DR. BUSCH: Yes, thank you. I'm happy to be here and to share a little bit of context because my concern and reason to come to the meeting was to try to put a broader perspective to a focused deferral.

And I think we've learned in the past that focused deferrals can have consequences, and both political and safety consequences. And I just want to share a broader context to these discussions that I hope you'll consider.

There are many ways that we can sort the donor base toward improved safety, and many of these have been considered over time. And what I've tried to do on these next three slides is just summarize the kinds of donor sorts that have been considered in terms of improved safety.

We have allogeneic and autologous donors at present. For example, autologous donors, their blood is not allowed to be given to other people. There has been great controversy over the years as to the relative safety of directed donors, and you heard today about the potential increased safety of apheresis donors.

Many of these relative safety issues have actually not been recently analyzed carefully. The frequency of donors, the concept that first time donors are higher risk I think is now well established that they're probably two to three fold higher in terms of incidence of the major transfusion transmitted viral infections.

In contrast, among repeat donors, there's a kind of old saw that the more frequently a person gives, the safer. In fact, recent analyses from the REDS group has indicated that the more frequent donors are actually no safer than less frequent donors; and further, that actually apheresis donors are no safer than frequent whole blood donors.

So some of these theoretical benefits, I think, are not borne out by data. There's good data on regional risk. And for many viruses actually, you can look at the United States and look at different collection regions.

The southeast U.S. versus the midwest, for example, dramatically different: 10 to 30 fold different rates of risk incidence. Collections at mobile sites, at high schools, colleges, etc. versus other sites, urban versus rural.

There's now good data coming forward that show that there's significant relative safety to donations given in different regions. There's a major focus now on incentives. Should we be paying donors to give more frequently or are there other types of payments such as giving donors time off work?

I think Alan Williams' recent data from the REDS survey group shows that actually time off work is a significant predictor of denied risk behavior. So the kinds of characteristics that -- donation related.

Then we can go on to demographic characteristics and I'll show some -- a little bit of data from this, and I think this was distributed to the committee. But there are dramatic -- significant differences in risk, and particularly the incidence rate of new HIV and other major viral infections distributed by these demographic characteristics.

And I think Alan also showed that the British donor deferral would impact differently on different groups. Again, I'll show some specifics on this. But in general, race ethnicity -- there are some highly significant correlates. The more educated donors are, the lower the incidence.

There's risk associated with country of birth. And just to recall for you the major outcry that occurred over deferral of Haitian donors, and currently there's still in effect a deferral of sub Saharan African donors.

So just the broader context that these geographic-based deferrals have been implemented in the past. Really travel history is what we're focused on now. In the past, there remained deferrals for malaria. There have been intermittent deferrals for travel to HIV risk areas, and now the consideration of British deferrals.

Obviously medical history and behavioral history and surrogate tests are other deferral criteria. Just a little bit of data to illustrate some of these points. And we're focused here on incidence. Actually, these numbers would be much more dramatic if we talked about prevalence.

Prevalence reflects lifetime accrued exposure to an agent, but the risk of blood is predominantly due to window phase. And therefore, most of our interest in relative risk for established agents for which we screen relates to the frequency of new infections or incidence.

And what you can see actually is some examples of how these potential sorts may be beneficial for one agent and actually detrimental for another. For example, for HIV there's a higher, but not significantly higher, incidence in males than females, but there is a highly significantly increased incidence for hepatitis B in males to females.

On the other hand, both HCV and HTLV are higher incidence in female donors, probably related to secondary sexual transmission from injection drug use. So, what might seem like a safer group of donors for one virus are, in fact, a higher risk subset for another virus.

If you look at age, pretty much across the board there's a age related higher incidence rate in younger donors, but then as donors age, they are less at risk of being exposed to these agents. Now, as you're aware, the older donors tend to be the better, well off donors who can travel.

As Alan indicated, a British donor deferral would actually bias towards exclusion of older donors and result in the needed replacement with younger donors.

Education is really probably a reflection of socioeconomic status. And again, there is a lower risk of infection with better educated donors pretty much across the board. The one exception is if you focus on high school donors, you need to focus on the younger high school donors who are still high school students versus older individuals who only completed high school.

And once you do that sort, you pretty much see a consistent decline across all viruses with the higher the level of education, the lower the risk of infection with these agents. Again, this is an example where the donors who you're seeing indicate a history of prolonged travel to Britain are the better educated donors, so on offset would occur in replacing those donors.

Race/ethnicity is actually one of the most startling predictors of incidence. Just one example here, hepatitis B surface antigen with a much higher incidence in black, non-Hispanic and Hispanic donors than in Caucasian donors.

Obviously many of these deferrals are not either practical due to the need to have an adequate blood supply, or ethically or socially acceptable. There's been discussion about exclusion for transfusion. And in fact, in France they've recently implemented exclusion of previously transfused patients from giving blood.

In fact, if you look at prevalence, the prevalence of all these viruses is higher in previously transfused patients, but that's because their risk of acquiring these infections from transfusion predated the introduction of screening.

So now that we're screening the blood supply, this slide just shows from REDS again that the rate of new infections is no different in transfused and non-transfused people. So an exclusion based on history of transfusion will have no beneficial effect with respect to current agents for which we're screening.

If there's an agent that may have been transfused in the past, theoretically there could be a benefit of excluding those donors. But one must be aware that about seven to eight percent of all blood donors have been transfused in the past.

So an exclusion of transfused donors, somewhat like British donors, would have an incredible impact on blood availability with really, I think, a negligible and non-quantifiable benefit in terms of safety.

I included in the distribution a manuscript that we published a few years ago which actually focused on what was at the time a major controversy. The age deferral issue came up because donors, particularly whole blood sector donors, were later developing classical CJD.

Those reports were coming to FDA, and FDA was taking the position that these products needed to be recalled and/or not distributed, and it was having a huge impact on the availability and financial issues around blood banking.

So what it led to was a sort of knee jerk reaction, well let's just exclude older donors because most of these CJD cases are occurring in older donors. And what we were able to show in this paper and pretty much undermine that policy was that actually the exclusion of the older donors would result in an increased risk; that donors over 50 had a two to tenfold higher incidence, higher risk than younger donors.

And that, as a consequence, if one were to exclude all donors either under 50 or under 60, you would increase the risk of the blood supply for these known transmissible agents by ten to 20 percent. And I think this was a significant factor in the decision by the blood organizations to not implement this policy and by FDA to eventually reverse that recall policy.

Now, the last point I want to make is that -- is alluding to the impact on donors. And I think until very recently, we've not had data to quantify what notifications to donors that they're deferred indefinitely or permanently on the grounds of non-specific test results or deferral policies has on these individuals.

And recently, the REDS group conducted a survey called the REDS Donor Notification Survey where about 4,000 donors who had been deferred due to test results, various ALT, anti-CORE, false/positive results for various markers were surveyed and asked about the impact of these notifications -- the effectiveness of the notification message and the impact.

And just a few selected results, I think, illustrate that a large proportion of these donors who were being given data that we think is pretty definitive -- we're convinced these donors are not infected.

We've done extensive testing and further testing, and many of these donors are brought up for follow up, additional testing. And they're basically being given a message that you're not infected with this virus, but unfortunately you had some results that are leading us to have to permanently defer you.

And what you can see here is that about 80 percent of these donors, equally split between a lot and a little, indicate confusion when they're initially notified of these results. And the survey actually was conducted in general about five, seven years after the notifications.

And you can see that many of these donors remain confused years later. Again, there's -- about 50 percent of these donors are indicating they're still confused about the meaning of those original notification results, although most of them now are a little less confused over time.

They also indicate a high level of anxiety with about 40 to 50 percent of these donors indicating that they were very, very emotionally upset when they were told of these results, and another 40 to 50 percent -- 40 percent or so indicating they were somewhat upset.

As with the earlier data, when you ask these donors are they still emotionally upset, this number drops to about half of that level. But many of these donors remain concerned and upset and confused about the meaning of these permanent deferral messages in the absence of any mechanism to reinstate them.

And finally, many of these donors, even though again our message was one of reassurance, have subsequently sought doctors' advice on what to do about this. And unfortunately, in the case of new variant CJD, I don't think we'll be able to give doctors much advice other than trying to reassure these donors.

Coincidentally, I just received a couple letters that I distributed to the committee during the break that are actually from donors that just wrote to my CEO just in the last day.

And I'd ask you to glance at those letters because I think they really point out the intense, you know, emotional experience that individuals go through when they are told they can no longer give blood, many of them after having, you know, became dedicated donors and feeling that a good, you know, meaningful component of their lives had been giving blood.

And the impact of these false notifications on these donors and the failure of a mechanism to allow these donors to be reinstated and appropriately reassured that their own health and that of their families is not at risk I think is an important consideration as you consider a policy that would impact a very large number of individuals.

Thank you.

CHAIRMAN BROWN: Thank you, Dr. Busch.

I have a question or two for you before you leave. I would imagine that if a statement were crafted that was a little less blunt, it might take some of the emotional backlash out of this.

In other words, instead of sending a note saying "sorry about that, but you're permanently deferred, you'll never be able to give blood again" -- which is unrealistic in the present context. If it were decided to exclude a proportion of British donors, one could send a note saying "you are temporarily excluded from giving blood for the following reason," and put a little paragraph in there why the position was taken.

It's not complicated, complicated. Until such time as we know that this doesn't pose a risk, then we will exclude you, but we will not exclude you permanently. The same thing, I am sure, is going to happen with the screening questions that currently exclude recipients of growth hormone and dura mater recipients.

These are not going to be permanent categories of exclusion. That's the first point.

And the second is that -- did I understand you correctly at the beginning of your speech to say that the data indicates that there is no difference in the risk of having any of these other transfusion related agents between professional donors, volunteer donors, apheresis donors, first time donors and multiple repeat donors?

Did I understand that correctly or did I miss a beat?

DR. BUSCH: Why don't I do the second one first. Yeah, no, there is a quantifiable, increased risk among first time compared to repeat donors. But within the repeat, volunteer donor sector -- so these are the volunteer donors -- although classically people always felt that the more frequently you give, the safer you are and that apheresis donors who are giving weekly, this kind of special, more committee donation program, are safer than whole blood donors, as we've begun to do analyses in the REDS group with huge databases to try to quantify and validate that, we've been unable to validate that.

There does not appear to be an increasing safety margin as donors give more frequently. This is all data from the volunteer donor sector.

CHAIRMAN BROWN: So, in other words, if you've given twice, beyond that it's a plateau?

DR. BUSCH: That's correct, --

CHAIRMAN BROWN: Okay.

DR. BUSCH: -- that's what our data indicates.

In terms of the first issue, you know, the concern -- from a blood bank operational perspective, that's pretty much what we used to do. We used to tell donors you're, you know, temporarily deferred; that there's a potential that we'll be able to reinstate you down the road.

What that results in is donors frequently calling back and saying "what's happened, where do I stand with this." Eventually, you know, the FDA has in the past come forward with reinstatement programs that allow for donors to go through follow up testing a year later, for example, that allows them to be reinstated.

In fact, those programs pretty much universally across the country are not operationalized, one, because they're frequently reversed as new tests come in and new questions arise. They're quite onerous in terms of the required testing.

But in addition, they're a regulatory catastrophe. Because if, by chance, eventually a donor who was reinstated gets implicated in another problem, immediately, you know, the FDA comes into your office and the first thing they look for is where's your donor reinstatement records.

And they want to go through those records and verify that those donors were completely, properly reinstated. So, for a variety of reasons, the truth is that donor reinstatement does not occur in this country, with very rare exceptions.

And this is even for agents for which there are FDA approved reinstatement programs. So for these reasons, practically at this point -- and, you know, what's the difference between an indefinite deferral, a temporary deferral?

These are very subtle and often non-defined distinctions. So at present, even though you can frame it just as you indicated, and we probably would, practically that's why I asked the question earlier.

You know, how long will we need to wait until people are convinced that this is not a problem and we can reverse this policy? And what I heard was, you know, it's probably five or ten years before we'd have a sense.

So, you know, do you want to tell people, you know, call back in a year or two? So I think practically this will be -- you know, unless there is some position of this committee that this should be a two year, you know, revisited, I think it would be inappropriate for the blood banks to communicate to the donors that this is a temporary deferral.

CHAIRMAN BROWN: Yeah, I understand that point of view. At least this is not complicated by the necessity of retesting. I mean, that's at least one thing we don't have to worry about.

DR. BUSCH: It could be viewed as a good or a bad issue. I mean, --

CHAIRMAN BROWN: Both, both. From the point of view of basic science, bad. From the point of view of practicality, good.

The final scheduled -- I'm sorry, is there a question?

Bob.

DR. SCHONBERGER: Mike, I'd like to come back to this question of deferring for history of prior use of blood products, which, as you know, is one of -- I feel is one of the best things you could put in place for building a fire wall between us and the expansion of any inapparent infection that might be occurring through blood and blood products via TSE agents.

And this number that you come up with of seven or eight percent, what I'm having difficulty with this is making that -- it seems to conflict with the experience of Marian Sullivan and trying to do look back studies where it seems like a much larger percentage than that of people who have received transfusions at least have died already by five years or so in the look back.

And presumably, if the people who survived transfusion are such a small cohort, a lot of them aren't going to be healthy enough to give blood anyway. And is that really a realistic number, or could it be smaller than that?

DR. BUSCH: I think that number is definitely accurate. You know, it's coming from -- we're required to ask donors have you been transfused in the past. So this is a required question of blood donors, and these are compiled, actual reports from blood donors.

I think the issue is -- you're right, you know, half of blood goes into patients who die, but actually only a small fraction of transfused patients die, probably 20 percent. And the distinction is, is that the patients who are dying get a heck of a lot of the blood.

So very ill patients consume a lot of blood. Eighty-percent or so of people who are transfused survive, and those people probably -- many of them, fortunately, currently become dedicated donors because they've benefitted from the transfusion process.

But the number of 78 percent I'm certain is correct.

DR. SCHONBERGER: Well, what if you excluded albumin?

DR. BUSCH: That's not included in that.

DR. SCHONBERGER: That's not included?

DR. BUSCH: No.

DR. SCHONBERGER: Okay.

CHAIRMAN BROWN: Questions from the floor?

DR. TABOR: Well, the question about history of transfusion is the one that predates the availability of most of the serologic tests we have, and it's clearly one that, sometime in the future, could be reexamined.

It's certainly been well documented that most people, for instance, of those very rare cases of individuals whose blood transmit hepatitis B, they've almost never had a history of transfusions themselves. So that question is -- that we ask donors is an anachronism and probably is an anachronism with regard to new agents also.

I'd like to also make a comment regarding the use of the term British donors. We're not talking about British donors. We're talking about red blooded, American donors who happened to have had enough money to go to England or to have been sent there by the military.

Where possible, I think we should not refer to them as British donors because that adds a level of connotation that we're excluding something alien. And we're talking about American blood donors who are going to be impacted by what we decide, and it's the American blood supply is going to impacted.

CHAIRMAN BROWN: For the record, that was Dr. Tabor from FDA.

So the transcript is hereby directed to strike out every use of the phrase British donor, which is, in fact, incorrect; and these obviously are American donors who have visited or lived in Britain.

Although I suppose British donors would still be included, wouldn't they?

(Laughter.)

CHAIRMAN BROWN: We haven't addressed that.

Larry.

DR. SCHONBERGER: I'd like to suggest to the Captain -- I guess it was Captain Gregory that presented to us where -- Rutherford, was it?

CHAIRMAN BROWN: Captain Rutherford.

DR. SCHONBERGER: Rutherford.

CHAIRMAN BROWN: Close.

DR. SCHONBERGER: Okay, sorry about that. Bruce Rutherford.

That when he talks of 55 years of data, you know, where there's been no cases and so on, that it would be more impressive if the military could institute or present sort of a more epidemiologically oriented study.

I would think that they are particularly uniquely suited to potentially get good data on the new variant CJD issues particularly, and they still would have time to set something like that up, since much of the exposure of the U.S. citizens to Europe, I would think, may well be military people who were assigned there during the '80s and so on.

Perhaps the military could identify these people. And certainly the Centers for Disease Control would be happy to help continue the follow up of such individuals if they would want to institute that.

It just struck me when we're talking about all these years of not hearing about things, when, in fact, we search often to look for tighter epidemiologic type of studies, and I would encourage that that be discussed.

CHAIRMAN BROWN: Yeah, I don't know we need to discuss it now.

But Captain Rutherford, you've got an offer for help if you -- from the CDC if you'd like to -- and I think Larry's right. You have an unusual opportunity, in fact, to assess this problem in the near future and CDC is a good colleague to have.

The final scheduled presentation is Dr. Richard Davey, who is the Chief Medical Officer for the American Red Cross.