Blood Safety Transcripts

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

Seventh Meeting
9:11 a.m.
Thursday, January 28, 1999
Crowne Plaza Hotel
14th and K Streets, N.W.
Washington, D.C. 20005

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

Members
Arthur Caplan, Ph.D.
Stephen D. Nightingale, M.D., Executive Secretary
Larry Allen
James P. AuBuchon, M.D.
Michael P. Busch, M.D., Ph.D.
Edward D. Gomperts, M.D.
Fernando Guerra, M.D.
William Hoots, M.D.
Carolyn D. Jones, J.D., M.P.H.
Dana Kuhn, Ph.D.
Tricia O'Connor
John Penner, M.D.
Jane A. Piliavin, Ph.D.
Eugene R. Schiff, M.D.
Marian Gray Secundy, Ph.D.
John Walsh
Consultants
Richard J. Davey, M.D.
Ex Officio Members
Mary E. Chamberland, M.D.
David Feigal, M.D.
Paul R. McCurdy, M.D.
CAPT Bruce Rutherford, MSC, USN
David Snyder, R.Ph., D.D.S.
Also Present
Dr. Jay Epstein, FDA
Dr. Eric Goosby, DHHS
CAPT Lawrence McMurtry, DHHS

C O N T E N T S

AGENDA ITEM PAGE

Call to Order; Conflict of Interest 4

Opening Remarks by Chairman 8

Centers for Disease Control Program for the Prevention and Control of Hepatitis C

Infection

- Harold Margolis, M.D., CDC, Atlanta 10

Predictive power of the Reactive

[Signal to Cutoff] Ratio of the EIA-1

Screening Test for Hepatitis C Infection

- Michael Busch, M.D., Ph.D., ACBSA and

Blood Centers of the Pacific,

San Francisco 39

Use of Alternative Confirmatory Tests

for Hepatitis C Infection

- Susan Galel, M.D., Stanford University,

Palo Alto 86

Public Comment 112

Lunch 140

Consideration of Questions for the Advisory Committee 140

Old/New Business 243

Adjournment 263

P R O C E E D I N G S

DR. NIGHTINGALE: For the record, it is ten minutes after 9:00. Good morning and welcome to the seventh meeting of the Advisory Committee on Blood Safety and Availability. My name is Dr. Stephen Nightingale. I'm the Executive Secretary of the committee, and while you all are taking your places and concluding your conversations, I will read the conflict of interest statement that is a legal requirement for entering into the record at these meetings.

The following announcement is made as part of the public record to preclude even the appearance of a conflict of interest at this meeting. General applicability has been approved for all committee members. This means that unless a particular matter is brought before this committee that deals with a specific product or firm, it has been determined that all interests reported by the committee members present no potential conflict of interest when evaluated against this agenda.

In particular, as specified in Title XVIII of the U.S. Code, Chapter 208(b)(2), a special government employee, which all committee members are, may participate in the matter of general applicability, for example, advising the government about its policies relating to the hepatitis C epidemic, even if they are presently employed or have the prospect of being employed by an entity, including themselves if they are self-employed, that might be affected by a decision of the committee provided that the matter will not have a special or different effect on the employee or the employer other than as part of the class.

The example given in 5 CFR 2640.203, which implements Title XVIII of the U.S. Code 208(b)(2) is as follows: "A chemist employed by a major pharmaceutical company has been appointed to serve on an advisory committee established to develop recommendations for new standards for AIDS vaccines trials involving human subjects. Even though the chemist's employer is in the process of developing an experimental AIDS vaccine and therefore will be affected by the new standard, the chemist may participate in formulating the Advisory Committee's recommendations. The chemist's employer will be affected by the new standards only as part of the class of all pharmaceutical companies and other research entities that are attempting to develop an AIDS vaccine."

In the event the discussions involve a specific product or a specific firm for which a members has a financial interest, that member should exclude him- or herself from the discussion, and that exclusion will be noted in the public record.

With regard to other meeting participants, we ask in the interest of fairness that they disclose any current or previous financial arrangements with any specific products or specific firm upon which they plan to comment.

If I could now ask the members of the Advisory Committee to identify themselves for the record, beginning in alphabetical order, starting with Mr. Allen. Mr. Allen?

MR. ALLEN: Larry Allen.

DR. NIGHTINGALE: Dr. AuBuchon?

DR. AuBUCHON: Jim AuBuchon.

DR. NIGHTINGALE: Mary?

DR. CHAMBERLAND: Mary Chamberland

DR. DAVEY: Richard Davey.

DR. EPSTEIN: Jay Epstein.

DR. FEIGAL: David Feigal.

DR. GUERRA: Fernando Guerra.

DR. HOOTS: Keith Hoots.

MS. JONES: Carolyn Jones.

CHAIRMAN CAPLAN: Art Caplan.

DR. NIGHTINGALE: Stephen Nightingale.

DR. McCURDY: Paul McCurdy.

MS. O'CONNOR: Tricia O'Connor.

DR. PENNER: John Penner.

DR. PILIAVIN: Jane Piliavin.

DR. SCHIFF: Gene Schiff.

DR. SECUNDY: Marian Gray Secundy.

MR. WALSH: John Walsh.

CAPT RUTHERFORD: Captain Bruce Rutherford.

DR. NIGHTINGALE: And for the record, I will note that Dr. Busch and Dr. Goosby are also present in the room, although not at their microphones.

Dr. Caplan?

CHAIRMAN CAPLAN: Well, I have to say for the record that I continue to be impressed at the reduction of ethics to a bureaucratic intonement at the start of every meeting that we do. It really does my heart good. Okay.

Anyway, the conflict of interest now being droningly clarified yet again, you will recall that last time we were stumbling toward some attempt to take a position on the lookback program, and somewhere between the activities of the United States Senate or the Bulgarian Communist Party, depending on your point of view, we kind of came up with a recommendation to urge a lookback, but left the meeting with the recognition that there may be different ways to do this and that we ought to consider when we talk lookback some of the experiences that centers have had and programs have had, and Mike Busch, in fact, volunteered to help shed some light--as did Jim AuBuchon--on what strategies for lookback we might actually be talking about.

So Dr. Nightingale and I have set up the morning so that we can listen to presentations on what various organizations, centers, groups, experts, have encountered when they've tried to get involved. I have to say that the Chair notes that while we have been talking about lookback and its pros and cons and merits in struggling with all this, a lot of places and programs have been doing it. That ranges from Defense Department activities to private centers moving forward, and so we are not operating in a vacuum, and I'm hoping that we can get some comment this morning that will help us understand not just whether HCV lookback is a good idea but whether there are particular specifics that we need to keep in mind in trying to give some advice about cost and benefit, safety, public health protection, informed consent, back to the American people.

So that's what the morning will be all about, and I think, unless there is something else I need to get on the table for the morning or something else anybody else wants to say, why don't we have Hal--excuse me--Dr. Margolis from the Centers for Disease Control and Prevention talk to us about the control of hepatitis C infection.

DR. MARGOLIS: I assume this is where you want me.

What I was going to do this morning is just give the committee a little bit of an update on some of the general lookback activities that we're moving forward with--"we" being CDC--and really in conjunction with a number of partners. And, again, because of the various issues that have come up about general lookback, I thought I might spend a little bit of time--this is not a data-rich discussion. It's a little bit more of a discussion of, Okay, so how do you get out there and do it?

The next overhead, Mary.

Just to put the paradigm back up for the group that has been presented now, I think, and refined and was presented at the last meeting, basically what we're talking about is that area in turquoise at the bottom which is looking at transfused recipients, transfused before July of 1992, and that being termed "general lookback."

Next?

One of the things--and, actually, I think a lot of the discussion at the last meeting really made us sit down and think real hard when we got the CDC group together, as well as some of our partners, and actually one thing that we have distilled out in terms of an issue of implementation is who is it that one is notifying in the two lookback approaches.

The targeted lookback, which I put down there at the bottom, primarily notifies persons or families of persons who have died. I think the data, as you saw the last time, showed that 80 or more than 80 percent of individuals who received a transfusion, in fact, have died; whereas, the general lookback is really targeted at the living individual. And I'm going to carry this through in terms of, as we have now been working on information strategies, that we are trying to identify, notify, and change behaviors in people who are alive--some of your patients and my patients. Not all of them are in health care encounters, but a fair number are.

Next?

The two approaches to general lookback are that of the very general, which we call the media and public education campaign--and for those of you at least in the Atlanta area, as we picked up Parade Magazine on Sunday, there was a big spread on hepatitis C, and the first two parts of what to do were people who have been transfused. So some of the messages are getting out. Some aren't always correct, but at least I think the transfusion recipient message is getting there.

Then the second part of this, which is some refinement of what you've heard from us before and which we're now working forward on and I'm going to give you some information, is: Are education campaigns truly directed at patient groups that are likely to have been transfused?

Next?

What I'm going to do is discuss a little bit about the media and public education campaign issues. Part of it is everybody has good ideas when it comes to health education, and sometimes you do need to collect a little bit of data and information. We have actually had a contractor who has now done what the public information people call formative research. So using some focus groups, some here actually in the D.C. area, some scattered around the country, an average of about ten people, various racial and ethnic diversity within the groups--these are adults between the ages of 35 and 60, transfused individuals over a wide socioeconomic range, and all of them high school education or higher.

Basically, these are three things that came out of these focus groups. First, you need to still get general information out about the seriousness of HCV infection. But they clearly said: Don't scare people, just tell it like it is.

The other issue is that--the key issue as we've been saying here, awareness of persons transfused before '92 are at risk of infection should be tested. What was interesting in some of their comments was that they assume that physicians, in fact, routinely do this, which I think, as I've heard a few chuckles already, and most of us would guess, they don't do it. But that is the assumption amongst at least these focus groups, and, you know, this is as best as you're going to get in terms of getting information.

Then lastly is the issue of motivating transfused recipients to actually go out and seek testing. So if the health care professional doesn't do it, then you've got to get the individual to go out and seek the testing and seek follow-up.

So those have been kind of now the guiding principles that at least we're moving forward with CDC activities over the next year, with some launches being as soon as March.

Now, one of the things I do want to point out is that as we have been doing this, we have been partnering, actually real face-to-face meetings, sitting down together with groups like the American Liver Foundation, the Digestive Health Foundation, Hepatitis Foundation, international, state, and territorial health officers, and the major manufacturer, which is Schering, of interferon, who have also been a major advertising player in the field. And we are now sitting down at the table together to try and at least get our messages on the same page, with the same factual background, and hopefully going in the same direction. So there have been a number of these meetings, and most recently is now bringing the manufacturer to the table with us to do this.

Next?

You know, you could have made this slide, because this is the thing that all the ad companies and everybody and all your public relations people tell you to do. So I've just put kind of a mix of things. There are a lot more, but in March, there will be some kick-offs of, say, yes, there will be press packets, there will be public information announcements, there will be PSAs available that will be put out around the country, and then various other issues in terms of consumers. So this is really patient material. So if you're sitting in your doctor's office, this is something you can pick up. Press releases, story ideas for magazines, transit ads, you know, the things you see on the Metro and the MARTA and wherever it is that you travel in mass transit. And even lastly, there really are story lines being developed right now for some of the popular TV programs such as "ER" and "Chicago Hope."

So that's at least what's probably going to happen over the next year with some coordination, and, again, as you can imagine for all of these, you know, the more money you put in it, the more you're going to get. CDC basically is putting in, just again for the information of the committee, about $1 million this year, remembering that we got no budget items or new money for any of this, so about $1 million is going in for these activities, including monies that are going in through cooperative agreements that are already in place to a number of the voluntary agencies and other groups that have been working with us on this over the last year.

Now, let me turn a bit to the other group that I talked about--so if I can have the next overhead?--and that's going back to the patients that, in fact, are likely to have been transfused. And this is something that I never talked to you about before because, quite frankly, before the last meeting we hadn't thought about it too much. I was actually taken a bit by some of the patient advocacy groups that got up and presented information in terms of at this point they had not really taken this on as a charge. And we feel that there are two pieces to this. One is educating the health care professionals who care for these patients--and who are these patients? I'll give you a list in a minute--and then educate the patients themselves.

So if I can have the next overhead, I've got some examples, and there's actually very scant literature in terms of who gets transfused. There was one survey, but I think most of the clinicians and others in this room can sit around and, you know, come up with some of these groups. And it turns out people with cardiovascular disease, GI disease in general, cancer, premature infants, pregnancy-related, the various anemias that require transfusion, and actually, orthopedic surgery and trauma, and, actually, there have been--there was one survey several years ago that at least looked at medical services and who were the patients in various medical services most likely to be transfused. But that gives you some ideas of who's out there, and many of them are still coming back to physicians or into the health care system.

Next?

So what we've done--and I'll just give you an example, and everybody can come up with their own example. But basically what we have done is we've taken lists of professional organizations that may deal with some of those transfused patients, and we've taken lists of voluntary health organizations and patient advocacy groups that deal with these patient groups, and we've at least put them together. And what the plan is--and, in fact, it's actually happening--is that we're hoping to have three regional meetings--next overhead. This isn't the right order.

At these meetings, we're going to have a half-day meeting where we bring groups of the professionals and the patient groups together and educate, number one, about the issue because we actually think many of them don't--yes, they've read the recommendations, but they don't see it in light of their own patient groups. So that's number one. And then basically spend the rest of the time brainstorming as to how can they get together the best message to get out to their health care professionals and to their patient groups.

So if you go back to the cardiovascular disease group, I would imagine that there should be something from the American College of Cardiology that, you know, puts it out in their monthly newsletter about the need for this. Hopefully, you know, they can generate some kind of a poster and patient information that sits in the waiting room. And then, in fact, the American Heart Association would get information out to all those individuals who have had coronary artery bypass surgery, which is a major transfused group in this country. And, again, those who are still alive, of which there's a fairly large number, are coming back to see health care providers.

So that's where we're moving in the next couple months, to try and make this happen and help groups craft the messages. Yes, at this point, we're basically saying to the groups we're going to have to get it out to you various patient and professional organizations. If we really absolutely--again, as I said, we have no resources at this point to put out a grant to every one of these groups, but there's a lot of leverage that can go on here. And, again, we already have a lot of materials that are developed that they can very easily take and modify and turn into their camera-ready and print and whatever kind of material they need.

So I thought this would be useful to kind of see where we're headed and how we feel--and, again, there are no data, but I think in terms of the logic, it says let's get to those individuals that we know have been transfused. Yes, there are many that are in disenfranchised groups that may never see a health care provider, and that's going to be the tough group. That's the tough group for everybody. Frankly, they're just as tough in terms of the notification because they're also the same people who have moved and haven't left a forwarding address or whatever address they gave you isn't the right one, and they're not going to get the letter you send out, either.

So we're all going to have to struggle with that, but I think that's where we are, and at this point, I guess I can answer questions.

CHAIRMAN CAPLAN: Well, I have to say, taking the prerogative of the Chair here, that you and Dr. Alter and the other people working on this attempt to do outreach, I think you really took our message to heart. It's very heartening to--heartening? It's very exciting to see these attempts to really develop an outreach strategy, work with the professionals, get out to the patient groups. I think this is a very exciting plan. It's one that I'm personally very, very pleased to see blocked in. I think CDC deserves some congratulations for putting that together.

Questions, comments?

DR. GUERRA: I guess, Hal, along with this effort, it seems to me that there must be another one in a parallel sort of way that will take information that is maybe even reassuring, or at least call attention to risk in those instances where I guess what we are seeing is that as more and more information gets out about hepatitis C and the specific groups that we are interested in trying to identify, and identify them, that then there is--not unlike what happened in the earlier days of HIV-AIDS, then school kids whose parents are infected are being stigmatized and/or other groups where there is an individual, a family member, a friend, or someone that they are in close contact with that is being identified as having hepatitis C infection, and that then those around them I think are being affected in some adverse ways.

I just wonder if this educational effort will hopefully try to allay some of those fears.

DR. MARGOLIS: The general--well, at two levels, yes, we think. Clearly, the information handed to the patient--again, at least I would use our--the one at least structure or story line we've been using, which is "If You Have Hepatitis C." That's the CDC pamphlet; I think you've all seen it. It clearly talks about the difficulty of transmission in the casual or even the household setting other than if you're having direct blood contact. You know, those are the medicalese terms. Now you have to get it out so that people understand that. And that's a message we feel--and also the focus groups said that--needs to go out to the general public, that, you know, it's transmitted by certain ways and there's other ways that it's not transmitted.

Unfortunately, as you know and I know, we'll get the phone calls to deal with the school systems and the legal challenges and that, but I think we're all prepared. We've been there before and hopefully it's--you know, hopefully it doesn't escalate. But we've all heard it already.

And so, yes, I mean, we see it as being that general information context about how this is transmitted and how it's not transmitted.

CHAIRMAN CAPLAN: Dana?

DR. KUHN: Dr. Margolis, has the CDC taken into consideration in its general public awareness of HCV campaign maybe, I guess, tactics in doing statistical evaluations on maybe a public mailing, similar to what HIV was through Surgeon General Koop? Have you looked into seeing what would be the statistical evaluation of the success and also what the cost analysis would be in doing something like that? Because it seems to me that that was very far-reaching and it was very informative of the public. I know we're looking into doing PSAs. Those get to be quite expensive. How does that compare to doing a general mailing of putting an H stamp on, you know, a letter that goes to every household in the United States?

DR. MARGOLIS: That discussion has been there. You know, somebody still pays for the mailing, and ultimately it gets very expensive, too. At this point that has still remained on the table as a possibility. The discussions within CDC and the consultants honestly feel that we need to still--well, clearly, get to the patient groups directly. I mean, that we see as priority one, and then various approach, which can still include a mailing.

I'm not aware in all of the discussions that anybody really has good cost-effectiveness data as to which--there are evaluation components built into all the things I put up here. Those are beginning, and, again, part of it is budget issues, but they're going to be done. Frankly, nobody has anything that can compare a mailing to something else at this point, and that's kind of the problem.

So a bit we're out, you know, kind of feeling for the best way. We don't know, is the bottom line, but it has not been dismissed as still part of this overall strategy.

Frankly, right now there aren't the funds to do the mailing. It does cost money. Somebody pays for that, and it's actually our agency if you're going to do the mailing.

CHAIRMAN CAPLAN: Richard?

DR. DAVEY: Yes, Hal, first I'd like to second the Chair's congratulations on the good job on this.

In terms of identifiable at-risk groups, perhaps there are some that can be targeted a little more specifically, the folks who experimented with IV drugs in the '70s, cocaine internasal with straws, et cetera. Are those groups going to be specifically highlighted in some of these PSAs, or are you just going to focus on transfusion recipients?

DR. MARGOLIS: All right. Let me tell you the other part to the reality. Part of the reality is that when you start looking at those other groups, somebody needs to be there to do the testing and counseling, let's not even talk about treatment. And given that, in fact--and that usually, based on our experience for HIV and sexually transmitted diseases, most of that occurs in the public sector.

There are currently no resources--and I'm telling you even state by state--in the public sector to handle that kind of an influx of requests for testing. So that we have very consciously for this year--now, I can tell you that our best guess is there should be resources in the year 2000. I can't talk specifically about the President's budget since it's not out there. But we're being optimistic.

In fact, we just met last week with surveillance coordinators from half of the states as part of the Council of State and Territorial Epidemiologists working committee, and they're already seeing screening going on in states in high-risk settings. The problem is that you can't go anywhere with it. Somebody gets the blood test, or they can't even get enough money to do the blood test.

So in this year's media campaign, we are not emphasizing or targeting those groups because they have nowhere to go for testing and counseling, and that is a sad fact. I'll put that perspective on it. But the fact is that people like Dr. Guerra, you start sending huge numbers into his health department and there is no way to--there is no capacity. There is no funding. And pretty much we're trying to work together to get those resources, and we have agreed that we are not making a major educational campaign this year. We'll start in 2000, fiscal year 2000, which isn't that far away, if we have some money that we can then get out to help states.

Now, many states are asking for money from their local legislatures--Florida has done it; we know several other states that have done it--to support HCV testing and counseling. But that's the dilemma we're facing, just to be frank about it.

So we've drawn the box around transfusion for the first one out and the general information. The second one out are exactly the groups you're talking about.

CHAIRMAN CAPLAN: Before I go to Jim, just so I understand, this year, if we have a targeted campaign centered on transfusion and aimed at doctors, patient groups, and sort of using them as an intermediary to reach out to higher-risk groups relative to transfusion, there will be a pretty rapid evaluation of that, so maybe that could then be used as a model to try and target other groups and get budget to back it up. Is that a fair--

DR. MARGOLIS: Yes. There's actually two components to that. There's a very large and fairly expensive evaluation of targeted lookback that's already underway with ACHPR and FDA, so the three agencies, and that protocol is actually in place and money is starting to go out to deal with that, as well as evaluation of the general lookback component, almost--we're trying in some communities to do that side by side.

So, yes, we should have information as best we can, you know, by the end of the year so that it can begin to help us with some of these other targets. Again, I think there's a lot to be learned from HIV, and, again, within CDC we are currently, for instance, developing a whole training module that is going into the HIV, STD prevention center, training centers. There's a network, I think it's seven or eight of them around the country, that have nothing in there about HCV right now. They have nothing in there about viral hepatitis, yet they're--you know, B also. And so that's being developed. That's already well underway, and that will be dropped in.

Again, part of the issue when you start dealing with some of the other high-risk groups is there aren't knowledgeable people out there to do the counseling right now.

So these are some of the things we are trying to do right now to get this up to speed.

CHAIRMAN CAPLAN: The only reason I ask that is I think if Steve will just make a note of this, at some point today we may be able to have the committee flag, attempt to set up an infrastructure for outreach and monitoring with focus and coordination, and then try to reinforce that budget priority with the administration, obviously with an eye on the cost-effectiveness of it. But that seems to me a place where we could be at least underlining the importance of doing it, if it's truly an audience or a baseline of ultimately four million that we're trying to find, somehow or another, and this blood-oriented project works and the HIV experience can be adapted and so forth. And I think we should try to reinforce that if it really turns out to be effective.

Jim?

DR. AuBUCHON: Just a commentary, and, Hal, you may want to comment on my commentary.

My perception is that CDC is approaching this in a process mode, that it is understood that hepatitis C has been with us for a long time and it will be with us for a long time. This is not a point-source outbreak of some rapidly deadly virus that is sweeping the country. It's something that we have to come up with some new tools, some expanded tools to deal with through a number of different avenues over a long period of time. And we are not going to solve this by the middle of February, or even the middle of February next year or the year after that.

I'm not sure that conception is always one that this committee has approached hepatitis C with, but I am very gratified to see some of the programs starting from CDC and through CDC and the state health offices so that we can deal with hepatitis C in the long term.

DR. MARGOLIS: Yes, you're absolutely correct. And I think while the word "epidemic" gets used a lot in the popular press, I think we all understand, or hopefully this group is understanding, yes, there was an epidemic and, yes, we have a tremendous disease burden to deal with. But this is a long-haul issue, and we need the process and we need the system out there to deal with it.

CHAIRMAN CAPLAN: Larry?

MR. ALLEN: Sir, of the overall percentage of people that you feel may be affected with hepatitis C right now, how many do you think this campaign initially will be able to reach?

DR. MARGOLIS: The estimates, again, the numbers this committee has heard is that we estimate that of--and really we're talking about three million who are the truly chronically infected. Six to seven percent acquired it from blood transfusions, so it has always been that this is a small piece of the pie.

What percent of those transfused individuals we may reach with this, I don't know. I would think it could be relatively high. But, honestly, we don't know, and I don't think anybody knows.

CHAIRMAN CAPLAN: Keith?

DR. HOOTS: This may be a premature question because it gets down to strategies for the targeted professional group. Since this is a general and not a targeted lookback, is the strategy kind of like--if you take orthopedists as an example, would the strategy be to sit down with them and say, all right, fine, if you had a patient who underwent any sort of surgery, don't bother trying to figure out whether they were transfused or not, just test them? Are we to the degree where those kind of decisions have been made yet? Or are they still being formulated?

The reason I ask that is, for instance, we know that a lot of homemade fibrino- (?) is used in patients who may never have even realized it, and so this is generalized and not targeted lookback. It just seems like if they get there, they ought to be tested.

DR. MARGOLIS: Quite honestly, I think those are the kinds of things when you bring those groups together and sit down and talk about it, then you're going to figure out what's practical. And we honestly haven't gotten there. You know, we've all had our discussions. Some of us know our own professional groups a little better than others, and so--but I think at the time we get people together, then we're going to hear the good ideas. And that's what we want to do, is get people together so that the good ideas get out there and get used.

CHAIRMAN CAPLAN: Someone over here with a hand up?

MS. O'CONNOR: My question was answered. It was about funding.

DR. GUERRA: I guess that I just want to be sure, though, that as we really take this campaign to scale to target the groups that have been affected by blood transfusions that we don't play down the other group, because the other group is the one that probably today is truly at greatest risk. And from our own experience, where we have, I think, used the capacity that we developed with our HIV-AIDS and STD staff, they're fast learners, and they have really come up to speed to really target that population that they deal with.

I guess in the short period of time that we've been doing it, we have already identified from those that have been tested 14 percent are positive for hepatitis C within that group that's coming into those programs. And they're a group that obviously carry with them some life styles and some risk factors that put a much broader community at risk. So we think we need to also educate people, professional societies, the practitioners, about that group that they need to pay more attention to.

DR. MARGOLIS: We fully agree. Maybe, again, to give a little perspective, the MMWR that came out in October had a CME piece in it. We've already had over 5,000 of those returned. And most of those--I mean, we're talking about in the 80 percent range--these are people in office space, more private practice, not public health settings, who are returning those.

So the point is that it's getting out. I think the information is getting out there. The fact is I'm going to duck out here for a couple hours in the middle of this meeting to go deal with a group on corrections. The corrections area is a place where you're seeing 30, 40 percent prevalences of hepatitis C. Texas has already had a commission. I have been involved in working with them to develop strategies. When you just talk about the number of people fortunately who are in corrections, not just incarcerated but in the whole corrections system, you're looking at a lot of HCV positives who can be identified. Again, it's how we're going to deal with that and set up ways to test, treat, and counsel.

CHAIRMAN CAPLAN: Well, maybe one last story before we move on. I did have rounds the other day at my medical school with some of the house staff, and we were talking about hepatitis C, and I asked them what the cause of it was. And they said, well, it's primarily a blood transfusion disease. So I kind of rolled my eyes, and I said, well, yeah, hmm, but I understand that there's stigma and people may not want to talk about life-style things that may have put them at risk. And I think it's very important that this focus be more as a pilot to try and get to a group than try to say that this is the top priority or the best pool to be fishing in for location of people at risk.

So I hope in that sense that the blood topic can carry forward some of the other things and muster the budget to help get the hepatitis C issue moving as a national priority. That's always been my hope. But right in my back yard, I had a startling little discussion just the other day. So that is a real problem. A real problem.

All right. Thank you very much.

One of the things we talked about at the last meeting--I may be the only person who remembers the last meeting, but one of the things we talked about at the last meeting in some depth was if you were going to do a lookback to this group that test repeat reactive to the single-antigen test, was there some way to deal with the--find trigger mechanisms or some way to get a signal ratio that made it possible to perhaps eliminate some of the false positives that you'd be producing by going into that group and make more efficient and effective and less frightening and most cost-worthy and better informed testing as part of that lookback.

Mike Busch volunteered that he had been thinking about it and working on some of the EIA-1 screening tests for hepatitis C and had done some thinking, too, about the predictive power of where that signal might be detectable and important.

I don't know how many of you had a chance to read this paper that he has produced. I know I've been on this committee too long because I think I understand this paper. But it is a very remarkable job that he has done, and it is exactly what I hoped we might have, and more than that in a lot of ways. So, Dr. Busch, why don't you perhaps summarize and lead us through what you found as you tried to explore the question of how to do that type of reactivity testing.

DR. BUSCH: Thanks. I first want to acknowledge the people who have been working on this pretty hard for the last couple of months, particularly Leslie Tobler in my group, who has really compiled and orchestrated pulling together all the data; Gary Tegtmeier from Kansas City, who contributed a lot of data to the analysis; Sue Stramer, who contributed data from the Red Cross system; and then Stella Quan from Chiron, who did RIBA-3 testing for us; and two people, John Dockter and Christine Giachetti, from GenProbe, who did a lot of the HCV RNA work.

Next slide?

As we've debated extensively the pros and cons of first-gen lookback versus second-gen, a lot of the issues we're very familiar with, the limitations of the first-gen test being that it wasn't as sensitive, perhaps picking up 70 to 80 percent of the infected donors compared to the second-generation test. But a substantial problem that we faced was the unavailability of confirmatory test data for a substantial proportion of the time that the first-gen test was in place. The confirmatory test that was licensed by the FDA, the RIBA-2 assay, was not licensed until after the second-generation test became available.

FDA did allow blood centers to gain access to the RIBA-2 assay for about the year before the second-generation test became licensed through an arrangement where Chiron Corporation actually opened a reference laboratory and using "homebrew" configured assay reagents prior--go ahead.

DR. PENNER: Mike, maybe for a lot of these people, it would be helpful to just describe what the tests are, how they're done, so they have an idea, instead of--

DR. BUSCH: Okay.

DR. PENNER: How the fingerprint is set up and what kind of assay it is.

DR. BUSCH: Different versions of the confirmatory--

DR. PENNER: I think it would make it easier to understand the second generation or third generation if you know what is different between the first and the second generation and so on for baseline.

DR. BUSCH: Well, in sort of broad terms, the first-generation test was composed--both the first-generation screening assay and RIBA test were composed exclusively of a very small region of the HCV genome. I think it only represented about 5 percent of the total virus, the so-called c100 protein. And that protein detected, again, about 80 percent of persons who were later determined to be infected based on the more sensitive assays.

In the first-generation RIBA test, the first generation, what's called recombinant immunoblot assay, similar to a Western blot except instead of spreading the viral antigens from a lysate of virus on a strip, you actually use recombinant antigens and place them on a piece of paper, essentially, in discrete locations.

The first-generation RIBA test simply included two parts of that c100 antigen, the 511 component and the overall c100 antigen, as well as some control bands. The second-generation, what was termed the first multiantigen assay, included several additional antigens--core antigens, c22C and c33--and that represented in total I think-- probably about 20 to 25 percent of the total HCV proteins were represented in the second-generation screening test, and the second-generation RIBA included the 511 and c100 antigens that were in the first-generation assay plus new bands corresponding to the c22 and c33.

So with each generation of screening test, in essence, there was a complementary confirmatory assay that basically divided the antigens that were in the screening ELISA into discrete bands so that one could interpret whether the reactivity that's just accrued reactivity level in ELISA was attributable to specific reactivity to multiple HCV antigens.

In general, one has to have at least reactivity to two of the HCV-specific antigens in the confirmatory test to be positive. You can't have reactivity to a certain level to any antigens in order to be negative. And if you have reactivity to one antigen, you're considered indeterminate.

Then the third-generation test basically added a new antigen, the NS5 region, and, again, reconfigured the confirmatory RIBA third-gen, which is still unlicensed, reconfigured the bands to include the NS5 and some increased accuracy with respect to the other bands.

That's a good question, and I wish I had brought slides because there are very nice slides which kind of depict how these things work. But the general principle is that the screening tests are kind of a gamish of proteins and the confirmatory try to divide up the proteins on a piece of paper so that you can evaluate the specificity.

So, again, the major problem, one of the major problems that led many of us to argue against doing lookback for first-generation was the general unavailability of a confirmatory test. Again, there was a confirmatory test that became available in that last year or nine months of first-generation screening. The first-generation test was in place for about two years, so for about the first year of that, there was no confirmatory test available to any extent. During that second year, the confirmatory test, unlicensed at that point from Chiron, the RIBA-2 test, did become available. And most of the blood banks in the country did begin to send samples to Chiron, and it became confirmatory data for that last year.

But the problem in great part was the unavailability of any confirmatory data for the first year. One of the things I think we'll come back to later is even during that second year when the RIBA-2 was available, it was not a licensed assay. And a question that has come up both with respect to RIBA-2 and current use of RIBA-3 is whether unlicensed versions of a confirmatory test area acceptable for use in triggering this notification.

We obviously were notifying donors at the time based on those data, but were not doing anything like reinstating blood donors because it was not an approved test so we couldn't do anything that would impact on safety of the blood supply. And I think the question we'll address later is whether these RIBA-2 data are acceptable for purposes of targeting notification. My strong feeling is that this was an identical reagent to what was licensed, and that data is extremely useful.

But, again, there was no data for that first year plus, and that became a critical concern because a high proportion of the donors we knew were picked up during that first year, and this would trigger lots of potential notifications, most of which we thought would be false.

So one of the things--so basically in embarking on trying to bring data to these issues, one of the first things we did was to look at the question of over time what proportion of the confirmed positive donors, and specifically the confirmed positive donors who were repeat donors, the donors who would trigger lookback, were found during the period of first-generation screening. And that's what this slide illustrates for two blood centers, Blood Centers of the Pacific and the Kansas City Blood Center, which did have specimens available to go back and do the RIBA-2 testing on all the samples from the beginning of screening.

These basically show the same principle, which is that the vast majority of the infected donors were removed--detected and removed from the donor base during the first months to year of screening. So you can see here we're dividing this, in essence, up into quarters over the first two years, so this is the first year of screening and the second year of screening at these two blood centers.

Mac, if you can push that up, you can see these are two separate blood center databases. And what you can see is that in the first several months of screening, half of the donors who were confirmed infected, repeat donors who would trigger lookback, had already been detected, and by the first year of screening, 80 percent of the infected donors who would trigger lookback were detected and removed from the system.

What this tells us is that if you're going to do first-generation lookback, you have to do it for the entire period because the period that we have the confirmatory data for really only detects a small subset, about 20 percent of the infected donors. So it really shows how--we call it a classic culling effect. You screen these repeat donors, and these donors are coming in on a regular basis. As they're detected as infected, they're deferred and removed from the donor base. So they're not able to come back in that second year of testing and be detected as positive. They in essence would be invisible to being able to trigger lookback if we were limiting it to the second-year time period when we had the confirmatory data.

Okay. I think we'll skip the next, which is in the paper, but it's just a detailed summary of those data in a tabular fashion.

We went further in the Kansas City data set. They actually looked at whether this culling phenomenon, i.e., that the majority of the infected donors were detected early and removed from the system, whether that would in turn translate into a reduction in the number of lookback notifications that would occur. So what they were able to do quickly was to go into their records and ascertain how many recipients would be notified from each of these donors during these serial quarters of time.

We do see the same phenomenon in terms of the number of products that were issued, prior products from these donors in the period in question. So we're looking at donors detected from first-generation testing from May of '90 through the spring of '92, when the second-generation test was licensed.

The lookback period we're looking at here extends from detection of these donors as infected back to the beginning of 1988. And what you can see is the number of products, it drops pretty much in parallel with the number of donors. So that, indeed, similar to what I said before, essentially during the first year of screening in the range of 75 to 80 percent of the lookbacks would have already been triggered from the donors detected during that first year of screening.

Interestingly, this table does include several individuals who were RIBA-2 indeterminate, and on RIBA-3 testing were RIBA-3 positive. Actually, this one aberrant result here, this period of time where theoretically everything is dropping nicely, but then all of a sudden there are 47 lookbacks triggered from these five donors. Actually, 40 of these lookbacks were triggered by one donor who was indeterminate on RIBA-2 but RIBA-3 positive. And we'll come back to that because all of these donors who were indeterminate on RIBA-3, about 10 percent are RIBA-3 positive, but they're all RNA-negative. So this is another issue that we'll be talking about later, whether lookback is warranted for the RIBA-2 indeterminates.

But, in general, what we see is a proportionate drop in targeted notifications that were triggered from these donors, and, therefore, again, the same point, that if we were to just do lookback for that last year, in general it was in July of '91 that the Chiron Reference Lab was allowed to accept samples and give data back to the blood centers. So if we just accepted confirmatory data from that later period, we would only notify 20 percent or so of the recipients found through first-gen.

Next?

Okay. So that was the problem that we recognized in actually discussing this with Jay Epstein. He suggested, you know, maybe you could look at S/CO. And we knew from other data--this is not in the paper or actually in your packet, but this is just data from the second-generation screening test, and I'll show you in a moment from the third-generation test. It shows the relationship that pretty much bears true for most screening tests relative to the confirmatory that the signal-to-cutoff ration, which represents the intensity of the light, if you will, that comes out of these plates in terms of reactivity of each sample, the level of reactivity--and this is calculated by taking the signal observed in the sample that contains the patient serum and dividing that by the cutoff of the assay. So any samples that would have an S/CO, a signal-to-cutoff ratio of 1 would be considered reactive and would trigger confirmatory testing.

But the general principle that the higher the level of reactivity of the screening test, the more probable the sample will confirm positive, is one that we know about for most tests, and it is well-known for the second- and third-generation screening assays. Actually, people in public health in general diagnostic settings not infrequently will use the screening results on HCV assays to decide whether a confirmatory test is even worth doing.

So what this says is that for the second-generation assay--and this is actually data from the Red Cross--that among the confirmed positive donors--for the second-generation test you can see that about 62 percent of all reactive donors confirm positive. And you can see that the vast majority of those RIBA-positive donors have very high S/CO ratios, greater than 3.5. In contrast, the vast majority of the RIBA-negative donors have very low S/CO.

Next slide?

This is just the same thing for RIBA-3, EIA-3. The same relationship there is true, that the vast majority of donors who confirm positive, again, about 64 percent of donors confirm positive that are EIA-3 reactive by RIBA-3, and virtually all of those, the so-called box-and-whisker plots which present the median, the 50th, and then the--I'm sorry, median, 95th and 25th percentile, and then the--I'm sorry. The median is the line in the middle. The 25th and the 75th are the two box edges, and then the 95th percentile are these whiskers. So, again, same principle bears true.

So Jay suggested looking at the first-generation S/CO and see how predictive that would be. So that's what we're embarked on.

Next slide, please?

We keyed in data from four centers, the two centers that I have been talking about--Blood Centers of the Pacific and Kansas--and then Sue Stramer sent us data from the Red Cross, and we keyed in data from two large Red Cross regions, keying in all the available first-generation EIA data and the Western blot results.

We also, just as an aside, looked at ALT and anti-core to see if that would anything in the mix, and it turns out it does not. But what you can see at each of these centers is really a very similar relationship just as we saw with the second- and third-generation screening test, that among the donations that are confirmed negative, they virtually all have S/CO values in the range of 2 to 3 or 1 to 3. The small proportion of donations that are indeterminate kind of have a broad range of reactivity, and among the confirmed positive donations, which represent in the range of 30 to 40 percent, the vast majority have very high OD reactivity.

So, again, these were all highly significant correlations between the reactivity and the screening test and the confirmatory results and similar across all the centers. So we combined the data--and that's actually I think the first new slide I distributed--into one large distribution analysis.

The next slide? Oh, we can skip that. It actually just summarizes. In the overall data set, I think there were close to 4,000 data points, so 3,750 data points. And of those, you can see, just these bottom-line summary points, that 60 percent of these were RIBA negative, 5 percent were RIBA indeterminate, and 35 percent were RIBA positive. And this is by far the largest data set, I think, of first-generation results that we sort of can look at that question of what percentage of first-generation EIA reactives are truly RIBA positive. And from this large data set, it's 35 percent of EIA repeat reactive donations from a group of large centers proved to be RIBA positive.

And then this presents the summary distribution of the S/CO values for each group, and you can see that same relationship we looked at the last four or five panels with the vast majority of the RIBA negatives falling below 2.5--approximately 95 percent of the samples fell below 2.5--and the vast majority of the RIBA positives really falling above 4, 3 to 4, and the indeterminates, again, kind of spanning an intermediate range of reactivity.

Next slide?

So if we begin to look at cutoffs, and if you want, there's this technique called receive operator curves that lets you look at a whole variety of cutoffs and kind of balance the advantages of setting a cutoff at a certain level with respect to the sensitivity of the rate of picking up true infections versus the specificity of the rate of false positivity. But as a first cut, we kind of looked at the data and said, you know, it looks like around an S/CO ratio of 2.5 will give us pretty much 90 percent detection of the true positives and only about a 10 percent failure to miss false positives.

So we looked at that and I'll present new data--and, again, that's being distributed--that looked at a variety of other cutoffs in moment. But if we just focus on the 2.5, what you can see from this data set of about 3,700 donations, that if a donation has an S/CO ratio of less than 2.5, only about 6.7 percent of those samples would confirm positive and nearly 90 percent would confirm negative.

In contrast, if an S/CO value on a sample is greater than 2.5, about 75 percent of those samples will confirm positive, and only about 20 percent will confirm negative.

If we ask the sort of classic questions of sensitivity, specificity, and predictive value and use RIBA confirmed positive as the gold standard, what you can see is that using an S/CO of greater than 2.5 would pick up 89 percent of the RIBA-2 positive donations. So that's this denominator of RIBA positives of 1,326, with the numerator the number that are greater than S/CO of 2.5, 1,180. So the sensitivity of using a cutoff of 2.5 vis-a-vis the RIBA positivity is about 89 percent.

The specificity would be the number of false notifications that would occur which would be the 299 of the total number of negatives, the 299 that would have an S/CO greater than 2.5. So the false positive rate would be 13 percent, and the specificity would be the 87 percent, specificity being defined as one minus the false positive rate.

The next question--move that up, please. Push it up if you would. The next sort of question in terms of as we send out these notifications, what's the probability that a person who gets a notification triggered from a donation that has an S/CO less than or greater than 2.5 actually got a unit of blood from a donor who was confirmed positive?

To answer that question, we basically plus the sensitivity and specificity data into a population study, and in this case, we really have all the data right in this table and derive what's called the positive and negative predictive value.

The positive predictive value is the probability, given a positive result, that this person is really infected. So to derive that, we take the number of truly infected donors, which is--the number of donors with an S/CO greater than 2.5, which are the group in which we're saying, if you will, the test is positive, we'll trigger a notification. So the number that are truly infected is the 1,180. The total number of notifications that would go out is the 1,576. So the positive predictive value is 75 percent. So from this analysis, 75 percent of people who would get a notification triggered from greater than 2.5 would indeed have gotten a unit that was infected, or was RIBA positive.

The negative predictive value, on the other side of the coin, of the 2,177 people who would not get notified, i.e., those with less than 2.5, from this data set actually 176 would actually be infected, so we would miss notifying 8 percent--of people who didn't get a notification, there would be an 8 percent possibility that they would be infected.

Next?

Just one issue now--it's one we'll come back to, but in my subsequent analyses, I'm going to exclude the indeterminates because they kind of confuse the analysis. But I do want to just address quickly to justify that what our analysis showed in terms of the rate of infection among the donors who had a RIBA-2 indeterminate result.

The bottom line here is in the two blood centers that had samples available, we had 69 specimens that were EIA-1 reactive and RIBA-2 indeterminate. And what we found was that among the RIBA-2 indeterminates, when reflex tested to the RIBA-3 assay, 16 percent, 11 of those 69, were actually RIBA-3 positive. But of those, when taken on to RNA analysis, none of them were RNA positive.

This has been really true of--an important distinction here, I think, is that we're talking about RIBA-2 applied to EIA-1 reactive donations. Now, the FDA guidance document, if you're using EIA-2 and you have a RIBA-2 indeterminate result, you either have to do lookback or you have to do RIBA-3. You have to reflex to the more accurate confirmatory assay. But if you're doing EIA-2 and you have a RIBA-3 result that is indeterminate, you do not need to do lookback. And that's because the RIBA-3 test is substantially more accurate, more refined, than the EIA-2 screening assay.

I would argue we're in the same situation here. We're talking about the first-generation screening test, and when the RIBA-2 assay, which is a substantially enhanced performance confirmatory test, it is reporting out indeterminates, but none of these indeterminates actually seem to be coming from infected donors. Some of them are confirming with subtle evidence of serology, but these are probably old cleared infections rather than infected, infectious donors.

So based on this, my argument would be that notifying RIBA-2 indeterminates is not justified. It's important to remember that from the EIA-1 assay, only 5 percent of EIA-1 repeat reactive donations are indeterminate. Again, about 30 to 35 percent are positive, and about 60 percent are negative. So this is a small piece of the overall pie, but the probability that indeterminate donors are infected and infectious I think is very low.

Next slide?

All right. In addition to doing the RIBA work on these donations, we also did a fair bit of HCV RNA work to look at several issues. One question we'll look at in a minute is even though we know from the data I just showed that using an S/CO of, for example, 2.5 we would miss notifying about 10 percent of the confirmed positives, one of the questions we asked is whether that 10 percent who had a low OD but were RIBA positive, is there a similar probability of infection in that group compared to the high OD.

So we did RNA testing on a large number of confirmed positive donations and examined whether the rate of confirmed positivity was--the hypothesis was that these low OD confirmed positives that we were missing, they may have a much lower probability of viremia, of true persistent infection, than the high OD confirmed positives. And as we'll see in a moment, that was true.

In addition, we wanted to look specifically at the relationship between RNA positivity and S/CO ratio. So in addition to looking at whether the S/CO ratio was highly predictive of confirmatory antibody results, the RIBA, we asked whether the S/CO ratio was as or even more predictive of RNA results, the true sort of marker of infectivity. And we see a similar analysis with the RNA positive samples having a much higher S/CO distribution than the RNA negative samples. This included 199 confirmed antibody positives and 184 antibody RIBA negatives that were combined. So it's that same kind of relationship.

Next slide? See, those numbers weren't right.

So then if we looked specifically at the question I posed a moment ago, what's the probability--given that you're RIBA positive off EIA-1, what's the probability that you would be RNA positive? There was an error in the denominators in the table that was in the paper, so this has been distributed now and this has been corrected.

What you see is that for the 31 samples that approximately 10 percent or 12 percent of donations that had lower S/CO ratio yet were RIBA-2 positive, the rate of RNA positivity is a little less than 50 percent; whereas, for the 90 percent of samples that high S/CO ratios, the highly reactive on the screening assay, about 85 percent were confirmed positive. Overall, among all the RIBA positives, 198, or 80 percent, were confirmed positive.

So, indeed, you know, if you will, of the 10 percent of confirmed positives who would not be triggered by the 2.5 ratio, half of those people are probably not viremic and infectious, anyway. So not triggering notification on that 10 percent one could argue is of less importance. Perhaps you could even factor it down and say in truth we'll only miss about 5 percent probably of the lookbacks that would be warranted.

Next slide?

All right. This is really hot off the press because after Jay read this document last week, he came back to me and said we better look at some alternative cutoffs. So this has been distributed to you folks, and what we're doing on the next two slides now is looking at--in essence, backing away, if we're not comfortable with the 2.5 cutoff, what would happen if we were to instead use lower-level cutoffs?

Obviously, as in any testing issue, as you lower the cutoff, you'll increase the sensitivity, increase the rate at which you would detect confirmed positives, but it's at a cost of poorer specificity, increased number of false positives. And this is what we see.

So if we start at the bottom here, which is where we were a moment ago, if we use the 2.5 cutoff, we would detect 89 percent of the RIBA positives and avoid notifying 87 percent of the false positives. If we instead push the cutoff down to 2.0, we will pick up more RIBA positives going from 89 to 91 percent, but we'll increase the number of false positive notifications from 13 to 22 percent. So--right, this--of people who would be notified--sorry. I'm going to say this again.

So if you use the 2.0 cutoff, the number--the percentage of people who will not get notified who shouldn't, i.e., the RIBA negatives, goes from 87 percent to 78 percent. So you'll be notifying inappropriately 22 percent of people.

And if you push it down even further to 1.5, you now would capture 95 percent of the RIBA-2 positives, but at the expense of notifying about 43 percent of the non-infected individuals.

The last slide we'll show of the same analysis for the RNA results. So based on RNA at the 2.5 cutoff, we would capture 92 percent of the RNA positive donations, and at the 2.0 cutoff we would capture 95 percent, and at the 1.5 cutoff we'd capture 97 percent. At these different cutoffs, in terms of RNA negatives--this doesn't even make sense. Let's forget this here. I think that may be inaccurate.

But the point I'm trying to put out here is that basically my recommendation, as sort of summarized in the manuscript, is that a 2.5 cutoff is a reasonable compromise. It would detect about 90 percent of the RIBA positives and 92 percent of the RIBA negatives. And if you go back to the immediate prior slide in terms of the specificity, it would avoid notifying--okay, that's inaccurate, that specificity one. Push that up higher. Good. It would avoid notifying 87 percent of the false positives.

As you compromise to consider a higher S/CO, you do indeed detect a few percentage more of the confirmed positives--in fact, with 2.0 you will catch 95 percent of the RNA positives, but you begin to compromise. Instead of failing--instead of notifying only 13 percent of false positives, you would notify 22 percent of false positives.

That's the data, and I'd be happy to answer questions or clarify.

CHAIRMAN CAPLAN: This is the darnedest six-week production I've ever seen. You must have been working on this Christmas Eve.

By the way, Mike, who helped support this, if you want to tell us, to get this done?

DR. BUSCH: My friends in the government.

[Laughter.]

DR. BUSCH: It's the kind of stuff that--you know, fortunately, we have various relationships with NIH in terms of the Rand study, for example. They also were helpful in arranging for GenProbe, who they're supporting and developing and demonstrating RNA assay to do all the RNA work. Just a team process.

CHAIRMAN CAPLAN: I'm very excited to see this work gets into the real nitty-gritty of sensitivity, specificity, what could be done at different cutoff levels. You didn't tell us much, although I think my question would be to run this repeat test on EIA-1, what are we talking cost--I mean per--

DR. BUSCH: There's no data to run. Again, these data exist. So what we're focused on here--

CHAIRMAN CAPLAN: I don't mean overall. I just meant for a single--

DR. BUSCH: Oh, how much is a screening assay?

CHAIRMAN CAPLAN: Yes.

DR. BUSCH: For HCV, it's around $2.50, I'd say, in the blood center setting. But, again, just to summarize to answer that question, what would this actually mean if the committee approved it?

The reality is none of the large blood centers have specimens stored away from this early period of time. So if those existed, this would not be an issue, because even though we don't have the data we could go back to the samples and retest them, and those samples do not exit. But the data, the reactivity data that we're discussing, does exist.

For example, the Red Cross system was able to ship up some boxes that represented three or four centers, and we went through them and just keyed it in.

So basically what would be entailed here would be--my recommendation would be any blood center would first go back and find out who their repeat donors were coming off EIA-1, and then they would have to go back to the donation test records, which FDA mandates that we retain, for those repeat donors at their center and ascertain what the signal-to-cutoff reactivity was, and then based on that data would decide where to proceed.

A comment in that vein is that actually for blood centers the easiest thing to do, given a decision to do lookback, is to simply let your computer run all your repeat reactive donors and send out all the notifications to the hospitals. The tragedy of that is that a substantial proportion of those notifications are from non-infected donors and will trigger both an enormous amount of work in the hospitals and in the large number of notifications to recipients who don't warrant it.

So really what we're talking about here in truth is more work for the blood centers to help sort these donations out into high or low probability.

DR. EPSTEIN: Mike, that was a beautiful presentation. I personally want to thank you for acknowledging my role in the interplay of ideas, but I had a mentor in science who said: Ideas are cheap, and it's the work that counts. So you and your colleagues deserve all the credit for this tour de force.

Just two comments. You remarked earlier about the question whether regulators would allow the use of unlicensed test results. There are a few tricky issues there, but let me say that we are already on record with both our March '98 and September '98 policy allowing the use of the investigational RIBA-2 whenever it became available.

There was the underlying legal concept, however, that that test subsequently became licensed, so it was for all intents and purposes the equivalent of a licensed test.Ê And there is another line to cross if we go beyond that and accept results which either never were submitted for license or never became licensed, which would include the in-house testing provided by Chiron for RIBA-1 or RIBA-2 as well as other forms of testing that existed early on such as the Abbott neutralization test.

My view on that subject is that this testing is in essence clinical diagnostic testing--it's not donor screening; it's not linked to donor re-entry--that we ought to look at it from the point of view of public health testing, and we ought to hold it to the clinical diagnostic standard, which basically accepts home-brew assays if they're performed under the controls of the CLIA '88 act.

So basically if you have a CLIA certified lab which is, in essence, what the Chiron lab was or the Abbott lab was, then I think for purposes of public health testing, clinical diagnostic testing, we really can get off that dime. So I don't think that that should cut down the debate. That's not to put aside some consideration of the accuracy of testing which was being done. But I don't think that we have to simply blindly say if it was not licensed, it was not good. Just to try to clarify that.

The second point that I'd like to raise with you, and it's just for comment, I think that PCR data are very important in telling us about infectivity. But there's a fly in the ointment with the lookback issue, as you well know, which is that you may be PCR negative at the time antibody tested. The antibody result proves you were infected, and the issue is were you infected at times previous when you may have donated.

And in the lookback scenario, if we're to be consistent with the decisions that have been made about limiting the lookback to 1988 based on the limit of record retention, then you're talking about going back between two to four years for results that were determined anywhere in the window from 1990 to 1992, looking back at transfusion records to 1988. Okay?

So the real question is: If at the point of determination PCR was negative, what is the likelihood that the donor was infectious two to four years prior? And that I think would be the correct way to frame the question.

DR. BUSCH: Right.

DR. EPSTEIN: So a little bit, my inclination would be to try to make the decisions based on the RIBA data, putting aside the question of the PCR data. I think the PCR data are informative, but unfortunately they don't answer the most relevant question.

DR. BUSCH: There are a number of publications, and actually a review paper that I think was published in Lancet about a year ago, looking at the predictive value of RNA for various transmission vectors or routes of transmission. Actually, virtually all the lookback studies that have had RNA data on the donation and asked the question of was RNA on the donation predictive of whether or not transmission occurred, have shown that it was virtually--in fact, to my knowledge, I don't know if there's a single RNA negative donation that was associated with a transmission event in the published literature.

So I agree with you the principle is right. Most of these people who we see as probably RIBA confirmed but RNA negative, I think they were infected at some point, but it's probably 10, 20, 30 years ago. We're talking about--

DR. EPSTEIN: But that's the question. Was it two years ago?

DR. BUSCH: Again, you know, I think there is data that addresses that question in terms of lookback from various regions of the world that has failed to demonstrate lookback from RIBA positive, RNA negative donations.

CHAIRMAN CAPLAN: Yes?

DR. PENNER: I'd like to commend Mike for this, too. I think he's just done a tremendous job of pulling all this information together, and I like the fact that it's from multiple centers and from independent laboratories. I don't want to argue with you on the data as it comes through.

But one item, though, I'd like to just maybe clarify for those who didn't understand totally what was going on here. It's kind of like looking at a fingerprint and you have one loop to look at, and that one loop may identify your culprit, but it also can identify about 500 other culprits. And if you measure two loops or three loops, then you've got a better chance of at least identifying your culprit. So that's what we've been doing with each generation, as Mike explained pretty technically. It's made a major change then in being able to identify this virus and not just say it's 500 viruses that might have been encountered.

Looking at that data, when we originally set up the EIA to begin with, it was very arbitrary. If I'm correct, I think you said we're picking up about 80 percent of the true positives with the EIA set at 1.

DR. BUSCH: Right. Based on the clinical trials of the second-generation test.

DR. PENNER: And so had we set it at 0.5, for example, we might have picked up 90 percent. But we don't know that. All we're saying is it was arbitrary, so--

DR. BUSCH: That's right. I think in truth the first-generation assay with very restrictive antigenic representation missed that 20 percent of donors, predominantly because those donors were infected with other sub-types of HCV, and that those missed units were not just borderline negatives that if you'd simply push the cutoff down, you would have picked them up. It was--

DR. PENNER: So, essentially, if I could just finish this line of thought, being arbitrary, we accepted the fact that we're going to miss some at that point, just in recognition of the problems we had with the assay, that it was only going to be able to do so much.

The other aspect, though, that I think comes up is I'm setting it at 2.5 and 2 and 1.5, I like the idea that you've gotten at least--giving us a perspective to the amount we'll miss. And since we're really dedicated to not allow any patients to be missed, if possible, then the question really comes down for this group to decide, I would think, as to what is acceptable or reasonable in view of the fact that you have an assay to begin with that is not going to pick up every positive donor and how many positive donors can you really get at at this point?

DR. BUSCH: I agree. That's the crux of it.

DR. PENNER: And I just like the fact that we've got some data--

DR. BUSCH: A couple comment--

DR. PENNER: --the cutoff.

DR. BUSCH: I disagree with the term "arbitrary." I think there's always a balance in setting a cutoff, but those cutoff distinctions are set in close conjunction with FDA based on extensive data on normal donor reactive rates and data from panels of transfusion-transmitted HCV and known high-risk people. So I think it's based objectively on hard data, but there always is a compromise in terms of setting the cutoff.

DR. SCHIFF: Mike, I'd also like to comment you on the efforts you've put forth.

A question about the testing for HCV RNA. They use TMA. Is TMA, which is a relatively newer technology, as sensitive as a qualitative PCR?

DR. BUSCH: Yes.

DR. SCHIFF: Are we missing some--

DR. BUSCH: No. We've retested actually a fair number of samples that had been previously tested by PCR, and TMA not only picks up all the RNA positives, but an additional subset. So in an analytical sense, this assay has a sensitivity down in the range of 10 to 20 copies per milliliter of input blood, and it's probably a lot more sensitive than current commercially available RNA assays like the Roche monitor test. The Roche tests, however, that are built now for blood screening, which will be coming soon, have comparable sensitivity to TMA. So this is actually a better assay.

DR. SCHIFF: Thank you.

DR. BUSCH: I just want to make one more response to John Penner's comment about, you know, how far down should we go. And I think what we know is that in the range of 2 to 3 percent of the general population is infected with HCV, and probably in the range of 5 to 6 percent of all patients transfused, whether or not you got blood from a known infected donor through lookback, are infected. So I think that's probably kind of the ballpark proportion of infections that one would want to strive to detect. So that the persons who were not notified were not substantially higher risk than the general population of previously transfused patients. You know, what additional notification would be warranted in the context of targeted lookback?

The other issue is this is all compromising, and the RIBA test is not perfect, and this was illustrated in the study where we actually picked up two individuals among the RIBA negatives that had, one of them definitive RNA, one of them borderline. Interestingly, the one that was definitely RNA positive had a high S/CO ratio. So RIBA-2 would not have triggered lookback, but the S/CO ratio would. So there's always some balancing.

CHAIRMAN CAPLAN: Mike, I just wonder if you want to comment, before I go over to Keith. You come down in the paper, on page 14, which if you have the manuscript you might want to take a look at because it's probably going to be something like a recommendation that might come generating out of that language. But you wind up recommending a 2.5 what you're calling S/CO ratio as an appropriate trigger basically to use given these problems of sensitivity and specificity that confront all tests.

One of the things you say in the paper, too, is that you're also relying a bit on other outreach efforts to notify people who might be missed throughout all this. And you've heard CDC comment about what they are planning to do in terms of working with groups and patient groups and so on to notify--try and get awareness going about who might be at risk within high likely to have been transfused populations.

Having heard what Dr. Margolis had to say, seeing those slides, do you feel pretty confident that the risk/benefit ratio--are you still comfortable--are you more comfortable having heard what they plan to do about using that as the backup or the safety net to the decision to use the 2.5 trigger?

DR. BUSCH: Yes, I think that's the critical additional piece of understanding that let's us be comfortable with these compromise positions.

DR. HOOTS: I also would like to commend Mike for what looks like an extraordinary amount of good work.

I was trying to do some quick number crunching, which has probably no relevance to reality, but based on all the numbers we've heard over the last few years, the transfused HCV community, what percent fell below screening, blah, blah, blah, and it seems like--and then all the difficulties of doing hospital-based lookback and the miss rate based on your historical data and others that Jim had done. It seems like adding this nearly one log sort of specificity is a tremendous potential if it could be applied; that when you get down to the real numbers of people, that that could be a significant number of people. And I think it's encouraging to think that if this could be done--and, again, we haven't talked so much about the logistics, but if you're down to numbers of individuals, if you take--and the way I kind of came up with this was taking the 350-odd-thousand who are supposedly transfused and still alive, multiplying out the dead patients below--before 1992 that we heard and that sort of thing, it seems like that would make a substantial number of people, even with the inefficacy of trying to do that, be targeted and actually leave. So I think that's really helpful.

I don't know that. It just seems when you start doing--and, again, all these numbers are obviously very soft. So you can't say, well, is it going to be an extra 300 people or an extra 3,000 people? But it's certainly enough people that in adding the specificity but avoiding all the huge work that would inevitably go down the drain with nobody being identified, I think this is very, very helpful.

DR. BUSCH: On that point, I've actually run some numbers myself. What I proposed to do is to check them with Miriam and Howard and see if we're on the same page. But I think it's interesting to do just what you said, look at how many notifications would occur were we not to do something like this from that first year of testing.

DR. HOOTS: Right.

DR. BUSCH: And then, you know, how many would occur if we were to set some cutoff and what the probability, given that you're going to notify or not notify, that those people were exposed or not. You're absolutely right. You'd prevent hundreds of thousands of unwarranted notifications at the cost of perhaps a few thousand exposures.

DR. HOOTS: That's exactly right. That's the kind of number I came up with.

DR. GUERRA: I also want to commend Mike and your group. I think that this really brings some science into what has been a very complex set of issues and circumstances.

How likely is it in studies like this, where you're dealing with some fairly large populations that are quite mobile at times and that perhaps are being served by a variety of facilities, for some of these to be mixed?

DR. BUSCH: To be--I'm sorry.

DR. GUERRA: To be mixed in terms of, you know, a donor in one center going to another center?

DR. BUSCH: Exceedingly small. Especially--by chance, we're looking at geographic--you know, we're looking at San Francisco, Kansas City, Detroit, and Baltimore.

DR. HOOTS: But in the instance of being in the--

DR. BUSCH: The same donor--again, once these donors are picked up, obviously they are sent letters. They are told they can't donate not only to the center where they gave the unit, but to any other blood centers.

DR. HOOTS: At any other center around--

DR. BUSCH: Right. So I would--although there is not a national deferral registry, the Red Cross system--I don't know if that point, but they do today--has a national deferral registry. So you couldn't give again at another center.

CHAIRMAN CAPLAN: Okay. Thanks, Mike.

Mac, do you think that coffee might be out there? Okay. Why don't we infuse ourselves with drugs and reassemble in, let's say, 15 minutes, so really be here by 11:00 sharp, and then we'll go to the presentation by Dr. Galel.

[Recess.]

CHAIRMAN CAPLAN: Well, the last issue we wanted to look at as part of dealing with lookback and EIA-1 repeat reactive donations, what happens when we're outside the realm of certain types of standardized tests, and we have got a presentation that I think will be very interesting for the committee.

Dr. Galel, why don't you proceed to tell us about your experience out at Stanford?

DR. GALEL: Yes, I have a few extra copies of my slides if there are any members of the committee that don't have them.

I'm grateful for the invitation to come and speak to this committee today regarding our experience with an extended lookback program, and specifically our use of unlicensed--the results of unlicensed supplemental testing to guide a lookback which has been extended to include first-generation HCV reactive donors.

Next slide, please? Can someone change the overheads, please?

First, I think many of you are aware that our center has a reputation for doing things differently, and that's not an accident. Our Blood Center was established in 1978 as an independent Blood Center under academic control of the Stanford University Medical School. And the establishment of such an entity was based on the recognition that the transfusion support package that's provided to patients begins at the collection, actually at the recruitment of donors, and that development of the best transfusion support package may involve modifications and innovation in the collection, testing, and packaging processes, and not just at the transfusion site, within a GMP environment, of course.

Next slide?

I think that we have a fairly unique approach to transfusion-related problems in that any transfusion-related problem is typically approached by a group of physicians, which includes physicians from the Blood Center, the Transfusion Service, physicians for the clinical services, and we bring in other specialists, such as infectious disease specialists, as appropriate for the given problem.

I think we first achieved national attention for innovation at the donor center side with regard to the treatment of cytomegalovirus as it pertains to transfusion support for premature infants. In the late 1970s, collaborative studies by Blood Center and Transfusion Service physicians in association with pediatric infectious disease experts identified transfusion-transmitted CMV as a significant cause of morbidity and mortality in premature infants, and we further established that screening donors for antibodies to CMV could avoid or prevent most of these transfusion-transmitted infections.

Therefore, our Blood Center established a program--I believe we were the first in the country that established a program to screen donors for CMV antibody and to provide blood from donors that was seronegative for CMV for patients at risk for CMV, and initially that was premature infants, and now we know it's now considered the appropriate therapy for all immunocompromised patients.

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I think we achieved the most attention for our surrogate testing program for AIDS, which was implemented in 1983. Again, this was a collaborative effort. In the early 1980s, our Blood Center and Transfusion Service physicians recognized that there was evidence for an asymptomatic carrier state for AIDS; and, furthermore, there was evidence in the literature that blood from asymptomatic carriers could transmit the causative agent of AIDS; and, furthermore, that asymptomatic carriers could be identified to a large extent by the presence of inverted CD4/CD8 ratio in testing of their lymphocytes.

So in 1983, our Blood Center implemented a screening program which involved testing of all blood donors for inverted CD4/CD8 ratio as a surrogate test for AIDS, and the results of this program have been published in a review article in Annals of Immunology reviews.

With regard to hepatitis C, again, Stanford evaluated this issue, and I just want to reiterate we evaluate every issue that comes along and decide what we think is medically appropriate. With regard to hepatitis C virus testing of blood donors, we implemented every new version of the hepatitis C test as soon as it became available, and with the implementation of each new version, including Version 3, we performed inventory testing.

From the beginning, all donor samples which were repeatedly reactive by supplemental testing--which were repeatedly reactive with a screening test were sent for whatever supplemental testing we could obtain in order to aid us in counseling our donors, which we felt was the most medically appropriate thing to do.

The issue of whether or not to do HCV lookback did not escape our attention. We discussed this internally and quite intensively on multiple occasions in 1990, 1994, and 1996, and we gathered physicians from our Blood Center, Transfusion Service, physicians for consumers of our blood products, which included hematologists, surgeons, obstetricians, et cetera, and we included infectious disease experts and liver disease experts.

The two main options that were discussed by this group included targeted lookback of recipient of prior donations, and specifically what we were considering was prior donations from donors who were later confirmed positive, and by confirmed positive, I mean a donor that was positive by any of the supplemental tests that were done, including the unlicensed tests.

Then the other alternative that was discussed was a notification campaign which would involve sending letters to all recipients of transfusions prior to 1992.

For these discussions, we used the following figures as estimate of the probability of infection. Our estimate of the probability of infection from recipients of prior donations of donors that were confirmed positive was 80 percent. Initially, this was based on data available for PCR testing of samples from blood donors who were confirmed positive by the various supplemental tests and literature which Mike referred to which shows that PCR positivity correlates with infectivity or transmission of disease to recipients. And now we know that this figure has been confirmed by lookback studies in Europe, although in Canada the number seems to be smaller.

Our estimate of the risk of hepatitis C infection among general transfusion recipients transfused prior to 1992 is in this range, and these figures are derived from several published reports, including a study by Zuck that was published in Transfusion, and Donahue, published in New England Journals, as well as testing of samples from some of our own transfusion recipients. And the incidence of HCV population--prevalence of HCV infection in the general population was considered to be 1 to 2 percent based on CDC figures.

The most striking number here is the comparison of the general transfusion recipient population to the general U.S. population, and in our opinion, there was very little difference in the prevalence of HCV among these two populations. And I would that in all of our discussions there was very little enthusiasm for a letter campaign to general transfusion recipients because the feeling was if the general U.S. population--there is no indication to test the entire general U.S. population, and it was hard to justify a very intense campaign, expensive campaign, for general transfusion recipients whose prevalence of infection was really not much higher than the general U.S. population.

On the other hand, looking at recipients of prior donations from confirmed positive donors, there is obviously a very high prevalence of infection. So that is the population that most of the discussion focused on.

Next?

Despite the apparent high rate of infection in those transfusion recipients, the group recommended in our first two meetings, in 1990 and 1994, not to pursue lookback for hepatitis C, and this was because--I guess the decisions were largely swayed by the feelings of our liver disease experts who felt that there was no effective therapy at that time and, therefore, little medical benefit to the individual to having that information. The information available to us at that time was also that there was little transmission vertically or horizontally, and, therefore, in contrast to the situation with HIV, there would be little, if any, public health benefit to identifying the infected individuals.

Furthermore, the liver disease experts had experienced some occasions of harm to the individual in which individuals who found out that they were--who were identified as being infected then lost their health and life insurance, and they felt that there was not enough benefit to outweigh the risk of this notification.

The situation changed, however, in 1996 when we had our most recent discussion, and the biggest difference was that effective therapy is now available and the liver disease experts felt more strongly that there was a benefit to these individuals to finding out that they were infected and having the opportunity to seek effective therapy. And, therefore, the committee changed its vote in 1996 and recommended that a targeted lookback for HCV was recommended on the recipients of confirmed positive donors, confirmed as I defined previously, and it was deemed appropriate as far back as records allow.

We did discuss the fact that lookback which extended back into the early '80s would be much more expensive than a lookback on later products because these records were all manual records, and the effort to identify the donors, the components that were made, and the recipients would involve going through large volumes of records and would be very labor-intensive. But the committee felt that we could not differentiate--once we decided that a notification was medically appropriate, we couldn't decide not to notify certain people just because it was more difficult to do so.

Even though we did decide to go ahead with the targeted lookback, we didn't implement the program because we were led to believe that there would be a Public Health Service campaign starting fairly soon, and we also heard that there would be an FDA memo coming out that would define the program, and we thought it was best to carry out our program in the context of the Public Health Service campaign.

When the FDA memo did come out, though, we found some significant differences between what the FDA was requiring and what we had decided would be appropriate. And we re-reviewed our plans and decided to go ahead with what we had planned. Specifically, we felt there was no medical justification for cutting off the notification process at 1988, and, again, our committee had specifically addressed this, and that there was no medical justification for excluding recipients of donations from first-generation confirmed positive donors.

We did understand t the concern about first-generation was the high rate of false positive reactivity. As I mentioned, we had performed supplemental testing on all of our donations from the very beginning of HCV testing, which is fairly unusual. At first, for about the first year of first-generation screening tests, we obtained RIBA-1, which was an unlicensed supplemental test, and you can see that there is a fairly high rate of supplemental test negative donors in this population. And then in the second year of first-generation screening tests, we obtained the RIBA-2 unlicensed supplemental test.

In summary, of all the first-generation reactive donors, just under 50 percent were positive by either RIBA-1 or RIBA-2, and just under 50 percent were negative by RIBA-1 or RIBA-2. So you can look at this in either of two ways. You can say, well, yes, there's a high rate of false positivity in this test and that almost 50 percent are negative by supplemental test. But you can't ignore the fact that just under 50 percent are positive by supplemental test, and, therefore, the recipients would be likely--recipients of products from these donors would be likely to be infected.

Our rationale for using RIBA-1 results was the evidence in the literature correlating RIBA-1 results with RIBA-2 results and also correlating RIBA-1 results with PCR results. I thank Mike for explaining all those tests to you.

I believe you've all seen a copy of this paper by Evans, which is actually from Irwin Blood Centers. This is the largest U.S. study of supplemental testing performed on U.S. blood donors, and you can see that in comparing the results of RIBA-1 test to RIBA-2 test on the same samples, almost all RIBA-1 positive samples confirmed as RIBA-2, which, again, confirms that there are infected donors in this population and that RIBA-1 positive donors are highly likely to be infected.

Summarily, the RIBA-1 negative donors are almost all RIBA-2 negative, so that RIBA-2 negativity correlates extremely well with--I'm sorry, RIBA-1 negativity correlates extremely well with negativity on the RIBA-2, which was ultimately licensed.

Next slide, please?

There's an even larger study published on French blood donors. I've given copies of these references to Dr. Nightingale and Dr. Epstein, and I have a few more copies if anyone wants them. This study is--the results are very similar to those that were found at Irwin Blood Centers. Again, the vast majority of RIBA-1 positive donors were RIBA-2 positive, and the vast majority of RIBA-1 negative donors were RIBA-2 negative.

So, in summary, almost all--from the two large studies, almost all RIBA-1 positive donors were RIBA-2 positive. That's 95 percent of them, so we felt fairly comfortable that a donor that was positive on RIBA-1 was highly likely, or just as likely to be infectious as a positive donor from RIBA-2; and, therefore, if lookback on RIBA-2 positive donors is indicated, then lookback on RIBA-1 positive donors should be medically indicated as well.

On the other hand, among the RIBA-1 negative donors, very few of them were RIBA-2 positive, and from the two studies combined, the prevalence of RIBA-1 negative donors that were RIBA-2 positive was only 2.5 percent.

We also looked at data correlating RIBA-1 results with the presence of virus as determined by PCR reactivity. As a result of three different studies published--well, two studies published in Blood Donors and our results, which are not published, and you can see that these are the RIBA results, RIBA-1 results. Among the RIBA-1 positive donors, almost all are PCR positive, and among the RIBA-1 negative donors, almost none are PCR positive.

The summary of those three studies, 82 percent of RIBA-1 positives were PCR positive, which is very similar to what you find in a RIBA-2 positive population, and only 1.5 percent of RIBA-1 negatives are PCR positive, which means that RIBA-1 negatives are highly unlikely to be infectious.

So our summary of these results as they apply to whether or not to do lookback is as follows: We felt that RIBA-1 positive donors are as likely to be infectious as RIBA-2 positive donors, and, therefore, recipients of prior donations from these donors are as likely to be infected as recipients of prior donations from RIBA-2 positive donors.

Next?

On the other hand, RIBA-1 negative donors are unlikely to be positive by what was later a licensed supplemental test and unlikely to be PCR positive, and, therefore, recipients of prior donations from RIBA-1 negative donors are probably no more likely to be infected than the general transfusion recipient population, which has a prevalence of infection of 3 to 6 percent.

So when we considered who to notify, we made the decision based on medical considerations, and specifically, we felt that the determination of who to notify should be based on the probability that that patient is, in fact, infected. Therefore, if targeted lookback is deemed warranted for recipients of prior donations from RIBA-2 positive donors, then it should also be warranted for recipients of RIBA-1 positive donors, or prior donations from those donors.

If testing of the general population of the U.S. is not warranted, that is, the population which has a 1 to 2 percent prevalence of infection, then testing of all transfusion recipients with a 3 to 6 percent prevalence of infection or recipients of units from RIBA-1 negative donors may not be warranted.

We did go ahead and proceed with our extended lookback program. We started with recipients of prior donations from all RIBA-1 positive donors, that is, including RIBA-2 reactive donors and RIBA-1 reactive donors. We're about 90 percent complete with this notification program. It's taken about six months. And I want to point out again that these are very, very labor intensive programs both at the donor center side and the hospital side, and there is no HCFA reimbursement for these programs.

The first column, which is the 1988-plus, is the FDA-mandated lookback. You can see that about half of all the components that are from these RIBA positive donors would fall in the definition of the FDA-mandated program. About 70 percent of the recipients of all of these products are deceased at the time of notification, and we stop there if we find out the recipient is deceased.

I should say this is in contrast to the HIV lookback where we proceed with trying to identify the next of kin, according to the FDA and HCFA regulations. With HCV notification, we stop and I think that is appropriate because of the low prevalence of infection among contacts of HCV positive individuals.

For the recipients that were notified, you can see that among the people that were tested, there was a very high rate of infection in about two-thirds of the tested individuals or greater.

The main point to see in this slide is that the probability that the recipient is deceased is no greater when you look at the components that were transfused prior to 1988 compared to the FDA-mandated program, and also about the same among recipients of first-generation products. And the prevalence of infection among recipients of those products is essentially the same as the prevalence of infection among recipients of the FDA-mandated program. Again, this is limited to the RIBA-positive donors.

When we had our own internal discussions about lookback, we did not plan to do lookback for the products from indeterminate donors based on evidence that there was only an intermediate chance that these donors were infected. But once the FDA guideline came out and recommended lookback for RIBA-2 indeterminates, again, we felt that we needed on a medical basis to include the RIBA-1 indeterminate donors as well because recipients of those products would have essentially the same chance of being infectious as recipients of RIBA-2 indeterminate donors.

Next slide?

So the conclusion so far from our lookback program is that approximately 70 percent of recipients are deceased at the time of notification. This is probably higher than what a community hospital would find in that the vast majority of our transfusion recipients are transfused for medical diseases such as hematology and oncology diseases. And a hospital that transfuses largely for surgical purposes would probably have a higher rate of surviving recipients.

In our experience, though, recipients who are alive--or I should say recipients of products that were donated prior to 1988 and recipients of products from RIBA-1 positive donors are just as likely to be alive and to test positive as recipients of the HCV Version 2 donors.

Next?

So, therefore, we feel it's medically reasonable to extend lookback donations prior to 1988 and to recipients of products from first-generation reactive donors, and that the specific determination of the appropriate targeted population for lookback should be based on likelihood of infection, with some consistency in medical rationale for deciding which patients should be notified.

Thank you.

CHAIRMAN CAPLAN: Thanks, Dr. Galel.

Questions? Jim?

DR. AuBUCHON: You stated that you have extended the lookback to transfusions occurring before 1988. How far back does your computerized record of component disposition extend? And how far back does your paper record extend? And how far back practically have you gone looking for recipients? 1980? 1975? 1955?

DR. GALEL: That's a very good question. I think one of the reasons that the FDA limited their regulation to '88 was because the FDA did not mandate retention of records beyond that. However, the AABB does. The AABB, since the initiation of HIV lookback, has required indefinite retention of records. So any hospital and blood center that is accredited by AABB would have records longer than--further back than 1988.

Our computerized records at the hospital side go back to 1986. In order to identify recipients prior to that time, we have to go to microfiche records, and when you're trying to identify the recipient of a frozen plasma product, which could have been transfused any time in a year, that is a very labor intensive search.

At the donor center side, the computerized records are about the same time frame. The main problem is to identify all of the components that were produced, and, again, in the early '80s, and even into the mid-'80s, the records of what components were produced and where they were consigned is all on hard copy and has to be gone through manually.

But we do have records back to approximately 1980, with a few records available prior to that.

CHAIRMAN CAPLAN: David?

DR. FEIGAL: Do you know what percentage of your patients who were positive already knew that they were positive?

DR. GALEL: Fifty percent. The total positive includes the people that already knew they were positive, so there's 26 patients so far that have been identified as positive; 14 of them already knew.

CHAIRMAN CAPLAN: Mike?

DR. BUSCH: Could we put back up the one overhead that had sort of the summary of the yield? Because I think although you pointed out that the death rate was comparable for the three groups, the other side of the coin, the proportion of recipients who might be alive and for which lookback was initially triggered was comparable for the three groups. The actual number of recipients found or the rate of finding recipients was dramatically lower for the early groups in the first generation.

DR. GALEL: Right, yes. I should say that this program was carried out under the direction of Dr. Menozi (ph), who is the assistant director of our Transfusion Service, and she provided me with this information. There is a greater difference in the number--between the number of components and the number of recipients notified.

I believe that for the extended program most of this difference is due to the number of products for which no recipient could be identified and the final disposition could not necessarily be determined. As I said, what we're using for these older units is issue records. So if the unit was discarded without being transfused, we would not find the recipient. Whereas, all the 1988 records are in the computer, and we know what the final disposition was of all those units.

So our problem with the older units is difficulty in identifying whether or not the product was transfused and to whom. So we still have quite a few units hanging out there with no recipient identified, and we may not be able to identify a recipient for some of those units.

DR. BUSCH: And I think that would bear true in every place that attempted to go back earlier. If you actually run the numbers, in the 1988 period 4.5 components would eventually find a recipient who could be tested; whereas, in the pre-'88 it's 25 components would need to be triggered--or a recipient who is actually traceable.

DR. GALEL: I would say this isn't complete data yet, but I think that the proportion would remain the same.

Yes, Jay?

DR. EPSTEIN: Thanks, Susan. I just want to comment. You know, you pointed out that the FDA recommendation limited the lookback, and that's true. However, it was consistent with the recommendation of this advisory committee after very thoughtful consideration of the difficulties of tracing older records related both to expected mortality as well as loss to follow-up, as well as the limitations of recordkeeping. And I think the general observation is that the ability to do this lookback is very intimately linked to the nature of the records that were kept, you know, how accessible are they. And that's going to vary very widely.

So I don't think it's at all a trivial point that there were only requirements for five-year recordkeeping. You know, we know that some institutions kept longer records. Indeed, there are probably institutions that have records dating back to when they became a blood bank after World War II. But those records may be sitting on pieces of paper in cardboard boxes, you know, in off-site warehouse archives. And the ability to do this really depends on the ability to trace the record.

DR. GALEL: Yes, I agree absolutely. Even if the records are available, it's not a trivial matter to use the records for this type--for this purpose.

CHAIRMAN CAPLAN: Okay. Thank you.

DR. NIGHTINGALE: For public comment, I am aware of several members of the audience who have expressed a desire to comment. I know that one of the public commenters has another commitment, a memorial service, so if I could invite Mr. Hall to present himself to the microphone, and if the other presenters would at their convenience present themselves, I'd appreciate it. If you could possibly keep your comments within five minutes, we would, of course, appreciate that.

MR. HALL: Dr. Caplan and members of the committee, my name is Mike Hall. I am here as the government relations director of the American Liver Foundation.

ALF, as you know, has 28 chapters nationwide and is a public health voluntary organization dedicated to finding preventions, treatments, and cures for hepatitis and other liver diseases.

On the assumption that brevity will be rewarded, I am going to make every effort to keep this under 5 minutes, and will make every effort to do that.

In November, you heard a very much longer statement from Alan Brownstein who is the president and CEO of the American Liver Foundation, and Dr. Adrian DeBuschelli who is the medical director. My comments are only to present a summary of what you have already heard from them. I have given Dr. Nightingale many copies. You all can have a copy, and I hope it will be read into the record in its entirety, so anther reason why we don't need to go over every single word.

The essence, I think, of what you heard from Dr. Adrian DeBuschelli and Alan Brownstein in November was that ALF strongly believes in the need for the target lookback to include those who receive blood from donors who tested HCV-positive between 1990 and 1992.

Let me read just one paragraph from this statement, and then I will summarize a few quick points. "ALF believes it is critical that the targeted lookback be expanded beyond the FDA guidance for the industry to include HCV-positive donors who are identified in the 1990 through the July 1992 time period. A timely evaluation of these lookback efforts should be conducted to determine what additional lookback steps should be applied to those who received blood prior to 1988. This expansion is important, as a lookback efforts to 1988 will only reach a portion of blood product recipients who were exposed to HCV. To further ensure maximum effectiveness and to reach all intended parties, the ALF strongly urges that these efforts be supported by a broad-based and well-financed national general notification campaign. Such a campaign should be implemented as soon as possible to alert all pre-1992 blood transfusion recipients about their risks of hepatitis C exposure and the importance of being tested. Special consideration should be given to how to explore the best ways of reaching women who received blood prior to 1988 due to C-sections and hysterectomies."

Just two final points on closing, and I understand that these are beyond the jurisdiction of this committee. However, we feel this body taking positions on these two items would be incredibly helpful to the overall cause.

First, I am sure you all know that the NIH held a consensus conference on hepatitis C, now more than a year ago, and made a series of very thoughtful recommendations on what additional research should be needed.

Our physician members spent a lot of time reviewing all those recommendations and concluded that at least $404 million over approximately 7 years would be needed, and the first-year increment of that 7-year plan would be $56 million. We would urge this body to make a statement of support for that NIH research that is needed to address the issues laid out by the consensus conference.

The other point that perhaps is beyond the jurisdiction of this committee that we would love to see you take a position on is the need for a nationwide public health education campaign to reach all Americans regarding the risk of hepatitis C. We feel this campaign should reach and be focused on target groups identified at special risk.

We also spent a good deal of time and talked with many CDC officials and feel that to do a credible job on this general campaign would require over $70 million.

Finally, we think that to keep the momentum that is necessary, we would like to see the Secretary Shalala announce a high-priority designation for hepatitis C as a significant infectious disease.

Thank you very much.

CHAIRMAN CAPLAN: Thank you.

DR. NIGHTINGALE: I see Ms. Hamilton making her way to the microphone. She will be the next presenter.

MS. HAMILTON: In lieu of safety, where is the land mine sign?

[Laughter.]

CHAIRMAN CAPLAN: They are all over.

MS. HAMILTON: Good morning. My name is Jan Hamilton. I am the Executive Director of the Hemophilia Federation of America. Thank you for once again the opportunity to speak with you this morning regarding our blood safety concerns.

Today's agenda calls for comments relative to the hepatitis C lookback campaign and subsequent notification of persons at risk for hepatitis C.

In the discussions we heard in November, we were told about the Centers for Disease Control comprehensive approach to a nationally focussed plan for the prevention and control of hepatitis C infection entitled, "A Prevention and Control Plan for Hepatitis C Infections," and the woes of finding dollars to fund the plan.

We heard about a pledged effort to continue the lookback and initiate the education plan. Because many of us know what it would mean to find after a prolonged period of time that you have hepatitis C and that it would have been better if you could have been treated early on to avoid the conversion to cirrhosis or liver cancer, this is an emotion-charged subject among many.

It is understandable that the more effort we put into finding these patients, the more expensive it is going to be. If the educational plan is implemented and thorough, people who have been transfused can be tested and subsequently treated appropriately, but we have to be thorough.

In any endeavor to accomplish a goal, there will be people who are not happy with the effort. However, perhaps in this endeavor, we can err on the side of caution and take all steps that can enhance the efforts toward wide-scale notification.

It is my understanding that National Notification Center could be ready to help with this project. We do not totally have to reinvent the wheel.

I had several questions for you today, and I am going to go ahead and tell you what they are, though most of them have been answered by Dr. Margolis.

What progress has been made in getting this massive campaign off the ground? What is the target date for launching the campaign? Will the consumer advocacy organizations be included and/or asked to assist with the campaign? Will local and State health departments be included, as suggested? Will any funds be appropriated to assist at these levels?

A deeper concern is simply which test will we rely upon, how far will the lookback really go, and most importantly, will there be follow-through.

I am not really a doubting Thomas, but there seems to be precedent for the concern. There have been promises made and promises unfulfilled in the past. We have been promised smaller pool sizes. Are they really? Is there any hard evidence that pool sizes were reduced to 60,000 or below, as promised earlier, a couple of years ago at the Shays Commission?

More recently, it was decided that all blood should be prefiltered before reaching the patient. How is that word being disseminated? How is it being enforced? Are we looking far enough and in the right places?

A few months ago, we were given the opportunity to express our preference regarding labeling of blood and blood products as related to CJD. We all came prepared with our input, although a decision had already been made because of the sense that CJD was not really a threat to the United States blood supply.

Now we learn of a new case of CJD in Utah where the young 34-year-old man has been a frequent blood donor and gave blood after the onset of specific symptoms.

While we understand that many say there is no proof CJD is in the blood supply, we need to be vigilant and keep watching. We feel Utah is a wake-up call that must be heeded.

Let us not fall into that same trap with hepatitis C. Take the lookback as far as possible. Don't get overconfident with results that seem to be definitive. Push the educational campaign forward. Funding for a massive campaign is imperative. Cooperation among Federal agencies, industry and consumer groups is a must. Let's make this an all-out war. The enemy is any contaminant of our blood supply. The attack needs to be focused and thorough, and we stand ready to do our part to help.

Thank you..

CHAIRMAN CAPLAN: Thank you.

Cory Dubin, I think is going to offer some comments, too.

MR. DUBIN: Good afternoon. It is always a pleasure to come before this committee because we always feel this is the forum we really get a chance to air out our concerns.

Let me state our position and then back up from then and explain it. The position of the Committee of 10,000 and our board met recently, along with our science and medicine working group. Some of you will laugh at this, but for the first time, members of our board, who you know in this room very well, were told that we were not being aggressive enough on this issue. We were a little taken aback by that, I might add, from our board of directors, but we are taking their advice.

Our position is that in order to effectively do this and do it right and do it ethically and serve as the prevention interest that we all seek, that C. Everett Koop-style letter needs to go out to every home in America, a "Dear Resident" letter.

As the individual from Stanford's blood bank said, we do not see any medical justification for a 1988 or a 1990 cutoff, and if we are talking about a donor cutoff from 1990, we would be lucky to get into recipients in 1988.

I think part of the problem, as we all know, is pre-this period, records were not kept very well, and there are serious problems with records.

I think rather than try to work around that or not address it frontally, we just need to say this was a problem. Between 1990 and 1997, we have tests and subsequent confirmatory tests that will allow us to do a more targeted lookback, and we support that.

The work Dr. Busch did indicates some of the ways we could do that targeted lookback and maybe rule out some of the false positive, but pre-1990, we are talking about excluding two-thirds of the potential recipients of contaminated blood, blood components that were identified by the Subcommittee on Human Resource in its report of March 5, 1998.

We believe leaving two-thirds of these people out of this lookback is not only ethically and morally wrong, it is wrong from a public health and a prevention standpoint, and we think it is a little bit of business as usual.

I think whether fortunately or unfortunately for us, HCV lookback has become a bit of a litmus test on what the system has learned, where we stand today, and whether or not we have learned the lessons of the 1980's in a fundamental way or whether or not other issues are still driving the equation.

We would applaud the Stanford Blood Services for taking a look at this in 1990 and again in 1994, but I think there are some assumptions that have been put on the table that trouble us.

For instance, equating the prevalence of HCV associated with transfusion recipients and the responsibility of a given Blood Center, whether or not to look back and notify those recipients with the responsibility of the Federal Government to notify the population about a potential or existing epidemic, we think that is apples and oranges.

The reality here is that blood banks provide a product, and associated with that product is a responsibility to notify the recipient if it is later determined that there is a problem with that product. We think that is a very different issue than the Federal Government's responsibility from a public health perspective to notify its citizens about an epidemic or a pending epidemic.

The two do not work for us. One is the responsibility that has a basis in tort liability, legal history, and product liability, and the other is rooted in public health concerns only. The equation of those two trouble us very much.

Is the implication that blood is socially owned? I do not think anybody at the table would say that, but certainly one could logically take the next step that that is the implication that blood is socially owned. Obviously, blood is a social good that we all believe is a necessary good. I do not think anybody would take that step, though, and so we find that assumption troubling because, in essence, you are really not addressing the question of I came into the blood bank or I was in the hospital and got units of blood, those units were bad. Do I have any remedy if I now have hepatitis C, whether that be a remedy crafted in a public health forum or crafted in a congressional forum or crafted in a Blood Injury Act, for instance? Which is one of the things we think need to be talked about.

One of our problems with the debate, again, is we are doing it in pieces, and we are not doing it in a landscaped perspective. We are not looking at a broad perspective, and, again, I am back to the Stanford example because it is fresh in my mind.

In 1994, a group of advisers and medical people met and decided there would be no benefit medically to telling people they had been exposed to hepatitis C and should be tested. Well, we certainly do not agree with that because I think we are pretty clear that hepatitis C is a lifestyle-impacted illness. Stress, alcohol consumption, and other things can impact whether or not you progress the disease and subsequent liver failure, and that is not even dealing with the informed-consent ethical question, which we think is pretty strong here.

I think from the Committee of 10,000's perspective, what we are saying is how much have we changed. How much has what happened in the 1980's impacted our decision-making?

As we look at it right now, we are not very pleased with the HCV situation. This has been debated for a number of years, and one of the members of our science and medicine team regularly says if it is serious enough and violative to screen for, then it should be serious enough and violative to look back at the point you develop this screening test and implement screening. Why aren't we looking back?

Understandably, in this situation, we face a situation where we are kind of between two historical periods. We have the 1980's, where we know we do not have a lot of records and there were problems and a lack of tests, and now we are into the second half of the 1990's where everybody has got much better record-keeping, with much better confirmatory tests. So this is a transitionary period.

Our perspective is we clean up the past, we do not spend 5 years or 3 years or 2 years debating how we are going to do it. We decide what is the most effective way to do it, and we do it.

We were pleased to hear from CDC that a national letter is still being considered. We were pleased to hear the progress being made at looking at it, the slides on a social marketing campaign, similar to what we have done in California with HIV, which has been somewhat successful, but I think we have still been dragging our feet for a long time.

I think there is a question of credibility. I think there is not only a question of recipient credibility and trust in the system. I also think there is a question of donor credibility and trust in the system, and I think we saw that in the 1980's around HIV when there was a perception in the donor population that maybe the Federal Government was not being absolutely candid and maybe there was more to this equation about the impact on donors.

I think we saw some drops in donor availability, if you will, as a result of that. I think we have a responsibility not only to the recipients, but I think it is to the American people, and I think it is time that we stepped up to the plate and took actions that demonstrate to the country that we mean business, and that when there is a problem, we are not going to debate it for 3 years or 2 years or 5 years, especially not when the disease we are debating is serious, chronic, and fatal in many instances.

It is time to do that, and we believe that is not happening. We are fairly frustrated with the debate, although we saw some things, as I said, that we were pleased to say today, and we have talked about a new paradigm. We have talked about the blood banking industry, the fractionators, and the consumers getting together and getting things done together in a new way. We would still like to see that happen. We are still waiting to see that happen.

We have seen some small movement in that direction, but I think we really are talking about a new paradigm, and I think what that really means is talking about what everybody's comfort zone is and what everybody needs to reach that comfort zone to ensure that we get to that point.

For instance, it is pretty clear to us that the blood banks are struggling, that a higher return for the product, if you will, would be a good thing. I think that is something we could all be working on together, talking to Congress. At the same time, there are things that would increase our comfort zone in terms of lookback, how lookback is triggered, when it is done, and how rapidly it is done, but as long as we continue to do things in this way, I think we stand in the way of reaching that place where we really get down to identifying what is needed to make the system work for all the players around the table, everyone, and then creating the structures and the systems like a Blood Injury Act, a no-fault Blood Injury Act, and other things that would allow that to function.

So, when we discover there has been a problem, the lookback is targeted, the notification happens, it gets done. There is not a perception that what is driving the bus is not just safety and people's health. We begin to move away from any perception that there are other issues involved in driving the equation that are not always on the table, and I think as far as the general public is concerned, we have to do that.

I think as far as the recipients of blood and blood products, we have to do that. I think we have to build a new kind of trust, not only between all of us who are involved with this, but the public at large, and I think we are again moving in a way that is not going to reach that goal. It is not going to get us to that goal, and I think we need to stop and look at it.

One last point. We can deal with our own perception of the morality and the ethics involved in this decision, and I think it is pretty clear to all of you how we feel about that, but I think we also ought to put that aside for a minute and talk about cost benefit to the society, in a societal sense.

We never really talked about what it costs this society to clean up the hemophilia mess, but we all know it is hundreds and hundreds of millions of dollars.

When we look at these issues like lookback, we do not really believe that one portion of this is on the table at all, and that is, if we exclude two-thirds of the potential recipients of contaminated blood, when a number of those people who were never notified and continue to do the lifestyle things that harm them, when they progress the disease and eventual liver failure, who is paying that bill? You and me, the taxpayers, the Federal Government, the society.

And we continue to do this, it seems to me, without taking that into consideration, understanding it very clearly, and doing the preventative measures that reaches those people, so maybe they can impact what happens to them.

Then, not only do we reach ethical standard that we are looking for, we reach a reduction in the spiraling cost of health care, and we reach a reduction in the cost of treating people that we might not have had to treat if we do the right thing.

So I think from our perspective in closing, we keep talking about this new paradigm, and the new paradigm is a landscaped look at what the implications of these things are in all of their angles, and a coming-together and understanding each others comfort zone and really working to attain it for everybody at this table, every stakeholder, all the interests, and then setting the Code of Federal Regulations, setting lookback recall and notification standards to reflect that consensus. I think if we do that, the impact will be fabulous for the people at this table and the American people as a whole, and I think it is long beyond the time we do it and long beyond the time we move away from the perspective of the '80s, which I think is still in some ways hanging over all of our heads.

Thank you very much for the opportunity.

CHAIRMAN CAPLAN: Thanks, Cory. It is always nice to hear someone come fresh to these issues.

MR. DUBIN: I am not sure how to take that.

[Laughter.]

CHAIRMAN CAPLAN: Experience.

The public comment certainly leads me to think that we still have some work cut out for us today in terms of making sure that we bolster perhaps the recommendation efforts to do outreach, both direct and general to the American people, and I do not want to lose sight of that as a recommendation area, especially given the CDC effort to try and organize an outreach effort that targets professionals, tries to find the at-risk groups who works with the advocacy organizations, using the blood transfusion-related transmission of what I think of as a case example or a pilot area and then taking it perhaps broader, but I hope that that is something that we might want to flag for the Secretary and comment that that really is going to require some serious budgetary support, both to get it done in the narrow sense and then, maybe as the valuative information comes in, to get it done in the broad sense.

What I would like to propose is this. I flagged this page 15 on Mike Busch's manuscript because it has a policy recommendation about trigger ratios that would lead to lookback in the Repeat EIA-1 reactive population, and the thing we were struggling with is a narrow focus. I am kind of hoping that we might be able to come to some consensus on what that trigger might be. I do not think I am betraying anything out of confidence to say that some people expressed to me a question that we might want to try and phrase a recommendation, somewhere along the lines that Mike Busch and his colleagues concluded within that paper, but maybe that gave more leeway to people who wanted to do more than that.

In other words, there is a way to do this, where you sort of say, "Well, that might be a useful cutoff or trigger to doing repeat reactive, but if someone wants to go on and do all repeat reactives because that is what they want to do, that is okay if that is kind of what they want to do." We are not trying to say this is the only way to do repeat reactives, but this is a useful guidepost, signpost to get it done, and it may turn out to be more costly for some people to do it this way than to just do them all, depending on the kind of bank they are running. The Stanford experience made me think of that, too. They may have good records and may be able to do much more effective lookbacks in some other places. So just keep that in mind. In looking at that paragraph, I would like to return there for some recommendation.

Then we have appended to your agenda a list of questions, and this is an attempt by your Chair and the staff to put the stake in the heart of lookback for all time.

If you were to look at these recommendations, you would see some pretty specific comments made here about the scope of direct notification, what is a supplemental test, even some commentary there about licensure and supplemental tests.

We have written them down. You do not have to use the overheads. We do not have to do our usual on-the-fly type thing here. This is a basis for our discussion.

I would like you to pay attention to them, consider them over the next hour as you eat lunch, be prepared to talk about them. I have told Steve that I am less sure that we should fool around much with licensure status, especially given some of the things that Jay had to say about what to do with unapproved tests, but we might just come up with a recommendation that says we want to see some prudent and reasonable discretion afforded by FDA to non-licensed tests in the course of lookback, and so we may not have to get as specific as we did here. They are not supposed to be final.

But I have a feeling, as I talked to you informally at the break, that there is a lot of consensus that somewhere in that lookback area for repeat reactive folks, that 2.5 number or something like it might be an area where we could get some agreement.

I think that some of the questions that have floated up on lookback, that Steve and I have presented to you about direct notification and what a positive supplemental test will be might be something that agencies could use and the Secretary could use to formulate some policy, and we may actually be able to get this issue done.

I do not want to lose sight of the comments about the overall education and outreach, things that the American people need to have, but I do not want to lose sight either of the fact that we can perhaps come to some closure on this issue. That is what I would like to do after lunch, to see if we can get there. If we get done early because we have a lot of consensus, that is great. I have a couple of other topics that you might want to talk about at a future meeting that I kept in my quiver, but right now my suggestion would be that you look at the last paragraph on the facts page 15, the manuscript page 14 to see if we can say something about the specific single ratio we might want to comment on as a way to get through the cost-effectiveness issue, look at the set of questions and answers about direct notification and what constitutes a positive supplemental test about guidance, and maybe we can push to a consensus on the issue of lookback. That would be no small achievement.

So why don't we meet back, if that is agreeable with the committee.

DR. NIGHTINGALE: One hour?

CHAIRMAN CAPLAN: One hour?

DR. NIGHTINGALE: 1:15.

[Whereupon, at 12:17 p.m., a luncheon recess was taken, to reconvene at 1:20 p.m., this same day, Thursday, January 28, 1999.]

A F T E R N O O N S E S S I O N

[1:20 p.m.]

CHAIRMAN CAPLAN: All right. If we could take our seats.

Somewhere it is written that if you end the meeting sooner than 5:00, you are not punished, and I do not know if that is in a biblical thing, or somewhere I seem to remember that, but my hope is--and I know it is a hope, but I would like to see us go at the issue of lookback and get done with it. I really do not want to be talking about this anymore. I would like to see this give some guidance.

If you look on your agenda, you will see the Advisory Committee was convened to consider options for implementing its prior recommendation to expand the current Hepatitis C Targeted Lookback Program to include recipients of blood from donors subsequently identified sa repeat reactive by the single antigen (EIA-1) screening test for hepatitis C infection that was licensed in 1990. So what we are talking about is considering options as to how to implement that recommendation.

As we have seen from our testimony this morning, there are a number of ideas about what we could do to implement that recommendation. One of them that I find particularly interesting and I would like to propose that we talk about it is the use of the S/CO ratio as a guidepost or a trigger to determine the appropriateness of lookback when you see a repeat reactive EIA-1.

In the paper that Mike Busch and colleagues presented, there was a suggestion that maybe 2.5 might be that ratio, such that would produce the most positive donors located accurately with the fewest false positive located.

Just so everybody is on the same playing field, and my dream of getting us to closure here, maybe we could agree that we will not talk, no matter what is going on, for more than a half-an-hour before we consider putting forward a motion about how to deal with implementing that particular reactive to EIA-1 extension implementation policy, since that is what I am driving for here.

Then, if we do that, we can consider a few of the other items that we have down on our question sheet as to whether we want to say anything about them. If that work could be completed, at the latest, by 3:00, then we would have a shot at coming back to a concern that many of the patient groups and public testimony presented and CDC was trying to wrestle with, which is the problem of public notification, both for all people who might have been transfused, whenever that was, looking backwards, and the more generic problem of what to do about the hepatitis C problem when it is not blood-based, which is not our problem, but clearly we are trying to perhaps urge the Secretary to use models of outreach with adequate budget.

Some people said to me, and I will just tell you, during the break, couldn't we get that letter out from Shalala or the President or whoever it is to every American household. My own feeling about that, just my feeling, is that if we urge budget to be made available, that is the way to get the letter out, or whatever the strategy is that will work most effectively, it is a money issue. I do not know whether it is a postcard, a letter, a TV announcement, messages beamed in from black helicopters flying over your neighborhood. Whatever it is, it is a money issue.

So my own feeling is the way we get the American people notified about what they need to know, whether they were transfused in 1955 or 1975 or it cannot be found by our lookback strategy, is to urge that this problem be treated seriously and that monies be appropriated. That obviously involves Congress, as well as what the Secretary is going to do. So my feeling is there that we might want to make a strong recommendation along those lines and then let that sort out.

Last comment. I do not think, even though Steve and I are in agreement about this, that the licensure issue on your question and answer sheet, I will just say for the record, I am leery to go there. I do not want to take away appropriate discretion from agencies about how to figure out what to do with licensed and unlicensed tests, and I think FDA is going to have to make some judgment calls about what to do, and if we try to write that here, we will really not do as good a job as they are going to do.

I think we can urge them to come up with reasonable and prudent standards that facilitate lookback, and that that is what we want to see done and that they should be thinking, as they try to decide what to do with unlicensed tests from long ago, but that is the goal is to facilitate lookback and then let them perhaps make it specific to requests or whatever, but that area, I personally am a little skeptical that we ought to try to micromanage.

Maybe with that preface, if people think it is reasonable to spend the next half hour talking about specifically how to implement our recommendation about lookback, is it the S/CO--the way I wrote it here, just looking at Mike's paper, I just changed it slightly--the use of S/CO ratios to determine the appropriateness of lookback for HCV, EIA repeatably reactive donations, for which RIBA-2 data is not available is warranted, and we believe a ratio of 2.5 is appropriate.

I do not mean that to say that if someone wants to look back at everything, they cannot. I mean, what we are trying to do is to say that is a reasonable standard to go to. If you are trying to figure out what to do, you may certainly go further than that, but that may be a good place to begin if we are in agreement. For about 30 minutes, let's try that.

DR. PENNER: Could Mike put the transparency up for Table 6A, which has the breakdown?

CHAIRMAN CAPLAN: Of the ratios?

DR. PENNER: 1.5 and 2.5 as to numbers of individuals that will be positive and sensitivity and specificity.

DR. GUERRA: Before they go into that, I wanted to ask Jay if this S/CO ratio--and being introduced for the first time, working in public health, it is not one that we use with some application in public health, but I see it here that it has tremendous application. What other use has it had in other assessments of risk for different population groups related to blood, blood products? Did this come up in the HIV, especially before the tests were available?

DR. EPSTEIN: Well, the agency often looks at the sample-to-cutoff ratio as part of test kit validation because it speaks to the question of where should you set the cutoff.

You are asking, though, where else have we applied that knowledge. Well, we have often utilized the signal-to-cutoff ratio when we have looked at testing error problems where there may have been a problem with three agents and where a manipulation of the cutoff might correct for a sub-potent reagent. That would be one example.

In the HIV area, part of the question that arose early in 1985 and 1987 was a validation of the Western blot, and there were papers published showing that there was in general a correlation between the S/CO ratio of the ELISA and positivity of the Western blot, exactly similar data as Dr. Busch showed for hepatitis C, but the conclusion was that we needed to rely on the greater accuracy of the blot because you did have this subset of low S/CO ratios where you still had had true positive.

I do not think that we have ever used the ratio itself in the diagnostic mode for hepatitis C or for HIV. The PCR is, of course, an evolving target, but there, the viral titer is reflected in the signal strength, and that is thought to have clinical implication, being able to lower titer, even if you do not eradicate virus. So there, that is analogous because it is a signal ratio, but it has a different meaning.

The idea here is that the antibody reactivity is an indirect measure of disease activity. It is not a straightforward correlation, and so, for that reason, we see it as a quintal test. It is either there or it is not there, and we do not make a lot of the signal strength, generally speaking.

The other issue that you get into is accuracy. As the signal-to-cutoff ratio goes down, the reproduceability of the screening test result also goes down, and that becomes an issue sometimes in trying to figure out whether a result was reliable. It is sometimes important to ask how reactive was that sample.

I do not think that there is any current general public health policy regarding screening tests where we used the ratio per se, other than to decide where to put the cutoff when the kit is licensed.

CHAIRMAN CAPLAN: Jim?

DR. AuBUCHON: I can offer a practical example, as alluded to this morning.

In New Hampshire, State law precludes us reporting a positive or reactive HIV test result until confirmatory testing has been completed. That will usually require 1 to 2 weeks for the sample to transit to the State laboratory and for us to get results back.

The physician may not have that luxury of time and may need a result quickly. If the result is negative, it is negative and reported. If it is repeatedly reactive, technically we cannot report that out to the physician or to the patient's chart.

We can, however, and do counsel the physician that a reactive result that is barely above the cutoff is most likely going to return as an indeterminate or negative on confirmatory testing, and if it is strongly positive, it is likely that it will be positive on confirmatory testing. That provides some of the information that they need to move ahead within the next few days.

DR. PENNER: I would like to commend the Stanford presentation and the group for having really taken the bull by the horns and gone ahead and dug out and continue to dig out as much information as possible.

I had asked to have 6A up just to take a look at numbers, and if we are correct, from going to 2.5 to 2, there are 32 patients of that 1,300 that would be missed. If we went from 2 to 1.5, it would be another 49 patients.

I do not know what the denominator is that we are really talking about for the country. Are we talking about 13,000 possibly or 130,000? Then we may be talking about 500 patients versus 5,000 individuals who would not be notified. I would like to get a fix on the numbers, on the people that we are talking about, instead of those big numbers.

DR. BUSCH: If these are the numbers that I have worked up, and I bounced them off Miriam, I think we are in the same ball park as the data that she summarized probably at the last meeting.

If we focus on that first year of EIA 1.0 screening, which is the period where we do not have RIBA data, and then assume that there were about 13 million donations, the repeat reactive rate during that first year, I have seen numbers in the range of .7 and .8. If we assume that probably 70 or 80 percent of those repeat reactive donors were repeat donors, because the blood supply had not yet been called of repeat donors who were reactive--in general, 80 percent or so of all donations are from repeat donors--perhaps this is an overestimate. So, in a sense, it is conservative.

If we assume that we had .6 percent of these 13 million donations were HCV repeat reactive, repeat blood donors, i.e., those who would trigger lookback, that would yield 72,000 repeat reactive repeat donors.

From the data from Kansas City that was in the paper that I showed, on average from those first-generation donors who would trigger lookback when they track their records, they had four distributed products. So four notifications would occur per donation. So that would be 286,000 notifications.

Given these assumptions, that would say if we were to simply require triggering lookback based on repeat reactive EIA, we would be triggering out 286,000 hospital notifications, which would in turn translate close to this number of attempted patient notifications.

DR. SCHIFF: It is actually 288,000, a little math problem there.

[Laughter.]

DR. BUSCH: Of these 288,000 products, if we looked at our rates of positivity, about 30 percent of these would be true positive based upon the data we saw today.

So, if we trigger these notifications, these recipients would get a letter that would say in essence that we know that there is some evidence of risk and approximately a 30-percent probability that you receive blood from a donor who was in fact antibody-positive.

If instead of that we were to do the sort, as we just indicated, about a third of these 286,000, or 95,000, would be confirmed positive based on the data, and two-thirds negative, 191,000.

John, if you could just push that up, the overhead, then people can see it as we move down it.

So, then if we use the 2.5 cutoff as just a working point for the discussion, that would say of these 95,000, about 90 percent of these would be over 2.5. So 85,000 of these would be notified by the over-2.5 cutoff, and 9,500 would not.

On this side, of the 191,000, again, about 90 percent of these would not be notified, but 19,000, 10 percent would have an OD greater than 2.5. So they would be notified. 172,000 would not.

So, from this strategy, greater than 2.5, if you sum this up, 104,600--and now I am mixed up in terms of Gene's comment, but approximately 105,000 recipients would be notified, triggered from a greater-than-2.5. For those recipients, the probability of true exposure to HCV seropositive donations would be 82 percent, so a much higher probability.

On the other hand, the less-than-2.5 would avoid notification--this should be 181,400. So close to 180,000-plus donations would not trigger lookback, and for those recipients, the probability that they received a donation from a subsequent RIBA-positive donor would be about 5 percent.

The concern here, obviously, is these 9,500 that may not get notified, and using the data that Susan showed us from Stanford, what they saw for that period of first-gen-triggered notification was that for every consenting negotiation they initiated, only 1 in 10 resulted in finding a recipient. So that would argue that if that bore true nationally, of these 9,500 notifications, half of the patients or some percentage would be deceased, and the other half, the majority would not be traceable, either due to record unavailability or inability to find the recipient.

So that would say that the failure to trigger these 9,500 notifications could result in about 950 recipients who would have been contacted were this group notified and not being notified. Of that group, you could further factor down that 80 percent were infected, and half of those who were already infected already knew they were infected.

So, in terms of notifications that would not be triggered, that would result in a newly identified infective recipient--

DR. PENNER: Around 500.

DR. BUSCH: Around 4- or 500.

DR. PENNER: If you move that up to the level two, you would cut that down by about a third. So it would be about 300.

DR. BUSCH: So it is probably something like that.

DR. PENNER: I am recognizing that none of these tests are that super accurate, and there are always mistakes and problems. When we set the original level at 1, that still missed a number of people.

I am willing to accept that perhaps we are not going to be able to get everybody notified, and there are some limits. I guess I would feel more comfortable, though, trying to get as close as I can, and I see the big breakpoint is at 2 because, when you go to the 1.5 level, suddenly then you get a very large number of individuals who have not been infected and are so-called "false positive." So the big change occurs at that point. Whereas, I see the difference between 2 and 2.5 is not too great for the number of false positive, but still leaves us with, unfortunately, a number who perhaps should be notified and cannot be and that might be in the neighborhood of several hundred. Those are my concerns.

CHAIRMAN CAPLAN: What we are talking about, it looks like there might be 100 to 150, if you move from 2.5 to 2, who would be notified, who would not have been, and you are probably talking another additional 75,000 notifications to get them or something? Is that how that roughs out?

DR. BUSCH: It would be 10 percent of those 180,000 notifications. So that is about a 10-percent increment in specificity.

CHAIRMAN CAPLAN: All right.

DR. BUSCH: So that would be 10 percent, about 200,000.

CHAIRMAN CAPLAN: 20,000.

DR. BUSCH: 20,000. So picking up those couple hundred additional infecteds would result in another 20,000 people getting a letter who probably were not truly infected.

CHAIRMAN CAPLAN: Numbers, the bane of little minds.

Go ahead. Dana?

DR. KUHN: That answered a great question that I had because I was going to ask what would be the numbers who would be notified who would be true positive and what would be the margin of error, which I think you said was about 10 percent, if I correctly listened to your presentation, that that could be a margin of error, and then how many would be spared the trauma of being notified of having a false positive test. So that answers my question there.

Going to another question that would be an important part of knowing this is the lookback using the EIA-1 test and then how much would we save by using a confirmatory test, the RIBA-2 test.

DR. BUSCH: Just one point, I have worked the number. With the 2.5 cutoff, what you are doing, if you run the numbers, there would be 452 false notifications prevented for every true notification that did not occur. That is at the 2.5 cutoff.

So, in other words, for every recipient who does not get notified that theoretically could have benefitted from the notification in terms of would have been determined to be infected by the program, 450 false notifications could be avoided at that bottom. It is basically juxtaposing that number at the bottom end, which was about 400 recipients who could have gotten infected, where we did not notify everybody who did not because we did a cutoff at 2.5 versus the 180,000 or so.

CHAIRMAN CAPLAN: It is fair to say, just to keep these numbers straight, that even if we looked all the way out, some number in the Stanford study was 50 percent, but some number will know. More ratio does not capture that.

DR. BUSCH: The other thing that I think Cory echoed clearly was a strong basis for many of us feeling first-gen lookback on balance was not worthwhile. Even with first-gen lookback, two-thirds of the recipients exposed to blood products and infected are not going to be found through targeted lookback. So all of this has to be in the context of the fact that everything we are doing is only going to catch a small proportion of the overall recipient pool.

DR. PENNER: I do not think that is an argument. You are not worried about those who are getting at least alerted to the fact and they turn out to be false positive. There is an alarm feature there, but I think we really are dealing with the people who need to know so that they can change their lifestyle and perhaps get treatment.

DR. BUSCH: Right.

DR. PENNER: So our focus ought to be directly on that and I do not think on the other.

DR. BUSCH: That is what I was addressing. As Cory said earlier, two-thirds of the recipients who got HCV from transfusions, the donors did not come back even for first-gen lookback.

DR. PENNER: Yes, and we will miss those, and I think all you can say is best effort and you try to do what you can.

DR. BUSCH: That is where there general campaign has to be strong.

In terms of the other question on cost, these samples are not available for further testing. So there is no option to go back to those specimens and do this RIBA testing.

DR. DAVEY: On that point, I think it is worth considering.

First, I would like to say I think this is an elegant solution to the problem we have been wrestling with, the S/CO ratio and the public education, but I think we do have to consider the workload that may be involved. If we are talking 72,000 reactive repeat donors, using Mike's number, that are going to have to be looked at, that means that we are going to have to go back to the test records, the test tapes, and correlate probably manually 72,000 test results with whatever the S/CO ratio is. That is a big job. It is a really big job. I think we have to consider the time involved that that is going to take, which is going to be considerable, the manpower that is will also take, which will be probably considerable, and the expense that will be involved. It may well be worth it, but there will be a price to pay.

DR. EPSTEIN: Along these same lines, another way of conceptualizing this is where does the burden fall. If you go all the way to unconfirmed without checking S/CO ratios, the entire burden falls on the Transfusion Service because you have a huge number of notifications.

If you go the other way, where you attempt to clarify the status of the donor either by reviewing a record of a supplemental test or a record of an S/CO ratio, you are adding a burden on the blood collection organization.

So part of what is really going on at the practical level is the hot potato. It is shifting where the burden of the work falls, and that is above and beyond the issue of impact of false notifications on recipients.

DR. PENNER: Are you saying that we are less effective than Stanford, that we are unable to rise to the challenge that this university has taken on and been able to complete, as well as the Canadian government and the United Kingdom?

DR. EPSTEIN: First of all, the situations in Canada or the U.K. are totally different. They have national health care programs. They have lifetime medical records, and they are able to do this kind of recipient search more effectively.

The question whether blood banks in general can do what the Stanford University system was able to do, I think is an open question. I am not sure that what Stanford did could be mandated as the standard because the condition of the records is going to vary quite a lot. The way that the integration exists or does not exist between the collection establishment and the Transfusion Service is going to vary a lot.

So I think that although it is easy to point to the model and say if they could do it, why can't everybody do it, but I think it is in fact a little bit more complicated than that.

The ability to do it is intimately linked to the condition of the records and the manpower that can be brought to the task.

DR. BUSCH: I think it is important to point out, Stanford is a small Blood Center that is linked to the hospital. All the blood they collect is issued to their own Transfusion Service, distributed from their own hospital. So they are even in a better situation than Canada or others. They basically have total control of the distribution of all their products.

MR. ALLEN: I am just curious. Going back with all the other issues that this committee has dealt with in years prior, has there ever been any polls regarding consumers, whether or not they want to be notified even if the letter does not apply to them versus not being notified?

I have been hearing lately about the cost and the burden of the work, and I have not heard anything about the burden that this new issue might put on a consumer who is already dealing with another issue. So I am just wondering about that.

DR. AuBUCHON: I do not have the data specifically in the form of a poll. However, Dr. Paul Holland, who is the director of the Blood Center in Sacramento sent a letter several months ago to Mike Busch and myself talking about their Blood Center's experience with lookback when they performed it on an experimental basis in the early- 1990's.

They made the point that when they were able to identify a recipient through the hospitals and they were able to document that the recipient was alive and did get the letter, two-thirds of the time, the recipient did not seek testing. So the point that Dr. Holland was making in his letter was that that is in essence is a poll. Apparently, two-thirds of the people did not wish to get tested or did not wish to follow it up.

I am not saying that those two-thirds should not have followed it up, but they did not follow it up.

MR. ALLEN: To me, it is different if the consumer chooses not to be tested once they have been notified versus not being given the benefit of notification at all.

MS. ALTER: Just two things. The first is that Stanford did notification based only on RIBA positive. They did not have to go back to records to determine what their sample-to-cutoff ratios were. So it is different than what we are discussing here.

The second had to do with we did do some focus group testing of transfusion recipients, and I say the "we" loosely. It is interesting. Their reaction was a bit different than I certainly expected. They said, "But we feel fine. Why should we be tested?" That was reflected in the messages, the content of messages that Hal put up this morning saying that you have to educate them about the disease in order for them to understand the need to be tested.

Unfortunately, they were not asked would you like to have been notified or would you like to be notified of this. So we cannot answer your question directly.

DR. GUERRA: I think the other concern that is going to drive some of this on the consumer side is that there is certainly a growing cadre of attorneys that are out there chomping at the bit to take information to the larger community.

One firm in San Antonio in a period of about a week after we took information to the community as part of a community-based campaign, they received over 300 calls, they told me, from people that had received blood transfusions that wanted some legal advice.

DR. KUHN: I think when you talk about consumers having the right to be able to make that choice of whether they will be tested based upon the information that they receive, that is very important.

I understand what you are saying and what CDC is saying, that they have done maybe some pilot support groups to find out that people would say they feel find, but I understand with my work that I had done with people with HIV, when they were given the option of being tested, many of them said, "Well, why should I? I feel fine." So we are dealing with the same kind of mentality.

The main thing is, are we giving these people the option and the education to know what is available to them and what they may be tested for or what kind of positivity test they had, and I think that is the issue, are we giving them that availability.

CHAIRMAN CAPLAN: One thing I would say about informed consent, we give out informed consent forms all day long at Penn. We have studied them a bit now, doing some of the first informed consent studies, and they are lousy. People do not get informed from informed consent forms. We all know it, but until we show some numbers, we do not want to believe it. We will have some numbers, and they do not.

It leads me back to this other point. The reason I keep harping on the budget for public education, professional education outreach is notification and lookback that goes on in a vacuum I fear will not produce much. Notification that goes on in the context of an aggressive public education campaign has a better chance of leading to an informed choice.

So, just sending letters through your mail-drop saying here is an opportunity, get yourself tested or there is reason for you to be concerned, personally I am skeptical about that, but I think if the campaign for public education, whether it mass mailing a letter to everybody and then doing the lookback in tandem or working with doctors and at-risk groups first and then expanding it out, that has to be there. Otherwise, what Larry and Dana are talking about, you do not just give somebody an opportunity. It is like Ed McMahon say you won a prize. You sort of get skeptical, even though the announcement is there that you won, because you do not really have a context for it.

I think the context is going to be very crucial here that we have to push both sides of this or the lookback will not be effective. Wherever we set this number is what I am pushing on.

Jim?

DR. AuBUCHON: I have a couple minutes of comments, and then, if I could, I have a motion to offer, if the committee would like to consider it.

The assistance that further scientific delving can offer us in improving the efficiency of lookbacks, such as what Mike has done this morning or what Stanford has talked about in terms of applying RIBA 1.0, it can certainly be very helpful, and if we had access to all of those data, we would be able to become more efficient and more productive.

However, we all recognize that any of this targeted lookback has limitations, limitations in terms of how far back the records go, limitations that Rick Davey just mentioned in terms of being able to pull up the data to determined the S/CO ratio. This all involves resources. Resources are not unlimited, unfortunately. We all wish that we had now the capability of identifying all transfusion recipients so we could contact them easily, but we do not have that system in place in this country.

I think there has also been recognition today that there are some costs to notification of those individuals who were not truly exposed to an HCV-infective unit, the psychological cost, possibly some personal financial cost for those individuals.

I think as a committee, we are approaching the point that we are willing to apply some science, like what Mike has done, to apply that information in order to hone down our approach to notification, with the understanding that we will miss some people. Exactly how many we can bear missing in this notification effort is open for debate, but we understand we will not have a 100-percent effective notification system no matter how we construct targeted lookback.

There was mention also this morning about cost-effectiveness considerations. I presented some data on cost effectiveness about a year and a half, 2 years ago, I believe, to this committee at your request.

Since that time, there are more data that have become available. Our most recent analyses based on published cost effectiveness of interferon therapy, of ribavirin therapy, would suggest that the cost effectiveness of HCV lookback, if Version 2 and Version 3 are included, is about $1 million per year of life extended, and that number becomes about $2 million per year of life extended if we include Version 1.0 donor testing.

I am not saying that that is good or bad or indifferent, but I will note that most commonly accepted medical and surgical therapies have a value that is less than $50,000 per quality-adjusted life year. That indicates that this is not a very effective use or is not as effective use of health care resources as many other interventions.

Also, data are accumulating from experience of other groups, other countries, other Blood Centers that have engaged in lookback. From the Stanford experience we heard about his morning, from the Cincinnati and Milwaukee experiences that were discussed at the previous meeting, and from experiences in Quebec and Denmark which are going to be published in next month's issue of Transfusion, all of these have very striking similarity in that approximately 1 to 2 percent of all notifications result in a recipient being newly found to be HCV-positive, 1 to 2 percent of all notifications, a small number and possibly an important number for those people who are found positive for the first time, but a small proportion, unfortunately.

Therefore, I think we should focus our efforts, blood bank efforts, public service efforts, where we all can do the most good. We recognize that overlapping efforts of education and lookback are important, and we can use data such as what Mike presented this morning to target our targeted lookback even better.

If we know that the signal-to-cutoff ratio is high in 1.0 testing, then certainly go ahead and notify.

I think that we should not focus our efforts in areas where we have a low probability of success. Most hospitals are not going to get very far in pre-1988 recipient tracking, Stanford possibly, a few other computerized centers possibly, but most could not.

The 1.0 EIA test that is repeatedly reactive, without any supplemental testing, is also not likely to yield very high probability results in terms of donor notification.

I think also we do need to be careful as we expand lookback to include 1.0, we do not want to give the public a message that if you do not get a letter, do not worry about it. We have to maintain our general education efforts, so that everyone who was transfused before '92 does indeed try to get tested.

Therefore, I would like to offer a motion for the committee's consideration.

CHAIRMAN CAPLAN: We are probably there on the time side.

DR. AuBUCHON: The committee reaffirms its understanding that recipients of transfusions should be made aware of the risks of HCV transmission associated with their transfusion.

The committee also reaffirms its comprehension of the situation that overlapping, multifaceted efforts are required to convey this information effectively.

At the same time, the committee recognizes that health care resources for this effort are not unlimited, and any program will necessarily fail to reach all HCV-infected recipients.

Furthermore, direct notification carries with it not only cost, but also negative psychosocial implications that gained increased prominence with reduced likelihood of infection transmission.

Therefore, the committee recommends with respect to expanding HCV lookback to include Version 1.0 anti-HCV testing; that donors testing repeatedly reactive in Version 1.0 testing be included in Targeted Lookback Program, if the blood collection agency has a record of a positive result in any supplemental HCV assay, or if the blood collection agency as other accessible data to indicate the donor is at higher risk of being truly infected for HCV.

CHAIRMAN CAPLAN: Discussion?

DR. GUERRA: Second.

DR. HOOTS: Second.

CHAIRMAN CAPLAN: Discussion?

DR. BUSCH: Yes. I guess the implication of that would be if you do not have confirmatory data, you do not have to do it, but how do you deal in the absence of confirmatory data and the absence of choosing to look further at the data to sort them into higher risk or not? Do you need to do it? Is it basically to some extent to the option of the center?

DR. AuBUCHON: I was considering situations that you mentioned from your data, Mike. For example, you said there were two Red Cross Centers that had data that you keyed in to calculate signal-to-cutoff ratios. If those data are available, then let's use them. If other centers have readily accessible data where they can perform similar calculations, let's use them, but I would think that is going to vary greatly from center to center, possibly even within one system, like the Red Cross system. Therefore, for Version 1 testing, there would be some consideration that each local blood-collecting agency would have to make as to whether or not they could provide additional information to stratify their donors.

CHAIRMAN CAPLAN: Jay?

DR. EPSTEIN: I think the decisional issue here is whether there should be lookback notification of any repeatedly reactive EIA 1.0 in the instance where the Blood Center cannot check or does not have available a further test result or a test ratio result.

The question is what is the default. I do not think it would be hard for this group to determine that if there is a supplemental test result, go with it, and I do not think that it will be hard for this group to in fact endorse some S/CO ratio. We all figure out our beltline, and there will be some consensus.

The decisional question is what do you do when you have neither. At that point, is the default that you notify because you had history of repeat reactive, or is the default that you do not notify because you have no basis to improve the specificity? I think that question needs to be isolated.

CHAIRMAN CAPLAN: What Jay just said happens to be, if you looked on your question and answer sheet, No. 4 under Roman Numeral I. It says do not proceed with direct notification unless the reactive ratio is equal to or above a certain value. So we tried to default that said do not, that way. That is a proposal, and we did not come up with the number, but we were saying indeterminate situations do this.

I do not think that, however, is in Jim's motion.

DR. BUSCH: But Jay is saying a different thing. What if you do not have an S/CO ratio?

CHAIRMAN CAPLAN: But that is not his motion.

DR. EPSTEIN: And the problem that i have is that in truth, everybody has access to an S/CO ratio. It is mandated by FDA that we retain records from the original screening. I support the consideration of the workload issues. Again, the issue is the shifting of the potato. Is the workload going to fall on the Blood Centers? In some respects, the easiest response for Blood Centers is just to make the computer generate a list and ship out to hospitals all 900,000-whatever notifications. That is a snap of a finger.

My concern is that the committee understand the issues and weigh in on a strong recommendation that the S/CO data be pursued. I think even within the Blood Centers, there is a misunderstanding of the burden. If you can eliminate based on S/CO, three-quarters of the triggers, you do not then have to go through all the consignee identifications, all of those letters to the hospitals, not to mention all of the hospital work around this.

So I think in the big picture, getting to that S/CO data will dramatically reduce the overall workload.

Art, I guess I felt I was responding on point because Jim's motion, as I understand it, leaves undefined what constitutes other evidence of increased risk. So it leaves open the debate what is that. Does that include a repeated reactive EIA, for example?

In other words, where do you draw the line on evidence of an increased risk? My problem with the motion is I might agree with it or not agree with it if I understood what would be captured in that bin, but I do not.

DR. AuBUCHON: By way of clarification, what was in my mind when I wrote that was that if the blood collecting agency had an experimental Version 1 immunoassay, strip immunoassay that was positive, that would be evidence of increased risk.

If they had data that were available and they could read it, enter it, and calculate an S/CO ratio that was high, that would be evidence of increased risk. I do not know what else might be out there in terms of additional information beyond the repeatedly reactive state of the donor, which, of course, got them in this hopper in the first place.

It was admittedly vague. I would anticipate that if this resolution were to pass, that definition would probably land in your lap, Jay. I understand the difficulties you would have in sorting that as well, but I anticipated that there would be some leeway here for individual blood collecting agencies to determine whether or not they truly had accessible data that they could help themselves, help their hospitals, and help the recipients where they sort out who was at risk.

CHAIRMAN CAPLAN: Yes, Dr. Galel.

DR. GALEL: I just wanted to point out that of the first-generation screening test of reactive donors, approximately 40 percent turn out to be confirmed positive.

So, if you say that you are not going to notify, unless you have some other reason to think that they are infected, like you choose to go through records, you are going to not notify a lot of people that were infected.

The FDA had previously decided that the recipients of indeterminate second generation and determinant donors should be notified, and those people are actually at lower risk of being infected than the run-of-the-mill recipient of the first-generation reactive donors.

So I would appeal for consistency here. If you think that a lookback from second-generation indeterminate donors is appropriate, then a lookback from all-comer first generation would be equally appropriate.

CAPT RUTHERFORD: Speaking for DOD, we do not wish to be put in a corner where we do not have the option to notify just based on a repeatedly reactive. If the committee decides to recommend the 2.5, that is fine. If you decide to locate the donor and bring that donor back in for testing and come up with a negative test, that is fine, but do not block out the first one.

DR. DAVEY: I am just following along a little bit on what Jay has said, and perhaps maybe a little clarification for Jim.

If I understand it, we are looking at again a tiered system of notification of 1.0 repeat reactives, and I would suggest that we certainly include all those who are positive RIBA, that we include all of those with an S/CO of 2.5 or greater, and the default would be everybody else with a repeat reactive of 1.0, which should be very few if we are mandated to keep the S/CO data.

CHAIRMAN CAPLAN: How does that square up, Richard, on the question and answer list under definition of a positive supplemental test? Do you see the questions that are under Roman Numeral II?

DR. EPSTEIN: Could I suggest that is not the place to go? Let the agency figure out which supplemental results should trigger it. The general principle is that if there are reactive supplemental results that meet some definition that FDA will promulgate, that will trigger the lookback because we are never going to ignore a supplemental.

I think what Jim is saying and what Richard is saying is that if you do not have a supplemental result, but you can check the S/CO ratio, you can limit the lookback to the higher ratios, wherever we set that beltline, and the only question that leaves on the table is, in Jim's formulation, if you did not have either piece of information and absent some other information we have not yet conceived of, you would stop. Whereas, in Richard's formulation, if you did not have available the supplemental result or the S/CO ratio, you would then notify based on the fact of repeat reactivity.

I think that that is the position that gets us closest to closure on the issue.

DR. AuBUCHON: Right.

DR. EPSTEIN: Jim, that is the point that I was trying to make. What it leaves open is, okay, so what if you do not have the additional information, are you saying you really stop there.

DR. AuBUCHON: Right. You have to find the differences.

DR. EPSTEIN: Right.

DR. HOOTS: I think you clarified it right down the line.

The other thing that does, it actually incentivizes blood collection services to find their signal-to-cutoff ratio. In other words, if they have to go way out of their way to do it, they are more likely to do it because otherwise they are going to have to do complete notification. I think that is not bad.

DR. BUSCH: I am concerned on that point. Again, from the narrow-minded perspective of a Blood Center administrator, who is strapped to just make the program function with any kind of break, even fiscal position, their easiest answer here is to ignore this tracking back to S/CO and just send out those notifications.

So I would urge that the committee put forward a stronger and perhaps FDA, some additional muscle behind, urging the Blood Center to deal with the S/CO data to preclude the downstream ramifications.

DR. HOOTS: I think you are absolutely right because they can pass the buck, and I think that is why we have to take a strong position to incentivize the former option to use the signal-to-cutoff ratio, rather than just leaving it up to them, but at least if we word it in such a way that that is what is understood to be expected, then the FDA can make it clear that that is what is expected, and still, you do not have the other people slipping through the cracks not being looked back to.

CHAIRMAN CAPLAN: Let's let Richard comment, and then we have got this motion up on the floor. We can decide what to do with it. We can decide if we want to pull back to the more Epstein-like proposal.

DR. DAVEY: Yes. I like the proposal that Jay and I kind of worked on here. I think it makes sense, and I appreciate the comments that perhaps we should be firm on that.

Just to reiterate an earlier comment, this is going to be a substantial burden on Blood Centers. It is going to take a lot of time. We are talking years. It is going to take manpower, and if there is any way the committee can find a way that will assist Blood Centers in performing this additional task on top of already the burden of lookback that is already required, I am sure it would be appreciated because somebody has to pay, and it is going to be primarily Blood Centers under this screen.

DR. SCHIFF: Art, is there a way we can amend the motion along the lines of Jay's proposal?

CHAIRMAN CAPLAN: It could be withdrawn.

DR. PENNER: Maybe Jim would accept a friendly amendment?

DR. AuBUCHON: Sure.

CHAIRMAN CAPLAN: Steve, would you like to articulate a somewhat friendly amendment, or do you want to pull it off the floor?

DR. NIGHTINGALE: I think the record would look clearer if we were to deal with Dr. AuBuchon's in part because Dr. AuBuchon had a relatively long preamble.

I think if Dr. AuBuchon wishes to proceed with his motion, I think the next step will be to take that motion, write it on a transparency, put it up here, and vote it up or down.

What I understand, I guess, the Epstein-Davey or the Davey-Epstein motion to translate to would be that a positive EIA-1 would trigger notification if a supplemental test were positive, if a signal-to-cutoff ratio of the EIA-1 test were greater than 2.5, or if no supplemental data were available.

DR. DAVEY: If neither one or two are there, then the default.

DR. NIGHTINGALE: Yes, the default, or if by supplemental data. I'm sorry. I meant if the supplemental test is not available and the signal-to-cutoff ratio is not available.

So, procedurally, Dr. AuBuchon's motion is on the floor and seconded. How does Dr. AuBuchon wish to proceed?

DR. AuBUCHON: I am not a parliamentarian, but I understand once a motion has been seconded, it cannot be withdrawn. It can be amended, however, the amendment voted on, and then the possibly amended motion voted on.

DR. NIGHTINGALE: Does Dr. AuBuchon have a copy of his motion?

DR. PILIAVIN: My understanding, and I have chaired a department for 3 years, is that--

CHAIRMAN CAPLAN: That disqualifies you completely.

[Laughter.]

DR. PILIAVIN: I actually had a copy of the book.

CHAIRMAN CAPLAN: The rules?

DR. PILIAVIN: The rules, which I never looked at, except once.

You can, when a motion is on the floor, withdraw it, with the consent of both the seconder and the person who proposed it. However, you can also rule a substitute motion or an amendment and then vote on the amendment and then vote on the amended motion. Those are the two things you can do.

CHAIRMAN CAPLAN: Robert Byrd.

[Laughter.]

CHAIRMAN CAPLAN: Okay. I would certainly entertain a decision from Jim about whether he wants to see that written and voted, or would you like to withdraw it and let us go to the cleaner version?

What I am fishing for here is I would rather see us, personally--my personal view is that if we can get the recommendation clean, we do not need to preface so much that we have got here, but if you want to move it forward and vote it--

DR. AuBUCHON: Brevity is next to godliness. Unfortunately, I am rarely there, and I am more than happy to withdraw the motion in favor of the, shall we call it, Epstein-Davey approach.

CHAIRMAN CAPLAN: The seconder was for--

DR. GUERRA: I will withdraw the second.

CHAIRMAN CAPLAN: That seemed to die a peaceful death.

All right. Now do we want to hear another motion? Do we have the amendment up?

DR. NIGHTINGALE: Since the motion is withdrawn, the floor would be open for a new motion.

CHAIRMAN CAPLAN: For a new motion, that is right.

DR. NIGHTINGALE: Does Dr. Davey or Dr. Epstein wish to make the motion?

DR. FEIGAL: While they are writing, I was thinking about Captain Rutherford's comment about not getting boxed in if you choose to notify all the 1.0's.

It seems to me that part of your perspective is that you have responsibility for the whole system, and actually, I think if you craft the decision-making that the Transfusion Service also wishes to notify everyone, then you get around the burden-shifting where the blood collection group can unilaterally decide that the Transfusion Services would like to do a broader lookback.

Now, when you have got these diffuse systems where there is multiple, multiple Transfusion Services, you probably do not have an effective way of making a decision, but that kind of philosophy would give the integrated services an option to make that decision, where you cannot be accused of shifting the burden because it is your burden either way.

CHAIRMAN CAPLAN: Yes. I was a little puzzled about getting boxed here because the recommendation--and I cannot wait to see this carefully crafted language, but it would be something like, at a minimum, with reactivity, do these things, do one, do two, and if one or two do not apply, then go to three. But there should not be anything inherent in the policy that says if you want to begin when you see reactivity, to a complete lookback that that is not--in other words, this is sort of the minimalist policy I see us constructing here.

CAPT RUTHERFORD: I took the original motion and one and two, and Dr. Epstein added three.

CHAIRMAN CAPLAN: Three gives you that, okay.

DR. AuBUCHON: Mr. Chairman, my only concern would be the ultimate characterization possibly by people outside of this room at the moment that matched your statement about minimalism.

I do not view any of this as minimalism. I think that we are looking at lookback through a number of different ways. We think everyone should be notified of their risk, and the question is just how should we do it and how should we apply our resources to get the most of how we are doing.

CHAIRMAN CAPLAN: How are we doing over there with our language? Is anything happening there while we are debating the normativity of concepts?

DR. EPSTEIN: I have some proposed language. I guess that is a motion.

The committee recommends that targeted lookback should be initiated based on a repeatedly reactive EIA 1.0 test result on a repeat donor unless a supplemental test result was performed and did not indicate significant risk of HCV infection that would be left for FDA to clarify, or no supplemental test result is available, but the S/CO ratio of the repeatedly reactive EIA 1.0 test was less than 2.5.

I will re-read the whole thing.

DR. DAVEY: As slowly as you can.

DR. EPSTEIN: The committee recommends that targeted lookback should be initiated based on a repeatedly reactive EIA 1.0 test result on a repeat donor unless, one, a supplemental test was performed and the result did not indicate significant risk of HCV infection in the donor, or, two, no supplemental test result is available, but the S/CO ratio of the repeatedly reactive EIA 1.0 test was less than 2.5.

DR. SCHIFF: Greater than or less than?

DR. EPSTEIN: Less than. We are talking about exoneration. In other words, we are saying notify everyone unless either of two conditions is met.

DR. SCHIFF: Second. Second the motion.

CHAIRMAN CAPLAN: Discussion?

Dr. Galel. I could not see you back there.

DR. GALEL: Sorry, Jay. I would suggest you add one more, except which would be a follow-up testing of the donor because some of these donors have actually been reentered based on follow-up testing.

DR. EPSTEIN: That is an excellent comment.

DR. GUERRA: I guess this also implies that S/CO ratio is one of the standards that is or will be in place in the blood industry. Is that correct, Jay?

DR. EPSTEIN: Say that again? I'm sorry.

DR. GUERRA: The S/CO ratio is something that is already accepted as a standard for the industry in whatever center they need to do this.

DR. EPSTEIN: Well, it is not currently a standard. It is an objective result of running the test, and I think we have to be a little bit careful because there is more than one test that was run, and we did not really get into a discussion of whether you are looking at Abbott and Ortho data and whether they are comparable.

DR. BUSCH: Represented both companies.

DR. EPSTEIN: Maybe we could have a comment on that.

But, no, there has not been a standard. We are simply saying you review the record of the test and examine it for this ratio. There was no prior standard set for that ratio, except that the cutoff of 1.0 was standardized.

CHAIRMAN CAPLAN: I think Fernando is also asking, if I hear the question right, are we setting up a standard of care as to inter-practice using these ratios, and my understanding is no. This is specific to this particular test issue. I mean, we are not going into policy that for now on S/CO ratios will be part of--do you know what I mean? I do not see us doing that at all.

I think in this area, we are trying to say for the lookback--

DR. GUERRA: This has a very specific application.

CHAIRMAN CAPLAN: It is a very specific application.

DR. DAVEY: It is not a test of record. It is triggering identification, and that is different.

CHAIRMAN CAPLAN: Right.

DR. PENNER: I guess I would like to reargue the point, the breakpoint as I see the S/CO ratios at 2 looks better to me because it would end up with more individuals who have been exposed to the virus at least being notified, admittedly at additional cost, but, obviously, when we look at the data that Mike has put together, it seems that that breakpoint is pretty specific and there is a big change.

I would much prefer, though, that all of the patients who have been exposed receive the notification, but I think in view of the circumstances, this might be a reasonable accommodation.

DR. BUSCH: Just to speak to that point, again, the numbers that we talked about earlier, just to re-summarize, as I just re-ran that, if you were to go from the 2.5--

CHAIRMAN CAPLAN: We are running them over here, too, but let's see what yours are. We will see if it is robust.

DR. BUSCH: What I got was if you go from the 2.5 to the 2.0, you will pick up another 2 percent of the infected donors, which would translate into about 690 additional notifications, but of those, only 100 would be estimated to be recipients who would actually be traceable by virtue of that parameter.

On the other side of the coin, that would result in an additional 9 percent of false notifications of non-infected donors going out, which would be 18,000 additional notifications to donors who were not infected.

So, to sort of juxtapose with the 2.5 cutoff again, it would save 450 false notifications per true notification. Whereas, this increment, if we go from 2.0 to 2.5, that number drops to 180 per 1. So, in other words, it is about a third. That little interval is about a third as good as the other portion.

DR. PENNER: I guess I am looking at it from the standpoint if I am one of those 100.

CHAIRMAN CAPLAN: Yes.

DR. NIGHTINGALE: Dr. Busch, we did a recalculation up here on the assumption there were 288,000, rather than 286,000 products, as you estimated again. A third were RIBA-positive. That would be 96,000 RIBA-positive.

If the cutoff was at 2.5, you would miss 11 percent, or 10,560. If the cutoff was at 2.0, you would miss 8,640, but if the cutoff was at 1.5, you would miss 4,800. If one-tenth, 1 out of 10, was notified, then you would miss, at 2.5, 1,056. At 2.0, you would miss 864, and at 1.5, you would miss 480. If one-half of those people already knew their status, at 2.5, there would be 528 people missed. At 2.0, there would be 432 people missed, and at 1.5, there would be 280 people missed.

I realize I read those faster than you might have liked, but does that appear to be consistent with your calculations? Would you accept that your calculations imply that moving from a signal-to-cutoff ratio of 2.5 to 1.5, you would go from missing 528 people to missing 280 people nationwide?

DR. PILIAVIN: Then you have to multiply that by 10 percent.

DR. NIGHTINGALE: I did that. We got it up here.

DR. BUSCH: I think that is correct, but I would strongly urge not going below 2.0 because I think the specificity loss there is horrendous.

As you just stated, going from 2.5 to 2.0, you gain, from you analysis, 90; from mine, about 100 recipients found. The other side of that coin is about 18,000 additional false notifications going out.

From my mind, I do not think that is worth it. From yours, it may be.

DR. PILIAVIN: I would like to call a vote on Jay's motion as it stands.

DR. NIGHTINGALE: Let me, as the secretary, get a clarification.

Jay, I believe your motion as it stands has two caveats. One, the supplemental test result does not indicate significant risk of HCV infection, or no supplemental test available, but signal-to-cutoff ratio less than 2.5. There was discussion about further amending that.

DR. EPSTEIN: I would entertain Dr. Galel's suggestion to add a third alternative, or follow-up testing of the same blood donor revealed a negative result on the licensed HCV 2.0 or 3.0 EIA screening test or a supplemental test result was obtained which did not indicate significant risk of HCV infection.

DR. NIGHTINGALE: Or follow-up testing is negative?

DR. EPSTEIN: Well, again, I am being fairly specific. I am saying that if there was follow-up testing, you are either looking for a negative EIA-2 or -3 because that is higher sensitivity, or you are looking for any supplemental test result not indicative of a significant risk of HCV infection, whatever that might be.

DR. NIGHTINGALE: Do you wish to clarify an interval within which the supplemental testing occurred or not? I think not, but I want to make sure.

DR. EPSTEIN: I do not think that is necessary.

DR. NIGHTINGALE: I would simply wish that stated for the record. Thanks.

CHAIRMAN CAPLAN: Well, there is a motion to call the vote. I think we can actually do this and sort of go with the two other issues, it seems to me.

Do you need the motion re-read?

[No response.]

CHAIRMAN CAPLAN: Got it? All in favor?

[Show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

DR. NIGHTINGALE: I had 10 votes in favor. Is there anyone who abstained?

DR. PENNER: I abstained.

DR. NIGHTINGALE: Dr. Penner and Mr. Allen abstained.

CHAIRMAN CAPLAN: The chair does not vote.

So we have got 10 yes, 2 no, 2 abstain, no chair.

MRS. O'CONNOR: There were no noes.

DR. NIGHTINGALE: I got no noes.

CHAIRMAN CAPLAN: Oh, excuse me. Two abstentions, no voting chair. Is that all the voting people?

DR. NIGHTINGALE: Once more, if I could.

CHAIRMAN CAPLAN: Hold them up high, though. I want to make sure.

[Show of hands.]

DR. NIGHTINGALE: Could I see a show of hands for the abstentions?

[Show of hands.]

DR. NIGHTINGALE: There are two abstentions.

Thank you.

CHAIRMAN CAPLAN: That motion carried.

The floor is now open for other motions, having pushed onto the implementation.

The Chair would be very eager to hear a framing of a motion about support of budget for public education and outreach. When CDC talked to us this morning and when we heard public testimony, there was a lot of emphasis that what can be done will be done within the confines of existing budget and whether it is a focused outreach to doctors and at-risk groups or a large national notification by mail, it is going to need money.

It seems to me if we are committed to a large national notification and also targeting the at-risk through transfusion, but in the long run, too, just the hepatitis challenge generally, we should, I believe, personally say something to the Secretary about making sure that the resources are there to do the steps necessary.

DR. CHAMBERLAND: Art, can I have a clarification? You are raising the suggestion of having the committee publicly put forth a need for fiscal support for a national letter, which has been discussed. Is this letter specifically to be targeted to the message is only to be focused if you had a blood transfusion, or is this a letter that would be wider and more comprehensive, include other risk factors for HCV? Could you clarify?

CHAIRMAN CAPLAN: Well, I have not even made a motion. I am just kicking around the idea of an outreach such as a letter. I am not even ready to say I think that is the best thing to do, but whatever needs to be done, it seems to me the resources have to be mustered to treat this as a priority of outreach, and I would be interested in how well the CDC effort goes in its focused effort. I hear the call for letters from public testimony, but it seems to me that is partly an empirically resolvable question as to what is the best way to go.

What I am more nervous about is that the resources have to be there to let it be done, whether they do it by letter, telegram. I would like to see the pot there, and I do not like to hear the rationale that it cannot be done because it costs too much. It seems to me the directive is to get the resources there to do what needs doing. That is what we should be telling the Secretary.

DR. PENNER: And you were not really talking just about blood transfusion. You were talking about more general--

CHAIRMAN CAPLAN: I am talking more general. I am trying to stay within our mandate, but urge us to slide toward more general.

MR. WALSH: In that context, prior to an actual motion, I would like to commend the American Liver Foundation for taking the initiative for their fairly aggressive awareness campaign, partially, I believe, funded by CDC. I think it is imperative that the message go out listing all the risk factors associated with HCV and not just transfusion-related risk.

I would also urge that this committee push forward a recommendation to make research funding available, as proposed by the American Liver Foundation, resulting from the NIH HCV conference, with due diligence, and that the Secretary does state that this is a high-priority issue for the American public.

CHAIRMAN CAPLAN: That one, you might want to actually take a little stab at the second one and make it into a motion there, it seems to me.

MR. WALSH: I will work on it.

CHAIRMAN CAPLAN: On the first one, I guess I would be interested to see if anyone does have some language they would like to put forward about urging the Secretary to make sure that the requisite resources are made available to treat the hepatitis C problem as a major public health challenge, so that the American people are properly notified. That is roughly what I am getting at here, those at risk.

What I am doing here is I am trying to be a little careful, like we were with the FDA. I understand that there is going to be some debate about what the beset outreach and public education thing is, and there are pro-letter writers and there are people who think it can be done by public service announcements and radio.

To me, it is the money. Nothing else happens unless there is the commitment of money. Then we can argue about piloting letters in parts of the country and see how they go and all that sort of stuff. No money, no nothing.

DR. KUHN: Art, I agree with you, and I think that what I would like to see is some kind of motion that not only do we request those funds for doing a public awareness campaign for the United States, but also in that recommendation, maybe somehow, some way, we encourage whomever this entity is going to be to consider a national letter that goes out to the American public.

That may not be a possibility, but I think it needs to be looked into, and the cost effectiveness needs to be looked into it versus maybe public service campaigns or the efficacy of certain modes of reaching the American public.

I think we need to not exclude a letter. I think it needs to have some validity to it.

DR. CHAMBERLAND: Yes. I would agree with you, Dana, that I think what you said is important at the beginning, and it was outlined on some of the slides that Hal presented. I think we all recognize we cannot rely on one single approach, one single modality to reach people, and that it really has to be a multifaceted approach, one of which one particular approach could be a letter, but on the other hand, I am sort of thinking back to the recent public discussions around the Census and sampling for the Census. People who have addresses and ways to receive letters may not necessarily be the people that are most at risk for HCV.

So I would be cautious in not wanting to hang your hat on one modality and sort of put that up there as the best way to go or certainly a high priority. It could be one of, but it should be just that, one possible approach.

The hepatitis folks may want to have a comment to make as well, since they have been struggling with this.

CHAIRMAN CAPLAN: Miriam?

MS. ALTER: Yes, we would love for you to have a recommendation urging the Department and Congress to appropriate funds for all of these activities, and we certainly support that, but, again, I think we are a little reluctant to have something so specific in there. Leave the money aside for a minute.

Unless the funding is also available for public sector counseling and testing, so that when you send this letter out, it cannot be a letter just saying transfusion recipients should be tested. It has to be a letter that gives equal weight to the importance of the other risk factors, and then people have to have a place to go.

As Hal pointed out this morning, there is no place for people to go right now unless they have a source of medical care, and that is probably the major reluctance we have at this point to go forward with a letter that would have to be very broad.

CHAIRMAN CAPLAN: That is why I was also steering off the recommendation about anything like a letter right now because, over the years, we have known from genetic counseling, from HIV testing, if you just tell people that show up and there is no place to get counseled or no further information, it is not so effective.

So, when I say put the resources forward to have an effective national notification program and take it as a public health priority, that is trying to give enough room to construct whatever this infrastructure is, to back up the notification.

You do not want to notify and then to have it fizzle because there was no place to go. That is not good. In fact, that is frustrating.

As somebody pointed out, if we have high rates in correctional institutions and stuff, they may not be getting the mail in the exact same fashion.

I do not know that we can micromanage this any more than we can micromanage as a group right now, things like supplemental testing and what is good and what is not, but I do think that from my point of view, it would be very important for us to send a clear message about the importance of the commitment to getting this risk problem and major public health problem in front of the Congress and the Secretary to take it seriously, to budget it for research and whatever the infrastructure is for notification. That is what I am fishing for here.

DR. SCHIFF: I certainly endorse what you are saying, but I would like to emphasize what Miriam has raised because I think we have got to be specific in this and recommend funding to find out a feasible way of establishing test sites.

This is what happens. You get all these people, "Well, I am at risk. Where do I got? I do not have this insurance," and Hal already alluded to that. I think we should put something in a little specific about that.

We cannot work out how to do it, but say that someone should work out a system of establishing test sites that do not exclude people who are not covered with insurance.

DR. GUERRA: I think there are some important opportunities to build into this, and one of those is through one of partnering because I think if we do this as a shared responsibility across public and private sectors and then if we could encourage the Secretary to bring into this discussion and the organization of a much larger effort, the managed care organizations, the professional societies, corporate industry with their health benefit plans, the tobacco settlement dollars that are going to be allocated in the near future, I think represent a very substantial amount of new funding opportunities in communities around the country. I think one could make a very strong case because of the lifestyle-associated conditions that sometimes affect this population.

Perhaps the recommendation should be to encourage the Secretary to begin to organizing a working group to identify the different elements that go into the construct of a national problem beyond just the public sector effort.

CHAIRMAN CAPLAN: Keith?

DR. HOOTS: I agree. I do not think we have to micromanage. I really trust CDC with putting this together.

I really would like a strong statement that says that present funding is inadequate by a log or more, maybe not in that exact frame, but that it is far, far below the needs to adequately meet this expanding public health need.

I do not think it makes any sense for us to, say, spend $50 million versus $55 million, but I think we should say that the present expenditures are grossly inadequate to meet the needs that have been identified by the U.S. public health services and its advisory committees. Just as they were with HIV, they should be expanded exponentially.

DR. KUHN: Art, is there a way that in a recommendation that we can emphasize asking the Government to utilize funds for testing sites and counseling sites?

I agree. I think that that is an important issue. However, I do think that if CDC is putting out public service announcements, that is going to warrant some fear in people, also, who watch it on television, and where are people who see that on television going to go to have those fears--

So I think it brings us down to the issue that there is a need for testing and counseling sites. So funding is going to have to be thought about putting towards in that direction.

CHAIRMAN CAPLAN: Since I see us tottering toward something here, maybe I can put a little proposal in a motion, something like the committee believes that in light of the public health challenge posed by hepatitis C, current funding is inadequate for notification, testing, counseling, education, and we could say treatment if you want to really go nuts.

DR. HOOTS: Why not?

CHAIRMAN CAPLAN: We urge the Secretary to take immediate measures to increase funding to meet this major public health challenge.

We have listed what ought to get done with it, without getting too specific. Notification is the letters and the announcements and all that, and the testing and counseling should flow, but they all connect.

I like Keith's point. That is why I am running a preface, although I hate prefaces generally, but listening to this $1-million budget thing does not move me. So I am pitching for a preface in that particular motion.

Anyway, did you get that one?

DR. NIGHTINGALE: Yes, I got it.

CHAIRMAN CAPLAN: So there is a motion.

DR. PENNER: So moved. Second.

DR. FEIGAL: Could I ask also about another venue? Much of the discussions have been part of the public sector response, which is appropriate because this is an advisory committee to the public health service, but one question that maybe Miriam or some others might want to comment on is, has there been any thought about whether the prevalence of this condition is such in the population that the kind of practice guidelines for what kinds of screening tests should do in adults has considered whether or not this is something that should be recommended.

Someone who has access to health care, who has health insurance, can get these tests done by their physicians, can get the treatment through their health plan. So far, the emphasis sounds an awful lot like this is something that you have to come out of your normal health care system and go to a special testing site and special counseling site to learn about. How do we mainstream this more?

I would imagine that in some communities, the prevalence of this is greater than the results you would get from Pap smears, for example. We would get more positive by testing the whole population for this than you would by doing Pap smears for that year on that population.

How do the practice guidelines about screening in adults come about, and is this something those groups should be looking at as recommendations as part of the overall effort?

DR. NIGHTINGALE: David, I have a comment. I have been in contact with the Agency for Health Care Policy and Research, Dr. David Atkins who works at a center whose name has recently changed, but it is the center that looks into such things.

It is not so much the role of hepatitis screening, but the priority for hepatitis C screening is under review at this time, and some of the recommendations are a bit outdated because they are based on premises that do not take into account advances in treatment at that point.

Dr. Margolis is at the podium and probably knows a lot more about this.

CHAIRMAN CAPLAN: I do not mean to interrupt about whether ACP or AMA or whoever has practice guidelines out here, the whole professional thing, but there probably is a way, with a friendly amendment, to say what that motion is, that the Secretary should work with private and professional organizations to facilitate these goals. That is what we are talking about here.

Not that I am not fascinated to get the answer, please go ahead.

DR. MARGOLIS: Well, ultimately, each professional or society has to translate ACIP or CDC public health service recommendations into their practice guidelines. That really becomes the reality, but the framework is there. I think your wording of bringing people together to do that--it is just basically taking the same thing and re-saying it into at times a practice guideline that often makes it happen.

We have seen this with any number of things.

CHAIRMAN CAPLAN: Would you consider that as a friendly amendment to urge the Secretary to--

DR. FEIGAL: Yes. I will give you your friendly amendment.

CHAIRMAN CAPLAN: Repeating what you said, to urge the Secretary to work aggressively with professional and private organizations to promulgate notification, testing, counseling, and therapy.

Other discussion?

DR. GUERRA: And explore other sources of funding. I would suggest the tobacco settlement that I think is up for grabs in some parts of the country, the States.

MRS. O'CONNOR: Art?

CHAIRMAN CAPLAN: Yes.

MRS. O'CONNOR: Over here in the corner.

One thing that I would like to add, frequently when we talk about notification or alerting people to things, we talk about it on a one-time basis, and from what we heard today with people who have been notified, why should I be tested, I feel fine, you really need to hit people over the head with the message, get it out into the general population, so that there is a discussion. Not only have they heard the message, but they have heard it a bunch of times, and maybe they know of somebody who has hepatitis. So they begin to talk about it.

I do not know if we can amend that. Do we have your amendment on the floor, Art, or is there an amendment on the floor for the work with private and professional organizations? Have we voted on anything?

CHAIRMAN CAPLAN: I think there is a friendly amendment out there that needs a second.

MRS. O'CONNOR: All right, I will second that. Then we can vote.

Could I call for a vote, too, or does that need to be somebody else?

CHAIRMAN CAPLAN: Sure.

MRS. O'CONNOR: I call for the vote on the amendment.

CHAIRMAN CAPLAN: Just to clarify, Dana was whispering in my ears, does that rule out letters or any specific thing, the way the amendment is.

No. In fact, it is meant to give a lot of leeway to make those things come together.

DR. KUHN: In the recommendation, I hate to get away from it because sometimes if you do not state it, it sometimes is overlooked. I think it still needs to be considered seriously.

I know I heard CDC talk about it, but, again, I think once you have it in writing, it is something that someone is going to visit, taking into account that, yes, there is going to be counseling, there is going to be testing, but it is a mode of notifying the American public in total, whether we know it or not, because there are people who do not have telephones, but do have a mailbox.

DR. GUERRA: And a lot that do not have mailboxes.

MR. WALSH: We are emphasizing, we are broadening the scope from just transfusions to the other.

CHAIRMAN CAPLAN: Yes, yes.

DR. NIGHTINGALE: I was asked if I wanted to re-read it or let them vote it, and I am not going to answer that question, but I am going to re-read it.

The committee believes that in light of the scope of the hepatitis C epidemic, current funding is inadequate for notification, testing, counseling, education, and therapy. We urge the Secretary to take immediate action to increase funding to meet this major public health challenge.

We further urge the public health service to work with professional and private organizations to promulgate appropriate recommendations for testing, counseling, and therapy, and to secure additional resources for these purposes.

DR. SECUNDY: That does not include the letter or the methods, which she was talking about.

CHAIRMAN CAPLAN: No, it does not, but it is the scope issue.

DR. KUHN: All Americans is what we are driving at.

CHAIRMAN CAPLAN: That is why I am not worried about not mentioning letters or PSAs.

DR. KUHN: All Americans.

CHAIRMAN CAPLAN: Yes.

DR. GUERRA: As we learned from the HIV epidemic, though, I think there is that population that is sort of invisible, who we are not going to be able to reach, those that are here in undocumented status, illegally working, seasonal streams.

DR. SECUNDY: Maybe the reference to working with organizations could be expanded to say something to the effect that in working with organizations to identify all effective methods for communicating with the public about these issues.

CHAIRMAN CAPLAN: I promise you, we will noodle that language to make sure it says all Americans and all effective means of communication. I mean, we will do that on the wordsmithing.

DR. GUERRA: And beyond all Americans, I think we need to--

CHAIRMAN CAPLAN: Right. Just land in airports and just be handed hep-C information.

[Laughter.]

CHAIRMAN CAPLAN: All right. So there is a vote out there. I guess it has been called.

All in favor of the motion, with a minor amount of wordsmithing to come?

[Show of hands.]

DR. NIGHTINGALE: I believe we have everybody.

CHAIRMAN CAPLAN: Twelve.

Any noes?

[No response.]

CHAIRMAN CAPLAN: Any abstains?

[No response.]

CHAIRMAN CAPLAN: Okay. Other items that people would like to put forward in terms of motions on the lookback question or other things that we have talked about today with respect to lookback?

DR. DAVEY: Art, I would like to suggest the following motion for the committee's consideration.

The committee urges the Secretary to consider providing appropriate support and resources for Blood Centers and hospitals in conducting HCV lookback activities. I think it is broad enough that it allows a lot of latitude for the Secretary, but it does raise the issue.

CHAIRMAN CAPLAN: Second?

DR. HOOTS: Second.

DR. PILIAVIN: Second.

CHAIRMAN CAPLAN: Discussion?

DR. PENNER: Were monies made available for the HIV in the same manner as we are talking about now? I do not recall what banks got any money to do anything.

DR. FEIGAL: You have to remember, the HIV lookback was done prospectively. There was no retrospective lookback. So it was a much smaller effort.

DR. BUSCH: There was a fair bit of support from CDC, actually. Many of the larger centers where the bulk of the lookbacks were occurring, such as New York, our own center, L.A., were funded by CDC to investigate and support the lookback efforts. It was under the guise of a cooperative agreement research protocol, but our center, for a period of about 6 years, supported all of the staff that were doing the HIV lookback program.

DR. PENNER: Jim, I did not get any of that money, did you? I think we missed out.

[Laughter.]

CHAIRMAN CAPLAN: Other discussion?

CAPT RUTHERFORD: Can we somehow include Government organizations into that? Because of the VA and DOD, if they are going to hand out money, we just might as well--

[Laughter.]

DR. DAVEY: I said Blood Centers and hospitals. Do you think that includes you, or would you like specifics? "Your Blood Center and Hospital."

DR. NIGHTINGALE: Should we wordsmith this?

CHAIRMAN CAPLAN: I would say public and private hospitals.

Other discussion?

DR. BUSCH: Just realistically, mechanistically, unless you give it more clarity where that money is going to come from and how it is going to channel, nothing is going to happen.

It would be possible, for example, for CDC to fund some of this, assuming the money they had the money given to them and earmarked for this.

I do not know whether a mechanism would be available to fund Blood Centers, for example.

DR. FEIGAL: Were funds available also for the hospitals, the Transfusion Services, or does this mostly go to the blood collection and testing part of the HIV lookback?

DR. BUSCH: At least in our region, the blood centers were funded to have nurses that would actually work with the hospitals to do the notifications. So most of the recipient tracing was actually done by the Blood Centers with the hospitals.

DR. HOOTS: Could we just clarify by saying by appropriate mechanism such as Government cooperative agreement? No, we don't want to get to that?

DR. CHAMBERLAND: I have a clarification here. CDC funding for lookback activities for HIV was in the context of a research cooperative agreement. We did not distribute funds solely to fund the operations of it, just to make that clear.

DR. BUSCH: Right. The objective of CDC on a sort of scientific basis was to ascertain what the rate of transmission was, what the impact of infection were in these recipients, the secondary transmission to sexual partners, things of this nature, which are the exact same issues as we are struggling with here. It was a mechanism, though, to support the overall context of the lookback recipient tracing acquisition program.

It was restricted to, I think, like five cities. So it was not a broad-reaching support.

DR. CHAMBERLAND: Right, and I think CDC's hepatitis branch is entertaining various possibilities of how some of that might be undertaken in the context of the HCV lookback, but my understanding of Rick Davey's motion was kind of more broad-based funding simply to fund hospitals and blood collection agencies and Transfusion Services to just do the work, to fund the people to hire. Maybe I am misunderstanding.

DR. DAVEY: The wording was purposely a bit general, appropriate support in resources. I would like to think that the Secretary, perhaps with some input, and staff could think a little out of the box here in terms of what can be done to assist the folks who are doing the job and incurring the expense. Maybe not funding. I am not specifically saying funding, but there may be other ways, alternative ways in which support can be given. This is a big undertaking. We want to do it, but I think it would be appropriate to raise this issue with the Secretary.

CHAIRMAN CAPLAN: One point I will make, before someone calls a vote on this--and if they do, then what I would like to do after that, unless there are other motions, is to think about new business for a second, just so you know where we are headed. So, if you have another motion, get ready on this lookback issue.

It may be a cry of the heart. Mike is right. It would be hard to say at that level that the Secretary would be held to account, but I do think if you pass that particular motion, then it will be up to the Red Cross and the VA and anybody else who cares to, to call the Secretary on it. Whereas, if you do not have it, it is a little harder to do.

So the leverage here probably from a real politic point of view is to have it and then we are looking for the support to invoke it.

Having said that, do I hear any motions to move for a vote?

DR. FEIGAL: Could I just make a comment?

CHAIRMAN CAPLAN: Yes.

DR. FEIGAL: Just to give you an idea of sort of what the logistics will be involved, the estimate before the lookback was expanded, in terms of the costs of lookback, was that it was going to be around $80 million, that that was the cost. Now it might be closer to 150, $160 million. That would have to be distributed somehow to the 5,000 Transfusion Services and all of the blood collection agencies as well.

When you think of the process of applying, of developing paperwork for reimbursement, of trying to capitate it proportional to the size of the program, the amount of the lookback, it would probably take longer to design more Federal programs than it would for us to discover the next viral hepatitis.

I think it is a very large logistical task, and I think it will require some thinking outside the box.

I am struck that we have had successful public health interventions in the past where we have done things differently. For example, a lot of the hypertension detection programs were organized at the county level and funded at the county level for a decade to find asymptomatic people and screen them, and that was a cooperative effort across public and private sectors.

So I think we probably do not want to be too specific, but I think if there is not money, it is going to be hard for these things to happen.

Our difficulty is we want the lookback to happen rapidly, and if we are talking about congressional appropriation and developing a mechanism to apply for the money and a mechanism to disburse it, either we think of an existing mechanism like an NIH grant that you could apply for, you are looking at an 18-month cycle to get your money.

DR. PENNER: I would agree with David. I think it would be a real mess to try to at least at this point offer anything that would be useful for the lookback on a community basis.

DR. BUSCH: I would agree with that in terms of the Transfusion Service side of this, but I think kind of partly what precipitated this was this issue of would the Blood Centers actually follow suit on the S/CO ratio investigation analysis.

I think if you are talking about the Blood Centers, you have got the Red Cross and the non-Red Cross, America's Blood Centers, which could in response to this proposal develop a request, perhaps suggest through Steve's office, that would say in order to implement this appropriately, we would need such and such a resource. So I think the Blood Center piece of this is much smaller, much more focused, and a request for some resources to allow appropriate implementation of this S/CO cutoff investigation, thereby preventing two-thirds of these notifications inappropriately going on to the Transfusion Services could spin right out of this.

DR. EPSTEIN: A part of this problem is that much of the economics could be solved by a pass-through cost. After all, the work of the collection services could be added as a charge on to blood distributed, and the work of the Transfusion Services could be added on to the Transfusion Service fee when a unit is dispensed.

You could argue that is not fair because it is future blood users paying for the problems of blood that affected past blood users, but on the other hand, you have an economic solution that is distributive, that is basically proportionate to the size of the work.

Where you run into trouble is with capitated reimbursement. I think that one major strike that could be pursued would be to essentially advocate that HCFA reimbursement recognize the need to accommodate these overhead costs of the operation of the Blood Centers.

Another point that I would make is that the total attributable cost that Dr. Feigal was discussing included together the testing and notification costs, along with the counseling, testing, and treatment costs, and the tricky point there is that they do not fall on the same party.

Nobody really thinks that it is the Transfusion Service, let alone the blood collection organization, that is going to be providing all of the counseling and medical management or cost of therapy.

So I think we are dealing with a complicated economic problem.

DR. SECUNDY: Let her worry about it.

CHAIRMAN CAPLAN: Let the Chair step forward and say the small proposal that is out there is going to bend under the force of these interesting points, but it cannot carry them right now, from Dr. Davey's.

I think we need to vote it, and then in a second, we will come back to talk about some other items in the new business area, such as this funding problem more generally for blood and so on.

I do see someone up at the mike.

MS. DUCCA: My name is Anita Ducca.

I just wanted to comment on the very funding issue you are now discussing. The Health Care Financing Administration has indeed proposed a regulation regarding reimbursement for outpatient services, and it does include Transfusion Services very specifically.

AABB, for example, is working on public comments, as we at Red Cross are doing so as well, and part of that is including development of economic and financial data.

Right now, I cannot tell you exactly what the impact of that is, but the proposed reimbursement rates are clearly well below the current costs.

I can remember $219 reimbursement just for a Transfusion Service procedure, a single procedure. So this particular conversation is very timely in light of the Health Care Financing Administration's efforts right now for Medicaid reimbursement.

DR. NIGHTINGALE: Ms. Ducca, for the record, could you identify your employer, if there is one?

MS. DUCCA: Oh, yes. American Red Cross.

DR. SECUNDY: I call the vote.

CHAIRMAN CAPLAN: Okay. Do we need a re-read of that one?

DR. NIGHTINGALE: To re-read, the committee urges the Secretary to consider mechanisms for support of Blood Centers and Transfusion Services for the conduct of the hepatitis C lookback.

CHAIRMAN CAPLAN: We will wordsmith that one up a little bit, too.

All in favor?

[Show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: Abstainers?

[No response.]

CHAIRMAN CAPLAN: The payment issue is why I was sort of smiling at Jay as he started to talk about that. It takes us into a lot of topics, and I would like to mention a few of those under the banner of new business, but before going there, I just want to make sure there is no one else with any motions on the matter of lookback or lookback-related.

DR. GUERRA: I am not prepared necessarily to offer a motion, but it is a question of the possibility of maybe having the group that is developing the marketing, the social marketing, the educational campaign for the CDC to maybe give us an abbreviated presentation at one of our next meetings. I think it would be very helpful.

I think the other is a question for Dr. Margolis and the hepatitis staff. Is there any component that is going to be targeted to school-aged children related to hepatitis C?

DR. KUHN: Actually, there is not at this point, but we have got several projects going. There is a hepatitis B adolescent immunization issues where there are actually curricula that have been build that are general hepatitis, and C is kind of the lookback to put that in.

There is actually one at UCLA. There are a couple of them out there that are actually being used now in a number of school systems.

In the current rush and everything, that has not been done, though there is some discussion with our Division of Adolescent and School Health.

Just to let people know, at CDC, there is now a working group with the Division of HIV/AIDS, Division of Adolescent and School Health that are kind of dealing with each of these issues, one at a time. So, within our bureaucracy, we are all finally talking to each other in trying to get these messages out. So it is on the agenda, but there is nothing right now.

DR. GUERRA: I just want to be sure we do not forget them because a lot of kids certainly receive transfusions.

DR. MARGOLIS: Right.

That is a different issue. The transfusion issue, I would say, is really we are addressing through what I was talking about today, with the Academy of Pediatrics, Society for Adolescent Medicine, and then other groups who may see them as patient and health care populations.

I think the more general issue about education, I guess we have separated it.

DR. GUERRA: I think they are combined, okay.

DR. KUHN: Art?

CHAIRMAN CAPLAN: Yes.

DR. KUHN: A comment I would like to make, as we are putting this hepatitis C and hepatitis C lookback to sleep, probably once and for all, I think the comment that I would like to make is that we have had hepatitis in this Nation for quite some time, and non-A/non-B becoming C for quite some time.

It seems to me, and I am a little discouraged about it, this has taken from really since the first test that we have had, the screening test, 1990 to 1999 to come up with some kind of a lookback and some kind of a public campaign to notify the American public.

The comment that I would have to make is that I hope that we do not have to repeat history like this and take such a long time to get people and the American public notified and then have an option of understanding what is happening to them and then also knowing how they may be able to treat themselves to take care of this disease.

DR. EPSTEIN: I appreciate the frustration that you are expressing, Dana, but I think there is a tendency to assume that we knew in 1989 what we know today. Unfortunately, that is simply untrue.

There was no therapy. The consensus on the effectiveness of interferon was really only established through the NIH consensus conferences, which was March '97. A lot was not known about the accuracy of testing, and a lot was not known about cofactors and progression of disease, such as the impact of alcohol consumption.

So, unfortunately, I would say that the thinking evolved because the science evolved. No one forgot the issue. You have heard Dr. Galel state that her hospital and transfusion organization committee revisited it again and again. Well, so did the public health service.

There were easily 10 different large public fora on this question between 1989 and the deliberation of this committee. So I think that it is an oversimplification to just say it took too long. What took too long was developing the insight about what to do, and I think that what is clear is that it was the feasibility of meaningful interventions that caused a meaningful rethinking of the importance of the lookback.

Once these things were recognized, it became very clear that we had a major public health problem and we had the tools to address it. The problem is you could have recognized you had a public health problem, but absent the tools to address it, it is unclear what the purpose would have been.

So I just contest that point of view. I think there is a little bit of historiography because it is founded on the premise that we knew then what we know now, but that is not a correct premise.

DR. KUHN: My comment was not to try to insult anybody, but I think that when we do come up with kind of diseases that we need to work a little more quickly, I think a little frustration--and maybe I should have defined it more, but it has taken us a long time since we have had at this committee to define lookback and to make some decisions on it.

Again, we have been evolving, yes, about the treatment of alpha interferon and its efficacy in populations, but we did know when we started this at least we could get information out to people that they could at least kind of short-circuit some of this disease by curbing some of their habits, and one of them was intake of alcohol.

CHAIRMAN CAPLAN: The Chair is just allowing this cathectic moment, so that these groups can move forward hand and hand to a brighter tomorrow.

[Laughter.]

CHAIRMAN CAPLAN: What I wanted to mention about issues that are still lying on the table for us to think about down the road, one is we may want to think about at our next meeting revisiting the leuko-depletion issue which continues to press. You will recall we have had testimony about people with different filters.

When I wander in the halls and listen to some of your fellow members of this committee, they say that this is inevitable, but it does tie into issues of payment and who is going to eat the cost and is this just another overhead addition to what a unit of blood costs a hospital, et cetera, et cetera. So there are certainly money issues around leuko-depletion.

Who is it? I guess the British decided they are going there. The Canadians have, too, and that is an issue we may have to revisit.

Another is the old standby which you never get to, hemochromatosis and the use of blood from individuals with that genetic disease, which is now still not used as far as I know. That might be part of a more generic discussion of marginal donors. I am personally interested in this ongoing problem of shortage of blood supply and different ideas about how to do that, and the hemochromatosis might be one example of a thing to talk about.

Artificial blood, blood products, genetic amplification to, if you will, create greater volumes are part of that, too. So I guess I would say something on the blood supply with hemochromatosis, artificial substitutes, what is happening there. Can we encourage that? Is it time to move things?

Some of you may have noticed, by the way, just this past week, there was a report from Chicago about an artificial blood substitute that was involved in a research trial that got shut down. It got a lot of attention with some very hilarious, if not sad, statistics about death rates in the active arm of the study. This was a no-consent emergency consent situation, with the media reporting 46 percent death rates in the active arm of the study, although they failed to report that the predicted death rate was, I think, 42 percent. At any event, the whole issue of how these products come in and who gets to use them first and so forth is part of that.

One other issue that has been haunting us a little bit, which people in patient groups whisper to me sometimes, is compensation, and that leads to more generic comments about blood policy that the Nation does or does not have. I do not think this group as constituted or chartered is going to wrestle with necessarily a no-fault policy or compensation policies, per se, but we might urge the Secretary and Congress to do something to systematically look there.

As I indicated, too, we might just go ahead on with the financing issue around some of the blood issues as well and whether that is hindering the supply and the safety, which are our mandate.

So those are ones that I can think of that we might want to spend some time on, either all of them or one of them down the road, and I just tossed them out there to see if other topics were on your mind that Steve and the staff should be thinking about.

DR. FEIGAL: Could I make a suggestion? Several of these topics, in fact almost all of them have been discussed by other advisory committees, and some of them have made recommendations, recommendations which we will probably accept.

So one of the issues to think about is sort of what is the role of this committee, when revisiting perhaps something that is already going to happen, if you will. That is a logistical one we can work out.

The broader problem here may be coming back to something this committee considered in the past which is do we have enough donors. We have looked at it with plasma, but I guess I was reminded by the impact of the severe storms of a few weeks ago where we ran out of blood in several parts of the country, and it really shows us how fragile and how tenuous the blood supply is at a time when we are considering whether things which will reduce the broad availability, such as exporting U.K. donors, might result in another reduction.

I think one of the things that might be helpful would be to look at the broad topics, starting from the top down in terms of taking a look at the whole system of how good is the supply for blood and blood components and what are the things that impact it.

As part of that, what the committee might need to do first is sort of hear some background and scientific presentations on these issues, some of which could also include informational updates on what other committees have already done, recommendations they have made, where those are in the status of implementation or modification or polite disagreement. That might set the stage better than picking any one of these to hone in on. So that might be a way of providing an overall umbrella to get started and then see if there are some things that are more overarching that would kind of give you the most bang for your buck.

It strikes me, we have gone through a period of where we had enough blood supply that we could do certain things to make it safer that gave us a smaller blood supply. We are only going to be able to do that so long before we need to build a new donor base that is crafted a little bit differently.

There have also been things that have been done inadvertently that cause changes in practices to avoid certain types of donors that have done these things.

One very useful agency-wide and very public benefit would be if we could actually reinvigorate the donation process and increase the blood supply for blood and blood components.

If we did hepatitis C notifications, there would be a certain percentage of regular blood donors who will become convinced that you can get hepatitis C by donating blood. It still happens with HIV. So whatever we do kind of influences this system, and so looking at the overall blood supply may be a way to actually get approval of each of these topics so you could focus the efforts a little bit more.

DR. HOOTS: I absolutely agree with what David said.

As people are doing behavioral studies about altruistic contributions to society, there clearly are trends that are counterproductive to blood donations, at least in the most recent decades of people coming into the adult population. They seem to be a little less willing to stick out their arms, and I think these are the kinds of issues--at least the studies I have seen summarized suggest that, and I think these are things that we need to maybe look at and have people who are experts in that particular area talk to us and perhaps that is another targeted thing that an educational program might down the road benefit.

CHAIRMAN CAPLAN: Jim?

DR. AuBUCHON: I would like to suggest that the committee consider these types of issues, but from a different perspective.

I do not think anyone on the committee has the misperception that we as a committee are in control of America's blood supply. I know the FDA does not have that misperception either.

So the question is who really is making the decisions, and is anyone really making a conscious decision in some of these issues. For example, nucleic acid testing is about to begin, but there has been no discussion at this level and really precious little nationwide discussion even amongst blood bankers about how that would be constructed and the ethical and medical and safety implications of that.

Leukocyte reduction, by the time this committee gets to discuss it, if we discuss it, it may well be a foregone conclusion in large measure because of marketing efforts by those who supply the filters and does some profit.

So I think it might be useful for the committee to consider how these kinds of discussions proceed and what is our role, really, other than coming along 10 years later and saying what we should do to pick pu the pieces.

MR. WALSH: I would also like to stress that I think the committee needs to keep in focus the issue of shortages of plasma derivatives, specifically IGIV and alpha-1 protease inhibitor. It is still an issue. There is still a critical shortage, and I would like the committee to revisit that at the next meeting.

DR. GUERRA: Art, along with the supply side of the discussion, I think the demand side is very important because there certainly has been a lot of changes in disease incident rates, with morbidity, and those serious type of traumatic injuries that today are being handled in ways that probably do not require as much blood and/or blood products.

I think if you look at any number of things that have occurred in the country that allow us to diagnose some conditions, to recognize them much earlier, diagnose them and treat them, so that we do not have to then deal with end-of-life conditions that require a lot of additional resources, and I think along with that, the increased life expectancy that maybe carries with it other burdens.

So, if there was some way to model the demand side of it to look at how we are able to keep up from the supply side, it could be very helpful.

CHAIRMAN CAPLAN: All right. What we will do is what always happens, which is we will lay in some plans to perhaps take a more systematic look at supply and demand and then allow for a particular understanding of some of the subissues to emerge. I hear a lot of interest in that particular topic, and we have not done much on supply and I think we should.

Then we will get hit by some pressing issue, and it will distort the agenda again, but in the hope of holding out that side of the ledger, I think Jim's question is important. I do not think we have any handle on controlling the Nation's blood supply, but since no one else does, we might as well pretend we do or something for the purposes of getting a look at supply.

Safety is crucial, and I guess David said it, too. If you are taking steps to maximize safety, you may inadvertently be taking steps to decrease supply.

You have got these public studies that show altruism on the decline, and I hate to say it, but a lot of the debate that I see about blood--and I am sure Jane has seen it over the years--is often ideological, not rooted in ideas about what really makes the blood supply, whether it is demand or whatever it going on. There is a lot of ideology that drives that.

DR. PILIAVIN: I, by the way, do not believe those public statements about the decrease in volunteerism, and there has been a lot of debate about it.

I see the every-2-year studies that come out from independent sector. I do not see any change in the last 10 years. There is this. It bounces up and down, but if you were to apply statistics to that, it would stay about the same.

There is one study that I saw, a comparative study by Greeley, that actually showed increases in participation on the part of the group we would call Generation X--that is the group we are also worried about--over the previous cohorts.

So I just do not think there is that much reason for viewing with alarm at this point.

CHAIRMAN CAPLAN: One thing we could do as we looked at the supply thing is to try to understand some of that debate just a little bit as backdrop.

The meetings I tend to go to tend to have people who believe in markets, people who believe in altruism. It is more political than it is kind of sensitive to the nitty-gritty demand for services, impact of safety steps, what things you are doing that might or might not be effective, including blood donors per se and so forth.

So I do think that is an important area for us to go to, and we will try to take us there with a kind of more educational discussion meeting coming up next that would at least then position us to see whether we want to look at marginal donors or changes and other things subsequently that might be useful recommendations about supply.

DR. BUSCH: I have just one concern. I agree completely with the need to focus on donor recruitment and broader policy issues, but I am concerned about one of David's comments on what I think are critical and immediate issues. FDA is already developing policy recommendations that I think perhaps have not been addressed at the level that this committee isn't really composed to address. For example, the leuko-depletion question, when that was voted on by an FDA advisory committee, the whole issue of cost effectiveness was not allowed to be considered. The British donor issue, which was reviewed by TSE recently, the broader issues of the impact of that exclusion on donor availability, the blood supply, was really not, I don't think, adequately voiced and discussed.

So, as you prioritize, I think there are some issues that may be coming down the pike that are going to become policy before this committee has even had a chance to review them. I want to be sure that as we advertise for the next few meetings that particularly those two issues, which I see as having a huge financial and blood availability impact, that this committee can voice their considerations.

CHAIRMAN CAPLAN: Okay.

MR. ALLEN: Just a couple of quick things. First of all, I would like to know if between the FDA and the CDC, do we have any type of policy or guidelines we use in order to get us to a lookback?

I understand what Dr. Epstein was saying about the length of time it takes to get things done, but 9 years, 10 years, is a long time for the individuals affected. I think that there may have been some things we might have been able to do earlier as far as education. I am not trying to demean anyone here or anything. I am just saying there seems like there could have been some things we might have been able to do earlier.

Have we learned anything from this issue that can take the next time this happens? Basically, beyond this committee, if this committee were not here, my question would be how long would it be before this lookback even got talked about. I do not know, and I am curious about that.

I am also curious about the fact that being that we are the Blood Safety and Availability Committee--and this is more something I want you to answer--how much concern should we have in terms of cost? I understand the need for cost, believe me. I understand what the Blood Centers are going through. I am getting a better idea every time we have a meeting, but I still think that it is almost a conflict to me to talk about recommendations as far as blood safety, but at the same time, we are talking about cost.

CHAIRMAN CAPLAN: On the latter point, I am not sure what the triggers are to look back in the world of public health, CDC, FDA, but on the latter point, most committees, scientific advisory committees, have no mandate or explicitly are almost prohibited from wrestling with matters of cost. They are left to political resolution.

We have a broader mandate. So we can think about cost. On the other hand, I think my response would be that cost should not hijack what we think about either. It is there, and we can certainly be alert to it. We have the luxury of thinking about it, but it does not have to buoy us either. I do not see us having to be buoyed by cost. If we want to put public health or the importance of public confidence or social solidarity or something ahead of that, that is fine, but that is one of the nice things we do, which I kind of appreciate, is we can talk cost here. It is one of the few times you can actually put those things on the table.

With that said, if you can talk cost, then you are stuck with the fact that no one has those numbers most of the time. It is sort of the plus and the minus.

DR. PILIAVIN: And also, people find it politically unacceptable.

CHAIRMAN CAPLAN: Yes.

MR. ALLEN: And I understand all that, but my point beyond that is where do we put the cost for the individuals, the family? How do we measure that cost? That is important as well.

I am not trying to take away from the job that these people have to do. I understand that, but--

CHAIRMAN CAPLAN: It is in that tension right here. I mean, I think that is where it is.

MR. ALLEN: Exactly.

CHAIRMAN CAPLAN: It is always there. The nice thing about this committee is it can come up to the surface a little more. It is always there. It is not that no one is looking at the cost. They usually just go home and count beans privately.

DR. FEIGAL: I did want to make some other comments, but I wanted to mention that one of the things that is explicit in FDA making decisions about enforcing both the Food, Drug and Cosmetic Act and the Public Health Service Act is that we are explicitly prohibited from considering cost.

It is not just our advisory committee. So, if we make a recommendation based on the safety of the blood supply, we do not take cost into account at all, unless you can make the case that the cost in and of itself will cause safety problems or other kinds of problems.

That creates an interesting tension for this committee in looking at an issue like Mike Busch raised with the leuko-reduction. If in fact this committee would look at this and say, well, gee, an advisory committee not allowed to look at cost, made the recommendation that this would increase the safety of the blood supply, and that is their recommendation--I am just echoing that at that point, not talking about what FDA is going with it. If that is the stance and this committee comes back and says, gee, it is very expensive, that is irrelevant from the FDA's decision-making process.

We have no authority to say that something which would on the basis of safety and effectiveness should be approved on that basis, it should not be used because of cost. So exactly how this committee interfaces with the Department, with agency decisions and so forth, it is kind of an interesting one. That almost, I think, is kind of an interesting topic in and of itself.

CHAIRMAN CAPLAN: I have a snipey answer for that and then a serious one. The snipey one is there is nothing, at least in my area of philosophy, to be bemoaned about the fact that we are going to give you explicit advice about a subject that you are prohibited from hearing.

Having said that, I would also add quickly that I think it is because we can work through the Secretary. We are going sort of above the agencies.

DR. FEIGAL: The Secretary also has to enforce the Public Health Service Act and the Food, Drug and Cosmetic Act. In fact, we only do it through her delegation, through her power.

So, in fact, you would actually have to change the law in order to allow cost to temper a decision about safety and effectiveness. The same is true in Britain. In Britain, they are not allowed to consider cost in the approval of pharmaceuticals.

The suggestion I have, though, that is sort of a practical one is that another thing for this group to consider might be a joint meeting with some of the other committees that consider blood, maybe not the whole committees, but to invite a Chair and a couple of seasoned or battered committee members to have some discussion about perspectives and jurisdiction.

There are times when we probably should meet together. There are times when sequentially it would make more sense because the issues are so different, and it would be moot if one committee did not recommend one thing, for you to pick it up. That might be another topic you might want to put in the agenda.

CHAIRMAN CAPLAN: That is a good idea.

In the interest of letting people to get to the trains and planes, I am going to now move that we formally adjourn. If you want to stay around and talk a little bit informally, the room is still ours. You do not have to run away, but I want to thank the committee for doing such a good job in wrestling with this tough issue of lookback.

[Whereupon, at 3:32 p.m., the meeting of Advisory Committee on Blood Safety and Availability concluded.]