I've listened to.

CHAIRMAN CAPLAN: Just trying to remember. If we were to, at this point, say that we want to reconsider universal leukocyte reduction in one year, does that take us past the three major studies that we heard are in the works? Would they be out by then? Yeah, okay. Comments?

DR. BUSCH: Well, I think we heard that at the ISBT in July, we would see results from, I believe, three of those studies, the Canadian--

CHAIRMAN CAPLAN: That's the Paris meeting?

DR. BUSCH: The Paris meeting. I think the Canadian prospective, sort of pre/post conversion wouldn't be available by then, but maybe there will be some preliminary data.

I think this type of proposal probably needs to be prefaced by something like, "At present the data do not support a compelling need to recommend universal leukoreduction. In light of the additional studies that are in progress, we recommend postponing."

DR. NIGHTINGALE: Actually, this is, I believe, a point of order. I did not bring my Roberts' Rules with me, but I think a motion to table is commonly performed across the street, and that might be the appropriate way to deal with the issue, if that is the sense of the committee.

DR. PILIAVIN: No, no, no. A motion to table is not discussable, and I don't think we want a motion to--something that isn't discussable by Roberts' Rules of Order.

CHAIRMAN CAPLAN: Actually, I know what we want. We want a second, and then we will have discussion. That's what we want.

DR. BUSCH: I second.

CHAIRMAN CAPLAN: That's the spirit. Now, we will have discussion. We don't have to kill it yet. We just have to talk about it.

So let's, for the time being, presume that we can write a preface, something along the lines to that motion, that given the state of the evidence, given further information that will be available in a relatively short period of time, we want to revisit, or something to that effect. We don't have to write that quite out yet. Comments?

CAPT. SNYDER: No. I was just going to say, instead of saying one year, just look at it at each--maybe updates at each meeting concerning the state of the science.

DR. PILIAVIN: I would take that as a friendly amendment.

DR. HOOTS: I'm going to speak against the proposal for the following reasons. I didn't hear any evidence yesterday that based on pilot data that's going to be used as the endpoint from those studies, that the likelihood is that studies are going to be coming out in the next 5, 7, 12 months, are powered to get the kind of incremental change--or the incremental difference to determine the incremental difference in survival or in length of stay, that we--that the pilot datas that we heard based on post-infection complications was likely to give a conservative 1-1/2 percent based on the pilot data, was what was proposed. And I just don't think that those studies are powered to take a 1-1/2 percent sort of difference. Particularly if you think about the studies that--I don't know. I mean, I haven't done these studies, but I've done large clinical trials with mortality endpoints, and violations of--I mean, protocol violations, where the intention to treat is obviously applicable, which it is here, are usually far in excess of 1-1/2 percent.

And so I just think that--I'm not sure that the data we're going to have six months from now, if we're going to use sepsis, mortality or length of stay as the indications, rather than the three already accepted manifestations already, are going to be there. I may be wrong. I hope I'm wrong. I hope the data is definitive. I just don't scientifically think the likelihood is very great at all.

CHAIRMAN CAPLAN: Jane?

DR. PILIAVIN: Okay. I knew I should have done more of a preface. My wish to delay is not based solely on the fact that we don't have these data. It's based also on my belief that we need to further consider a variety of other issues that have been raised. One, of course, is the cost issue. One of the things that some of these studies may tell us is the extent to which if you decrease hospital stays, you can therefore decrease costs, and that would be, at least, a step in the direction of being more aware of possible cost savings that might pay for this, since we're worried about--at least I'm worried about the cost of this in the larger economy of the medical care system.

Another issue I think we need to talk about is blood supply. Between now and whenever we make some final decision on this, we need to know what's going to be the impact on the blood supply of removing all of the donors with sickle trait, for example. As a sociologist, I am also very concerned about issues of donor alienation within certain communities that are hard to recruit, were we to simply say that people with sickle trait can no longer donate. So I'm concerned about those kinds of donor relations issues that might result from this.

I'm also concerned about issues of supply from the point of view of the reliability of the people who make the hardware that we're going to need to do this, and the possible monopolistic control over prices that might come down the pike once we've made this universal.

What else am I worried about? I just wanted to make clear that it is not simply the data with regard to the benefits to a wider variety of patients that I'm concerned about. Concerned about all of the things that we've talked about, and that we don't need to rush headlong into this decision because this is not an issue of an epidemic. We don't have to go ahead and do this now. The only real reason that people are proposing that we do it now is that all of the other countries have done it. We know, however, that they did it for the wrong reason. They did it because they thought these filters were going to help then with the NVCJD issue. Now there's evidence--or at least it's been suggested--that these filters don't help with that problem. They help with certain things that we know about that are good for certain patients. I just don't see the urgency of doing this, and we know perfectly well that it will be unrescindable if we go ahead and do it.

So for all of these reasons, I am proposing that we not rush headlong into this today. I assume that eventually we will end up doing this, but we will end up doing it with a lot more knowledge and with a lot more control possibly over what these costs that we have only estimated at half a billion a year may be.

So that's why I--I'm sorry to have taken that much time, but since my proposal was being interpreted rather narrowly in terms of the reasons for doing it, I thought I needed to expand on it. Thank you.

CHAIRMAN CAPLAN: We'll come around, come to Ron, come down.

DR. LOPES: I just wanted to comment or ask. I think the 1-1/2 percent that was mentioned by Dr. Moore was the minimum difference in postoperative infection that would be necessary to recoup the cost. If we look at the mean data that Dr. Blumberg presented, the available means suggest a bigger difference.

MS. LIPTON: I was just going to say a couple things. I guess I agree with Dr. Hoots, that I don't see what any of the studies that are currently designed, what different information that's going to give us. If we think 500 million is too much, then what are we willing to say it's worth? Is it nothing? Is it that we're waiting to see if it doesn't cost us anything to do it? Is it 100 million, is it 200 million? And that sort of troubles me because I don't think if we send it out there for further study, that we have a clear concept within this committee of what we're looking for. What's going to make the difference?

I also think that the whole issue of cost is a terrible one. I think that the current inpatient reimbursement and the hospital structures that have grown up around inpatient reimbursement and the diagnosis-related groupings, have seriously affected blood safety and availability in this country. We have to somehow as a committee deal with that. I think we do try to. But I don't believe that within this committee the issue is one of the tradeoffs in process versus product. I think that it is our obligation to take both of those tasks on and they have to be parallel tracks. We don't have the luxury of solving one problem first, and then going to the next. To some extent you have to take the issues that get posed to you at the time and deal with them.

I also really agree with Dr. Blajchman, that this is a battleground we're on here today that has maybe nothing to do with leukoreduction and has everything in the world about how we're going to deal with things like virally-inactivated products, because there you'll have things that cost a lot more, and we're going to be talking about trying to get that, quote, benefit, out to a bunch of patients, where we're going to say, "Well, they don't need this benefit."

And so I just think that we need to be very careful, as a committee, in thinking about, is our obligation to worry about the rest of health care, or is it really to say our job is to worry about safety and availability? I think availability is an issue here, and I think we need to address that.

But I--I guess I come down on I think we have the data to know whether to go forward or not today.

DR. GILCHER: I think to not vote for universal leukoreduction would be a giant mistake. In my 30 years in transfusion medicine, there have been few, if any, measures that impact positively on every single blood product that we produce, and this one does. If we were to look at the cost of NAT testing, we would have a very difficult time being pro, for it. Nucleic acid testing for HIV currently costs in the range of $4 to $6 per donation, and it's certainly going to go higher. It's close to 100 million a year to detect somewhere between 6 and 10 individuals. If only one-half to two-thirds of those individuals live one year, which is what the current statistics show on people who are transfused, the cost to detect one individual with HIV, where we would prevent a transfusion-associated HIV in someone who lives beyond one year, is going to be between 10 and $30 million. That's looking for the needle in the haystack and removing the needle.

This process of leukoreduction impacts on every single blood product, and improves the quality of it.

Am I in favor of NAT testing? Absolutely, I am. That's a cost we have to bear. When we look at what we heard yesterday, which is the analogy of process and product, I think the missing piece here is what the patient perceives they want, and I think, clearly, as far as I'm concerned, the patient wants to be transfused with something that is as close to zero risk as possible, and they want to know that that's what we are doing.

The passenger in the airplane wants both the product, the airplane, and the process, the patient, the navigational ground systems, et cetera, to be the best possible, and one doesn't supersede the other. And I think that's absolutely true here. Process and product don't supersede each other.

Again, in my opinion, I think it would be a giant mistake to not vote for universal leukoreduction.

DR. DAVEY: I'd like to just speak specifically about the need to--or the suggestion to reconsider in a year. I appreciate Jane's sentiments and all the comments around the table, and I'll have some more to say about that later.

I do think though, we've heard enough information now and in the past to make a decision today, and I think it's our responsibility to make a decision today, up or down. If it's down, we can reconsider again in a year or two based on additional data. If you feel that cost is important, put it in your basket of things to consider. If you feel that problems with patients getting the wrong blood are important, put it in the basket to consider and make a decision. But I think we have a responsibility to decide today one way or the other.

CHAIRMAN CAPLAN: Paul?

DR. HAAS: As I sat here yesterday, I felt like a ping-pong ball, because I found myself moving back and forth in terms of the pros and cons of this issue. And last night, when I was thinking about this, I remembered all these dollars the government's spending to bring me here. And I'm supposed to be an economist and supposed to know something about at least the general principles of costs and tradeoffs.

CHAIRMAN CAPLAN: Given what they're paying you, don't go too far on that one.

[Laughter.]

DR. HAAS: But since they're paying me so much, I'm going to take more than 30 seconds.

And it's painful for an economist to being part of a discussion where constraints, restraints aren't up in the forefront, because they're always there. To talk about quality without some type of constraint misses an incredibly important point. Yet, there's a part about economics which I also find disturbing in the sense that an awful lot of economic analysis is done in the short run as marginal analysis. We engage a lot in comparative statics. We find proxy data to try and look at some real problems.

And I want to reference Jim AuBuchon's study. What I've read of Jim's stuff, he does very careful work, but when he made his presentation--"but" is not the word I want there; that always implies something's wrong--Jim very clearly stated yesterday that it's awfully hard to measure the benefits of what we're talking about, to put your hands around the benefits are extremely difficult. And when you start looking at the benefit side, as I understand it as a non-scientist, that there are benefits immediately to the patient, there are future benefits in terms of follow-up care. People mentioned some psychological benefits of doing this, and there's probably all types of other potential benefits out there that either I didn't understand, or didn't come up.

And the problem with dealing with cost benefits analyses, is the further you try to push into the future to understand the benefits of an action today, the more difficult it is to try and measure that benefit. It becomes a guess. And I think Jim, rightly so, made that comment yesterday. So then we're stuck with looking at the rather substantial cost. We can't throw that away. We can't just assume everything is free.

But it seems to me that there's another possible approach to this. We all know that constraints are real. We know what the reimbursement system is. But if we have a process which is considered therapeutically beneficial to not think about pushing--let me say it another way--to fail to push that process forward because of the constraint, basically says, in a public system of reimbursement, that those who set the reimbursement rates never get the message that the reimbursement is insufficient to accomplish the goals that society seems to want in terms of blood.

And I think yesterday, that teeter-totter example that is so vivid in terms of the tip on the product side and the raise up on the process side, but I also have heard already this morning, and certainly have heard yesterday, that this isn't an either/or proposition. These two factors do fit together and all of that teeter-totter--I am certain it made an image in my head--I'm not so sure it's a fair example, because we're not dealing with an either/or situation.

So it seems to me that our issue is that if we really believe that there are therapeutic benefits to leukoreduction, then it's also incumbent upon us to take the challenge to get the resources to make sure it goes forward, not to stop the discussion because we're afraid that we won't get the reimbursement.

So I think that--I know the tradeoffs, but if I can understand the scientific arguments correctly, I think we sell ourselves short if we don't push to get the resources that are necessary.

MR. WALSH: Mr. Chairman?

CHAIRMAN CAPLAN: Yes.

MR. WALSH: Following up on what Dr. Haas said, I think from a consumer perspective, clearly we cannot afford to err with respect to safety issues. And we had enough testimony yesterday to establish that there's at least three groupings, and possibly a host more, that will benefit from leukocyte reduction.

I think it's--one of our charters, when this committee was first formed, was to increase the confidence level, public confidence, in a safe blood supply. And I think not to support leukoreduction at this time, it would be a terrible mistake. I think that if we're talking about--everybody nets it out as a cost benefit analysis, and obviously the data's not in on cost yet--I think it's incumbent upon this committee to take the responsibility to bring the people before the committee to discuss the cost and address the reimbursement as directly as possible. We have DOD, FDA, CDC and HRSA at the table as advisers. Where is HCFA? And I think that we really--

FLOOR: Here.

MR. WALSH: Well, you should be at the table.

The reimbursement issue is real, and it's real for plasma users, plasma derivative consumers every month, and I think that the blood supply in general, we need improvements. We have to look forward to a pathogen inactivation cost downstream. We're not even prepared to draw the line in the sand here as it relates to cost. But on the safety issue, I don't see how this committee cannot support the leukocyte reduction.

DR. HOOTS: I agree, John, and I didn't come into this discussion with a lot of foregone conclusions. I clearly read with great interest--and I would really--I didn't get a chance yesterday. I'd really like to congratulate all the panelists, and particularly the chairs for the cogently-presented data. And I think the fact that we're having such trouble is just a pure indication of how multiple smart people can come to almost diametrically-opposed positions about something that is very important. But for me, it breaks down much as John has alluded to.

First, every tough decision we've had to do on this committee, I've kind of prioritized because I think that's what everybody in this room does inherently. You prioritize safety and then decide the impact on availability and decide if the negative impact on availability is going to compromise safety, and then finally come to what's it going to cost society to do it if you reach that conclusion.

I honestly believe, I can't prove it because obviously people smarter than I haven't been able to prove it, but I honestly believe there are people out there who would benefit for those three acknowledged acceptable indications for ULR who aren't getting it, and as a clinician and having to deal every day with the inherent difficulties, both of education, communication, et cetera, trying to devise a system that is fail safe to make sure that those who aren't getting it get it not only is very cumbersome in terms of energy, but I'm not convinced, based on my own experience, that we get there very easily, if we ever get there at all.

Now, does that then turn around and justify doing something for everybody? Well, the first question I have to ask myself there is, does it do harm to the people you're going to do it who might not benefit from it? And that's why I tried to pin people down so much about that yesterday, and I think I'm still believing that pre-storage, if not 100 percent safe, is very, very safe, so that we're putting very little risk on the individual. So then you come to the risk to society, which is clearly a blood availability issue, which brings us to the second point, and I don't look at that with any easy or conclusive way to say that it is not--that we can inherently prejudge that. I don't think we can.

Then you kind of have to look at it. Will the potential benefit--and I think Ron was getting at this. We've made decisions for plasma safety that have looked at relatively infinitesimal risk advantages that are rather costly, and I look at this in that context and I think it has been universally--or not maybe universally; it's not that it hasn't been debated; but it has been pretty well accepted by smart people like the ones in this room, but also the society at large. Are the benefits potentially here equal to or greater than that without--with comparable cost? I come down on the side that I really think it is, which then comes down to a question of cost, and I think that's obviously an issue.

I'm very--I've been disturbed from the moment I sat down on this committee the fact that in our culture, and I think Dr. Blajchman so well articulated it yesterday, that that goes immediately to the top of the discussion. I think that should always be at the bottom of the discussion when you're talking about something like blood. And it's a reality check, and I do not for a moment underestimate the impact that it has had on the blood-banking community in the United States, because pencil-pushing people, accountants, bureaucrats, and people in legislative positions have not been able to see past the end of their pencil on the point of cutting dollars. But that doesn't make it right, and it also doesn't make it precedential that we have to decide important issues based on that.

I honestly believe that it is incumbent on this committee, probably as much as anything else, to do everything in our power to keep the pressures on the people who do make those ultimate decisions to not let them get off with doing the wrong thing because it happens to be expedient for their own economic reasons or for short-term societal economic issues.

So I don't think that's the reason you make the decision.

I also am concerned about the precedent, and Ron alluded to this as well. If we continue--we are obviously--I'm very concerned about the availability issue, but I'm not so concerned about the cost issue except if we allow it, if we sit idly by and allow it to impact availability for some of the reasons that people talked about yesterday. I don't think that's something we should do.

So to make a decision that is as important as this one because we're concerned that we will have another unfunded mandate I don't think is reason not to make the right decision. We should push to make sure that it's not an unfunded mandate.

Secondly, I'm also concerned--and this may make the least sense of all, but it's analogous--I think there are some analogies to plasma safety. Incremental safety steps are important, and even on the economic side, I think that we fool ourselves if we think if we save today's dollars, that they're going to be available to go to tomorrow's advances.

In fact, my experience is to the contrary is true. That is, if you don't make the incremental changes, if you don't raise the baseline cost of the right product, the next time you go to do it, the increment is that much greater, it's that much more problematic, because then you have a percentage jump that's far greater. And I think that that's a mistake that we sometimes fall into because we're shortsighted about, well, if this is a--this is going to have another unfunded mandate, and again, I just don't think that we should allow ourselves off the hook as committee members with unfunded mandates. Even though we don't make the final decisions, we certainly--if we can influence safety decisions, we sure as heck ought to try to influence economic decisions as well.

CHAIRMAN CAPLAN: The chair recognizes passion, but let's go briefer.

Yes.

DR. EPSTEIN: Not my style.

[Laughter.]

DR. EPSTEIN: Let me just quickly say that FDA raised the scientific question in '98. We were advised that science favored universal leukocyte reduction. We then moved to the implementation issues.

I think the argument that we shouldn't be acting as if there's a crisis fails to recognize that we haven't been acting as if there's a crisis. I mean, we have not, in fact, pushed since 1998. We have tried instead, in a measured way, to try to figure out the implementation issues, and many of those are still on the table with the current guidance.

So my first point is that a decision, should it be made, should recommend universal leukocyte reduction can be tempered by a gradual case of implementation fully recognizing the implementation issues.

So then what's the fundamental question? The question is whether universal leukocyte reduction as understood at this time is a flawed concept on medical and scientific grounds, or whether we're really only debating an implementation issue.

Now, my view is--and I have suggested that we should try to distinguish scientific, economic and political forces when we make decisions. So my view is that on the science, what we know is that the known benefits may not apply to all the patients. On the other hand, the potential benefits to all patients may, in fact, be very large if the issues of transfusion-related immunomodulation prove to be real.

The problem that that poses for me as a policymaker and others who may think about the global system is whether we should be taking this as a precautionary step, and there are two issues on the step with the precautionary measure. One is the benefits that could be reaped now with respect to reducing immunomodulation, and the second is the benefit that could be reaped now creating a safeguard for transmission of cell-associated pathogens.

I don't think we've had very much discussion about the precautionary problem in this decision, but that has been a factor to FDA's thinking.

Let me quickly then say with respect to the economics, the problem is that resources are needed to improve the system, not just the product, and that we seem to be stuck in a zero-sum game where we ought not to be stuck.

That then plays into the issues of politics. The consumer wants optimal safety, but we don't have a clear message to communicate. Why? Because the benefits to all consumers are not obvious or proven.

The blood banks are caught in a bind. Why? Because they're stuck carrying the cost without a system that establishes reimbursement. The treaters are stuck in a different way because on the one hand, they are divided over the science, and I think it's fair to acknowledge that, but also, they're concerned because they're not hearing that a step in this direction will assure them of the safeguards on having the right products available for the right patients at the right time. In other words, we could create problems in the system, and that's fair.

So my basic view is that the science favors universal leukocyte reduction for two reasons: one, it assures that all the people with known indications get the right product; and two, it has benefits as a precautionary measure. And I put that on the table because I think that's an under-discussed issue.

DR. NIGHTINGALE: I would make one additional comment that is purely on the political level. This committee has been asked to consider this issue at this time. There is no guarantee with an incoming administration and all the other things that can happen in twelve months that this committee would be asked to consider this issue twelve months down the road.

CHAIRMAN CAPLAN: I can say one other thing, I think, political about this just for consideration. If we used a raw number of $500 million, just $500 million, in my experience, that is eminently suited to an unfunded mandate. That won't even get anybody blinking over at certain agencies, some of whom are here.

But I don't know that the case will get heard per se at that amount of money. I mean, it may cause pain and anguish all around, but I would say $500 million up/down in the current budget expenditures--we're going to have to package something that says continued increments of safety are going to have to get into a package of reimbursement. We can't go one by one, they won't pay attention, is my personal hunch about that.

DR. NIGHTINGALE: If I could make a slight emendation of that, we do not fund $500 million unfunded mandates from petty cash.

CHAIRMAN CAPLAN: Well, a billion here, a billion there.

Mike.

DR. BUSCH: Yes. I agree with Jay that medical--scientifically, the question, I think, that that university group first considered--does the benefit outweigh the risk--and the question that FDA addressed, I would vote yes, that this is a safe product and it has benefits clearly for some people, and in general, I would be in favor of recommending it generally for all blood products, and I think we'll move there.

But I think the cost is so far out of line from the other safety measures that we've debated and struggled with and that I know blood banks will do anything to save a quarter a blood donation, they'll cut back on this or that, and here we're talking about $40 per unit.

So it's really--and I don't know how to deal with the cost issue because I think this is so--you know, this is an order of magnitude greater than all of the other cost issues we've debated in the past.

I guess my feeling would be--I don't understand what an unfunded mandate means in political terms, but could we recommend this contingent on the funding being made available for it?

DR. HOOTS: The problem with that suggestion is that in this country, unlike Canada, the government does not provide the funding for the entire health care system, so that unfunded mandates in the context of your previous comment are an everyday occurrence here.

CAPTAIN SNYDER: Can I just make an observation? From what Jay said, you're moving towards universal reduction, but you're not doing it at one--you're implementing it slowly, a planned, careful implementation. Am I reading that right?

DR. EPSTEIN: Well, let me put it slightly differently. FDA was convinced by its advisory committee in '98 on scientific grounds--we recognized problems of implementation which are huge, and so we've tried to move in a gradual way.

However, we've come to an impasse because what we now see is that absent a mandate, this may very well stop.

FDA's position remains to encourage wider use of leukocyte-reduced products. We do not at this time have the ability to mandate it without a regulation because we don't mandate things without regulation.

So I had thought back in 1998 and in 1999 that a guidance which was not binding on the agency, not binding on the industry, but a statement of the view of the FDA in favor of and encouraging leukocyte reduction, would have caused the industry over a period of years to do this, and there were earlier projections that that's just what would have happened.

But we've sort of stalled at the 50 percent point, and so the industry--you know, part of the industry is poised to go forward and accomplish this and part of the industry is poised to stop here, and so therefore we have a question in front of us, which is, is it incumbent on us as a regulatory agency to mandate this because we think that it's for the public health good, or do we just stop at this level?

So I think the question as framed today isn't the same as the question as framed in '98.

CAPTAIN SNYDER: But let me carry that one step further. From what you just said, and dropping back to Dr. Lee's presentation this morning, the quality issue, the quality control issue, the cost thereof, is still an unknown quantity to you; is that correct?

DR. EPSTEIN: Well, we're engaged in a process of developing guidance. I mean, the one thing that we're firm on is that the products need to meet defined product standards, and one of the difficult issues in this field has been to define both the product standard--you know, 5 times 10 to the 6th, 1 times 10 to the 6th percent recovery, et cetera--and also the quality assurance process.

So we are committed to refining the expectations for products labelled as leukocyte reduced. I mean, we think that's a given. You know, we're going to do that regardless. The question, however, is whether it should be the routine practice or not, and there are only two ways that we're ever going to get there. One is if it's voluntary and the industry accepts it as the current state of the art and simply goes there; the other is if we mandate it. But in either scenario, we need to have a defined product standard for products bearing that label.

CAPTAIN SNYDER: Can I follow with one other thing?

Let me ask you this. Would it be helpful, Jay, for the committee to basically back the FDA's current plan of implementation and to encourage strongly the move towards universal, or is that just leaving it still wide open?

DR. EPSTEIN: I think that would be helpful. You know, it doesn't get to the core question of whether it should be made the routine product, but I think it would be helpful.

COLONEL FITZPATRICK: Back in 1998, we dealt with the recommendation of the BPAC in DOD to determine whether or not we should try and budget to implement universal leukocyte reduction because that process takes a while. That process is currently ongoing, and in Fiscal Year '02, we should have the money available to do that.

I came to the meeting thinking that I had everything all worked out and have been ping-ponging myself, because myself and three other people have to make those decisions as to policy for DOD as to what we're going to use.

Based on what we've heard from Dr. AuBuchon and others, I was disappointed that we didn't get alternatives, that we were told it would cost $600 million; yet there, are in the peer-reviewed literature, suggestions that infections are decreased, mortality could even be decreased, and hospital stay could be decreased, and all those would have impact on cost.

There is Dr. Blajchman's number needed to treat model, which I was very impressed by and did not hear evidence from other panelists to refute, but merely questioned.

We heard examples from a small hospitals where there were actual dollar savings computed at that hospital by implementation. We have Dr. Gilcher's example of successful implementation without impacting supply, and it would appear that the treaters in his area are not up in arms, telling him that he shouldn't be forcing this down their throat.

Given all that, and the budget cycle that I have to deal with, my conclusion is that I will continue on the course with DOD that we are currently on and I will ask that those dollars remain in the budget so that we can implement universal leukocyte reduction in the coming years, not only for those reasons, but for an observational reason that goes back to the Vietnam War.

During Vietnam, people were treated with old packed cells or, in some cases, thawed deglycerolized red blood cells. There is in the literature studies that appear to be valid that show that those people that received the thawed deglycerolized red blood cells did better than those people that got old packed red blood cells.

Given all of that together, and to be brief, I think we will continue on our course at this point.

Thank you.

CHAIRMAN CAPLAN: It seems to me it may be time to move the question on Jay's motion.

DR. PENNER: Could I get one more comment just in regards to the donor reduction in donor population, and it was mentioned obviously that we've talked about on the patients who--one had a spherocytic problem and then we had patients with hemoglobinopathy, such as sickle cell.

I would contend that in some cases, it's probably worthwhile to remove those units from the general pool, that the possibilities of a glutination of cells, pulmonary edema, pulmonary disease, pulmonary obstruction, may well be a part of that process of using cells that do not filter well, and that perhaps we're doing a service by eliminating those from the population, because I don't think we have the data to support the fact that they are as effective totally as those who pass through the filter. So we might need more information on that, but I don't think it's a down side for reducing the donor numbers.

And then I'd have to just reaffirm and agree with what the speakers have already gone over. I deal with a lot of community doctors as well as residents and house staff. Most of them, as I've mentioned before, don't have a clue as to whether they should be ordering leukocyte poor, they're not even sure what it means in many cases, and I know that patients with rheumatoid arthritis, immune deficiency disorders, are getting blood that is not filtered because the doctors don't have any concept of it. You can say that's an educational problem. It is an educational problem, but it's not easy to fix, whereas it's easy to fix providing blood that does not have those components.

The last thing, I'd just refer to the fact that from our informal poll, it's obvious the committee members, with one exception, feel that there is a better product if it is filtered, and why can't you provide that for the community if you believe it yourselves?

DR. DAVEY: Mr. Chairman, a point of clarification. Are we going to vote on that motion and then propose a different one and have further discussion?

CHAIRMAN CAPLAN: Yes.

DR. DAVEY: All right. Thank you.

CHAIRMAN CAPLAN: If there is another motion. Far be it for me to predict that. But let's vote on this one.

All in favor of the motion to reconsider this issue of universal leukocyte reduction in one year.

[Show of hands.]

CHAIRMAN CAPLAN: Opposed.

[Show of hands.]

DR. NIGHTINGALE: Keep your hands up. One, two, three, four, five, six.

CHAIRMAN CAPLAN: That motion is defeated.

DR. NIGHTINGALE: We have 15 voting members. One, two, three, four abstains. Four abstains. Five, six, seven, eight, nine, ten.

The vote is ten against, two for--that's twelve--and we have three abstentions.

Did I get the numbers right? These actually are important.

CHAIRMAN CAPLAN: Yes. Just one abstention. And who else abstained?

DR. NIGHTINGALE: Did anybody else? So it is eleven no, two yes, and two abstain, for the record. The motion is defeated.

CHAIRMAN CAPLAN: The floor is open to any other motions on this matter.

DR. DAVEY: Mr. Chairman, what was the--could you maybe restate for the committee the suggested wording that was in the material we had? Maybe, Stephen, you have that, something about that we would recommend that the FDA move to appropriate rulemaking to mandate URL? I mean, I thought that was a reasonably encompassing phrase.

DR. NIGHTINGALE: Because there has been a suggestion that the influence of the executive secretary may have been--I'm going to respectfully decline to participate in the formation of a motion. This is why we pay you--

[Laughter.]

CHAIRMAN CAPLAN: Something like there are two possible things I can think of that are out there that we might want to consider. One is that we mandate universal leukocyte reduction be implemented as of whatever today is; another is that we urge that the FDA move toward the implementation of universal leukocyte reduction consistent with development of appropriate guidelines and standards, policies. I mean, it's a slightly different--one is to encourage going in a direction; one is to say start now and get the regulation in now--I mean as soon as reasonable.

John, you're looking--

DR. PENNER: I would like to propose, then, a motion that universal leukocyte reduction be implemented as soon as feasible for the benefit of the population, the recipient population.

CHAIRMAN CAPLAN: That motion has been made and seconded that universal leukocyte reduction be implemented as soon as possible for the benefit of the population.

DR. PENNER: Feasible.

CHAIRMAN CAPLAN: As soon as feasible. Excuse me. As soon as feasible.

DR. GILCHER: Second.

DR. NIGHTINGALE: Is there a reason for the last eight words?

CHAIRMAN CAPLAN: He just wants to say it will be implemented as soon as is feasible. We can presume our motives are benign.

DR. PENNER: Just take off the last, then.

CHAIRMAN CAPLAN: All right. That's seconded. Discussion there. Karen?

MS. LIPTON: I guess I would like to see some discussion somewhere in there about the issues of availability, that as long as we understand what feasible means and what issues we're concerned about as the FDA moves towards rulemaking.

I think I heard some concerns expressed about the guidance that's out there. If that were to be implemented as a rule, I absolutely believe it would have a very serious effect on supply and would increase the cost beyond what it needs to be. So I don't know if we could capture some of the concerns that come in feasible, but I think that would be helpful.

DR. PENNER: I would agree to a friendly amendment. It's obvious that this is not something that has to be installed momentarily, but the direction is there and we're just considering that we're in agreement with the direction and it's going to proceed, and we're just supporting what has been in the pipeline.

CHAIRMAN CAPLAN: Mary?

DR. CHAMBERLAND: Given the FDA's statement that their full intention to put into place some standards which seemed reasonable and appropriate, and given that it would appear that the FDA is going to get some comments on the proposed guidance, also not unexpected, but it seems like, as the course will unfold, there will be a guidance for implementation, not for just draft comment, and given that currently, you know, there's been various figures put out there, but you know 50/60 percent of blood products being transfused are already leukoreduction, one could argue that absent universal leukoreduction, with a significant proportion not being leuko reduced and some sort of a guidance, in essence you're sort of conducting I don't want to say a pilot study, but we would see how the implementation would fare in a venue of not universal, but a significant proportion being leuko reduced.

And I think it would give us a pretty good idea of what the impact might be, some of the concerns that have been expressed, Karen's concerns and others, about supply, availability of filters to do it, issues related to what do you do with products that don't filter, et cetera. I guess what I'm saying is it's sort of in support of this recommendation that as soon as feasible means that we would have a period of time where there would be leukoreduction done under some standard, and we would have an opportunity to see how that worked, if you will.

DR. HOOTS: I just wanted to ask you're talking about having a roll-out period, essentially, a defined roll-out period; is that--

DR. CHAMBERLAND: As I understand it, leukoreduction is being done now without any standards in place--no?

DR. EPSTEIN: FDA put forth standards in 1996.

DR. CHAMBERLAND: Oh, that's right. I'm sorry. But the revisions that have been proposed are significantly different in several aspects.

DR. EPSTEIN: Yes. The key thing was to define a more comprehensive quality control program.

DR. CHAMBERLAND: And a CMV component.

DR. EPSTEIN: Well, that's a new proposal. The testing of units released as "CMV-safe" is a new proposal.

CHAIRMAN CAPLAN: Ron?

DR. GILCHER: I think it's extremely important to support universal leukoreduction. In terms of the time frame, I think that that really needs to be defined once the proposed guidance document has gone through all of the reverberations that will occur, and basically it has been defined. And then an implementation time can be put in place, with which everyone can live. I don't think we could put the implementation time in place right now.

CHAIRMAN CAPLAN: Well, one set of issues is what does feasible mean, and filters and what to do with unfiltered blood probably falls in there. You might take a friendly amendment, which I wrote up on the table, should be implemented as soon as feasible with a minimal impact on supply, if you want to drive the supply thing forward as a separate issue. I wouldn't say that's quite feasibility, but--

Karen?

MS. LIPTON: Actually, I have a question maybe for Dr. Lee or you, Jay.

When you were looking at the guidance, were you looking at it as if we're really in a selective leukoreduction sort of arena? Had you thought about what would happen if you went to universal leukoreduction with this particular guidance? Because I think that's what I'm struggling with, that I agree with, and I can't remember who it was in the audience who said it's almost as if it's putting so many barriers up that it's almost as if you're moving away from trying to implement it, and I wonder if you really could do a total supply of leuko-reduced red cells, platelets out there with this guidance that's currently proposed. And did the Agency think about that or were they thinking about a dual inventory?

DR. EPSTEIN: Our concept was that the guidance would apply, both presently and should universal leukoreduction come into place. However, this is why we publish guidance for comment. We expect feedback, and if we've created an inconsistency, I will address it. But I think a deeper point, perhaps, is that one might be willing to live with this guidance if it was for selective products and not live with universal.

MS. LIPTON: And I don't think we can tolerate it with universal.

DR. EPSTEIN: I think the implication is that it would be helpful if people would comment on that very point when they look at the guidance. But, certainly, it was FDA's concept that we were putting forth a product standard, independent of whether it was the routine product or a selective product.

DR. NIGHTINGALE: One consideration I would like to remind the committee is that in our particular role, we are dealing with questions of general applicability. The converse of that is that we do not want to get into the area of micromanagement or even day-to-day management. The recommendations don't go directly to managers. For example, specifying a specific time frame is something that is really not contemplated here right now. Now, you may wish to vote for that if you do, but there are problems in getting too specific here.

DR. HAAS: Well, I agree with the nonmicromanaging it. But the way we have it stated, I think leaves too much--we're hearing this discussion right now, which I think is very intense. My mind keeps going back to your comments earlier this morning, Mike, about those issues. And I don't know how to capture it in one sentence. But I think if we leave here just with that one sentence up here, that that's going to float out in the press, et cetera, and carry meanings that we don't really mean. I think that this encouragement to move forward is one with some caution because there are concerns out there. They're very real.

DR. NIGHTINGALE: Dr. Haas has actually said what I had wished I had said.

DR. BUSCH: I think, in addition to the need to sort of work with the regulatory implementation issues, and I know FDA's intent is to have procedures that are viable from the blood supply perspective and want to establish a threshold that is safe, but is obviously achievable, also. So I think that's going to take a back-and-forth, with not only reviewing this and commenting on it, but actually trying to implement elements of it and generating data to feed to FDA to indicate whether the one-time 10 to 6 standard is feasible, et cetera.

The other thing is the money side, and we heard Colonel Fitzpatrick comment that he's gotten an allocation for 2002 that he thinks is lined up to pay for this. And maybe a statement from this committee that this is not an imminent need, but it should be moved toward it as soon as feasible, but with a time line expectation that would allow people to go to Congress and say that this has now been, if you will, mandated downstream in two or three years. We need the money to flow in.

I understand, to some extent, the issues about taking several years for the DRGs to catch up and having an earmark. But a time line may be useful, both with respect to the regulatory issues that I think need to be worked out and the funding issues.

CHAIRMAN CAPLAN: Well, one thing I'm hearing you might want to say under universal leukoreduction should be implemented as soon as feasible, we might up an, A, we should strive to minimize impact on supply; B, we should make sure that, as we've said in the past, appropriate funding goes with such mandates; and, C, the FDA should be encouraged to develop a reasonable set of guidelines to implement universal leukoreduction because that's what you're talking about. You're just trying to get them to do it in a way that's attainable and safe or something like that.

But we could run three, I might suggest, although the powerful committee chair and the powerful executive secretary are somewhat modestly trying to hold back here, but we might suggest something, we should strive to minimize the impact on supply; as in the past, the committee has indicated we want to see funding follow attempts to improve the safety of the blood supply; and that we want FDA to implement a practical set of regulations for universal leukocyte reduction because that's what your--

DR. NIGHTINGALE: Dr. Caplan, I'm speaking purely as a bureaucrat here and not in an attempt to influence the policy, but the committee could make more than one recommendation.

CHAIRMAN CAPLAN: Maybe we'll try it FDA should proceed to implement a practical set of guidelines for ULR--to implement--to construct, I mean.

DR. NIGHTINGALE: Are you amending a resolution that's on the--

CHAIRMAN CAPLAN: I'm just putting up some possible language.

DR. NIGHTINGALE: I'm asking the chair do we have a motion that has been moved and seconded on the floor? A lot of people are going to be looking at this transcript, and I'm just asking--

CHAIRMAN CAPLAN: No, no. I'm just putting on some language here that we might want to add either Recommendation 2, 3, 4. Just think about it. If anyone wants to move it, you can move it.

Ron?

DR. GILCHER: The comment that I want to make is addressed to Dr. Epstein, and that is the issue of selective versus universal. For many blood centers, we already have gone to a universal leukoreduction within our particular areas. And I think that the draft guidance document must clearly, when it's accepted, specifically be for universal leukoreduction because it really applies to all leuko-reduced units, and many of us have already achieved that.

DR. EPSTEIN: Well, again, I think that the guidance, because it only addresses the product standard and, of course, the licensing process, is neutral to whether it is or is not universal at a particular center or nationally. It's simply a product standard. And, again, I would emphasize that this is the draft guidance. It's a proposal. It's not intended for implementation at this time and is subject to comment. And I thank Mike for his trust that we will try to do something rational in the end.

DR. GILCHER: But the point that I'm trying to make, Jay, is that if one looks at the guidance document from the standpoint that it would address selective leukoreduction, as opposed to universal, we could end up with it being very restrictive and with a lot of constraints in it that would, in fact, hamper the process. I think you've alluded to the fact that you do want the comments so that it will not be so restrictive that it would hamper the process. That's what I'm driving at.

CHAIRMAN CAPLAN: Well, I have a suggestion about how to proceed at this point. We do have a motion on the floor, it's been seconded, and we've discussed whether we want to make the recommendation that universal leukoreduction should be implemented as soon as feasible. We might then move on to what are now up there as A, B, C and just make some other recommendations. But how about we move the question?

DR. DAVEY: Mr. Chairman, I'd like to make a comment on this. I think this is a key vote for us right now; that is, whether to move to universal leukoreduction or not. And so this is the crux of what we've been talking about for the last couple of days.

I have a couple of comments on my own I've jotted down. This is an extremely difficult decision, at least for me. I think that the group that was brought together yesterday presented their issues very clearly, in the most clear manner for the committee to consider. I think the arguments for voting yes for this are powerful. I think the strongest one is that we're not going to make mistakes. Dr. Ness said that, Karen has seconded that. That's very important. I think Jay's argument about the precautionary principle has to be taken seriously, single inventory reduction, CMV testing, they're all positives for doing this.

But I think there's also some very strong arguments to not vote for this at this point. I can't escape the importance of doing the critical research that we need to do to really learn about the immunomodulatory effect. I think we know it's there, there's evidences there, but we don't have the answers. If we vote this, at this point, research in this areas will essentially be moot because it will have no impact on whether or not we adopt a national strategy or not, and I don't think the research will be carried out that we need to know. So I'd hate to put a damper on the necessary research we need to know.

I would suggest that the NIH or others pull together a task force to clarify the research that needs to be done, and needs to be done quickly, and fund it.

Secondly, about the issue of mistakes. Right now people who need the material pretty much get it. I think, also, it's important not to make the analogy to what we've done with plasma. Issues on plasma safety affect all recipients equally. Right now the people who need this product essentially get it. And while mistakes do occur, I was encouraged by what I heard about the Trapp study--the Seattle representative mentioned it--that people who did get the wrong material seemed to do just fine, in terms of their comparability to those that did get the right material in that particular study. So I do think that, while those mistakes happen and are of concern, they are mistakes of process, as Dr. Vamvakas pointed out and not particularly of product.

So I kind of feel right now that we should allow hospitals to make these decisions on blood safety based on, in this particular issue, based on their clinical judgment and on their available resources. It might be the right thing for a specific hospital, group of professionals, Transfusion Committee, whoever, to decide that the best use of their resources is to hire a new technologist or to implement a bar code system and not 100-percent ULR, while another hospital, like Johns Hopkins, feels that, no, let's do the 100-percent leukoreduction. It's their option. It's their option now, and it could be their option tomorrow. We're not restricting anybody from going to 100-percent ULR. It's just that I think we should leave the option open for some hospitals to decide otherwise. Cost is important. Hospitals have to make decisions on cost every day about everything they do, and it certainly applies to this issue right here.

This issue has been around for 30 years. It's not HIV, it's not HAV, it's not a new scourge to the blood supply, it's a concern we've been looking at. I don't think we've learned a lot new today that we didn't know six months or a year ago. I think we can learn more in the future. Data has been accumulating, and we know it benefits certain patients. We need to know how it benefits others and if it benefits others. Deciding on this today will preclude that information, I believe.

So I think I believe, at this point, that the adoption of ULR at a specific hospital remains within the purview of the practice of medicine. I think we're not quite there to mandate this for everybody in every circumstance. We've got to encourage necessary research. I think we need to do it to get the remaining questions lined up, and then review this situation again.

So I can't support this resolution, as it stands.

CHAIRMAN CAPLAN: Do you want to move the question?

DR. PENNER: Call the question.

CHAIRMAN CAPLAN: All in favor of the Penner motion, universal leukocyte reduction should be implemented as soon as feasible, indicate aye, in favor, hands up high. Hold them up high.

[Show of hands.]

DR. NIGHTINGALE: Ten vote yes.

CHAIRMAN CAPLAN: Opposed?

[Show of hands.]

DR. NIGHTINGALE: Ten for, three against, and I have two abstentions.

CHAIRMAN CAPLAN: So that motion passes.

The floor is open for other motions. And let me say, by the way, Stephen and I talked. We do have something I personally consider very important, equally important, in fact, to leukocyte reduction, which is efforts to monitor what the blood supply is so we can know what the impacts of things are on supply, but we'll do that in April. We absolutely will come back to whether or not that's what we need to do to make sure we have numbers and understand what's going on out there in a reliable way.

So having said that, other motions/recommendations?

Larry?

MR. ALLEN: This isn't a recommendation, but along the lines of what Dr. Davey was mentioning, what we're doing this is a recommendation. This is not a mandate, my understanding. And any mandate will come through the FDA, rather.

DR. NIGHTINGALE: I am delighted to have the opportunity to clarify and confirm Mr. Allen's query. This is an Advisory Committee. The mandate of this Advisory Committee is to advise. The charter of the committee is that we advise the secretary and the assistant secretary of Health. Those are the wordings in that charter. It is the mandate of the secretary and the assistant secretary of Health, the latter of whom has not yet been named, to take such action as they wish on this matter.

CHAIRMAN CAPLAN: John?

DR. PENNER: A second proposal then to include some of the things that were brought up. I don't know if you want to propose it.

With regard to the universal leukoreduction, the committee would recommend, also, that A, B and C.

CHAIRMAN CAPLAN: As they're sort of up there, with some wordsmithing?

DR. PENNER: Yes.

CHAIRMAN CAPLAN: Second to a, you seem to have all said it--okay.

DR. HOOTS: Second.

MR. WALSH: Second.

CHAIRMAN CAPLAN: Okay. Mr. Walsh, Dr. Hoots second.

Second Penner motion, strive to minimize the impact on supply. The committee recommends that with respect to universal leukocyte reduction, should strive to minimize the impact on supply. We'll get the subject of that sentence right. Funding should follow for the following. And we're looking for FDA should proceed to implement a practical guidance for ULR, I suspect something like that language.

Okay. Discussion?

DR. BUSCH: Just to try to put some teeth into this. One issue would I think be that the committee would like to be briefed on the success of these efforts over time. I was wondering whether there would be an appropriate recommendation for some kind of, you know, assigning the authority to track these three items to the Blood Safety Committee or somehow define who's responsible for trying to follow up on these critical issues.

DR. PENNER: I'd accept that addition.

DR. NIGHTINGALE: Dr. Busch, I was typing when you were talking. Could you repeat that for me.

DR. BUSCH: I was just trying to get some additional clarification as to who--the actions of government should strive to--and who should be responsible for assuring that there is focused attention on these issues? Some activity, perhaps, of the Blood Safety Committee or that there be established a committee of DHS to--

DR. NIGHTINGALE: Yes. And I think there, of course, as, Mike, as you know the answer to that question is not a simple one, and as you also know, with an incoming administration, there may be some reorganization of effort. That was why I chose to put the word "government." But, in fact, probably a more appropriate word, given the nature of our charter, would be department, rather than government. Is that okay, Dr. Penner? Can I use "department," rather than "government"? Or Department of Health and Human Services--DHHS?

CHAIRMAN CAPLAN: In that spirit, Steve, can we ask that, as a fourth, minimize impact on supply, assure adequate funding for this effort, FDA should proceed to implement a guidance?

DR. NIGHTINGALE: Let me ask Dr. Epstein if it would be appropriate here to suggest proceed with regulation? We're making recommendations to the secretary here. We don't advise the FDA. The secretary advises the FDA, and I cannot overemphasize the importance of that point.

DR. EPSTEIN: I think it would be helpful if there were a clear statement advising the FDA to proceed with the regulation. I think it's moot to advise us to proceed with a guidance because we've shown you we're doing that.

DR. NIGHTINGALE: I agree.

CHAIRMAN CAPLAN: And then Mike Busch is asking for is that we ask for some report back to the committee by appropriate agencies about implementation.

MR. WALSH: And not to complicate the funding issue, I think that we need to ask the secretary, recommend that the secretary appoint an ex officio representative of HCFA to participate on this committee. I mean, we need to engage in an ongoing dialogue with HCFA to address these reimbursement issues. Because although we don't have a national health system, you know, where HCFA goes, the majority of third-party payers go, and at least give consumers a foothold or some leverage to negotiate for a proper reimbursement.

CHAIRMAN CAPLAN: The chair would suggest that we might separate that.

MR. WALSH: No objection. Under new business.

DR. BUSCH: I just think that third issue on the FDA proceeding to implement regulations has lost the flavor of what the original intent was, which was that these regulations be balanced to not adversely affect availability in excess of QC. I think there are a lot of concerns with the current draft document that the tone, and the tone of all of these, is to really be careful as we proceed.

CHAIRMAN CAPLAN: Do you like language such as practical and sensible regulation? I mean, I'm looking for something that isn't--

DR. NIGHTINGALE: That, Dr. Caplan, is a precedent.

CHAIRMAN CAPLAN: I don't want to say that they've never done this before and that we're pioneering new terrain, but--

[Laughter.]

MS. LIPTON: I think Mike is right, that really what I was thinking of was making sure that any regulation that comes out is going to balance all of these. So I'd like to see it amended the way Mike talked about it. And practical and sensible is fine. Jay is always practical and sensible.

CHAIRMAN CAPLAN: Sometimes. There's another way to do this, which Steve will like because he won't have to type it so quickly, we might have, for the record, a little wordsmithing after we're done that says the committee is very sensitive to the fragility of the blood supply as it addresses leukocyte reduction, something like that, and wants its regulatory--what it's trying to achieve here has to be sensitive to that, the fragile nature of that enterprise.

DR. NIGHTINGALE: Yes. I think one of the few things that I am comfortable guaranteeing about the incoming administration, which I have not met, is that they will retain the sensitivity of their predecessors towards the fragility of the blood supply. Because if they don't, I won't be around.

CHAIRMAN CAPLAN: That's an easy sentence to preface. In particular here, I understand what people are fishing for, in terms of how regulation unfolds, I think.

Keith?

DR. HOOTS: I was just going to make sure we put those clarifying terms in.

DR. NIGHTINGALE: Give me--if we're still--you seconded, Dr. Hoots, so tell me what to type.

DR. BUSCH: I think we've heard two things, and I agree with Art's comment that I would like to see the proviso there, in regard to universal leukoreduction, the Advisory Committee is concerned about the potential impact on availability and resources, and therefore recommends--about the impact of ULR on the availability of blood and resources to support this, and therefore recommends--

MS. LIPTON: My only last concern, too, and we don't have to put it in, but with availability, I mean, there was some significant discussion about African Americans and a concern about minority--availability for minority populations. We talk about this whole sickle cell issue. We don't have it anywhere specifically in there, but maybe we could say availability particularly for minority populations.

CHAIRMAN CAPLAN: I've got that for the record. We'll go back and add that in.

Are we almost ready for--

DR. NIGHTINGALE: Does the wording on the screen accurately reflect the motion of Dr. Penner that was seconded by Dr. Hoots?

DR. HOOTS: I think Dr. Penner took the friendly amendment from Dr. Busch about the clarifications under issue regulations--the tenor of the types of regulations, which Jay has already said they will obviously do, but we just, the whole idea is not to just tell them to do what they automatically do, but to say that the regulations are going to have a--how the regulations are written are going to have an impact on this whole issue.

DR. NIGHTINGALE: Is that good? Okay.

CHAIRMAN CAPLAN: I'm starting to think we might want to move this motion along.

DR. PILIAVIN: Call the question.

CHAIRMAN CAPLAN: All right. On the Penner proposal, as up on the--it's being edited as we speak--in that language, exactly as it is, just a snapshot in time, without my reading it, all in favor?

[Show of hands.]

DR. NIGHTINGALE: I think we have 14 votes.

CHAIRMAN CAPLAN: Opposed or abstained?

[No response.]

DR. NIGHTINGALE: The motion is approved; 14 in favor, none against. The chair does not vote except to break a tie.

CHAIRMAN CAPLAN: Any other motions?

MR. WALSH: I move that the Advisory Committee recommend that the secretary appoint a representative of HCFA to serve as an ex officio member of this committee.

DR. HAAS: Second.

DR. NIGHTINGALE: I'm sorry. I did not see the second. Dr. Haas, thank you.

CHAIRMAN CAPLAN: Discussion?

[No response.]

CHAIRMAN CAPLAN: Very interesting.

All in favor?

[Show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: That was a little Bulgarian Communist Party moment there.

Other motions?

[No response.]

CHAIRMAN CAPLAN: Just in terms of I will keep the floor open for other motions or things people want to think about with respect to universal leukoreduction. But while you're thinking, if there's anything else you want to say or put out there, I do want to say, first of all, I thought the presentations and the discussions were really remarkably on point. That was a tough issue to wrestle with. And I think it would be a mistake, and I hope that we might want to consider encouraging continued research.

We've been told a few times that research may die under a mandate, and I'm not sure that that has to happen if we at least flag that we would like research to go on in this area because it will take a while to implement this. So I wouldn't expect this to be done, the United States to be in universal leukoreduction by Monday morning. I think it will take a while. There still should be studies, and then obviously there's obviously evaluation that can come afterwards. So that's something to think about.

The other thing I was going to ask the secretary, as long as we're pondering other things we might say, do we want to remind them of when the next meeting is?

DR. NIGHTINGALE: The next meeting of the Advisory Committee will be Thursday, April 26th. And I am going to check on a calendar that I have brought for just such a purpose. Those of you who have Palm Pilots might beat me to the calendar. Thursday, April 26th, and Friday, April 27th, are the dates scheduled for the next meeting.

The August meeting is scheduled for Thursday, August the 23rd, and Friday, August the 24th, of 2001. We do have signed contracts with this hotel to hold meetings here on those dates. We are currently negotiating with this hotel for meeting dates in the year 2002. We are also mindful of potential conflicts in January of 2002 that we will strive to, and in April of 2002, that we will strive to avoid before we announce the dates for the 2002 meeting. The committee is chartered through September 30th of 2002.

CHAIRMAN CAPLAN: And at our next meeting we are certainly going to get to this question of is there adequate means to collect information on supply? The chair is very concerned that we take a look at this since much of what we talk about has to do with supply, impact on supply, what we can do to increase supply, shortage, and yet I'm not persuaded personally that we have adequate data.

DR. NIGHTINGALE: I had added at what was close to the last minute an agenda item for today, that what, in brief, was intended to do was solicit public input into the questions of, A, whether and, B, how the government should act to monitor the blood supply of the United States. This is a complex technical question. I do not think, at this point, after this very productive, but at least for me, very exhausting meeting, that this is the appropriate time to solicit that. However, I will be at work on Monday morning. My telephone number is 202-690-5558. And I am putting that in the record because I solicit input from all interested parties on the committee and of the public at large in how best the government can do this. We would appreciate your input very much, and this will be a scheduled agenda item in April, pending approval by the incoming secretary or designee for Blood Safety director.

MR. ALLEN: Based on the statement that Dr. Lipton made, I'd like to just put on the record that we revisit this issue about the deferral, so people with sickle cell trait, we can get back to them.

DR. NIGHTINGALE: Absolutely.

MR. ALLEN: Also, maybe get in touch with some of the manufacturers and see if we can work out this issue or if they're working on the issue of the filter problem.

DR. NIGHTINGALE: Absolutely.

CHAIRMAN CAPLAN: Mike?

DR. BUSCH: Yes, Steve, as you're well aware, there's been a lot of interest and activity related to international blood safety. And there's been discussion amongst a sort of working group that this committee would be an excellent forum to have a meeting dedicated to a review of the problems with respect to international blood safety and the need and opportunities for collaborative U.S.-International both service and research activities.

And I'd like to ask whether it's possible to schedule one of the next several meetings on this topic.

DR. NIGHTINGALE: I thank Dr. Busch for bringing up that comment. I would state for the record that, in fact, there have been discussions in which I have participated about the feasibility of having that be the agenda item at the next meeting.

As I've indicated, I will propose precisely that to the incoming secretary or designee when that person takes office for Dr. Satcher on February the 1st. My only reservation is that if I speak for that person, it is quite likely that someone else will be speaking for him or her on April the 26th.

CHAIRMAN CAPLAN: The chair has been urging that we get to the international issues, too. So I think we'll definitely try to get that on our agenda, if not April, then after. It just seems to have a coordination there.

The chair should note that he, personally, is available to go to Paris to monitor the data reports coming out in July.

[Laughter.]

DR. NIGHTINGALE: So is the executive secretary.

DR. HOOTS: Just this is way off in left field, except that I think it's relevant to something that particularly Rick was just saying about ongoing research.

Perhaps in the context of that whole international thing, there's been a real debate of late about interpretation of the Helsinki accords with relation to ongoing research that is or isn't ethical outside of countries that have established standards of care. And one of the things I think I would be disturbed is if our actions today were immediately assumed to be standard of care because it's a recommendation, and therefore were to preempt research possibilities by U.S. investigators outside the U.S. for these very important questions.

So I would just like that to be an agenda item maybe for discussion during that international thing.

DR. NIGHTINGALE: And not a recommendation at this meeting?

DR. HOOTS: I would entertain--but I just didn't want to go too far off in another direction. But I would entertain it as a recommendation, if somebody wanted to second it.

DR. NIGHTINGALE: You're the recommenders here.

DR. DAVEY: I'll second that, Keith. I support it.

DR. PILIAVIN: Could you rephrase it.

DR. DAVEY: I do have concern about--well, we can rephrase it something like the committee--

DR. PILIAVIN: I mean just state it again.

DR. DAVEY: The committee supports continued research in this area, as appropriate. Something like that.

I do have concerns, as I mentioned earlier, that this may contribute to the restriction of research, but let's do what we can to encourage it. So I would certainly support a motion something along those lines, Keith.

CHAIRMAN CAPLAN: So there's a motion, which I'm not sure Dr. Hoots articulated, but he made it. And then it was seconded and somewhat expanded upon by Rick Davey.

So we've got the Advisory Committee supports continuing research with respect to universal leukoreduction, both here and overseas.

DR. DAVEY: Leave that last phrase off.

CHAIRMAN CAPLAN: What?

DR. DAVEY: I don't think we need that last phrase, personally.

CHAIRMAN CAPLAN: Oh, just continuing research? Okay.

DR. BUSCH: This is a difficult issue, and I don't know the answer. I know we just submitted a grant that was going to continue to follow this phenomenon of micro chimerism. And we had to recognize and had criticisms in the review that, you know, how can you do this research post-universal leukoreduction?

Could you actually randomize patients, after this policy becomes effective, to nonleuko-reduced blood in this country? And if the answer to that is no, can you honestly go to another country that doesn't do universal leukoreduction and do research that would address the pros and cons of this procedure?

I mean, de facto we make these policies, and we preclude ethical considerations of these--

CHAIRMAN CAPLAN: Part of the answer just to that is we can do research elsewhere when the background risk profile is different. But what I wanted to do for now is to encourage research because even though we're moving toward or I gather our recommendations are that we move toward universal leukoreduction, consistent with keeping the blood supply intact and not being burdensome, it's going to take a while, and we want research to continue now, even though we've made this recommendation. There will be study areas where this is possible to do over the next couple of years, I imagine.

DR. NIGHTINGALE: Even though the--

CHAIRMAN CAPLAN: Here.

DR. NIGHTINGALE: --hour is late, I must, as the executive secretary of the committee, make a comment about conflict of interest.

This is yet another example, I believe, of the chemist that I have been telling you about for the last 12 meetings. There is a proposal by individuals that would affect many people around the table, including the executive secretary, who spent much of his life in academic medicine, to support research in an area.

I see this agenda item that has come up as a matter of general applicability. And I wish to state it for the record that that decision, while it was made on the fly, that it was made in public, and I will finally state that I not only encourage, but beg all of you to continue to keep the notions of conflict of interest and fairness at open public meetings foremost in your mind.

And I also encourage members of the public who might feel differently from the on the fly or considered views of the executive secretary to make their views known in public. The executive secretary's feelings will not be hurt if you do.

Thank you.

CHAIRMAN CAPLAN: Any further comment on the Hoots' motion?

DR. BUSCH: I would wonder, and I'm sure this won't fly, but if we preface this with something to the effect of given the modest safety benefits of universal leukoreduction, the Advisory Committee supports--

DR. NIGHTINGALE: Would--given the continuing controversy in the field?

DR. BUSCH: Over the safety benefits, over the efficacy. I mean, it's really, you know, the reason the ethical issues--

DR. NIGHTINGALE: Well--I'm sorry.

DR. BUSCH: The reason the ethical issues will come up, I mean, you present this to an IRB committee, they're not going to get into all of these nuances. The issue is, is there a significant adverse effect that would preclude a reasonable person from using nonleuko-reduced blood?

DR. HOOTS: And that's exactly why I wanted to propose that discussion because I think that is very important, and there clearly are times where, according to Helsinki, it is inappropriate. I, personally, don't think this is one of those times, and that's the reason I proposed that.

DR. NIGHTINGALE: Dr. Hoots, I'm using a formula here, but there's a reason for it, does the language that is currently on the screen accurately reflect the proposal that you have made and Dr. Davey has seconded?

DR. HOOTS: Yes.

DR. NIGHTINGALE: Dr. Davey?

DR. DAVEY: Yes, I have no real problem, Steve. I wonder whether instead of controversy, though, we might want to say continuing uncertainty or something like that. Let me think about it. Controversy implies, you know, controversy. I think there are questions out there that need to be answered.

DR. PENNER: How about continued need for information in the field?

DR. HOOTS: Continued unresolved scientific issues?

DR. NIGHTINGALE: Or better still, bear with me, folks--

DR. EPSTEIN: Steve, what about continuing scientific debate?

DR. NIGHTINGALE: Just unresolved scientific issues?

CHAIRMAN CAPLAN: And then we'll go to Ed.

Well, that sounds a little consensus-like to me. So maybe I hear someone moving this question along.

DR. HOOTS: I think I move the question.

CHAIRMAN CAPLAN: All in favor of the Hoots' proposal?

[Show of hands.]

DR. NIGHTINGALE: I see 14 hands up.

CHAIRMAN CAPLAN: Opposed?

DR. NIGHTINGALE: I see no hands up.

CHAIRMAN CAPLAN: Abstained? Okay. All right.

The chair wants to thank the committee for a lot of good work. If there is any new business at this time that has to be introduced, let's do that, and then we'll adjourn.

CAPT. SNYDER: It's not new business, but can we scroll back up to the top?

CHAIRMAN CAPLAN: I don't know if that's within our technological--

[Laughter.]

DR. NIGHTINGALE: How far up?

CAPT. SNYDER: The reason I'm asking is we still haven't, in this portion here, we're talking about universal leukoreduction. What do we mean? Do we mean pre-storage or do we mean post-storage?

CHAIRMAN CAPLAN: Pre.

CAPT. SNYDER: Don't we want to say that?

CHAIRMAN CAPLAN: There's a way--

DR. NIGHTINGALE: Well, let me ask this for the record. Was it implicit in the committee's previous motions that the words "universal leukoreduction" implied universal pre-storage leukoreduction?

DR. GILCHER: Yes.

DR. NIGHTINGALE: I think, for the record, look, I would appreciate a motion for this. This is a big deal. Dr. Snyder, you can't vote, but you can propose.

CAPT. SNYDER: I make a motion that we amend the first motion to read--

DR. NIGHTINGALE: Or all of the motions, I believe.

CAPT. SNYDER: All of the motions to read pre-storage universal leukoreduction.

CHAIRMAN CAPLAN: Second?

DR. BUSCH: Second. I would like to add to that cellular blood components. We got into the discussion yesterday about frozen plasma, et cetera, and I don't think, at least to my mind, there's not an indication for recommending further filtration of a cellular blood component.

DR. EPSTEIN: And to be a little bit more technically precise, nonleukocyte cellular components. Because, after all, there are DLI, and there are stem cells--

CAPT. SNYDER: Friendly amendments.

DR. NIGHTINGALE: Hold on for a minute. If I can just leave that right there because, I'm sorry, I was typing and did not get the friendly amendment.

CHAIRMAN CAPLAN: What's the phrase?

DR. BUSCH: Of nonleukocyte cellular blood components.

DR. PENNER: That's a footnote.

DR. BUSCH: As Jay pointed out, you have to preface that with nonleukocyte cellular blood components because there are specific components that do contain leukocytes.

DR. NIGHTINGALE: I'm sorry, Mike. The pointer is jiggly, and--

CHAIRMAN CAPLAN: Nonleukocyte cellular, when he gets there.

DR. NIGHTINGALE: I'm sorry.

CHAIRMAN CAPLAN: Yeah, yeah. Okay. Move the question?

All in favor?

[Show of hands.]

CHAIRMAN CAPLAN: Opposed? That's a unanimous.

Any other new business?

MR. WALSH: Just as a point into the future, I'd like, several members of the committee and I have talked about as we approach the availability and supply issues that we pay direct attention to the access issues related to reimbursement specifically. And I think that the committee needs to address, and we will develop some agenda items to be able to highlight the issues that we'd like to discuss in the future, but we feel that that needs to be put on a higher level of priority.

CHAIRMAN CAPLAN: One thing I did when I went back home yesterday is I actually pulled out our agendas. And one interesting fact about our group is we are about almost 50/50 on what might be called process versus product issues; that is to say, we spend a lot of time on, I don't say we've solved them, but we've talked a lot about issues that advance process and issues that advance product.

We are definitely heavy toward access at the beginning of the committee. We haven't been there so much later. We spent a lot of time, if you remember, originally looking at shortage and cost issues for consumers, and we've shifted more toward the product and process for getting the product, blood, lately. So it may be time to remind the executive secretary that we should take a look back at access issues that we haven't done.

But I was interested, when I was thinking about the see-saw in my own mind, to see where the agenda went. We're not too bad in terms of trying to struggle with what we can do to get more blood availability and what we can do to make sure it's safe, although we could argue about whether we should be 50/50, but we're at least at 50/50.

So we've got to get access back. We haven't been there for a while. We occasionally do ask people to come and report to us about such things, so that may be something we need to check in on because we've got a slew of recommendations and advice to the previous administration. And one way to alert the new administration to all of the wonderful things we said was to check back in with the old advice.

Any other new business?

[No response.]

CHAIRMAN CAPLAN: Thank you.

[Whereupon, at 12:07 p.m., the proceedings were adjourned.]

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