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Blood Safety Transcripts - April 1997

MEETING OF THE ADVISORY COMMITTEE ON
BLOOD SAFETY AND AVAILABILITY

Day 1 APRIL 24, 1997


P R O C E E D I N G S

PARTICIPANT: I'd like to call this first meeting of the Advisory Committee on Blood Safety and Availability to order. I am Dr. Paul McCurdy, the acting executive secretary for this first committee meeting.

I would like to welcome you all to the meeting, and apologize for the slight delay that has taken place this morning. There were some things that came up, that needed some administrative details that needed to be taken care of.

I would like to start off by listing the committee members, and asking each one when I call their name to raise their hands, so that the group in the audience can see who the committee members are.

Dr. Arthur Caplan is the chairman of the committee. Dr. Janice Albrecht. Mr. Larry Allen. Dr. James Aubuchon. Dr. Michael Busch. Dr. Ronald Gilcher. Dr. Edward Gomperts. Dr. Fernando Guerra. Dr. Paul Haas. Dr. William Hoots. Dr. Carolyn Jones. Dr. Dana Kuhn. Miss Tricia O'Connor. Dr. John Penner. Dr. Jane Piliavin. Dr. Eugene Schiff. Dr. Marian Secundy. Mr. John Walsh, (who is -- some of you have seen a list; he is no longer prospective, he is a member). And a consultant to the committee, Dr. Kristine MacDonald.

In addition, there are some representatives of federal agencies who are ex officio non-voting members of the committee. Dr. Eric Goosby, representing the Office of the Secretary. He had to step out for a minute. I am (Dr. Paul R. McCurdy) representing the National Institutes of Health. Dr. Mary Pendergast, Food and Drug Administration. Dr. Mary Chamberland, Centers for Disease Control and Prevention. Dr. David Snyder, Health Resource Service Administration. And Captain Bruce Rutherford, Department of Defense.

I would like to make one more comment. The committee members should recall that they had received a fair amount of advice on ethical issues in the packets that were sent out to them. If they have any questions about these, Dr. Richard Reisberg is here today and will be available for questions privately or otherwise, or by phone at some time in the future.

Now I would like to turn over the chair to Dr. Arthur Caplan.

PARTICIPANT: Thanks, Paul. This Advisory Committee on Blood Safety and Availability is going to meet today to grapple with some interesting and provider issues. I have been asked to chair.

One of the things that the committee should know, which they haven't heard me say, is that I asked for two conditions in order to do this job. One was that if we were going to wrestle with fairly clear-cut issues like the ones in our agenda, that we would be able to meet more than once. So that is a possibility, if that is the way we decide to go, and secondly, that we have a little bit of staff support. Dr. Gusby and others have assured me that we are going to have somebody that will work with us if we have questions or problems or things that we need to address.

We have a charter that tells us that we are going to be advising DHHS about policy matters. I know that many of you have said to me as we have started out the morning that one of the things you have been trying to do is go through your packets and try to get up to speed. I think that is a lot of what we are going to be presented with today, is to try to get information pertinent to the questions that we have been asked to address.

Before I come back up here though and say a few more words about the charge and the committee's operation, I think the way to move is to have some of the officials that are eagerly awaiting our advice say a few words to us about how they see the committee's function and why we have been called here. So I am going to ask Dr. Joanna Guford if she would come up here and speak first.

PARTICIPANT: Thank you, and good morning. First of all, on behalf of the Secretary, I would like to thank the members of the committee who have agreed to take on this responsibility, and especially Dr. Kaplan for agreeing to chair the committee.

I think it is obvious that in taking on this responsibility, you really are becoming the focal point for a very unique intersection of multiple interests and expertise to advise the Department on the safety and availability of blood supply to the country.

As you have seen from the material in the package that you received, the ability to make blood and blood products safe is a very complicated orchestration of both the public and private organizations working together to really maximize availability and safety.

I wanted to provide a little bit of background on the impetus for establishing this advisory committee, and some general sense of the role that we hope it will fulfill. Each of you was selected for your experience and expertise in specific areas: consumers, advocates, bioethics experts, public health law, health educators, transfusion medicine, hematology. This very diversity I think will be the challenge facing the committee, but also is critical to the success of the committee, because it is a unique forum.

We have wanted to start this meeting by reviewing what may be familiar to many of you, but we thought it was important to start with a background base of information on how blood safety activities are organized within HHS. Then tomorrow I gather there will be another presentation on the private sector for-profit and not-for-profit segments of the collection, processing and delivery process.

After my remarks, we will hear from representatives of the FDA, CDC and NIH, speaking briefly about their roles in the blood safety process and indicating their hopes from the committee's guidance.

As many of you know, in July of 1993, Dr. Shalala requested the Institute of Medicine, or IOM, to review the events of the early 1980s relating to the transfusion of HIV through blood products to persons with hemophilia living in the U.S.

A key component of this request was not only to look at the facts, but also the decision making process and the coordination of blood safety activities within the government and in the government's relationships to the other organizations that are involved with blood products. The hope of this investigation review was to minimize the risk of any similar tragedy in the future.

The report, the executive summary of which you received in advance of this meeting was issued in July of 1995. At that point, Secretary Shalala appointed a senior level task force to review each of the 14 recommendations contained in the report, and to try and respond to each of the issues raised in the context of the current structure perhaps some ten years later from the focal point of the concern.

The task force concluded that most of the IOM's recommendations have been addressed by improvements introduced since the mid-80s. However, they did identify aspects of the Department's organizational structure surrounding decision making on blood safety issues that could and should be strengthened.

Two major changes resulting from this report were the formation of the blood safety committee within HHS, which brings together the heads of CDC, FDA, NIH and the Health Care Financing Administration in regular meetings under the chairmanship of the Assistant Secretary for Health, who has been designated as the Secretary's lead blood safety director for the Department.

This group began to meet in January, 1996, and creates a high level forum for decision making, priority setting and high level inter-agency review of problems and coordination on key issues in a timely fashion. We really believe a year into this process that our ability to communicate and coordinate within the Department has been improved, as well as the accountability for the actions taken to address any problems identified. There is obviously more work to do always in this area, but we think this vehicle is a very good start in departmental coordination.

A second result of the action on the report was the establishment of this Advisory Committee on Blood Safety and Availability. The purpose of the group will be to essentially provide us a perspective from outside of government to look at the public health data available, consider the overall interactions of the various components of the American blood supply system as they affect availability of products for persons who need them, and to offer up a consumer and societal perspective that includes a balancing of costs, risks and benefits as guidance to the Department. I think this area is a classic intersection between individual concerns, public health concerns and overall societal interests.

This is clearly not a simple task, and you will see that as you get into the agenda today and tomorrow, and as the chairman said, in other meetings as you decide to convene. But we do believe this is quite a unique forum where these issues can be debated by individuals from varying points of view and backgrounds.

There are also a number of formal and informal work groups on blood issues within the Department that you may already be aware of, but I want to mention them briefly. My colleagues from the various agencies may expand on them in their remarks.

First, the FDA has a well-defined scientific advisory committee, the Blood Products Advisory Committee, whose primary mission is to provide expert scientific advice to the Commissioner of the FDA on regulatory matters relating to blood safety. The issues discussed in this group are usually highly technical, and focus on the scientific aspects of blood banking, blood product development, transfusion services, and distribution issues.

The overall Public Health Service within the Department also has an inter-agency working group on blood safety, comprised of representatives from NIH, FDA, CDC, the Health Resources and Services Administration, HRSA, and the Department of Defense.

This group meets at least monthly to assure maximum coordination among all the key elements of the Administration's blood safety program. This working group provides regular updates to the Department's blood safety committee, chaired by the Assistant Secretary for Health.

To assist this advisory committee in its work, the charter provides for up to six ex officio members from the federal government to be present in an advisory capacity. These are non-voting members that have already been introduced, but their role is to really make sure that the committee has available to it whatever data, research information they wish to have, and if particular activities or reports need to be commissioned, they are charged to cooperate in that process.

Dr. Eric Gusby, who has been introduced from the Office of Public Health and Science and the Office of the Secretary, will coordinate this secretariat effort.

So if there are any questions on this general background, I would like to turn over for brief presentations to first, Dr. Claire Broom from CDC, then Mary Pendergast from the Food and Drug Administration, and then Dr. McCurdie I believe will represent the National Institutes of Health, to review their involvement in the blood safety issue.

PARTICIPANT: Good morning. I also would like to add my welcome and thanks to the committee. We will very much appreciate your careful consideration and input on the kind of difficult issues that we face.

As we all know, the U.S. blood supply is currently safer than it ever has been. But at the same time, since we do use blood as human tissue, it does have the potential for transmission of infectious diseases. Trying to balance the complexity of insuring a safe blood supply, while preserving the availability of this crucial product, is a difficult charge.

Dr. Guford alluded to the tragedy of HIV transmission in the early '80s. I would just like to remind people that whereas I think we have dealt very successfully with the risks from HIV, we continue to have threats to public health from the blood supply, most recently, for example, transmission of hepatitis-A, and bacteremia from albumin. So this is definitely a current and ongoing issue.

Now, how does CDC interact in this complex system? We don't have any regulatory responsibilities for blood products. I think it is important to make that clear at the outset.

For those of you who may not be as familiar with the federal government, CDC is the federal public health agency, the sister agency of NIH and FDA. Our charge is to work with the states to detect and investigate threats to public health. We also have substantial intramural, epidemiologic, and laboratory expertise, which can be rapidly directed to respond to acute threats. So we frequently are the rapid response arm for investigations, in addition to providing ongoing, longer term studies. We work in close partnerships with the states to actually implement public health programs.

How does this apply to blood? There are three main areas that I would like to mention briefly. One is surveillance. That is a key CDC function, and it is absolutely crucial with the blood supply to enable rapid detection and evaluation of threats.

The second is epidemic investigations of outbreaks due to blood and blood products, and then special studies to assess the risk of specific agents.

The third is developing prevention and control measures to address recognized, new and uncharacterized threats to the blood supply.

In addition to these three factors which look at risks from the blood supply, there is another important area where I think CDC contributes in general and could be helpful to the committee. That is, since we are a public health agency responsible for a large variety of organisms and diseases, we can help provide background scientific data that relate to the importance of availability of blood products.

For example, when we have shortages due to withdrawals, that may result in absent or diminished supplies, for example, of rabies immune globulin. So we need to know what are the risks from rabies, what is the need for that product, how do you balance these competing important public health issues. So CDC will be pleased to help you with providing baseline data and surveillance information. We also have some handle on state programs and needs for some of these biologics, obviously in very close working relationship with the FDA.

Let me just say a few words in more detail about the three areas of activity. For surveillance, we do this partly through looking at specific diseases. So for example, for HIV/AIDS, we do surveillance for AIDS cases, and we particularly look at any which appear to be related to transfusions with screened products. So we will do in-depth investigations to continue to monitor whether there is ongoing risk of transmission of HIV. And of course, this becomes very important with the assessment of the p24 antigen screening; is that helping to diminish the very low risk of HIV transmission from the blood supply.

Similarly with hepatitis. Well, let me say one other thing with HIV. We try to be out in front of potential problems. So for example, there have been recent reports of divergent strains of HIV, the group O infections in the United States. We actually have field stations and samples. We try to see what is happening to strains, are they detectable by the routinely used serologic screening tests. So we can identify whether we may have any problems with the screening that is done in the U.S., should such strains become more common in this country.

Another disease specific system is hepatitis. We have active surveillance for hepatitis in sentinel sites, and then more general hepatitis screening. This has obviously been important over the history of blood safety, but we continue to be on the lookout for new strains of hepatitis. We do get blood specimens. These were useful for identifying hepatitis-C, for example. So this helps us in characterizing new agents.

We also are in the process of developing a pilot project to set up a surveillance system for bacterial contamination. We want to find out whether that is under detected. So working with the American Red Cross, the American Association of Blood Banks and the Department of Defense, we will have a pilot system implemented this year.

Now, these surveillance systems are fine if we know what disease we are looking for. What about unrecognized threats for diseases that may not have been clearly associated with transfusion?

There are two things we do. One is, we have collaborative agreements with the Hemophilia Association and the hemophilia treatment centers to look at essentially all cases of acute disease in the hemophiliac population, which of course has a very, very heavy usage of blood products. We are working to expand that system to monitor on an ongoing basis any apparent changes or risk in the hemophilia population.

The second area is, we support sentinel emerging infection sites. We now have seven population-based sites around the country, where we do intensive investigations of serious unexplained illness or death. We ask specifically about prior receipt of transfusions.

So that is our overview of the range of surveillance activities we undertake.

In addition to surveillance, we do investigations and special studies. Just very briefly, I'll point out that in collaboration with the FDA and the states, we have done follow-up investigations of the hepatitis-A transmission. We have also looked in depth at the bacteremia transmitted from transfusions, and determined how widespread that was with the contaminated albumin product. Those are just examples of acute response.

However, we also think it is very important to set up longer term studies to assess risk from transfusion. You will hear later in some detail about the studies that we have done with Kreutzfeld-Jacob disease, to try to assess whether or not there is risk associated with transfusion. I won't say anything more about that now.

We have also been trying to assess whether there is any risk of Shagas disease. In addition to setting up a surveillance system, our laboratories have developed the confirmatory Western blot assay for T. cruzi. So here is where the intramural laboratory capacity can contribute to an urgent public health question: is there is risk -- or how do you deal with it, if there is a risk of transfusion-associated Shagas disease.

Finally, in prevention and control, I'll just mention some very broad categories. We have worked, particularly in the HIV area, to both develop and evaluate donor screening. We try to use tools such as the morbidity and mortality weekly reports to get information out rapidly, to do communication.

We look at the effectiveness of policies of what is happening with the use of the p24 antigen testing to try to assess the impact of that's happening.

Then we do formal education programs. You will be hearing about this subsequently with the hepatitis-C discussion. That is just an example of the kinds of education programs that we can undertake.

So I guess the two points I would like to make in summary are that the capacity the CDC has for surveillance, laboratory research and epidemiologic investigations, we think can really help the country respond to the impact of infectious disease threats to the blood supply, and we will be very anxious to provide whatever information can be helpful to the committee in their deliberations.

I have talked from the CDC perspective. I hope it is very evident that we don't do these activities in a vacuum, that we worked very closely with the other federal agencies, with our state and local health department partners, and with the private sector in carrying out these responsibilities.

Now, there are two things that I would particularly like to draw to the committee's attention, in terms of how we think this important committee can make a real contribution that is complementary to other bodies and advisory groups in the blood products area.

As Dr. Guford mentioned, I think that a broad range of expertise on the committee is very important for dealing with issues that are not clear-cut. We wouldn't be asking you if it was simple to get the answer in some of these areas.

We hope that your range of backgrounds will really help us address both what we know scientifically, and areas where we don't know as much as we should, in order to come up with wise decisions which protect the public from threats to the blood supply, but also insure that important products are available to address equally important medical and public health needs.

So I think the charge to be wise in these difficult decisions is one which is a definite challenge.

The other area we would like to draw to your attention -- I don't think it is on the agenda this time, but I think we would be very appreciative of the committee's input -- is in identifying improved mechanisms to communicate both the recognized and the potential risks from blood products.

Because of the nature of the product, we really cannot guarantee that we will be one hundred percent safe. So I think trying to engage on the issue of labelling or informed consent and how that might appropriately be used for blood products would be a very major contribution the committee can make.

Thank you very much.

PARTICIPANT: Good morning. I am Mary Pendergast, Deputy Commissioner at the FDA. I too would like to start by thanking you on behalf of the entire Food and Drug Administration for agreeing to be on this committee.

Issues surrounding the blood supply and blood products are very difficult, and we appreciate and admire your willingness to engage on these issues and help us. Later today you will hear a presentation about the FDA's regulatory activities, and I won't repeat that here. Rather, I am going to ask you to focus on the conceptual problems that face the agency, as we attempt to regulate the blood system in this country.

I would like to share with you a little bit about the way the world looks from where we sit. The core question that Congress has asked us to address as we regulate blood and blood products is whether they are safe, pure and potent, or put more simply, safe and effective. But there is no statutory guidance as to how safe or how effective the products must be.

So the decision as to safety and effectiveness becomes one that is not completely tethered at any one fixed point, but one that can, and I submit must, change over time.

The question of the mutability of the safety and effectiveness determination can perhaps be best illustrated by reformulating the question the FDA must address. When we say a product is safe and effective, we do not mean that literally. There is no drug, vaccine, medical device or blood product that is one hundred percent safe and one hundred percent effective. They all fail in some patients, and they all cause undesired side effects.

Rather, the label safe and effective is one that we attach to a product once we have decided that its risks outweigh its benefits -- its risks are outweighed by its benefits. Freudian slip, there. But that risk benefit ratio decision is not purely scientific. It reflects societal values. When FDA's risk-benefit decisions are not concordant with those of the society or parts of it, there is frustration with and loss of faith in the agency.

We need your help in ascertaining where that set point in the balance of risk versus benefit should be made for blood and blood products. We already know the tragic consequences of when FDA set the regulatory point too low, and when we waited for scientific certainty before acting in the face of AIDS. But we are also concerned that we can set the regulatory point too high, where blood and blood products would be nearly one hundred percent safe, but also in very short supply and out of the economic reach of most Americans.

So we look to you for advice on how safe is safe enough, how risky is too risky. Do we set the ratio to accommodate the needs of people with life-threatening illnesses, like some severe hemophiliacs, so they have access to products with reasonable prices? Or do we demand that the risks be very, very low to accommodate the very low benefit to be gained from patients whose physicians prescribe the exact same products for very minor problems? Do we order the use of ever-new tests in order to close the HIV window by another few days or another week, at a cost of tens of millions of dollars per case of AIDS avoided? Or do we forego that level of certainty because it is a level of safety that is out of line with other public health decision making and will raise costs to the consumer to exceedingly, if not astronomically high levels? Or as you will debate here, how far should we go in protecting against CJD?

From FDA's perspective, this committee's role is to complement our scientific abilities and our Blood Products Advisory Committee by providing a public forum to address the societal issues, by giving voice to the diverse interests of consumers, industry and health care providers. This committee will also help the Public Health Service as a whole be responsive to public health concerns relating to blood safety and availability.

The FDA can regulate to any set point society wants to demand. Although we are no means perfect, we take our responsibilities seriously. At the present time, roughly 80 percent of all of the blood supply in this country is under court ordered supervision. Earlier this month, we criminally prosecuted an employee of the New York Blood Center for his failure to properly test blood for infectious agents. In order to stem the sloppy manufacturing practices of some plasma fractionators, we have revised our inspection program, and given the lead on those inspections to our field force, who by their critical eyes will help bring plasma fractionators up to the highest of all quality standards.

In order to speed up and sharpen our emergency response to problems in the blood system, we have integrated our blood area into our longstanding emergency operation system, so that the first response to a potential crisis will be handled by trained crisis managers and our on the spot field force, rather than by Center for Biologic Scientists, who are unable to command the necessary resources to respond quickly.

So far, no one has severely criticized those actions. But when we proposed PCR testing for hepatitis-C in non-virally inactive immune globulin, in order to protect against hepatitis-C transmission, our heads were handed to us, because companies pulled the non-PCR tested products off the market. What are you doing, some in the public health committee cried. There will be a shortage of rabies immune globulin. What are you doing? You can't prove that hepatitis-C is transmitted through these products. You are regulating against a theoretical risk. What are you doing?

That was the question that was asked by the same groups who criticized us when we acted too slowly against the face of uncertainty when there was HIV as the issue.

So what should we do, is the question you will help us address. We will bring you our issues. We will provide you with our science. We will give you any information that we can, and we will listen attentively, and we will follow your lead as we go forward.

We all share the goal of improving the blood system in America. We seek to restore public confidence in the ability of our institutions to handle new threats. This advisory committee has the opportunity to focus a spotlight on public concerns in the blood area, and to provide broad-based input into public health decision making. This will contribute greatly to sound decisions and public trust.

So again, I would like to thank you for your willingness to serve on this committee. Thank you.

PARTICIPANT: Some of you have an agenda that shows Dr. Ruth Kirstein, deputy director of the NIH, speaking next. She unfortunately had another commitment that made it impossible for her to get here, so I will tell you a little bit about the blood safety activities of the NIH. Most of these activities are centered in the National Heart, Lung and Blood Institute, the NHLBI, but there is also a very active program in blood safety areas at the Department of Transfusion Medicine in the clinical center housed in this building.

The role of NIH is to support research. The lion's share of the research supported by NIH comes in the form of investigator initiated grants. An investigator has an idea for pursuing a research project, sends a request for financial support to do that project to the NIH. It is reviewed by peers who assign priority scores and ultimately those of the highest priority, the highest scientific merit, get funded and move forward.

We also used a contract mechanism, and what we call RFAs, or request for applications, where we indicate an intense interest in a particular field, but ask for individual investigators to submit research proposals addressing some of those interests.

Much of the work at the NIH, the National Heart, Lung and Blood Institute in the last 10 or 15 years in blood safety has been devoted to studies of infectious disease that may or may not be transmitted by blood transfusion. One of the relatively early studies was a transfusion transmitted virus study, TTVS, that was started in the late 1970s. It was focused on the transmission of hepatitis by blood transfusion, determined that most of the hepatitis at that time was what was known as non-A-non-B, that is, it was neither hepatitis A, for which we had a test, nor hepatitis-B, for which we had a test, but non-A-non-B, neither of those for which we had no test.

They did suggest the value of some surrogate tests, which were put in place sometime later, when it became more apparent that non-A-non-B hepatitis was a real disease that led to some degree of chronic liver disease. We now know -- Dr. Broom mentioned this -- we now know that virtually all of non-A-non-B hepatitis is hepatitis-C. The repository of samples from donors and recipients from the TTVS helped demonstrate that indeed, most non-A-non-B hepatitis was hepatitis-C.

This repository has been used repeatedly to look at other infectious diseases that might be transmitted by blood transfusion, and has proved to be invaluable in that area.

A more recent study that is supported by the Institute is the REDS study, the retroviral epidemiology in donor study. It was instrumental in demonstrating with help from CDC and FDA and the private sector that an idiopathic, or what appeared to be idiopathic reduction in certain types of lymphocytes, CD4 lymphocytes, was not a transmissible disease, but was not something that should concern transfusion medicine. Initially, it was regarded as a possible similar agent or similar disease to HIV infection, for which we didn't have a test, and there was a lot of concern.

We are also now supporting work leading to -- which we expect will lead to nucleic acid-based assays for HIV, HCV and probably hepatitis-C virus, and probably some other viruses along the line as well.

Here is where the role of the NIH intersects I think most directly with the role of the committee, assuming our contractors develop these tests, and they demonstrate that they are useful, should they be used. What is the cost for the test going to be? Is it going to be five, ten or more dollars per unit? Is it worth it to prevent five or ten or maybe 15 HIV infections per year, to prevent maybe 50 to 100 infections by hepatitis-C virus per year.

This is not a role that the National Heart, Lung and Blood Institute plays. We develop the research, provide the science, and groups such as this committee will decide how it is going to be used. Ms. Pendergast also dealt with this subject as well.

One or two final comments. The Institute supported through the request for application mechanism a request for research applications mechanisms several years ago, work to develop bacterial and viral inactivation of bacteria and viruses in cellular blood components.

Work begun under that research now supported by private industry was reported in the latest issue of the journal Transfusion, that arrived on my desk I think yesterday or the day before, that communications are now under way for an approach to inactivating viruses and bacteria in platelets. It remains to be seen whether this will be a safe and effective approach to the problem, but it is the sort of thing that the NIH does try to do.

Thank you.

PARTICIPANT: Thanks. I would like to say a few words about how I see the charge to the committee. But I am going to warn my new colleagues that I am going to give you an opportunity in just a second to ask questions while we've got people here from our agencies that have presented their concise and simple ideas about the things they would like us to give them advice on. If you would like to ask questions while we have them here, about the charge, about the role, in just a second I am going to open the floor up to committee members, to anyone who wants to put a question or clarify that.

What I think about this committee and its functions, I think that there are agencies out there, HHS, CDC, FDA, NIH, that do have to make policy calls, do have to resolve questions that go beyond either science or empirical fact. I think they are seeking advice and help from a broadly constituted body about where to draw lines and about how to resolve certain questions about public health and public policy, over which there may be legitimate dispute and disagreement.

At the same time, one voice we have not heard from that I want to put on the table, that has been important in why we are here, is Congress. Congress clearly has an interest in the blood system, its availability and its safety. There are many groups who have gone to Congress over the years and spoken in front of various committees that have asked for advice, a body like this, to exist, to insure that the blood supply is safe, to insure that the blood supply is available and adequate for America's needs.

So what I would add to what we have heard already about the charge to this committee is that we are here to speak for the community, the public, the different interest groups that are out there that supply blood and that are going to use it, that rely on it frequently, as in the case of hemophiliacs, or that may require use sporadically in the case of any one of us who may find ourselves in need of a transfusion.

So that presence, the Congressional mandate, to create us, to give advice to these agencies, to make the American people feel that we are looking out for their welfare and their interests, is one that I think you all should be aware of, and it is one that I am keenly aware of, as to why we are meeting and why we have been created.

The other more practical comment I want to make before giving anyone who wants to a chance for a question or seek clarification from our agency presenters this morning is, I did a very prudent thing, and I just want to let the reset of the committee know. This was probably be one of my more decisive acts. I asked John Penner if he would be willing to chair, should I have to go out of the room or step out just for today. When we have lunch and maybe even if we can agree to eat dinner in the vicinity of one another tonight, we can talk about the possibility of selecting a deputy or something; you never know what might happen to the chair, seized with panic or overcome with delight. But John for now will do that if I have to for some reason step out.

All right, let's open the floor to the panelists, if you would like to address a question to any of the agency officials who have been here and told us of their vision of what they would like advice about. If you do that, I think it would probably be a good idea just to say your name again.

(End of Tape 1, Side 1.)

PARTICIPANT: I would be interested to know how the FDA sees the output from this committee being integrated with the output from the Blood Products Advisory Committee.

PARTICIPANT: Do you want to take a stab at that, Mary?

PARTICIPANT: Sure, I'd be happy to. The Blood Products Advisory Committee is principally a scientific advisory committee to supplement the scientific activities of our own staff.

Historically, we recognize that there was this societal or broader question that sometimes crept into the risk-benefit decision making that the FDA made. From time to time, there was some consideration as to whether or not the BPAC should take on questions such as cost, availability and the like.

I think it is fair to say that we were roundly criticized by some for taking on those societal issues in that forum. So basically, what we have done is, we have stripped away in a sense the kind of public policy considerations from the BPAC, so that it is more a scientific advice organization. We will be then looking to this committee for the kind of broader questions that we need to address.

So if you need to know, for example, what -- I'll make this up, but whether the sensitivity and specificity of a test for the detection of some disease is well quantified by some company in their application, the BPAC might be able to help us with that. If it is a question of what is the appropriate level of false positives and false negatives for a serious disease, such that that is where we should set our approval level, that might be something that we would bring to you.

PARTICIPANT: Do you want to add to that, too?

PARTICIPANT: Yes, just one other comment for the committee. I think the committee was also structured quite purposefully to provide advice to the Secretary and the Assistant Secretary for Health in the role of director of blood safety for the Department, with the idea that one of the charges of this group is looking at the whole federal apparatus and how it links to the private sector in the production of blood products.

So I think it is beyond FDA alone, CDC alone, NIH. It really is looking at how all of it comes together and intersects with the public interest. So I just remind you that that also is a really important issue for us. It is bigger than one agency in terms of the advice that we are seeking from you.

PARTICIPANT: I was wondering as a kind of a follow-up, is it the understanding of federal agencies that this committee can have an influence on the priority to which those committees that make scientific assessments would have on their agendas? Questions were raised here about, what are the facts, how quickly can we get those facts, can we thereby influence their collateral assessment of these issues.

PARTICIPANT: Absolutely. I think that is exactly the kind of thing that you can help us with, is relative priority setting, moving things higher on the agenda that you think have that urgency. We would feed that into the advisory committees for scientific researchers in each of these agencies, to move ahead with that.

PARTICIPANT: Any other questions about charge, purpose?

One other comment I would make. If you look, we have a charter for the Advisory Committee on Blood Safety and Availability. It does talk about a range of issues, that the committee shall provide advice to the Secretary and Assistant Secretary for Health at HHS about including implications of blood safety and availability, various economic factors affecting product cost and supply, definition of public health parameters around safety and availability of the blood supply, and broad public health ethical and legal issues related to blood safety.

So if you look at the charter that was issued by Secretary Shalala, you have a very broad charter. Some of you may be thinking, well, over the next two days of our first meeting, we have some issues which we are going to hear about shortly regarding hepatitis-C, and look back on CJD disease, and these have been provided to us by the agencies. They are areas where they are trying to make some decisions and are looking for some help. But we can add issues to the agenda.

The agenda we started with was one brought to us by the organizing federal agencies who are looking for some consideration of problems that they see pressing. But the mandate is broad, and if we see others issues that we think need a look, in terms of blood safety and availability, then we can set the agenda and ask that those be held. As I said before, we will meet to talk about those.

So for committee members, it is very important that if you think of something or believe there is something that ought to be on the agenda, or that a meeting ought to be held, you communicate that to me, and I will be sure to set the ball in motion to see if we can have those things discussed and addressed.

So we are not simply reactive. We can be proactive, we can ask questions, we can move through the issues here pertaining to blood in ways that the expertise of the committee may bring issues to light or questions to light that may not be at the front of the priority list for the agencies, but that you all may feel are important.

The way the rest of today is structured is, we are going to have a presentation on the regulatory framework that the FDA uses with respect to blood. I think Mary Gustafson has entered the room and is going to be prepared to give us that presentation.

There is a slot there for Dr. Zutt, from the New York Blood Center. He isn't here yet. We will move him on the agenda. He had some emergency come up. He is going to be here either late today or tomorrow, so he may be moved, but we will get a chance to hear from him.

The other small item that a few of you asked about already is, if you didn't fill out your paperwork at the break, please go up to the authorities at the back of the room and finish completing your notarization and employment forms and other detritus of government service.

I'm going to ask Mary Gustafson to step up to the podium at this point to give us that overview. Then after she speaks, we'll take a break, and then we'll come back and begin listening to some of the issues that come up about hepatitis-C. As Mary is done, I will again open the floor for the panelists to ask questions or offer comment about the regulatory framework.

PARTICIPANT: Thank you, Dr. Kaplan. If I could have my first slide.

The Food and Drug Administration regulates blood and blood associated products through the authority of two federal statutes. These are the Federal Food, Drug and Cosmetic Act and the Public Health Service Act. These laws have transcended to their present form by stages through this century.

The early predecessor to today's Public Health Service Act was the Biologics Control Act of 1902. This act was passed following the deaths of ten children who had received injections of diphtheria antitoxin contaminated with tetanus.

In 1901, there was a serious epidemic of diphtheria, resulting in a great demand for diphtheria antitoxin. The tetanus contamination was traced to an infected horse, whose serum was used in producing the antitoxin. A special committee of bacteriologists convened to study the matter, and concluded that the event was preventable, had only special controls such as animal testing been employed in the manufacturing process.

The 1902 act required that biologics be manufactured in a manner that insured safety, purity and potency. Provisions of the early law included establishment and product licensing, labelling requirements, inspection, suspension or revocation of licenses, and penalties for violations.

In 1944, the original law was incorporated into a larger, more comprehensive law, the Public Health Service Act. The core of the original law became Section 351 of the larger law, intended to have broad powers aimed at disease eradication and promotion of public health.

A key provision of the Public Health Service Act is that U.S. license is required for shipment of biological products in interstate commerce, and is required for shipment of biological products into and out of the United States.

Human blood was not an item involved in interstate commerce in the early part of the century. Widespread use of blood and its derivatives dates back to the years around World War II. The use of blood and blood derivatives became prevalent during the Second World War and during the postwar period, establishments known as blood banks began to appear. Blood and blood derivatives were from the onset considered to be a biological product, subject to the licensing provisions of the Public Health Service Act when shipped in interstate commerce.

Consequently, in 1940, normal human plasma, a component of blood, was licensed, and in 1946, the first federal license was issued to an establishment to manufacture whole blood.

When blood and blood products were initially licensed, their characterization as biological products was unquestioned, even though the original wording of Section 351 did not specifically cite human blood and blood derivatives as products covered by the act. They were considered to be analogous to therapeutic serum, which was one of the categories of products explicitly covered in the act.

However, this analogy was challenged in the courts. In 1965, the United States prevailed in a case against Charles and Maxine Blank and others involved in operation of their blood bank. On appeal by Maxine Blank in 1968, her conviction was reversed, on the grounds that the products involved were not analogous to therapeutic serum. That is, they were not biological products and not within the scope of the statute.

This resulted in Congress in 1970 amending Section 351 by public law to specifically include blood, blood component or derivative. Thus, the federal statute now clearly specifies that blood is a biological product, subject to the applicable provisions of Section 351 of the Public Health Service Act.

Section 351 requires that any establishment that manufactures a biological product that is offered for sale, barter or exchange in interstate commerce hold an unsuspended and unrevoked license for that product. This is our statutory basis for requiring licenses for biological products.

Blood is also a drug. It meets the definition of a drug under the Federal Food, Drug and Cosmetic Act. The predecessor of the modern Food, Drug and Cosmetic Act was the Pure Food and Drug Act of 1906. This early law was passed following disclosure of unsanitary and uncontrolled practices in the meat packing industry, and the popular book, The Asphalt Jungle by Upton Sinclair.

This early law only addressed the purity of foods and drugs and was silent with respect to their safety and efficacy. The drug's act was strengthened in 1938, however, when over 100 people died after ingesting elixir of sulfanilamide, in which the drug was dissolved in propylene glycol rather than alcohol or water. Although sulfanilamide went into solution more readily in propylene glycol than in either alcohol or water, propylene glycol, or antifreeze as we know it is extremely toxic.

The 1938 law was the birth of the modern Federal Food Drug and Cosmetic Act, and included the requirement for safety as well as purity. On the heels of the thalidomide tragedy, the law was further amended in 1962 to include efficacy as well as safety. It was also in 1962 that the first prosecution of a blood establishment occurred.

Food Drug and Cosmetic Act charges were levied against the defendant, as well as charges against the Public Health Service Act. Successful prosecution confirmed that blood is a drug.

In 1978, the Food Drug and Cosmetic Act was further amended in order to encompass the regulation of medical devices under the federal statute. Today's Food Drug and Cosmetic Act requires among other provisions that manufacturers of all drugs and devices, regardless of whether they operate in interstate commerce, register with the FDA and list products they manufacture. The law also has prohibitions against adulterating or mis-branding any drug or device.

The regulation of biologics and thus blood has evolved organizationally as well as by legal authority. The original Biologics Control Act was implemented by the hygienic laboratory of the Public Health Service, which was actually an arm of the Department of Treasury. The hygienic laboratory formed the core of what was to become the National Institutes of Health in the 1930s.

Soon after the enactment of the larger Public Health Service Act, the focal point for administration transferred to the National Microbiological Institute of the NIH. In 1955, the responsibility for biologics regulation was transferred from the National Microbiological Institute to an independent division of biologic standards within the NIH. In 1972, the regulation of biological products was once again transferred. The division of biological standards became the Bureau of Biologics within the Food and Drug Administration.

Although biologics had been considered drugs for some time and confirmed in litigation in 1962, the FD&C Act authorities had never been fully integrated into biologics regulation. Some features, such as provisions for requiring investigational studies under an investigational new drug exemption, were readily adopted, but the full gamut of regulation under the FD&C Act did not happen until after biologics joined FDA.

In 1982, the Bureau of Biologics merged with the Bureau of Drugs to form the Center for Drugs and Biologics. In 1988, the drugs and biologics components were once again separated to form separate centers within the FDA. A 1992 restructuring, when Dr. Kathryn Zune became center director, has resulted in our current structure of program directed offices within the center.

Today, the Center for Biologics is one of five product related centers within FDA. It is joined by the Centers for Drugs, Devices and Radiological Health, Veterinary Medicine and Food Safety and Nutrition. The centers' programs are supported by the Office of Regulatory Affairs, which among other functions directs the FDA's field investigative force.

The FDA exercise of statutory authorities involves three levels of control. These include premarket approval prior to a drug, biologic or device coming to market. After marketing, FDA performs active surveillance to monitor compliance with requirements and detect and identify problems. The FDA also has the authority to enforce compliance.

Premarketing approval involves review of applications prior to approving the product for general marketing. The approval mechanisms differ somewhat, depending on whether the product is a biologic, a drug or a device.

As mentioned earlier, biologic products require a license prior to shipment for sale, barter or exchange in interstate commerce. Until recently, each biologic license granted required submission of separate applications for the establishment and the product being licensed.

We are in the process of merging the established license application and the product license application into a single biologics license application for the granting of a single license for the marketing of a biological product. Drugs that are approved under Section 505 of the Federal Food Drug and Cosmetic Act requires submission of a new drug application.

Some products regulated in conjunction with blood products are approved as new drugs. These include plasma volume expanders and the anticoagulant containing blood collection containers used to collect blood from donors and process components.

Medical devices regulated under the Federal Food Drug and Cosmetic Act have yet another application review process, depending on the clarification of the device, based on risk. The devices considered to be of highest risk, termed Class 3 devices, are approved through a premarket approval procedure. Devices of lesser risk, which are Class 1 or Class 2, are cleared for marketing by claiming substantial equivalents to a product already legally marketed.

Surveillance activities for the purpose of monitoring FDA regulated products after they are marketed include inspection, lot release for some biological products. Lot release consists of approving each lot of a product before it is released for marketing. Lot Release can involve physical testing of a product within the Center for Biologics or the review of protocols that include the results of lot release tests performed by the manufacturer.

Another mechanism for surveillance is by review of reports that are required to be submitted by manufacturers. These include error and accident reports required to be submitted by biologics manufacturers, adverse event reporting for drugs and biologics, medical device reporting, and fatality reporting, a requirement for blood collection and transfusion facilities.

In addition, prior to approving a drug or biologic for marketing, manufacturers are sometimes asked to perform additional studies post approval. These studies are generally undertaken to monitor the product once it is in general distribution, and can vary greatly in scope, purpose and content.

One of the most valuable of the surveillance tools is the inspection. Inspections are conducted as part of the pre-approval process for biologics, drugs and Class 3 medical devices. Inspections to monitor a manufacturer's adherence to current good manufacturing practices are conducted on a routine basis. For most biologicals, these inspections are on a biannual cycle.

Inspections are also performed for cause. For-cause inspections can be initiated for a variety of causes, including complaints, product failures and adverse event reporting.

When a manufacturer or a product is found to be out of compliance, several enforcement options are available. Generally, if products are not severe to warrant immediate action, a firm will be sent a warning letter. The warning letter is a notice that conditions are not acceptable and that the firm had better correct deficiencies. If deficiencies are not corrected or conditions are egregious, or a hazard to health exists, further action, either administrative or judicial, are taken against the product, the firm and/or the responsible individuals.

Administrative actions are available under the Public Health Service Act for licensed biologics, and include revocation of license and suspension of license. Revocation is warranted when a firm fails to live up to the terms of its license. It is a process that requires notice and opportunity for a hearing before the license is revoked. If grounds for revocation exist and further, the conditions represent a danger to health, a license can be suspended. Suspension is an immediate summary action without recourse by the establishment.

Products are also subject to action by the agency. You are likely to hear quite a bit about product recalls. Recalls in most cases are voluntary actions, taken by manufacturers to remove a violative product from the market or to correct violative labelling of a marketed product.

The recall action is taken rather than have FDA request judicial action to seize the product. A firm's voluntary recall of the product addresses the problem more quickly than can occur with judicial action, and is the preferred action by the agency.

Civil and criminal penalties can also be taken against the firms who manufacture and market FDA regulated products and the individuals responsible. A firm can be enjoined by the courts to stop violating the laws administered by the FDA. Injunctions can be prohibitory, which in effect put the firm out of business, or in the case of most biological products, the injunction is mandatory. Because of the scarcity of the biological product, the violative firm is ordered by the court to operate in compliance with the Food Drug and Cosmetic Act.

Firms and individuals can also be prosecuted for violating the FDA administered laws, or violations of the U.S. Criminal Code.

Blood and blood derived products that are regulated by FDA fall into distinct categories. The hematologic products are those that are derived from blood or more recently, manufactured by recombinant technologies. These products are fractions of blood, more specifically, the plasma portion of blood, that is separated further by various chemical and physical means or proteins analogous to native blood programs that are intended to replace missing factors in the blood or treat a variety of hematologic or immune conditions. Some plasma proteins are also utilized as an additional ingredient, such as stabilizers and other blood products such as vaccines.

Blood-derived hematologic products include coagulation factors such as factor eight or anti-hemophiliac factor, albumin and immune globulins, both for general use and specifically selected antibodies to fight specific infections such as hepatitis or rabies. These products are prepared and marketed similar to other biological products, such as vaccines.

Safety and efficacy are studied in trials conducted under investigational new drug exemptions prior to a manufacturer's filing a license application, to allow the commercial marketing of the product.

There are generally a very limited number of manufacturers who prepare each product. In some cases, a single manufacturer may manufacture the product. For those that are prepared from human source material, the products are prepared from pools containing plasma from many donors. All of these factors contribute to concerns when problems occur, such as immediate need for a product when a particular disease outbreak is in a given area, for example, an outbreak of hepatitis-A, when a pool of plasma or plasma fraction is or is potentially contaminated, or when a manufacturer experiences production problems, good manufacturing practice breakdowns or decides to discontinue the manufacture of the product.

The second category of products are the traditional whole blood or blood components intended for direct transfusion or for manufacturing into fractionated blood products or medical devices. Unlike the fractionated products that are prepared in a few manufacturing sites by a limited number of manufacturers, blood and blood components are prepared by a large number of sites throughout the United States. Although much production is controlled by large corporations, the collection and processing is performed in centers throughout the country to appeal to and accommodate the donor base.

Some blood and blood components are shipped interstate and are required to be licensed. However, other blood centers do not operate in interstate commerce and are not required to have licenses. They are not required to have premarketing review of their facilities and products, but are responsible for adhering to published standards for the establishment and products that are subject to good manufacturing inspections by FDA investigators.

A third category of blood establishments are transfusion facilities that neither collect nor process blood, but merely store blood components collected by others, perform compatibility testing with prospective recipients, and maintain records of blood storage and transfusion.

In 1980, the FDA entered into an agreement or memorandum of understanding with a sister federal agency, the Health Care Financing Administration. Because of the requirements of Medicare/Medicaid laws, the Health Care Financing Administration performed surveillance activities over many of the same facilities that were also inspected by the Food and Drug Administration.

In order to reduce duplication by the federal agencies and reduce the burden on the regulated industry, the FDA agreed to relinquish inspectional surveillance of facilities that transfused blood collected by others. In return, the Health Care Financing Administration agreed to adopt FDA requirements for the transfusion facilities. Therefore, although FDA does not routinely inspect transfusion facilities, they are required to adhere to FDA product standards and good manufacturing practices.

Many of the decisions to regulate similar prepared blood and blood components in this tiered fashion were due to resource constraints and levering resources. Although FDA does not view such stratification as affecting public health, we do hear concerns expressed by the regulated industry of a perception of class differences among those regulated differently. That is, it is the perception that licensed blood banks are held to a higher standard than registered unlicensed blood banks, or that transfusion facilities do not view themselves as responsible for adherence to FDA's current good manufacturing requirements.

The third category of products are medical devices used to process or test or administer blood and blood components. Some in vitro medical devices are regulated by the Center for Biologics evaluation and research as licensed biological products. These products include a licensable biologic component and are tests that are required or recommended to test another licensed biologic. These include serologic and infectious disease tests to screen the blood supply. The licensing of these products as biologics predates the medical device amendments to the Food Drug and Cosmetic Act, which was not enacted until 1976. By that time, the biologics regulators had numerous precedents dating to 1949 for regulating reagents under the Public Health Service Act.

When the Center for Devices and Radiological Health was founded to implement the medical device divisions of the Food Drug and Cosmetic Act, it entered into an inter-center agreement with the Center for Biologics, to address medical devices used in conjunction with blood processing. It was agreed that certain tests required or recommended to screen the blood supply would remain licensed biological products under the purview of the Center for Biologics.

Other medical devices used in conjunction with blood banking would be regulated under the medical device amendments, but would be under the jurisdiction of the Center for Biologics. These include other in vitro tests with blood screening claims and devices associated with blood collection and processing.

In the 1980s, it was also agree that any HIV test, regardless of claim, would be regulated by the Center for Biologics.

I have discussed the statutory basis for regulation, but have not yet discussed other regulatory tools. These include regulations in various guidance documents prepared by the agency. The statutes are the laws enacted by Congress and must be obeyed.

Regulations are an agency's interpretation of the laws that it is required to implement. Regulations are promulgated following the Administrative Procedures Act. This act requires that any proposed regulations be published as a proposal for public comment prior to becoming final. Following a public comment period, the agency publishes the final rule and must address any comments made to the proposal and changes affected based on those comments in a preamble statement. Upon the publishing of the final rule, the regulation has the force and effect of law.

Regulations covering the manufacture of blood, blood derived and blood related products are found in Title 21 of the Code of Federal Regulations. The applicable regulations are found primarily in parts 200, 300, 600 and 800.

In an ideal world, the rulemaking process is an ideal mechanism. No one will argue with that. However, in times of rapid change, rulemaking, because of the layers of review and checks and balances, becomes a rigid, cumbersome process. For that reason, regulations tend to be general statements.

It has been found that additional information needs to be supplied to provide insights into the agency's position regarding ways to achieve compliance with the regulatory requirements. There are also times that it is important to provide information to the public and regulated industry in a more timely fashion than can be provided through rulemaking.

For these reasons, the agency has come to depend on variety of guidance documents. These guidances include guidelines, statements of policy, points to consider documents, blood recommendation memoranda, reviewers' guides, compliance programs and policy guides, and I'm sure, others. These documents delineate the agency's position.

In recent years, the blood program has taken new or controversial issues to its Blood Products Advisory Committee, prior to issuing or publishing a guidance. Recently however, the agency has committed to a rules-based approach to issuing guidance documents. The agency published a document entitled Good Guidance Practices in February of this year.

This document is the agency's new policy and procedure for developing future guidance documents. It providers for public input. Additionally, guidances are divided into levels, depending on importance and impact. Level one documents are published for public comment prior to implementation unless there is a critical need such as public health concerns to consider the document implementable upon initial publishing.

Level two documents are of less controversy or impact, and are issued upon implementation. All guidance documents will be subject to comment throughout their lives. In the blood program, we are currently evaluating how our documents will fit into the good guidance practices.

This concludes my presentation on the framework for FDA regulation of blood products. I hope it will give you a point of reference for your discussions later today and tomorrow.

Thank you. Are there questions? I thought I was following Dr. Zuck, who will give you a very good description of current good manufacturing practices. Therefore, I didn't go into the basis for those too much. But he does have quite a bit of his talk dedicated to that.

PARTICIPANT: Kathryn, I was wondering if you could just say a word, if you know about it, the regulations of this interstate production and use of blood. Are there any at all? I don't mean for you to give us all 50 states, but --

PARTICIPANT: They vary quite a bit. Some states have actually just adopted the federal requirements, that if you meet federal requirements, you are okay within the state. Other states, such as New York and California and probably some others, have very individual state requirements.

There is no federal pre-emption for biologics regulation. Therefore, the states are free to have any type of regulatory structure they care to have over blood.

Thank you.

PARTICIPANT: Well, thank you for that tour through the woods of regulation. I will point out to the committee, if at any time others move to the slides, those seats out in the front there can be occupied for viewing the visual presentations as they come up.

At this point, I think what I would like to do is allow us to move to our break. We are in the clinical center, which means that for the purposes of this break, you are on your own to wander out there and find coffee. I didn't get the location of the bathrooms, but I assume they are pretty clearly marked, out the door out there.

I would like to get us back together pretty close to 11, and we'll pick up the overview issues at that time.

(Brief recess.)

PARTICIPANT: We do have another talk with slides, so if some of the committee would like to go out to the more comfortable audience seats, that would be great.

We are going to be hearing from Dr. Paul Meade, who is going to be giving us an overview on FDA policies related to hepatitis-C and look-back issues. I'm just going to wait another minute to allow people to come back into the room, and to ask people in the back to take their seats.

Again, this talk is really an overview to help bring the committee up to speed and to allow us to have a common framework to understand the regulatory issues. So we are not going to have questions from the floor, but we will have the opportunity for the committee to put questions to Dr. Meade at the conclusion of his remarks.

Also, one other small housekeeping item. For members of the committee, I am struggling mightily to allow us a space where we can eat lunch together and actually look at one another. I think that is going to happen. Even if we can't secure a common room, I'll be looking for a table. So keep an eye on me, keep on eye on Dr. Gusby. In the lunch area, the cafeteria, we will try and see if we can sit together during lunch. That would be a strongly desirable thing.

Dr. Meade.

PARTICIPANT: Thank you, Dr. Kaplan. This morning I am going to summarize the FDA policies related to look-back for transfusion transmitted infectious agents, such as HIV, HBV, HCV and HTLV. Then I will set the stage for the other speakers by reviewing the chronology of the HCV look-back issue, and presenting some issues for consideration in addressing the potential utility and the optimal design of a program of transfusion recipient notification for HCV.

Now, the issue at hand is whether and how to focus a program aimed at the identification, notification, testing, counselling and treatment of persons who may have been infected with HCV through transfusions, and, assuming that such an effort is appropriate, what will be the most efficient way of identifying the largest number of HCV infected transfusion recipients. One option for discussion is a directed look-back program, the general features of which I am going to describe.

Look-back refers to two procedures. First of all, product retrieval, which is the tracing and retrieval of previous viral marker negative collections from a donor who now tests repeatedly reactive. It may be necessary to perform product retrieval with the introduction of a new assay or a more sensitive assay, or also, when a donor may have been in the infectious window period during prior donations subsequently seroconverts.

Now, that window period is that time interval between infection with the virus and the appearance in the blood of a viral marker, such as an antigen or an antibody, which is detectable in a serologic test for that marker.

The second part of look-back is recipient notification, the tracing, notification and counselling of recipients of these prior negative units, when the donor now tests positive.

There are two reasons for performing look-back. When a donor now tests positive on a viral marker test, product retrieval can be performed to interdict earlier potentially infectious viral marker negative donations which may have been made when the donor was in the infectious window period. Secondly, to notify transfusion recipients so that they may be tested and counselling regarding the risk of disease, the availability of treatment, and prevention of secondary transmission.

Recipient notification is a concept that did not exist prior to the mid-1980s. It was a response to heightened concerns about blood safety resulting from the AIDS epidemic and the availability of more tests and more sensitive tests, as well as improvements in computer capabilities for tracking biological products and transfusion recipients. Prior policies were limited to retrieval of products.

The current look-back policy for HIV consists of both look-back procedures. Recommendations for product retrieval when a donor now tests repeatedly reactive and for recipient notification related to prior collections from a donor currently testing positive for antibody to HIV were put in place in April, 1992 as part of the FDA recommendations to blood establishments entitled, Revised Recommendations for the Prevention of HIV Transmission by Blood and Blood Products.

FDA also published a final rule in September, 1996 to require certain look-back procedures for HIV. Analogous procedures for HIV-1 p24 antigen screening related to retrieval of prior collections when a donor now tests repeatedly reactive and recipient notification when that donor tests positive on the neutralization test for antigen, we are recommending an FDA memorandum issued on August 8, 1995.

The HIV look-back rule, current good manufacturing practices for blood and blood components, notification of consignees receiving blood and blood components at increased risk for transmitting HIV infection, was published in the Federal Register on September 9, 1996. The final rule states that if a donor tests repeatedly reactive on a screening test for antibody to HIV, the blood establishments should promptly quarantine previous collections of whole blood, blood components, source plasma or source leukocytes intended for transfusion from that donor from the past five years, or back to the time 12 months before the last negative antibody screening test.

If the date of the last negative test is known, units collected more than 12 months prior to this date need not be quarantined. If the date is not known, all units collected previously should be quarantined.

Just to illustrate this, when the blood establishment goes back in time from the current collection and looks at the data in the most recent negative screening test for HIV-1 and 2, if the time interval between that date and the prior collection was greater than 12 months, that prior collection need not be quarantined.

I would like to briefly explain the rationale for this time period of 12 months. In some cases, the donor may have tested negative by this previous test while in the window period. In the vast majority of cases, this is less than six months, during which the donor tests negative or HIV antibody, but may be infectious. Estimates predict with about 95 percent confidence that HIV infected persons will test positive or seroconvert for antibody to HIV within six months from the date of infection.

To provide an additional margin of safety, FDA has extended the period of look-back to 12 months, approximately a 99 percent confidence interval, so that virtually all donations collected during the window period are included.

Blood establishments should also quarantine previous collections of plasma from the past six months, if intended for manufacture into injectable products. This refers to unpooled units of source plasma or recovered plasma. This time period is limited to six months, because that represents the practical limit of time that plasma for further manufacturing generally remains in inventory prior to pooling. To avoid a shortage of injectable and non-injectable products, the final rule exempts from quarantine pooled source plasma and source leukocytes intended for further manufacture into those products.

In addition to quarantining prior collections that they hold, the blood establishment should also notify consignees such as hospital transfusion services and manufacturers of plasma derivatives, of the repeatedly reactive HIV screening test result, so that they can promptly quarantine prior collections intended for transfusion or unpooled units of plasma from that donor until the donor status is clarified through further testing.

The blood establishment is also required to promptly test the current donation using a licensed additional, more specific test for anti-HIV-1, and to notify consignees of the result.

Consignees such as hospital transfusion services should be notified of the additional more specific tests for anti-HIV-1, so that they can release those quarantined units if the test is negative, or destroy those units if the result is positive or indeterminate. Notification of consignees regarding the results of the additional more specific tests will also enable those consignees to carry out notification of transfusion recipients, if the supplemental test is positive.

Now, for simplicity, I have omitted the HIV-2 testing provisions in the final rule from this testing scheme. When the repeatedly reactive screening test that was initially run is performed using a single virus test for antibody to HIV-2, or a combination test for antibody to HIV-1 or HIV-2, a second screening test for HIV-2 which is different from the original HIV-2 test, must also be performed. Prior collections may be released from quarantine only if the donor is tested for antibody to HIV-1 by a licensed, more specific test and the result is negative, and if the screening test is repeated using a different EIA test for antibody to HIV-2, either a single virus or a combination test, and the result is negative.

So release from quarantine is not permitted under any other test results.

Transfusion recipient notification is required when the incensed, more specific test for HIV-1 is positive, or when the second different EIA test for antibody to HIV-2 is repeatedly reactive.

Now, upon completion of the additional more specific testing, the final rule also requires hospital transfusion services that do not participate in Medicare to take steps to notify transfusion recipients as appropriate.

Now, these are hospital transfusion services which are not subject to the Health Care Financing Administration's regulations on condition of Medicare participation for hospitals, as stated in HCFA's final rule, which was published concurrently with this FDA final rule. These transfusion recipients shall receive notification for the purpose of testing, for evidence of HIV infection, early treatment if indicated, and counselling to take appropriate precautions to prevent the further spread of the virus, such as to sexual partners.

The transfusion service shall notify the recipient's attending physician, the physician of record, and ask him or her to inform the recipient of the need for HIV testing and counselling. If the physician is unavailable, or declines to notify the recipient, the transfusion service shall notify the recipient and inform the recipient of the need for HIV testing and counselling.

The notification process shall include a minimum of three attempts to notify the recipient, and be completed within a maximum eight weeks of receipt of the results of the licensed more specific test for HIV. The transfusion service is responsible for notification, including basic explanations to the recipient and referral for counselling, and shall document the notification or attempts to notify the attending physician or the recipient.

So that is a summary of FDA's policy for product retrieval and recipient notification for HIV.

Now, the usefulness of recommending similar actions for hepatitis-B surface antigen, anti-hepatitis-B core antigen, anti-HCV and anti-HTLV-1 has been discussed at several public meetings of the FDA Blood Products Advisory Committee over the last five years. For each of these viral markers, it has been necessary to examine the probability of units from prior collections being infectious, based on the significance of the subsequent testing information.

Although FDA believes that currently there is a very low risk of transfusion transmitted HBV, because of the sensitivity of screening tests for HBV infection, and although there is a continued absence of a licensed supplemental test for anti-hepatitis-B core, and anti-HTLV-1, FDA has determined that quarantine of certain end date prior collections from seroconverting donors will provide an added safeguard to the blood supply. Such a policy also creates a consistent approach to inventory management of products from all such donors.

As a result, FDA has developed a policy on product retrieval for HBV, HCV and HTLV-1. That is, the quarantine of products from prior collections of seroconverted donors. On July 19, 1996, FDA issued a memorandum to all registered blood and plasma establishments which recommended product retrieval for HBV, HCV and HTLV-1. This memorandum was titled, Recommendations for the Quarantine and Disposition of Units From Prior Collections from Donors with Repeatedly Reactive Screening Tests for HBV, HCV and HTLV-1.

The FDA recommendations concern the quarantine and disposition of prior collections of blood, blood components and source plasma, extending back five years, from a donor who subsequently tests repeatedly reactive for hepatitis-B surface antigen, antibody to hepatitis-B core antigen, antibody to hepatitis-C virus or antibody to HTLV-1. If there is a record available of the donor's last negative test result, then quarantine of prior collections need only extend back to 12 months before the test.

Blood establishments should also notify consignees, such as a transfusion service, physician or fractionator, et cetera, of such products, and request a quarantine of those products. This recommendation is directed at in-date unpooled units that are in the blood establishments and consignees' inventories, not products which have already been pooled or further processed.

In the July 1996 memorandum, FDA also recommended additional testing of the donor's current repeatedly reactive sample to determine if products may be released from quarantine or if they should be destroyed. For units previously distributed, consignees should be notified of the results of the additional testing, so that they may either release or destroy those products as appropriate.

However, in regard to products already transfused, FDA did not recommend consignee notification for the purpose of recipient notification for HBV, HCV or HTLV-1 in this memorandum.

The issue of recipient notification for units potentially contaminated with HBV or HTLV-1 was discussed by the Blood Products Advisory Committee at a meeting in September, 1991. The advisory committee recommended that additional information should be obtained before recipient notification could be considered for HBV. Additionally, the committee decided that the data available at that time did not justify recommending recipient notification for HTLV-1, and advised FDA to consider such recommendations for HTLV-1 when additional, more specific licensed tests become available.

Now, despite the continued absence of such a test, a guidance document was developed and discussed by the Blood Products Advisory Committee in December, 1994. This guidance document resulted in FDA's 1996 memorandum on product retrieval, which I just described.

It has been FDA's intention to clarify its policy on recipient notification after additional input is obtained through mechanisms appropriate to address the legal, social and economic aspects of this issue. Today, the Public Health Service brings before this committee the issue of the usefulness of recipient notification for HCV in the context of public health.

In summary then, look-back policies currently in place for these transfusion transmitted agents include both product retrieval and recipient notification for HIV, but only product retrieval at the present time for HBV, HCV and HTLV.

The question of whether recipient notification should be recommended for these agents awaits public discussion of the issues involved.

I should point out that for HTLV, blood establishments voluntarily initiated notification and counselling of recipients of blood or cellular components from donors who have a confirmed positive test for HTLV-1/2 antibodies when antibody screening was implemented in 1988 and 1989. Since the number of infected donors identified was small, a sequential targeted look-back program was recommended by the American Association of Blood Banks, AABB, and implemented without much discussion or controversy.

HCV look-back. Prior to the availability of assays for anti-HCV, on October 16, 1989, an inter-agency group of federal health officials from the FDA, NIH, CDC and the Veterans Administration met to discuss HCV look-back. On October 31, 1989, the FDA's Blood Products Advisory Committee determined that there was insufficient information available concerning hepatitis-C infection to propose either product retrieval or recipient notification for products derived from units potentially contaminated with hepatitis-C virus.

In April 1991, this point of view on hepatitis-C look-back was addressed in CDC's morbidity and mortality weekly report, Public Health Service inter-agency guidelines for screening donors of blood, plasma, organs, tissues and semen for evidence of hepatitis-B or hepatitis-C.

In the discussions of the Blood Products Advisory Committee and in the MMWR product retrieval for HCV and targeted look-back tracking prior recipients of blood products from donors who now test positive for anti-HCV, or general screening programs for populations at increased risk of HCV infection, were not recommended at that time for the following reasons.

Number one, the lack of availability of a licensed more specific test for anti-HCV could lead to the possibility of a high rate of following up of false positives on the screening test. As you know, a specific supplemental test for anti-HCV is now available.

Secondly, the anti-HCV screening tests were not able to distinguish between ongoing infection and recovery. Thus, the meaning of the repeatedly reactive result for any one individual would not be clear. It is now clear that most anti-HCV positive individuals have a chronic transmissible disease.

Also at that time in 1990 and 1991, many HCV infected donors would have been deferred as a consequence of earlier screening policies. For example, donor exclusion due to history as a response to the AIDS crisis and implementation of testing for surrogate markers, that is, agriculture-B core and ALT for non-A-non-B hepatitis. This deferral would make re-donation, and therefore detection of HCV infection, less likely. This is still true today.

The available knowledge on routes of transmission for HCV other than parenteral was limited at that time, reducing the usefulness of medical counselling. This is still the case today.

Lastly, because of labelling limitations of approved indications for alpha interferon therapy, only selected persons were eligible for treatment for hepatitis-C infection, and the potential long-term benefits of such therapy were not known. This is also still true today. Labelling limitations still exist, and the long-term benefits of such therapy are still not fully understood, although we now know that some patients do benefit from this therapy.

The screening of blood donors for antibody to hepatitis-C virus was implemented in the United States in May 1990, when the FDA licensed the first solid phase enzyme immunoassay for EIA for the detection of anti-HCV. This assay detected antibody to the C-100-3 antigen of HCV.

In March 1992, the FDA approved a multi-antigen screening test with increased sensitivity which, in addition to detecting antibody to C-100-3, also detect antibodies to additional HCV antigens, C-22-3 and C-33C.

In June 1993, FDA licensed an anti-HCV supplemental test, the RIBA 2. At the FDA Blood Products Advisory Committee meeting of December 1993, HCV look-back was again discussed, primarily because FDA had licensed this additional more specific test. In addition, it had become clearer that antibody positive persons were highly likely to be harboring a chronic transmissible infection.

The committee unanimously endorsed product retrieval from previous collections from donors who test repeatedly reactive for anti-HCV, and who do not have a negative test result on a licensed supplemental test. That is, the supplemental test is positive, indeterminate, or was not done.

By a vote of five to four, the committee marginally endorsed consignee notification for purposes of recipient notification for such products, but reiterated many of the reservations described earlier related to the lack of an established public health benefit in performing this activity. This reaffirmed FDA's feeling that there was a need for further public discussion.

In December, 1994, product retrieval for HBV, HCV and HTLV-1 was discussed at a meeting of the Blood Products Advisory Committee. As I described earlier, an FDA memorandum to the blood and plasma establishments which recommended product retrieval for these agents was issued on July 19, 1996. Recipient notification for HBV, HCV and HTLV-1 was not recommended by FDA at that time, due to the need for a full discussion of this topic.

Currently, recipient notification is required for HIV, but for no other transfusion transmitted disease.

In decision making, whether to recommend recipient notification for a particular transfusion transmissible infectious agent, it may be helpful to address an antecedent set of issues. These broadly applicable questions merit consideration in addressing the potential utility and the optimal design of recipient notification for HCV.

First of all, is HCV infection a significant medical condition? What is the incidence and prevalence of the disease in the overall population? Is infection at an epidemic level? If so, is it a new epidemic, or is it an endemic condition? What is the risk of transmission of the infection by transfusion? What percent of the overall disease frequency in the population is caused by transfusion? More specifically, is transmission by blood transfusion a large enough part of the total community transmission to merit special public health measures? What is the risk of disease following transmission of the infection? What is the accuracy or specificity of the tests for markers of the infection? Is there a supplemental or additional test of greater specificity than the initial screening test that is commercially available? Do the tests distinguish between a chronic carrier state and being in a state of recovery from the infection? Are there opportunities for intervention sufficient to warrant recipient notification? Are interventions available? Is the disease treatable? If so, is early treatment more effective than later treatment? Can avoidance of co-factors such as alcohol be recommended to the recipient? Is there significant risk of HCV secondary transmission and disease? What are the routes if any of secondary transmission of the infection? Is it transmitted parenterally? Is it transmitted sexually? By household contact, such as sharing toothbrushes and eating utensils, by other types of contact? What is the efficiency of transmission by these different routes? Is there opportunity for prevention of secondary infection? Can an intervention in lifestyle or activities prevent secondary transmission?

Also, what ethical considerations are involved in the decision to notify or to not notify recipients? For example, does the recipient have a right to know or a right not to know that they might have received HCV contaminated blood? Should recipient notification if recommended be prospective, that is, subsequent to promulgation of a policy from this time forward? Or should it also be retrospective? For example, should the recipient notification program be intended to capture all prior collections before screening was implemented, or to capture seroconverters after screening was started?

The cost effectiveness of recipient notification needs to be examined. Who should bear the cost, the patient, the blood center, the government? A discussion of these factors that I have listed may suggest whether recipient notification for HCV is justified.

It has been estimated that only three to four percent of HCV infected individuals report recent transfusions. Targeted testing of all recipients of implicated transfusions would include a high proportion of individuals with false positive ELISA screening test results, because of the high false positive rate of those tests at a time when additional more specific assays were unavailable. This would result in psychological harm, and unnecessary medical expenditures for these individuals.

In attempting to answer the question of the usefulness of recipient notification for HCV, we may be able to draw a little bit on our experience from studies of previous look-back programs, such as for HIV. These studies show that the overall yield in efficacy of HIV look-back programs are poor. Look-back appears to be an ineffective way of finding transfusion transmitted cases of HIV infection.

Experience with a general look-back effort, that is, the contacting and testing of all transfusion recipients, indicates that the number of persons who can be recontacted after six to 12 months is low.

In a general look-back effort in the San Francisco area, as reported by Mike Busch, only 4.4 percent of 17,331 persons notified by individual letter, who were transfused during the risk period prior to screening for HIV actually sought testing.

Shortly after anti-HCV kits were licensed, at least one blood center initiated a pilot study of general HCV look-back, a transfusion recipient education program about hepatitis-C as reported by Tom Zack in 1990. Following a widely publicized large-scale targeted community education and notification campaign, a very small proportion, an estimated one to five percent, of the transfused population living in the area were tested, and only 6.2 percent of recipients who actually sought testing had a positive test result on an anti-HCV supplemental test.

Therefore, based on these two studies alone, if directed look-back on transfusion recipient were conducted for HCV, we might expect on the order to 4.4 percent times 6.2 percent, 4.4 percent being those notified who actually seek testing, times 6.2 percent, the proportion of positives, or 0.27 percent of notified individuals to be positive on the supplemental test for HCV, not all of whom would actually have a chronic HCV infection. Thus, directed look-back for HCV might be an extremely ineffective way of finding transfusion transmitted HCV cases.

Thank you.

PARTICIPANT: Well, thanks for that overview. What I would like to do at this point is bring our committee back up here. Maybe while they are returning on that journey, I can ask a question which you may know the answer to.

Could you tell us, what are the policies in place for just routine blood screening by insurance companies or health providers for HCV at the present time? In other words, if I apply for life insurance and I ask to take an HCV test, as I would an HIV test by many companies, if I go to the doctor and just have a routine physical, will my blood be examined, as it often is now for HIV presence? Would they include HCV?

Related to that, what is the policies in the organ donation-tissue donation world about HCV?

PARTICIPANT: I believe the answer is no. For insurance screening, I don't believe a test for anti-HCV is run. We know of course that a test for anti-HIV is routinely performed, but HCV, no, I don't believe so.

PARTICIPANT: And the organ tissue?

PARTICIPANT: In the organ tissue domain, there is screening for antibody to HCV of the donor's blood.

PARTICIPANT: Why don't we open the floor to the committee for questions? Please identify yourself when you ask, if you have a question.

PARTICIPANT: A couple of questions. One, you described an HCV look-back as far as retrieval, but you didn't give us what the criteria were for release. Is it RIBA 2? Is it HCBRNA?

Secondly, if there is a release step, then what happens in terms of those donors' position on an exclusion list? Are they removed from the exclusion list? Do they come back into the blood supply? Is there increasing availability of donors?

PARTICIPANT: You are talking about release of prior collections that had been previously quarantined because of a repeatedly reactive anti-HCV test?

PARTICIPANT: Right, and you said that when the donor comes back and you retest them, and if the donor is negative you release those units, is that correct?

PARTICIPANT: Yes, that is correct, the units are released.

PARTICIPANT: So what happens to those donors? Do they remain on an exclusion list, or do they go back into the donor pool?

PARTICIPANT: They could go back into the donor pool based on possible re-entry using the supplemental test for HCV.

PARTICIPANT: So would you then describe that as a positive return on the first step of look-back?

PARTICIPANT: As a positive return?

PARTICIPANT: Yes, in terms of increasing the availability of donors, since clearly, in all the steps that we have gone through before, every step is reduced to the potential donor pool. Now by doing testing, you re-enter people into the pool.

PARTICIPANT: Certainly, yes, if the donor can be shown to be not infected after all, he would be able to be reinstated as a donor.

PARTICIPANT: The second question I had was, in terms of the projected numbers you used, when I was reading the document you prepared, there were some ranges. Would you describe this as a best case or worst case scenario, or what are the confidence intervals to arrive at 2.7 percent of identification of an HCF infected individual who might benefit from that determination?

PARTICIPANT: Well, I should point out that the rough calculation that we did, at which we arrived at 2.7 percent, or something in that ball park, that calculation is dependent on the 4.4 percent of people who actually do seek testing. I don't know, in any type of look-back program, what the range of expectation would be for the percentage of people who would actually seek testing when you do that type of general look-back. Perhaps we can have comments on that later this afternoon in the CDC part.

But the calculation took the 4.4 percent times the 6.2 percent, which is the percentage of those that tested positive in this particular case to arrive at the 2.7 percent. So they are both subject to a range of variability, depending on the particular viral marker that you are doing look-back for, the population in the area.

As to those ranges, perhaps we could get a better feel for that this afternoon.

PARTICIPANT: Is that RIBA 1 or RIBA 2?

PARTICIPANT: Those were RIBA 2 positive people, 6.2 percent.

PARTICIPANT: The real population at risk recipient notification from a practical standpoint as a result of transfusions that were contaminated with HCV, were people transfused before 1990.

PARTICIPANT: That's correct.

PARTICIPANT: Now, this program you're talking about, if it would be put in place, would it relate to these people at all? Or that is too far back? Those are the people where you are going to find large numbers, and we know this is a chronic disease. If you identified them, you might be able to do something for them.

(End of Tape 2, Side 1.)

PARTICIPANT: -- blood center. It may be a falsely low value. A number of those individuals may have received your communication and ignored it, because either they had already been tested, which was pretty common, I guess, for anybody -- there certainly was a lot of publicity about the fact that if you received blood, you were at high risk, and therefore there may be a significant under reporting. When you start then doing cost effectiveness analyses based on the estimate of return, you need to take that potential into account, because we may underestimate the potential benefit of HCV look-back.

PARTICIPANT: I'm a person who likes statistics, and I'm looking over this information. I'm not sure if it is going to be shared with us later on or not, but since discussions began in HCV look-back or HCV in October 16, 1989, do we know what may be the morbidity statistics of HCV, since those discussions began? That may have some kind of bearing on whether or not look-back is going to be necessary or not.

PARTICIPANT: I think we'll hear the latest statistics from CDC this afternoon.

PARTICIPANT: Dr. Hufnagel will probably have some comments on that. Others out there?

PARTICIPANT: I have a question about look-back myself. It seems to me that the FDA has required look-back since 1996 on HIV. Did I follow that right?

PARTICIPANT: Actually, since 1992, with a memorandum for blood establishments recommending both product retrieval and recipient notification.

PARTICIPANT: And aside from Dr. Busch's study, what else is the FDA doing to determine both compliance and the success rate of people coming in who have been notified and seeking testing? In other words, if there any more information from the FDA side about how well that policy is being looked at with HIV?

PARTICIPANT: There may be. I don't have that information. That would certainly be very interesting to look at.

PARTICIPANT: Related to that question, in the FDA's role in look-back, what discussions have taken place at the FDA? I'm just curious, if there is only a four percent return to test rate, even with the qualifications we have heard, is the agency thinking about the effectiveness of that policy?

PARTICIPANT: I think that is certainly one of the options. There are some pros and cons. Really, I just touched upon that general look-back. We need to hear more in depth about the pros and cons of the different types of look-back for recipient notification that could be used. I really just gave you a brief sketch, and didn't go into some of the advantages of doing that.

PARTICIPANT: Last question. Do you know off the top of your head, what is the FDA evaluation and monitoring infrastructure for the HIV? Is there a unit that would do what Dr. Busch did in his San Francisco based study, or what the Zuck study did in Cincinnati? What type of compliance and monitoring and assessment goes on?

PARTICIPANT: As you know, FDA routinely annual inspects all blood establishments. Examination of their compliance with look-back policies is scrutinized during those inspections of the facilities of the blood establishments.

PARTICIPANT: With data?

PARTICIPANT: It is routinely reviewed, yes.

PARTICIPANT: Other questions, comments? Yes, way down in the lower section.

PARTICIPANT: I have two questions. Your perception as to the changing technologies from the point of view of diagnosis and diagnostic assets, do you see pending perhaps two or three years down the road application of PCR in diagnostic capability in attacking this issue?

PARTICIPANT: I'm sorry, I couldn't hear the last part of your question.

PARTICIPANT: Do you see the potential for PCR diagnostic capability impacting this issue in any way?

PARTICIPANT: Yes, I certainly see the potential for PCR as a diagnostic tool, and perhaps also as a donor screening tool. There has been much discussion recently of PCR testing that would be used to screen plasma pools.

This is an issue before the agency right now. We see that as an additional donor screen that will result in improved safety of the blood supply. So yes, I see a role both diagnostically and in donor screening for PCR, very much so.

PARTICIPANT: But specifically from the point of view of look-back?

PARTICIPANT: Specifically from the point of view of look-back?

PARTICIPANT: The look-back issue.

PARTICIPANT: Yes, I think it may be useful there also, absolutely. It is tough to envision to what extent it can be useful, but I think that it is certainly going to play a role.

PARTICIPANT: My second question relates to the gap years. The first generation screening procedure was somewhat inefficient, in that it picked up only about 65 percent affected donors. With the introduction of the second generation procedure, which is so much more efficient, there certainly was a gap, in other words, about 25, 30 percent of individuals who were infected and who were not being picked up.

PARTICIPANT: Yes.

PARTICIPANT: Has this issue been considered in discussion?

PARTICIPANT: In terms of look-back? Again, I think this is something that we are going to hear this afternoon, looking at retrospective look-back prior to the introduction of the first screening test, between that time and when the tests were improved, the second generation, and up to the present time. I think that all of those time periods can be examined and potentially designing an optimal program. So we will hear more about that this afternoon.

PARTICIPANT: Are there any considerations for special population groups that occasionally serve as donors, like populations of immigrants and those that are of questionable status, being either documented or undocumented, or those that engage in a variety of occupations that cause them to be somewhat mobile, seasonal and migrant farmworker families, in terms of look-back or in terms of screening?

PARTICIPANT: I'm personally not aware of studies that have been done looking at different populations. Perhaps someone here may be, but I'm not.

PARTICIPANT: Maybe you could explain how the look-back applies to fractionated products that have been in use.

PARTICIPANT: Fractionated products that have been in use? Our look-back policy for product retrieval will be to quarantine -- or is to quarantine prior collections from the past six months that have not been pooled.

PARTICIPANT: What about those that have already been used?

PARTICIPANT: Those that have been pooled for purposes of further manufacture, we are talking about plasma now, those are not subject to quarantine under our current policies, for the reason I mentioned, concern with ultimate shortage of the products, as well as for HIV. We feel that those plasma derivatives, due to the production processes used in producing those derivatives, are extremely safe.

PARTICIPANT: What is the assurance of the effectiveness of the post treatment procedures?

PARTICIPANT: What is the -- ?

PARTICIPANT: In other words, when the so-called sterilization procedures are applied to the products that are sent out. We already have data as to the efficacy, or at least the efficiency, of that system in screening out any of the viral entities. But we don't have all of that information. How does that apply? What about the hepatitis, HCV and some of the others? How effective is that neutralization process?

PARTICIPANT: I think that is a good question, but I don't have the numbers. I would be hesitant to give you any that may not be accurate. But I think that is something that should be looked at. That is another consideration, I think, as we address look-back programs.

PARTICIPANT: When the questions of that nature come up and hang there, we will try and make a note of them, so we can return back and see if we can get to the issue of safety and efficacy. Other questions?

PARTICIPANT: I'm Jay Epstein. I direct the Office of Blood Research and Review in the Center for Biologics at FDA.

The question, how well manufacturing procedures clear or inactivate viruses in derivatives has been intensively studied for the last two decades for different agents. The answers however are agent specific. What we can say about HIV is that the two primary inactivation methods which are heating processes, which since 1987 have been very similar to pasteurization, that is to say, heating in a liquid state at 60 degrees Centigrade for a period of up to ten hours, and solvent detergent inactivation, which is a chemical disruption procedure, both are extremely effective procedures, where the log 10 inactivations are as high as one can measure. In other words, we estimate them to be in ranges exceeding 19 logs. They are extraordinary.

Basically, you have essentially with solvent detergent inactivation instantaneous clearance of as large an inoculum as you can add, the upper limit of which is approximately 10 logs. We know that the exposure to the agent goes on for hours, whereas the inactivation of 10 logs is instantaneous.

So we believe that that is extremely effective inactivation. Likewise for the pasteurization processes, data from the Centers for Disease Control generated in 1985 indicated that in the liquid state, one log is removed in about 30 seconds, and the exposure time in that procedure is 10 hours. So once again, we are dealing with an extraordinary overkill, an extraordinary safety margin for those manufacturing procedures.

Now, the situation for hepatitis-C is different in the following way. There is a major contribution to viral clearance and inactivation obtained for HIV from the fractionation procedure per se. In other words, the process of purifying the derivative for certain of the derivatives, such as immune globulin and albumin renders them already safe above and beyond inactivation.

That is not true for the clotting factors, where we have of course the historic tragedy that the viruses were not removed. Indeed, they might be concentrated in the clotting factor. So for the derivatives, we are dependent on the inactivation procedure per se, not just the manufacturing.

Similarly for hepatitis-C. The transmission of hepatitis-C by an intravenous immune globulin product in 1994 demonstrated that there was a delicate balance between the antibody and the viral safety, and that fractionation alone did not render the product safe. Once again, however, we do know that the viral inactivation procedures are highly effective at clearing hepatitis-C. We do not have the same ability to measure the capacity as we do for HIV, because of limited size of the inocula and the absence of any animal model or in vitro system in which readily to assay it.

But we do know that the inactivation procedures are highly effective for hepatitis-C. It is an envelope virus. The envelope is stripped. It is also quite heat labile.

So in distinction from HIV, where all except the clotting factors are rendered safe by the purification process and above and beyond that we have inactivation, for the clotting factors and for HCV, we are more directly dependent on viral inactivation, but where those procedures are in place, we know them to be highly effective.

I can't give you the same level of quantitative statement. I know those inactivations to be in excess of six logs. Actually, Ed Gompers is one of the world's experts on that subject and might be willing to comment. There have been chimpanzee studies, for instance, to try to answer that question.

PARTICIPANT: Other questions?

PARTICIPANT: (Inaudible.)

PARTICIPANT: To make the puzzle more puzzling, there is actually another kind of look-back that has not been mentioned, and I think should be mentioned for just the point of clarification. That is what I call the reverse targeted look-back. The example of that is where a recipient turns up positive, and the blood center is notified, but the donor can never be found again, perhaps has died. There may be other recipients, and one can then reverse a target at look-back. So there is even more than just the general and the targeted. There is what I call the reverse targeted look-back.

PARTICIPANT: One last question, then I think we will move to lunch. There is yet even another type of look-back, which is the general advertisement that has appeared, saying if you received a blood transfusion in a newspaper ad or other type of public service announcement, do you happen to know -- or I can even open this up for comment from anybody on the committee -- the efficacy of that, in terms of moving people to go to their doctor, or alerting them that they should seek out medical advice about exposure to a blood transfusion, just the general public service announcement or advertisement that sometimes appears? Does anybody have any experience with that?

PARTICIPANT: Tom Zuck's paper, which is in our packet, really did that. Basically upon licensure and initiation of screening in 1990, the Cincinnati region served by his blood center, they actually through public mechanisms announced to both physicians, the medical society and to the lay press that this test is available, that anybody who was transfused prior to mid-1990 were at risk for infection.

So those numbers that you saw, the very low yield, were derived from a setting like that. Unfortunately, the Liver Foundation activity didn't attempt to build in any effort to monitor yield. One of the things that I liked very much about the DHS proposal is the intent to develop a mechanism to monitor the impact.

In response to the other question about who actually (words lost). I think Tom's paper has a very interesting observation in that respect. The recipients who sought testing, the vast majority of those people were recipients who had been transfused only in the several years prior to screening, in fact, after some of the surrogate measures and exclusion measures had reduced the risk. So about 80 to 90 percent of the recipients had been transfused within the several years prior, and the infection rate in that group was dramatically lower, only about five percent, and the much smaller percent of older transfusion recipients who responded had infection rates of 40 percent.

So the issue of who actually comes back in relative risk are critical determinants of yield.

PARTICIPANT: Mike, I think in that study also, the estimate was that of transfused people living in the area, somewhere on the order of between one and five percent actually did come back and seek testing. So again, very low yield.

PARTICIPANT: One last question.

PARTICIPANT: My experience of the response of the recipients is going to be directly related to what their relationship is to those who are asking for them to return. If the individual is asked to return with a public announcement, I think you will seldom see them. If it is a letter from the local Red Cross, you will seldom see them. If it is a letter from the hospital in which they were treated, I think there is a better response, and if it comes from a physician, it will be even better than that.

So there is a different type of organization that has to be followed if you want the people to come back.

PARTICIPANT: Let me thank you for that presentation. What we will do now is break for lunch.

(The meeting adjourned for lunch.)

PARTICIPANT: And it is the single major indication for liver transplantation in adults. So it goes from being a disease that didn't have a name five years ago to being what hematologists see the most.

Its clinical features. The acute disease resembles all acute viral hepatitis; you can't tell it apart from the other forms. The incubation period is about seven weeks. Only a third of patients with hepatitis-C virus infection, acute infection, become enteric and symptomatic. The other two-thirds have an asymptomatic infection. This is typical of viral hepatitis, isn't it?

Nevertheless, if their blood is actually tested during that episode, almost all of them have marked elevations in their enzymes. So they have an acute hepatitis, even though it may be asymptomatic.

Now, tests for hepatitis-C are good, but they are not perfect yet. Testing for antibody to hepatitis-C shows that 50 to 70 percent of people who present with the acute disease will have antibody when they present. A month later, that is up to 90 percent. That is with the current assays.

With the assays of the future, so-called EIA-3 and RIBA 3 and so forth, that percentage may go up. But one of the problems with anti-HCV testing, unlike in hepatitis-A or B, the antibody may not be there when the patient becomes sick, and you miss some patients, so you have to do follow-up testing at one month.

The tests for hepatitis-C virus RNA are also very good, but they are not perfect. Over 95 percent of people at the onset of their illness will be PCR positive for hepatitis-C virus RNA.

The disease interestingly is rarely fulminant. Most large series of fulminant hepatitis include zero cases of fulminant hepatitis-C.

This is the virus. We don't have a good picture of what the virus looks like, but there is a very good picture of its genomic structure. It is an RNA virus. It has a single molecule, single stranded molecule of RNA with a single large open reading frame that reads out a large polyprotein and has all these proteins that are named up there, beginning with the structural proteins core and envelope, followed by the non-structure proteins, which ar the enzymes that allow the virus to replicate.

Now, the importance of showing this genomic structure is that the test for hepatitis-C uses recombinant proteins from various regions of the genome, and the current assay, so-called EIA-2 and RIBA-2, there are four proteins, one from the core, one from NS-3 and two from NS-4.

Here is the serological course of acute hepatitis-C. It looks like every other form of hepatitis. The enzymes go up here, the ALT goes up to quite high, and then it comes down. This patient has an acute self-limited illness. The symptoms come on after the enzymes have been elevated for a week or two, and then they go away.

The serology is that antibody appears during the acute illness, sometimes not quite at the same time as symptoms. So there may be a delay. And antibody persists pretty much for life in most patients.

Here is the RNA, the virus, the measure of the virus. Negative to begin with. Most people become positive for RNA within a week or two of exposure. It is there right away, at least when you use PCR. It persists through the acute illness and then goes away.

This is from Dr. Alter's studies of post-transfusion hepatitis. In follow-up it is repeatedly negative, the enzymes are repeatedly normal. This patient really recovered from hepatitis-C. So this is acute resolving hepatitis-C.

But it is important to stress that this is not typical hepatitis-C. It is atypical because this patient recovered. A much more frequent scenario is the following, that the patient develops acute hepatitis followed by chronic hepatitis, and here is the same format to begin with: ALT elevation, symptoms, antibody development, PCR positivity. But in this patient, the virus remains in the serum, persists in the enzymes, although they are intermittently normal, pretty much elevated over long-term follow-up. So this patient develops chronic disease.

I show in this slide a couple of features that make the serology of hepatitis-C a bit of a nightmare. Occasionally, patients will be PCR negative, particularly when their enzymes fall to normal. In fact, in this patient, if you look at him in 12 weeks, you would say, he is recovered from hepatitis-C. His enzymes are normal, his symptoms have gone away, he is PCR negative. Goodbye, don't come back to see us anymore, you're recovered.

But no, that is not the case. The enzymes go back up. This is a real case. This is really the results that were obtained in a patient. So this makes it difficult. You need to get some follow-up on everybody to make sure they haven't developed chronic hepatitis, and there is no one perfect test to show that they are developing chronic versus resolving their hepatitis. Only time tells for sure.

So the most characteristic feature of acute hepatitis-C is this propensity to lead to chronic disease. Before we had serologic tests for hepatitis-C, several groups have shown that after acute disease, 60 percent of people have elevated ALT levels. So the previous estimate was that 60 percent of people developed chronicity. With a test for the virus, that has gone up to 85 percent of people remain persistently viremic after an acute episode. In fact, in some surveys it is 100 percent.

I do think some people recover. It is not very many, and 15 percent is a good estimate. There are no clearly distinguishing features of chronicity during the acute phase.

Here is the data for saying 85 percent, three different studies. ALT elevations in 62 percent, 70 percent, 60 percent, but viremia in a good percentage of patients whose enzymes had fallen to normal. So here, about a quarter of patients after acute hepatitis-C have normal enzymes and follow-up, but they are persistently viremic.

What about tests for hepatitis-C? I have talked about antibody to hepatitis-C, and of course, these are ELISAs or EIAs. This is now applied to all blood products in the United States. The current assay is very sensitive, and in most surveys, post-transfusion hepatitis-C has virtually disappeared. That is quite an amazing breakthrough, and a marvelous development, frankly.

The trouble with EIAs, as you know, is, they have false positives. Indeed, in blood donor populations, there are more false positives than true positives. So there is a specificity test. It is called a -- it is not really a confirmatory test; it is called a supplemental test. It is a euphemism, called recombinant immuno blot assay. It actually performs very well in detecting true positives.

Then you can test directly for the RNA by PCR, and there are other tests. I guess PCR is the Cadillac of tests for detecting hepatitis-C virus infections. It does have some problems, though, as all tests have problems. The problems with PCR are its reliability. It is not a standardized test. There are commercial PCRs for hepatitis-C, but I don't believe any of them have been licensed by the FDA. Even though they are very nicely standardized, they don't always perform well in the field.

This was a survey from Europe, where they sent a panel of 22 samples to 31 laboratories. These were research laboratories. These weren't just routine testing laboratories. Only five of the 31 laboratories had faultless results. This survey has been reproduced now with the use of a commercial assay, and still, there are false positives and false negatives. So I frankly think that the PCR is much less reliable than EIA. It cannot replace EIA as a screening test because of that.

Well, one thing about hepatitis-C virus, and probably the important biological fact is its heterogeneity. By that is meant that no two hepatitis-C virus genomes are exactly the same. There are about five and a half kilobases, and there have been no two clones developed that have exactly the same sequence. There is considerable heterogeneity.

If the heterogeneity is great, if it is a 30 to 40 percent difference between two isolates, you call those different genotypes. There are at least six genotypes of hepatitis-C. If there is 15 to 30 percent difference, that is still a lot of difference between a virus. That is the subtypes, and there are over 40 subtypes of hepatitis-C.

Different isolates. By this, we mean two people with the same subtype that you test. There may be five to 15 percent difference in nucleotide sequence. Then even in the same patient, the same blood sample, if you clone different clones, you will get one to five percent difference, and that is called quasi-species diversity. Quasi means partial or half or a bit, not quite different species; quasi-species. And hepatitis-C virus circulates in the blood as a quasi-species swarm, it is called. This probably accounts for why so many people develop chronic infections, and that you may develop an immune reaction to one quasi-species, but the other one escapes. It mutates frequently, and therefore it probably escapes the immune system.

Here is a phylogenetic tree showing the six genotypes; they are quite different. If you make an estimate of the duration of time it took for different isolates, say a 1A isolate, to separate from a 2A isolate, how long in time that is evolutionally speaking, it is infinity. It is a long time.

The little ball here represents a different isolate. These are the genotypes. In the United States, the major genotypes are 1A, the prototype virus that was first discovered in the U.S., and 1B, which was first isolated in Japan. Those are the major genotypes. Genotype 2 is about ten percent of patients and genotype 3 about ten percent, and these are rare.

Now, Dr. Alter and Dr. Margolis are going to talk about transmission, and so I'm not going to go into the issues of transmission, only to say that hepatitis-C virus is by and large transmitted by the parenteral route. This is not a very contagious disease, and is usually -- in most patients you find a history of parenteral exposure. Some you don't. That will be dealt with by Dr. Margolis.

Now, what about the disease? What are the complications from getting acute or chronic hepatitis? Acute hepatitis rarely causes fulminant disease. Chronic hepatitis though is a problem. The problems are mainly three: cirrhosis, hepatocellular carcinoma, and some extra hepatic manifestations. These are somewhat rare.

Cirrhosis. What percent of people with chronic hepatitis-C develop cirrhosis? I wish I had that piece of data, because that is what everybody asks, and it is very hard to say. We guesstimate that about 25 to 30 percent of people with this infection develop cirrhosis. What that means is that most people don't. Most people have this chronic infection, and it may go on for life, but they don't suffer end stage liver disease from it, or disability, most people.

But these data are a little bit weak, and they are based on follow-up studies that only last from ten to 20, maybe 25 years. At that point, 20 to 30 percent of people have cirrhosis. The question is, what about beyond that? Does the rate keep going up? And will eventually 100 percent of people develop cirrhosis if they are followed long enough, if they don't die of another cause beforehand?

This is particularly a problem in young people with hepatitis-C, in their 20s. They may have mild disease, but you ask the question, at age 60 will they have cirrhosis and disability? We just don't have those data.

Hepatocellular carcinoma develops in a small percentage of patients with cirrhosis. Maybe 25 percent of people with cirrhosis, if they live long enough, will develop cancer. So this is a smaller percentage. Extrahepatic manifestations are rare, but they are quite severe when patients develop them, and perhaps one or two percent of people develop these complications.

So it has a spectrum. Acute hepatitis-C develops, goes to chronic in about 85 percent of people. The chronic infection can be mild or it can be severe. Severe disease will lead to cirrhosis eventually. The shortest period is probably one to two years. The usual period for this development is probably one to two decades.

But there are people with mild disease. And of course, many people with chronic hepatitis-C don't know they have the disease at all. This is a silent disease frequently, until a patient develops cirrhosis or end stage liver disease. My estimate is that only 20 percent of people who have chronic hepatitis-C virus infection have symptoms due to their hepatitis-C. So it is often a silent disease. How severe you think this disease is really reflects the bias of ascertainment, how the patient came to see you, how was the condition discovered. Was it because of a blood donation? If you see patients who are just blood donors and have hepatitis-C detected, you will come back with the feeling, this is a mild disease, not many people are very sick. Well, it goes with the territory. Most blood donors are expected to be healthy if they donate blood. It is not always true, but they are expected to.

Was it picked up on a routine physical examination or a screening by a chemical test? Here again, you're talking about the milder side of the spectrum, or evaluation of symptoms for another illness. If they come in because they are tired, or they have symptoms of liver disease, then you're talking about a different spectrum of disease. You are talking about the top of the iceberg, the people who have more significant disease. This is the disease that we see usually in referral centers with liver disease groups, and we are impressed that this is a serious disease.

Blood donors. This is a study that we helped Dr. Alter do amongst a large number of volunteer blood donors that were referred here after they were found to have anti-HCV, confirmed by RIBA-2. This shows you that even though most of these were healthy blood donors, 86 percent were viremic. So most of them have chronic hepatitis-C virus infection. Sixty-six percent had ALT elevations, so two-thirds of them you would say have chronic hepatitis, at least as defined biochemically.

Now, we did liver biopsies on a cohort of these patients, and what we found was basically, everybody with hepatitis-C virus RNA positivity has chronic hepatitis on liver biopsy, even those with normal ALT levels.

But by and large, the disease was mild in this population. We biopsied over 80 patients now; we have only found one with cirrhosis. That patient had very high enzymes; he was quite symptomatic, actually. It was amazing that he had donated blood. He had cirrhosis, and we referred him for liver transplant. This was a person who was a blood donor.

Is this a severe disease or a mild disease? It depends on your bias of ascertainment again. Here is a very interesting study from Ireland. It is a study that is going to provide a lot of interesting information about hepatitis-C. But it shows you the mildest form of the disease.

This was an Irish outbreak of hepatitis-C that was linked to an IV RH immune globulin that was used in the late 1970s. It was prepared locally in Ireland. It was prepared not by the typical cold ethanol fractionation methods, and it transmitted hepatitis-C. This didn't become clear until the 1990s, when a large number of women were found to have had hepatitis-C, who had no history of exposure to hepatitis-C. The funny thing was that they were all married, they all had children, they were all about the same age, and they were all RH negative. That gave them a clue that something had happened with RH immune globulin.

They screened over 50,000 women given the immune globulin, and found 417 who had antibody and were PCR positive. ALT elevated in 62 percent, exactly the same as in blood donors. PCR positivity was about 85 percent, exactly the same as in blood donors. They did liver biopsies in over 200 patients. Virtually all had chronic hepatitis, cirrhosis only in 2.4 percent. So in this cohort of young women who had had the disease for 17 years, cirrhosis was only in a small percentage. The question is, when these women become 50 and 60, will this still be 2.4 percent.

I think it is also important to show that hepatitis-C is an important cause of end-stage liver disease. In the United States, 30 percent of liver transplants done in adults are for hepatitis-C. It is an increasing percentage. It is the number one reason for transplants in adults now.

Now, what about therapy? I guess that is what you asked me here to talk about. The current status of therapy is not completely satisfactory. There is something licensed that has been proven to work, and that is alpha interferon. This is the dosage. It is recommended now for 12 months.

This results in a sustained loss of virus and normalizations of amino transferases in only a small percentage of patients. The usual range is 15 to 30 percent of patients. So it is actually the minority people who have a long-term response to interferon, and that has been the problem.

Here is the response that we hoped to get. This is a typical complete long-term sustained response, where the enzymes become normal in interferon treatment, and the virus goes away, and when you stop interferon, they remain negative for virus with normal enzymes. There are people that have been treated with this response over ten years ago, and today they still have normal enzymes, they still don't have virus.

So in some patients, it looks like it is a cure. If only this were the majority of patients. The trouble is that many people, after you have a nice response to therapy, relapse, and they have only a transient response. This is what plagues us in therapy with interferon. Despite a six-month course, despite the side effects and expense, they don't seem to have had a benefit from it. They relapse. Then of course, some people don't respond much at all.

Let me give you what we call a response. We talk about an end-of-therapy response. That means that at the end of treatment, they are better. But what we hope to achieve is a sustained response. That is usually measured at six months after treatment.

The basis for definitions can be biochemical, virological or histologic. For what we call a cure, what we want to see is all three of these better.

Virologic responses are probably going to be the gold standard. If the virus is gone and remains negative, the minority of those people relapse. In fact, I haven't seen such a relapse after a virologic response that lasts 15 months after stopping therapy. So that seems to be the gold standard. The trouble is, we don't have much data on the gold standard.

Here is a recent meta-analysis of all trials of -- 20-some trials of interferon therapy for six months, compared to placebo. It shows you that interferon certainly is better than placebo. You get an end of treatment response, and half the people get better, have normal enzymes on treatment, and about 20 percent of people have a sustained response.

Now, sustained response here is a normal ALT level, six months later. This doesn't happen spontaneously. We rarely see a spontaneous improvement in this disease.

Well, what about going from six months to 12 months? This has been an important step. By going from six months in green to 12 months in blue, you don't get a much higher end of therapy response, but what you do get is a higher sustained response, up to 35 percent. Again, this is an ALT response. It is not a PCR response.

What predicts whether a person responds? Well, there are several factors of predictor of response. One thing is genotype. If you are genotype two or three, you are much more likely to have a response to interferon than genotype one. The problem with this is, most patients are genotype one.

I want to show data from a couple of large, very good trials recently. They are in the works, about to be published. One is on a new type of alpha interferon called consensus interferon. They compared it to the currently licensed brand of interferon called Intron-A, or interferon alpha-2B.

This was a large study, where they used three different doses of consensus interferon for six months versus the regular alpha 2B for six months. Sustained response rates, the same, 11 percent.

So as far as virologic cure with six months of therapy, these large trials suggest that it is about 11 percent. That is not very satisfactory.

Now, here is a recent study that is published, again using virological end points. End of treatment sustained response with 12 months of treatment. The response rate is 16 to 17 percent. So as you can see, interferon does give some long-term responses, but what has plagued us is the frequency of relapses and the relatively low rate of long-term beneficial responses.

So we need new approaches to treatment. I have a list here. There are really not many that have looked very promising. The most promising one I think right now is a drug called Riboviron. It is a nucleoside analog. It has been around for a long time.

The current interest is in the combination of interferon and Riboviron in hepatitis-C. It really looks like this might be another step in the right direction towards higher response rates.

This is a study from Sweden. A hundred patients, randomized, double blind control trial. They either got interferon alone or interferon plus Rivoviron. Well, interferon plus placebo versus interferon plus Riboviron, for six months, not 12 months. The end of treatment responses were the same in the two groups, but the sustained responses were higher with the combination: 45 percent. Now we are talking something that we can be a little more proud of, if you are having 45 percent loss of virus, sustained loss of virus.

Well, this leads up to the consensus development conference that was held one month ago here at the NIH on the management of hepatitis-C, with all the controversies and difficulties surrounding the management of this disease. The NIH felt that it was warranted to bring together a panel to put together a statement concerning therapy.

Let me just give you their recommendations regarding therapy of hepatitis-C. This is straight from their statements.

Currently available therapy for chronic hepatitis-C is clearly indicated for patients who have persistently abnormal ALT levels for more than six months, positive HCV RNA, who have viremia, and a liver biopsy showing hepatitis with either portal or bridging fibrosis, and at least moderate degrees of inflammation or necrosis.

What they are seeing here is that therapy is clearly indicated for people with significant histological changes on liver biopsy. Patients with milder histological disease, patients with compensated cirrhosis, who already have cirrhosis, are children. Patients under the age of 18 or over the age of 60 should be managed on an individual basis or in the context of clinical trials.

Here, they are equivocating. They are saying, in this group of people, you may want to weigh the benefits, risks. You may want to wait until better therapies are available, maybe wait for Riboviron to be available, or wait for the next generation of medications to be available. In this group, where therapy is clearly less beneficial, either because they have mild disease or they have advanced --

(End of Tape 2, Side 2.)

-- interferon, but should be considered for liver transplantation. And patients with normal ALT values, blood donors often, with normal ALT levels or just minimal elevations, should not be treated outside of clinical trials.

The reason for that is that there are instances of patients getting worse with interferon therapy. So we recommend with normal enzymes, that you not treat such patients.

Contraindications to therapy. Major depressive illness, cytopenia, active substance abuse, hypothyroidism, renal transplantation and autoimmune disease. Therapy should not be limited by the mode of acquisition.

Well, that is a little bit of an update on hepatitis-C, its clinical syndrome and its therapy. I will just end with needs for the future, which should be a bigger slide. But the central issue is that we need better understanding of how the virus replicates, how the immune system interacts with the virus. We need better tools. We need cell culture studies and animal models, and we need better and new antiviral agents.

Thank you very much.

PARTICIPANT: We have some other talks coming up, so what I thought I would do is let the panel ask questions, and I promised I would open the floor up. I know there is a mike at both ends of the -- (recording interrupted). While they are deliberating about that, I have one.

I wonder if you could tell us, Dr. Hufnagel, in the course of the disease, about the use of alcohol and other things that individuals might do to slow the damage that the virus might do.

PARTICIPANT: Well, there seems to be some synergy between alcohol use and hepatitis-C as far as injury to the liver. We generally recommend to patients with chronic hepatitis-hepatitis-C that they not drink. That was the recommendation of the consensus panel. If you have a patient who insists on drinking or is not going to do what you tell them, it is very important that they be told not to drink more than one drink a day, so to limit it to mild alcohol use.

As far as other, diets and so forth, it is hard to say that any of that is very beneficial. You look for other causes of liver injury in these patients and try to reduce those. For instance, if they have iron overload, which a lot of patients with hepatitis-C end up having, they may benefit from phlebotomy and so forth.

PARTICIPANT: (Inaudible.)

PARTICIPANT: The question here is on timing of treatment, does it make a difference when you begin to control damage.

PARTICIPANT: Well, there have been a lot of studies trying to predict which patients will respond and which won't. One of the factors that does fall out frequently is the duration of disease. It is usually estimated duration of disease; we don't know for sure.

People who have had the disease for a shorter period of time have a higher response rate. However, when you control for other factors, when you control for severity of liver disease, when you control for genotype and for the level of virus, that falls out as a risk factor. So it makes sense that you should treat people early.

Also, the idea behind treatment is to prevent cirrhosis. That is the idea. It is not really to get rid of cirrhosis, end state liver disease. That of course would occur -- you would want to treat someone before they had cirrhosis.

So I would say that yes, we would like to treat people earlier rather than later. But the data on whether it is more effective is really not quite clear.

PARTICIPANT: (Inaudible.)

PARTICIPANT: Yes, that's a very good question. The question is about the level of virus and whether that has a prognostic -- is prognostic of severe liver disease or not. It doesn't appear to be, so in this respect, hepatitis-C is different from HIV, for instance. Viral load does not seem to predict severe disease.

Some of our healthy blood donors with very minimal liver disease had very high levels of virus, and some patients with advanced cirrhosis have low levels. So it doesn't seem to have the same prognostic factor. But that is really being looked at again in a prospective manner. It may be very important. There may be periods when the level of the virus is important.

PARTICIPANT: (Inaudible.)

PARTICIPANT: Lavidamine has been used in hepatitis-B, but it hasn't been used in hepatitis-C. I guess we assume that it won't work. I don't know that there has actually been data on it, but it shouldn't work against this RNA virus.

PARTICIPANT: Other panel questions?

PARTICIPANT: Do you know if there is a viral load at the clinical level in an inoculant (words lost)?

PARTICIPANT: The question here is, is there any amount of virus that is not trigger disease or threshold.

PARTICIPANT: Do you mean exposure?

PARTICIPANT: How many viral particles do you need to have say in a concentrate that is being administered? A dilution of 80 liters or 8,000 liters, and you have one unit in it.

PARTICIPANT: I should know those, but it is not too far from one. In looking at chimpanzee studies, inoculation studies using inocula, the end point titer for infectivity is very close to the measurement of RNA estimate of genomes. So it doesn't take a lot of virus to infect a person.

Also, the inoculum doesn't seem to matter, or the outcome doesn't seem to depend on the level of virus that you are exposed to. A small inoculum versus a large inoculum may change the incubation period, but it doesn't do much to the disease. Thus, post-transfusion hepatitis-C is probably no worse than needle stick hepatitis-C.

The disease is much worse in older people. The other conundrum here is that the young people that you see wi this disease generally are doing quite well, and they have mild disease. The older people with the disease are not doing very well.

The other problem is that older people don't respond as well to interferon as younger people. So we are faced with treating people with milder disease, and we are worried about that, because they don't have severe disease. But on the other hand, the best estimate is that many of them will ultimately develop severe disease.

PARTICIPANT: (Inaudible.)

PARTICIPANT: Not as bad, but yes, a lot like hepatitis-B.

PARTICIPANT: Another committee member question down here?

PARTICIPANT: (Inaudible.)

PARTICIPANT: The question is, is there genetic resistance -- do humans have any genetic resistance to hepatitis-C? None has been identified. Of course, everybody is running out there after the HIV experience, which is very exciting, to see if there is some resistance to hepatitis-C.

For instance, most drug addicts, by the time they have been using drugs for a year, are infected with hepatitis-C. The fascinating thing would be to look at those people who have been abusing themselves for some time and have not got infected, to see whether they have some natural resistance, some receptors missing or something. Those types of studies are now under way.

PARTICIPANT: (Inaudible.)

PARTICIPANT: Hepatitis-C vaccine? I don't think there is any available yet. The experimental vaccines have been developed, recombinant proteins, mostly envelope proteins that if you give to chimpanzees or to mice, they raise antibodies to the envelope, but they are not very protective. The chimpanzees were only partially protected with a recombinant E vaccine. Furthermore, when they were challenged with other genotypes, the chimps were infected.

The antibody that they got in chimps was very low level, and did not persist very long. So I think in hepatitis-C, we are stuck, like the HIV groups are, too, with a virus that mutates frequently, for which you don't develop a very good immunity. It is not like hepatitis-B, where it is very clear right away that there was a good immune response. Anti-HBS was protective here. There are hints that there are neutralizing antibodies. There probably are, but they are only partially neutralizing, and they neutralize only some quasi-species. So there are major hurdles to overcome yet in developing a vaccine.

PARTICIPANT: If Dr. Hufnagel would indulge me a little bit more, since this is very relevant for the committee and the audience, I'm going to take at least two more questions from the committee. Then if members of the audience would just come up to those mikes, maybe we will just do three or four out of the audience, for just a couple more minutes.

Let's go down to the second row back here.

PARTICIPANT: (Inaudible.)

PARTICIPANT: This one is, did the consensus conference look at follow-up with asymptomatic patients, and when will some recommendations come out about that?

PARTICIPANT: You mean, how to manage them?

PARTICIPANT: (Inaudible.)

PARTICIPANT: I don't believe they really came up with such recommendations. What we say is that the patient you're not going to treat with mild disease should probably be seen every six months and have a repeat liver enzymes, monitor for symptoms, see if the field doesn't change and indications for therapy don't widen.

There are long-term studies going on now of asymptomatic patients with hepatitis-C. Dr. Alter is doing one of the better ones on a cohort of blood donors. We have done liver biopsies in about 80, and we hope to repeat those biopsies after five, ten years to see if this is a progressive disease in every patient, how can you predict those people who have progressed versus those who won't. Can liver enzymes tell you who is progressing or not? I think so, but that is my bias. It hasn't really been shown.

PARTICIPANT: I'm just going to follow that up with two quick questions. Is that consensus conference published yet, the one that took place a month ago?

PARTICIPANT: Well, it is on the Internet. The final statement is not out. They hope to have it out within the next week or two, and it will be distributed widely.

PARTICIPANT: Is there any guidelines in there about diagnosis, about standard of care for routine physical exam looking for hepatitis-C, as part of an examination or routine health monitoring?

PARTICIPANT: Not about routine health monitoring, no. There was about diagnosis and diagnostic test, which test to use, the role of liver biopsy, so forth and so on, alcohol.

PARTICIPANT: Do you have a view about that? Should people make that part of a routine health screen at this point, looking for hepatitis-C, given this high presence of the virus out there?

PARTICIPANT: I don't personally think so. I think it could be aimed certainly at high risk groups, people who have used drugs at any time in the past. That is a very frequent story, a person who played around with drugs in college once or twice, and 20 years later they come in and say, I'm getting tired, and they have chronic hepatitis-C. It looks like it just came on, but it didn't; it has just been there 20 years, incubating.

PARTICIPANT: Let's go up here to Dr. Alter, and then we'll go to Eric over there.

PARTICIPANT: Thank you. Jay, a very balanced and excellent summary. I agree with everything you said. I just want to re-emphasize something that you said. The figure of 20 to 25 to maybe 30 percent cirrhosis is all derived as you said from post-transfusion studies in elderly patients. I think that is going to be the worst case scenario.

The rogam study that you mentioned, as well as another rogam study in Germany, and now a study of recruits, young U.S. Air Force recruits, who are being observed 50 years later, all suggest very low mortality, cirrhosis rates maybe of two percent or in that range after roughly 20 years.

I don't think there is any reason to suspect that it is going to take a sudden up-turn in 30 years. So if the rate were to continue like that even after 60 years, you would be under 20 percent cirrhosis, even in the young people. Not to say they shouldn't be treated, but just the big picture.

PARTICIPANT: Can you give the committee a feeling for the relative efficacy of (words lost)?

PARTICIPANT: I believe the question is, I talk about the 15 to 30 percent whose ALT is normal or PCR negative. Do the other 70 to 90 percent actually have some benefit from treatment?

This is controversial. There are groups that have shown that even in the non-responders, the liver biopsy is improved compared to people who haven't been treated at all. I think the question is, is that improvement just transient while they are on therapy or not.

There are also some people who seem to benefit even without losing the virus, and whose enzymes don't become normal, but they almost become normal. So I think the question is, when I say that the cure rate is 17 or 20 percent loss of virus, the other 80 percent may have a slight benefit from it. The question is whether it is lasting or not. That is difficult to say.

PARTICIPANT: The purpose here is to talk about HCV look-back. Your excellent summary of interferon in treatment is a big help. It is one of the driving forces behind the interest in look-back, is the ability to possibly treat patients who are identified.

Another possible public health benefit would be the ability to intervene to prevent secondary transmission. I wonder whether just for the purpose of rounding out the discussion, you could tell us what the current approach is to preventing secondary transmission, and what the actual percentage risks are for family members and other contacts.

PARTICIPANT: The question is inter-familial spread of hepatitis-C, and whether people who know they have the infection can do things to prevent its spread to others. Is that the question?

Well, there are some very simple things. What was recommended by the consensus conference was not to share toothbrushes and razors, to be careful with cuts and so forth. Beyond that, it is difficult.

Actually, the evidence for sexual spread is not very great. It is seen slightly more commonly among -- and this will be covered by the CDC, I should probably leave it to them, but there is a very little benefit that would come from identifying patients as far as cutting down on spread. I think the major benefit would be for their own health, whether they could straighten up what they do to help their health as far as alcohol use and for a small percentage to be treated.

I think as far as look-back is concerned, if the treatment was very good and it could eradicate it in 90 percent of patients, there would be no question. What is difficult is that the treatment isn't very good. It is very expensive. There are side effects. Sometimes I worry very much about whether in some patients we do more harm than good.

That is why I was very happy that the consensus conference said not to treat patients with normal ALT levels, because I think you are just setting yourself up to cause more harm than good there.

PARTICIPANT: I might say that I think the committee even at this early stage of its development could endorse the toothbrush recommendation.

PARTICIPANT: My name is Terry Rice. I am the vice president of the Hemophilia Federation. I first would like to thank Dr. Hufnagel for all of his research, back into the early 1970s, where I personally believe the medical community, industry and the regulators had not taken your research more seriously, particularly with the core antibody surrogate testing, I may not be here today with the reasons I am here today in the hemophilia community.

My question is, within the hemophilia community, recent studies have indicated that genotype 3A is sevenfold more likely to be within the hemophilia community than in the general transfusion recipient HCV community. Very much similar to the IV drug abusers of other nations and this nation having hepatitis genotype 3A as a more predominant genotype than would be normally expected.

Since interferon has a greater success ratio in treating the genotype 3A, which I happen to have, which I happen to be taking interferon, which I happen to have gone from 300 on my ALT down to zero, my viral load has gone up from 100,000 copies to zero, and it has been sustained for about 18 months, that perhaps within at least the hemophilia community, there could be a little more vigilance to determine genotyping and the benefit of current interferon therapy.

I do know that the reason I am where I am today is because of my proactive stance in these issues, in uncovering the likelihood of my success with my particular genotype, as opposed to taking the status quo line that I was only going to have a 17 percent chance of long-term response.

PARTICIPANT: I'm not sure I followed it all.

PARTICIPANT: Genotyping for special populations, more efficacy there, is it worthwhile to --

PARTICIPANT: Well, genotyping is a little difficult. I agree with you, it is always easier to make a decision to treat someone with genotype 2 or 3.

But on the other hand, there are people with genotype 1 who respond. What we generally recommend is to base the decision of therapy based on the clinical disease. If a person has significant clinical disease, to try therapy, even if they are genotype 1. If they don't respond, you learn very quickly. You can actually learn within three months, and can stop if you're not getting a response.

In patients with hemophilia, I think there is a situation where liver biopsy is not necessary, also. So you really need to make the decision as far as therapy based on other clinical features, the enzymes and those types of things.

PARTICIPANT: Well, I think we have extracted about as much information as possible. Thank you, Dr. Hufnagel, for that excellent presentation. I'm going to ask Dr. Margolis if he will step up to the podium now, and we are going to have one more presentation after this by Dr. Alter. So we will break again for some questions. I think we are going to slides again?

PARTICIPANT: Yes. Thank you. The presentation I am making is a combined effort between Miriam Alter and myself. Miriam, who is the chief of our epidemiology section, is in the audience, and as we come to some of the questions, both of us will be answering questions.

I go back to something that Dr. Kaplan pointed out this morning. There are a number of issues that have come up in terms of what should we do as people became more and more aware that there was a very large number of HCV infected individuals in the U.S. population, some of whom have acquired their infection by transfusion.

This statement, taken from a report from the Committee on Government Reform and Oversight that was published in August of '96, basically charges HHS to take steps to insure that an estimated 3,000 living recipients of blood and blood products who were infected with HCV before 1990 are notified of their potential infection, so that they might seek diagnosis and treatment.

In fact, prior to that, the Public Health Service, CDC, FDA and NIH in meeting and discussing about the general issues of HCV infection and the fact that most people were not aware of their infection, had developed an options paper which is in your handouts, discussing these issues, discussing these issues relative to the transfusion recipients, and some of the data and the underpinnings of that that I am going to discuss this afternoon.

Again, to have the committee deal with some of what I see and what we see as questions, one of the questions are, what strategies should the PHS, HHS develop to identify persons who might have acquired HCV infection from transfusion, determine their infection status, counsel them concerning medical management, and recommend precautions such that prevention can occur, and how do we put this in the context of, as I will show you later, and as everybody in this group is so well aware, of an estimated four plus million individuals who are infected with HCV in the United States.

Some review. In terms of potential sources of blood-borne virus transmission -- and I will show the data from our experience in the U.S. Again, this has been replicated everywhere. Again, direct parenteral exposure, either via transfusion of blood or blood products, or sharing of contaminated needles among injection drug users, is the primary source of HCV infection.

Clearly, other contaminated instruments, be they in the traditional medical setting or non-traditional medical setting, can cause transmission or can transmit the infection. Probably the one that we are most familiar with is transmission in the hemodialysis setting, in terms of traditional medicine. Then there have been a number of other potential sources, most of which in the U.S. are really not -- or have really not been shown to be a substantial cause of infection, though again, if any time you are sharing blood for whatever reason, the potential is there for transmission.

Then we get to some of the more -- what I might call problematic, or the dilemma areas. That is, yes, transmission occurs between sexual partners, between household members from infected mothers to their infants, occasionally from patients to health care workers, and possibly from health care workers and possibly from health care workers to patients.

When one goes to the top of this list -- and I'm not going to spend time in my discussion presenting data -- the risk is definable, but the efficiency of transmission is low. Even while sexual transmission occurs, it is inefficient, compared to HBV, which I think everybody is familiar with, and HIV, and within households, transmission is low, and probably when it does occur, it most likely would represent inapparent parenteral exposures.

We know that there is a low rate of transmission from infected mothers to their infants. These are more -- at this point, the potentials are there. Yes, the reported surgeon in Spain transmitting to several patients, but in fact, a defined risk has really not been achieved.

A slide familiar to the people who are involved in blood banking and transfusion issues, but for the others, viral hepatitis in fact was a common result of blood transfusion back in the '60s. The most important thing that changed that risk of transmission was moving from paid donors to volunteer donors, and then helped along by hepatitis-B surface antigen testing in its most primitive ways at that point, and now with essentially third generation tests that are used widely.

Coming down here to the point of there being decreases in non-A-non-B hepatitis in the mid-80s. Presumably this is all HCV transmission going on from blood. It really had to do with exclusion of potentially AIDS positive or AIDS high risk donors, and then today, where we are with an estimated one in 100,000 risk of transmission from a unit today.

However, the more important issue in the U.S. today is that of transmission from illegal drug use, with there being high prevalences, and I'll show you some data of HCV infection among injection drug users. In the United States, it is the most common identifiable source of infection.

Data has begun to emerge of other drug use, namely that of intranasal cocaine use, with the real contribution to transmission unknown. But I think there are now a number of series that have shown that some HCV positive individuals show this as their only potential source of infection, and we see this in surveillance data from the U.S., though as was pointed out here, it is actually rarely reported in new or acute cases of hepatitis-C.

Just to emphasize the point, as Jay pointed out a minute ago, in terms of HCV infection among injection drug users, these are data from Baltimore. Within six months of admitted injection drug use, we are looking at 60, 70 percent of individuals being positive, maximizing it around 90 percent, and that is in contrast to HIV, which stays in the 20 percent range. HPV takes a little bit longer to get there.

The dynamics, the epidemiology of this, in terms of early acquisition, are really not known, and are an important area of research in terms of issues of prevention. But nonetheless, the point is that this is a major source of infection, and this risk group is highly infected. If one looks at national surveillance data -- now, let me take a moment to talk about surveillance for viral hepatitis in the U.S. Some on the committee are probably not aware of the various systems. In fact, the system that we use at the Centers for Disease Control that has the greatest longevity and most valid information is called the sentinel county study of viral hepatitis, in which four counties in the U.S. had all cases of reported viral hepatitis, tested serologically, in order that back in 1979 and 1980 we could begin to define non-A-non-B hepatitis.

If one looks at national surveillance, the problem is that for either non-A-non-B hepatitis or hepatitis-C, we really have very poor data, because it has in general not been a very reportable disease, and people haven't done serologic testing. So I am going to use data that comes from the sentinel county study.

You may say, do these four counties represent the U.S. Yes, for hepatitis-A. For hepatitis-B and we think for hepatitis-C, they really do represent the U.S. They weren't necessarily picked, the four counties -- just so people are aware, one is St. Petersburg, Florida, Penallis County, Birmingham, Alabama, which is Jefferson County, Denver County, Colorado, and Tacoma, Washington, or Pierce County.

But it turns out that at least for the other types of viral hepatitis, they have well reflected what goes on in the U.S., based on looking at hepatitis-A and hepatitis-B, which are better reported from all states.

That said, if one looks since the early '80s, you see that injection drug use has accounted for about 25 to upwards of 40 percent of all cases of acute hepatitis-C in the U.S. Even back 10 or 15 years ago, transfusion only accounted for 20 percent of cases, and now actually since 1995, we have seen no cases of acute hepatitis-C that are attributable to blood transfusion, remembering the total population of these four counties represents about two million individuals. So we are actually at the point where we may not see acute hepatitis-C, given at least the current estimated risk of transfusion transmitted HCV.

However, the gastroenterologist or hepatologist seeing patients has a different view of where HCV infection comes from. We try and contrast this in some best summarized data, where if we look at individuals with chronic disease, and this is taken from a number of studies, few of which are actually population-based, but you could estimate that around 50 percent of people would say that -- again, your history would suggest that their infection came from transfusion.

That ranges -- the high is 50 percent. One population-based study that we have done at CDC, looking at chronic liver disease had about 30 percent being transfusion associated. However, with illegal drug use accounting for almost another 25 percent, and that again is in contrast to current acute cases, and somewhere there is obviously a continuum going from today back through the last 40 or 50 years. As you see, that become an important estimating point as we begin to say who might have acquired their HCV infection from transfusion.

That is where I now move to prevalence data, prevalence of HCV infection in the general U.S. population. Again, many are familiar with this slide, but let me go back and give you a little data about where this comes from.

These are data derived from the national nutrition and examination survey, NHANES, which is what is down here. It is a survey of about 30,000 individuals who represent statistically the general U.S. population. This was conducted over a four-year period in communities around the U.S., representing non-institutionalized individuals, so people in jails or any incarcerated individuals, people in the military, homeless individuals are not included in this survey. It is probably a conservative estimate of infection, since obviously some of the groups I just mentioned would be expected to have a high rate of HCV infection.

What you can see is that there are obvious differences by racial and ethnic group, in terms of prevalence of infection, with most of the infections occurring in the 30 to 50 plus age group. We only have data -- and I use 1990 as the midpoint -- from NHANES-3. Unfortunately, we don't have data from NHANES-2, so we can't tell you precisely whether this is a very large cohort effect, but I think that would be our best guesstimate, that this is a cohort. Now, in data that I didn't show, incidence of hepatitis-C, in other words, new cases of hepatitis-C, has dropped dramatically in the U.S. So it is going to be very interesting in about seven years to see what happens back here, in other words, how flat this stays, and if this cohort moves along.

Nonetheless, if one turns that prevalence data into estimates of population, and the prevalence figures are here, and this is where we come up with the 1.8 percent of the U.S. population being HCV infected, do your multiplication by the various population groups from the census, and here is where the estimate of about 3.8 million Americans infected with HCV come from.

Now, a couple of other kind of unpublished -- and you asked a couple of other things. Could we have learned a couple of other things about this, such as, what proportion of these people had a blood transfusion, and what proportion of these infections came from injection drug use. Unfortunately, when I was involved at that time in 1984, we put that questionnaire together, obviously asking much about sex and drugs in 1984 wasn't something you did in a national survey. So in fact, there are no data about those risk factors.

Transfusion was frankly something we just probably forgot to ask. Again, it was the use of this data set -- remember, it is a nutrition survey, and some of us have only begun to use it recently for looking at these types of diseases. Those questions will be in the next HHANES, which is being put together right now.

One of the other things is, if you look at these 400-plus HCV positive individuals, which we have actually done at this point, about 85 percent of them are HCV RNA positive. So that fits with some of the previous data you heard, in terms of how many may be viremic. Unfortunately, the ALT testing that was done at that time was not done with a method that would have best preserved ALT, and so we only see that about a little over 50 percent of this group had abnormal ALTs. The problem is, that is probably a significant under estimate, just because of the methodology. Again, people weren't looking for that at that time.

So I am trying to, -- as you heard this morning, we do surveillance. One of our approaches to surveillance is serologic surveillance. This actually is turning out to be an important way to figure out what is going on.

Given that information, one begins to now say, what do we do in terms of prevention. I just put the obvious, that both implementing and then ultimately evaluating prevention strategies has to focus on early identification of individuals with chronic infection. Presumably, from the Public Health Service standpoint, it is trying to reduce transmission, and from the personal health point, it is the issues that Dr. Hufnagel talked about.

Here I want to make a break in the flow. For a moment, I'm going to talk about testing. Dr. Hufnagel brought up many of the issues about testing. You saw this slide in a little different context, so I'm not going to go through it. But the point is, if we begin to start going out there and recommending that a lot of people be tested, one has to understand some of the performance of anti-HCV testing.

As was pointed out earlier, in a low prevalence population, such as among blood donors, even among this rate of EIA-2 positives who were repeatedly reactive, when one does RIBA testing, what you see is that you have a high rate of false positivity. Just to move it into the mathematics of it, again, a test with a high sensitivity, which the current test has at 90 percent, and a very high specificity. However, when you are in a high prevalence population, yes, a single positive test has a high positive predictive value. In other words, the sensitivity is here, and when you look here, out of this total group it says that you're going to find most of them and be able to say, that person is infected.

However, that is the person who walks in with disease, most likely. The person who walks in to be screened and is the blood donor in the low prevalence population, is over here, and that is where you see very low positive predictive values. Even if you push up specificity and sensitivity, it isn't going to help you much. So a positive test requires additional supplemental testing or confirmation to find out if that is really a true positive result.

Now back to the issues at hand, but I felt I had to add a few more things about testing. The options in the Public Health Service option paper were to have targeted look-back of transfusion recipients, public service announcements -- I think that is the wrong word, really it is public education, and then education directed at health care professionals in terms of getting them to do the right thing, either in terms of identifying patients who may be at risk, or when an HCV positive individual comes in, to do the right diagnostic workup.

One of the issues is, what is the estimated number of persons with transfusion acquired HCV infection in the U.S. So we took the NHANES data, HCV distribution by age, and we estimated what proportion of those various age groups might have acquired their infection by transfusion, using the best incidence data we had.

That included what I already told you was not necessarily very good, which was the viral hepatitis surveillance program data, and actually some sentinel counties data, which I just didn't put on this slide.

So if you then look at the numbers -- again, these are some of the numbers in the document, and this is where they came from. I actually have these in hard copy, so if later we want to xerox them for the committee, we can do this. But these were the estimates we made in, we thought, an average case scenario, taking the six to 11 year old who would have acquired their infection somewhere in the late '80s, to the 60-plus year old who would have obviously acquired their infection at a time when probably half of HCV infections came from blood transfusion.

When you do the multiplication, you come over here and you get this estimated 300,000 individuals at about an overall seven percent.

Well, rather than do -- I didn't put it all together as a full sensitivity analysis, but let's take a little worse case scenario, where we would raise some of these likely proportions of some of these age groups somewhat higher. Yes, you can almost increase this by a third.

But the thing I am trying to point out is, if you disagree with me that 40 to 49 year olds, that 20 percent of them acquired their HCV infection by blood transfusion, so you are going to increase this by another 90,000 or 100,000. The point is, this total number does not get very large relative to the whole four million individuals who are out there. That is where I am trying to make this estimate, in trying to decide where to focus activities and how to focus them, this was our thinking in doing that.

One of the other issues that comes up is -- and I won't use the word cost, though I guess this committee can use the word cost, but let's deal with prevention effectiveness. This morning you heard some estimates of what happens when you have a targeted look-back and what might you expect to find.

These are some data from Dr. Obischon, working with Dr. Alter, trying to rework some current estimates that we think are probably reasonable. Again, going through some assumptions in terms of what I will call prevention effectiveness. We didn't put cost in here. We can talk about cost, and people will have data about that. But it is fairly costly. But we haven't turned it into a cost effectiveness analysis.

So again, looking at this period -- this is a more recent period, this isn't a pre-screening period, with assumptions that few people would argue with, in terms of annual number of donations, donations from repeat donors, donations per year per donor, and then making some estimates of anti-HCV reactive donors with the highest rate being in 1990 when screening was first initiated, and then first time donors -- or repeatedly reactive donors coming in, actually falling dramatically after that. So one would estimate that there may be as many in that five-year window of 98,000 HCV positive donors who might have transmitted.

Then what we did is just put the poor man's sensitivity analysis, but making the assumption that there were three recipients per donor versus five recipients per donor. Then we begin to start looking at some of the numbers, in terms of recipients to be notified, recipients who were estimated to be alive, fairly reasonable estimates at least from the U.S. experience, and then estimates of recipients who respond to notification and of those, ones who might be anti-HCV positive.

Some people would stop at this point. You can then begin to put the final prevention part of this, or the medical outcome --

(End of Tape 3, Side 1.)

-- consensus statement recommendations as you just heard from Dr. Hufnagel. Even estimating that 70 percent of these individuals would have an abnormal ALT, we are looking at 26,000 to 43,000 recipients eligible for therapy at 70 percent, probably a reasonable number. But the issue of sustained response using 15 percent coming down to numbers, which are substantial, but relative to that whole 3.8 million individuals, it actually becomes a very small number.

Again, I think it is how you view this, as to where your prevention effectiveness occurs, or identification effectiveness, so to speak, as to whether you look at this number, or whether you look at this relative to the whole population.

A summary slide of the issues about targeted look-back of transfusion recipients. The pros focus on a select group for whom you know who you are looking for, and can go back and begin to look for them. Clearly, the issue of supporting the individual's right to know about their potential risk is very important.

Some of the negatives have been that many notifications would be potentially based on false positive results. Unfortunately, as I think you heard from some of the data this morning, many recipients are untraceable, and poor response in past programs, and I'm sure there will be more discussion about this. Looking at the whole hepatitis-C picture, at least as we have looked at it from a public health perspective, it really only accounts for a very small proportion of all infected individuals.

This last statement really has to do with the prevention message. That is, in terms of counselling, most of the counselling has to do with individuals' medical management prognosis, risk of transmission in terms of sharing those objects that might transmit, such as razors, toothbrushes, sexual transmission. Unfortunately, we don't have as precise a message as we would like because we can't ascribe absolute risks. As most of us know, that becomes a difficult issue when talking to patients.

Let's talk about some of the other issues in terms of what are some of the alternatives, which were the options as presented in that document.

Where might we go with educational messages, and beginning to tell the public? As we know, that has already begun. It has begun with not necessarily the Public Health Service, but with some of the voluntary organizations who talk to us and help to frame those messages, and frame them in a way that begins to tell who is at risk of HCV infection in the general population.

Information needs to be out there about the consequences of infection. Somehow, the consensus conference has to be translated so that the public understands that. Need for early diagnosis and possible treatment. I would say as we have looked at this, these messages really have not been put out there in terms of the general public. And recommendations to prevent infections include also preventing -- getting hepatitis-C into the drug use prevention and the drug use treatment message, which it clearly isn't at this point. Again, that was actually part of -- at least, the gist of that was in the consensus statement, and we feel that is an important part of the whole issue, and will ultimately help in terms of safe blood supply.

Is some of this happening? Yes, some of it is happening. Some of it is happening fairly quickly. As I said, the American Liver Foundation, the Hepatitis Foundation International, the American Digestive Health Foundation in their digestive health initiative, which is going on right now, or at least the groundwork for it is being laid, of which hepatitis is now their major focus. This is the same group that worked on helicobacter a number of years ago, and in fact, they are looking with us, the Public Health Service and those of us at CDC, to begin to develop some of these messages and figure out ways to get them to the public, which includes the general public and certain target groups. Clearly, the blood transfusion services and getting that message out too is important. Professional societies have been involved in this, and as I have down here, I think every one of us in the Public Health Service have been involved at this point.

You have all seen the yellow eyes. There are new ones now that talk about transfusion specifically. I just didn't have the latest slide.

It turns out, as somebody said, this has not been evaluated, and does it get the person to a physician? It clearly gets the person to a telephone. The American Liver Foundation's phone calls went up about 100 fold once this thing came out. There has been no evaluation of what happens downstream, and we feel that is an important component of this.

Again, that is the work in progress. Many behavioral scientists are already beginning to think about it, and I can tell you, within our own group we are beginning to deal with this issue.

I tried to put in pros and cons for some of the issues for the committee. It clearly reaches the broader population, but I think these are the questions: can we influence those at highest risk? I think there are some data from HIV and some of the other experiences now over the years, including even hepatitis-B with immunization, that you can begin to do this. It is just how you craft the message.

This is one of the big issues that is going to come up, and was raised many times actually in the consensus conference. Yes, if all four million individuals want testing and need diagnosis, most of them don't have third party coverage, and how is the study going to cover it. I think this is something we have to think of, much as was thought of for HIV.

We think the other equal part of this is educating the health care professional. While the hepatologists, and now probably a substantial portion of gastroenterologists are well aware of the issues, the primary care practitioner, be it the internist, family physician, obstetrician-gynecologists, who are also seeing positive individuals or people who come to them with a positive result, are not aware of what to do.

The issues are listed here. I think they are pretty self evident, but I think we have plenty of information that suggests that they are not doing the right thing. In fact, that is one of the things we at CDC are beginning to do now, to do some surveys to look at primary care physicians and what their current practices and attitudes are in terms of HCV infection.

Where do we go with this? There are a number of coalitions working on it. Just to tell you, we at CDC actually are trying to go with the high tech. In November of '97, November 22 -- we moved it to Saturday -- we are going to have a satellite teleconference that we are trying to downlink to everyone in the U.S., or at least health care providers. We will have some of the same people who have been speaking here today, and others, both talk about diagnosis, medical management and prevention and counselling, and targeting this at the primary care physician.

So we think it is extremely important that when that individual who finds out about this via whatever mechanism, from their blood bank, from reading Newsweek or the newspaper, show up in the physician's office, that the right thing is done. We know that that is not happening.

What I am going to do is skip to this slide, because I think this puts it together in a picture. You have heard some of this already this morning. Here we are today. In 1990, HIV testing began. The Congressional charge to the department was, do something back here. There is obviously -- though at a very low rate of infection, there are issues about recipient notification here. The questions become that of targeted look-back versus public and provider education.

We feel, and I think the data supports, that this is the option for this group all the way back. Unfortunately, in here, it becomes a difficult message, because I don't think we want to tell everybody who has had a blood transfusion to go get anti-HCV testing during this period of very low risk of infection. I think that is something that clearly the committee is going to discuss and debate and probably help us with.

We feel that going forward, you already heard that product withdrawal or recall -- I probably don't have the right words, but one half of the look-back situation is going on here, but recipient notification is not going on, and that is very reasonable, and would then put this whole picture together.

With that, I will stop.

PARTICIPANT: Let me again go to the committee members first and see if they have any questions they would like to address to Dr. Margolis.

PARTICIPANT: Do you have any data on whether or not when you (words lost) notify a patient, whether that would make a difference in the response. For example, if you had somebody that got a transfusion years ago, and you notify them, and you (words lost) versus looking at people who got a transfusion recently, would they have a better likelihood of seeking (words lost)?

PARTICIPANT: What is the relevance of time and how long time has elapsed, in terms of being alerted by a retrospective look-back to act?

PARTICIPANT: First, let me tell you that in the area of HCV, we at CDC have not looked at any of these issues. Miriam Alter, who was recently in Australia, pointed out that of a targeted look-back that was going on there -- and again, these are more recent, at least we think they are more recent, though all that data wasn't there, but half of these people already knew that they were -- had already sought out counselling and actually knew that they were infected.

We heard some ongoing studies in Canada, but what isn't known is whether the individual who is closer to the time versus those who are out ten years, in fact, are going to respond differently. I don't know if others in the audience have any information.

PARTICIPANT: (Inaudible.)

PARTICIPANT: Of HCV infection in geographic -- actually, when one looks at the NHANES, which breaks the U.S. into these four large census tracts, there really aren't substantial differences. I don't think that -- again, in terms of looking at prevalence in the population, such that it would make a difference as to recommend something differently for one part of the U.S. versus another.

I will only actually go back to hepatitis-B, where there are some substantial differences. Yet we realize that people move around, and the U.S. in fact is pretty homogenous when you look at people over their lifetime. So I don't think there are any data that would support us to want to make regional differences, in terms of messages.

PARTICIPANT: It seems as though more people get hepatitis-C from intravenous drug use than from transfusions. Is testing drug abusers for hepatitis-C common in the drug treatment programs in this country? Has that been looked at?

PARTICIPANT: The question here is, how common is testing for hepatitis-C by the drug using population?

PARTICIPANT: These are anecdotes, I can't tell you what the real thing is, but I think more and more drug treatment programs have become interested in this. However, as I showed in that prevalence by time of injection drug use, what most of them find is exactly what you see on that slide. By the time a person comes into drug use, which tends to be several years already into their injection habit, coming into a treatment center, they are already positive.

The difference probably -- there are some good data in adolescents, where the numbers are a bit lower. We see that for hepatitis-B, and actually, that is probably true for hepatitis-C. But again, how widely this is done across the U.S., I obviously don't know.

PARTICIPANT: Just a question, and it could be an anecdotal answer. If you were looking at that look-back from 1990, or even the 1990 to '97 population on the three to five possible recipients on average of a particular unit of HCV infected blood, would you care to comment on the record keeping, the ability to really find names to go back? I'm sure it varies, but what is your rough estimate of the possibility of actually tracking specific names?

PARTICIPANT: I'm hoping that is going to be discussed in the next talk. Obviously, not being a blood banker, I think it would be better for the blood banking community to give us that perspective.

PARTICIPANT: Two quick questions. On the NHANES prevalence data, could you tell us what serologic test was used?

PARTICIPANT: It was done with EIA-2. In fact, all the positives were tested with supplemental. It was matrix testing that was used for that. As I say, they have all actually now been tested for HCV RNA.

PARTICIPANT: The second question was a follow-up to the one that was just asked. Within the IV drug using community, have any -- given the limited medical resources, have there been any treatment trials? Or what is the status of treatment for a person who goes through IV drug rehab and might have hepatitis-C? Are those people treated?

PARTICIPANT: I don't know. Jay, do you have any -- you're the one who is closest to the treatment issues in that.

PARTICIPANT: Would you repeat that?

PARTICIPANT: Oh, excuse me. The question was, among injection drug users who come into drug treatment centers, have there been either trials, or what is the likelihood that somebody would be treated, including one who has had a successful drug treatment?

PARTICIPANT: It seems to me if the public health impact look-back gets into questions of treatment, then the public health impact in IV drug users also in addition to prevention has to consider treatment. I just wondered if there was any data about how that is being handled.

PARTICIPANT: I am fairly certain there are no clinical trials in drug using populations. There are several investigators who are very interested in getting those started, but there is quite a bit of resistance to treating individuals with an injectable medication who are injecting, one, or who have recently stopped injecting, as well as the fact that individuals who continue to inject are constantly re-exposing themselves to the virus. I think that has a lot of significance with respect to any benefit you might get from therapy.

I know that some individuals wouldn't even consider treating a drug user who had not stopped using for some prolonged period of time, but I'm not sure that there are any standards with respect to that time.

PARTICIPANT: Thanks.

PARTICIPANT: Maybe time for one more question over here.

PARTICIPANT: I am interested in knowing whether or not some of these co-exist in the same individual, like young children with hepatitis-A and/or hepatitis-C infections, what that experience has been.

PARTICIPANT: Overlapping certain groups of hepatitis.

PARTICIPANT: Yes. A, I think we have not looked at, but in terms of markers -- again, part of it becomes risk groups, so hepatitis-B and hepatitis-C clearly are seen very commonly and overlapping, and in that group hepatitis-A also -- injection drug users have a prevalence of hepatitis-A virus infection that runs in the 60 to 80 percent range also. So within some risk groups, clearly all types of viral hepatitis occur.

We haven't looked hard at our sentinel county data to look at that overlapping some of the other groups. But I do know that in some other parts of the world, you see -- in people that tend to get hepatitis for whatever reason, you tend to see more markers in certain groups. If you had one marker, you may have a higher prevalence in it than would be expected for the general population. I guess that is the best way to put it.

PARTICIPANT: Thank you. I'm going to ask Dr. Sayers to come up here to talk to us about some of the blood center issues with hepatitis-C. While that is happening, I will tell you, for those of you who are consulting your kidneys and other bodily functions, we'll take a break after this presentation and questions. Then when we come back, we're going to have a period of some open public comment. I know there are at least two individuals that are going to speak during that time.

PARTICIPANT: Thanks. I have to say that this committee alone is much larger than the audience that is usually attracted to my presentations.

I'm going to mention some blood banking issues as they relate to the identification of persons who may have become infected with HCV virus by transfusion. On other occasions when talking on a topic like this, it has been alleged insistently that blood bankers talking about these matters inevitably bring some unseemly self interest to the topic.

So by way of a preface, lest any of you think that I am going to be talking with some sort of narrow partisan agenda in mind, I'm going to list some qualifications alphabetically.

I am a blood banker, but I also have a history of having treated patients, both oncology patients and patients with congenital coagulation disorders. I am also a recipient of blood derivatives.

Having reviewed that packet that came up beforehand, and having heard the colorful history of HCV look-back that Dr. Meade related this morning, I am really surprised that we haven't come to a decision on the question of targeted or directed look-back a lot sooner. I feel that if there really were some compelling reasons to do this, we would have had ample opportunity over the past five or six years to decide how we should set about targeted look-back.

I am only going to, in the interest of time, make four points. They have to do with issues raised by Dr. Meade, issues raised by Dr. Gomperts, by Dr. Schiff and by Dr. Gilcher. I am going to emphasize the point that at least from the blood bank perspective, this is not a new disease. Any sort of targeted or directed look-back is going to be fraught with efficiency questions, it is going to be fraught with inconsistencies. I want to say something about the prevalence of HCV as we see it in the segment of the community that we as blood bankers deal with. Then I'm going to say something about targeted look-back, even if recipients are identifiable, how targeted look-back cannot be achieved with a single episode of serological testing of recipients.

Let me just start with slides reminding us of what testing is being done. This is a reminder of the screening tests that we have invoked for donating blood. It seems as if we have been testing for syphilis ever since the waters receded and the Ark rested on dry land again.

As far as hepatitis-B is concerned, we have been testing since '71. Then there were these halcyon days, when all we were interested in was Duffy and what have you. Started testing for antibody to HIV in '85, for CMV in '85 and '86. It was then, only then, even though we recognized that there was post-transfusion hepatitis, which had not been eliminated by the introduction of hepatitis-B surface antigen testing, it was only then that we tried to come to grips with these surrogate tests, B core antibody and alaminotransferase, with what we were then regarding as non-A-non-B hepatitis.

So there was this long period of time until in 1986 through 1988, these surrogates we introduced in an attempt to reduce the risk of post-transfusion non-A-non-B hepatitis. We then started testing for HTLV-1 and then were able with the introduction in 1990, some four years after the introduction of the surrogates, only then were we able to come to grips more specifically with hepatitis-C, and were able to understand that a lot of the hepatitis that had been transmitted back prior to this time was in fact hepatitis-C. Something like 90 percent of the post-transfusion non-A-non-B hepatitis was hepatitis-C.

Then we come into the first point that I want to emphasize. Against the background of this chronology of events, the first point had to do with emphasizing that HCV is not a new disease. Unless that point is emphasized, it could be assumed that lessons we have learned from HIV, particularly as they apply to look-back, could equivalently apply to look-back for HCV.

It was interesting to me this morning, that even while we are talking about HCV look-back, HIV this morning got much more of a mention that HCV ever owned. The ingenuous transfusion recipient, or to use the more wretched new jargon, the ingenuous consumer, could really be pardoned for thinking that he or she is uniquely exposed to HCV as a result of transfusion by virtue of some donor risks, which are akin to those in donors that set the stage for transfusion transmitted HIV.

It is not the case. We have known about transfusion transmitted hepatitis-C since the '70s. We knew once the hepatitis-B surface antigen test was introduced, that there was a significant sized group of individuals who had failed the surveillance safety, as it were, that was being provided by hepatitis-B surface antigen testing.

The point that I want to make in terms of this not being a new disease has to do with our knowledge of what was going on in 1981. Now, bear in mind that in 1971, blood bankers were testing only for syphilis and only for hepatitis-B surface antigen. But for reasons that do not bear unravelling at the moment, I had squirreled away some samples from donors back in 1981. Actually, I had intended to do ion studies on them, serum ferritin, but quite forgot what serum ferritin had to do with blood banking, and lost these samples until they were recovered from the ancestral vaults, relatively recently. They had been kept in frozen storage, and we subjected them to second generation HCV testing, and also supplemental test analysis.

We were able to show that back in 1981, something like 0.6 percent of the donors, albeit healthy individuals, ostensibly healthy individuals who answered no to the question, have you ever had hepatitis, have you ever been exposed to hepatitis, 0.6 percent of individuals were indeed positive in the supplemental test for hepatitis-C.

Bear in mind too that back in 1981, these donors did not have their units intercepted. They did not have their units intercepted. So back in 1981, 0.6 percent of those donated units were going to transfusion recipients.

In 1990, 1990 was the period that the hepatitis-C viral antibody test was introduced. So between '86 and '88 and 1990, remember from those earlier slides, that was the period of time that the surrogate tests were introduced.

How effective were those surrogate tests? Well, they certainly reduced the prevalence of hepatitis-C antibodies, confirmed by supplemental tests, from 0.6 percent to something like 0.3 percent. So the surrogate tests were effective. How effective were they? Something like 50 percent.

Then in 1992, when another generation of HCV assay came on board, the prevalence of hepatitis-C had dropped to something like 0.1 percent amongst the donors. Again, these units were not intercepted, but obviously these test positive units had been intercepted.

I said also that I was going to make some point about efficiencies and inconsistencies in what we might consider as a reasonable path to take for look-back, particularly directed or targeted look-back.

This Venn diagram looks at the surrogate test results for ALT in something like 65,000 donors at the time that the hepatitis-C assay was initially licensed. So at that point, we were able to look at this large group of donors and answer the question, how many of them who were truly HCV positive had the surrogates actually identified, and how many that were truly positive had the surrogates actually missed. So that is the number, 65,000, and these are the actual number of individual donors that were positive for surrogate markers for hepatitis-B, for HCV, and this is just a mutant six that crept in and has no relevance.

What are the messages then from this illustration? The messages are these. Certainly, the surrogates did work for this segment of the HCV truly positive donor population. They worked as far as ALTs were concerned for that segment. For the majority of individual donors that were found to be truly reactive for HCV, the surrogates had been ineffective.

I would make the point though that back then, nobody was arguing that core antibody positivity should provoke look-back. Nobody was arguing that ALT reactivity should provoke look-back. Nobody was even arguing that a combination of both markers should provoke look-back. In fact, had look-back been triggered by individuals who were reactive for both markers, then certainly something like 50 percent of those individuals did turn out to be individuals who were reactive for HCV.

Now, we still are doing some of these surrogate tests. It gives me an opportunity to pontificate about the usefulness of core antibody as a surrogate marker. Recently the IOM has suggested that core antibody is a marker of a lifestyle. That is one of the reasons why continued use of core antibody is a reason for deferring donors is justified.

If it is indeed a marker of a lifestyle, and if we were confident about its usefulness, I suggest that there might well already have been recommendations that we should be informing recipients of blood provided by donors who seroconvert to core antibody. We should be telling recipients of those seroconverting core antibody units that they received blood from an individual who now has a lifestyle marker, which presumably infers some infectivity. Certainly those recommendations haven't emerged. Neither have the recommendations emerged that we include in our counseling for core antibody positive donors that they should question their lifestyle activities. We have uncovered in them a marker which suggests something about their lifestyle deserves scrutiny.

I want to say something about look-back that is targeted exclusively at transfusion recipients, especially in the sense that this will direct some special public health effort at a group that represents only a small fraction of those at risk. We have heard from the other speakers, particularly Dr. Margolis, that the transfusion recipient as representative of the group of individuals nationwide that has hepatitis-C, is really in a very small category.

This is a slide that I got from Dr. Miriam Alter. It reminds me that by comparison with my obviously not-for-profit illustrations that I have used up until now, that certainly the CDC is able to product what are really extravagantly decorative illustrations. But it is an opportunity to remind you that as far as blood transfusion is concerned, a scant 2.1 percent of risk factors are accounted for by that group.

Is there any other evidence that we need a broader net if we are going to consider look-back? A broader net than targeting or zeroing in on transfusion recipients. This is the dependence of HCV seroprevalence on the degree of donor screening. What essentially I have done here is look at seroprevalence on this axis, and donor characteristics on this axis. These are repeat donors, these are first time donors, and these are autologous donors. This solid bar are the donors that are confirmed positive by the supplemental, and these are the donors that are initially reactive in the screening test.

The point that I would make is that if you look at autologous donors, those are individuals who elect to have blood drawn from themselves in anticipation of surgery requiring transfusion at a hospital. Their prevalence of confirmed positivity for hepatitis-C antibodies is something like twice that of the prevalence of antibodies in repeat volunteer donors.

Now, the cynic could argue that instead of targeting transfusion recipients from the period of time that blood was tested neither by the specific nor by surrogate markers, instead of targeting those transfusion recipients, if one wanted a larger yield of individuals who are potentially candidates for treatment, then you need go no further than ask the community at large, have you ever been a hospital patient, or have you ever donated an autologous unit for yourself. These autologous donors are reasonably representative of the hospital patient base at large, and these autologous donors are certainly not individuals who have been transfused before. Some of them have, but they represent a minority.

We would get a lot more mileage testing the large group of hospitalized patients for hepatitis-C than going through the exercise of attempting to identify previous transfusion recipients.

The last point that I want to make briefly has to do with what I said before I made that point. It is not only HCV that carries a higher prevalence in the autologous donors. It does not matter which marker you look at; these are autologous donors, these are homologous donors. It doesn't matter which marker you look at, core antibody, ALT, syphilis, B surface antigen, HTLV and HIV. It does not matter which one you look at. The hospital-based patient population at large, the autologous donors, all have a higher prevalence than do the blood donor community.

The last point I wanted to make in terms of a targeted look-back had to do with the notion that I do not believe that a single interception, a single test, even if one were able to identify these transfusion recipients, would be sufficient.

Why do I say that? I've got here HCV antibody positive donors at the blood center in Seattle, between the period of time over here, when the first HCV antibody assay was licensed, to over here in October '93 when I stopped collected data.

On this axis then, the prevalence of HCV antibody. You can see, when that assay was first introduced, there was a much higher prevalence, a prevalence that would have been a lot higher but for the fact that some of the infectious donor base had been culled by use of the surrogate markers.

What happened here? Here, in May of '92, was the introduction of the second generation HCV antibody assay. There was an increase in the prevalence. Now, this is looking exclusively at donors, but we could say with confidence from looking at the shape of this curve before the introduction of the second generation test and the shape here after the introduction of the second generation test, that we had some donors here who were negative in the first generation assay, who have continued to donate, but who now seroconverted in the second generation assay. It is highly likely that the same is going to be true for transfusion recipients.

Targeted look-back is only going to be as successful as the test that is used to identify the presence of HCV is sensitive. An individual who is a candidate for targeted look-back, who is negative in current HCV assays, cannot reassure himself or herself totally until he or she is subsequently negative in increasingly sensitive HCV assays, PCR, for example. So any targeted look-back, in fact, any look-back is going to be limited by the knowledge that the ability to isolate and identify individuals who may have very low levels of infectious virion, very low levels, our ability to identify those individuals is going to depend on improving sensitivities in the HCV assay.

I haven't really said anything about the difficulties inherent in a targeted look-back as they relate to tracing individuals. I'm almost loathe to say that, because any insistence on the part of blood bankers that targeted or directed look-back is hugely time consuming and hugely inefficient, any insistence on that score is really regarded as disinterest and an attempt on the part of blood bankers to distance themselves from this exercise.

All I would say though is that in our own experience with look-back for HIV, something like 2.7 families out of six move every year in the States. Hospitals close down, women marry and yes, they do still change their names occasionally these days. Targeted look-back is not an easy undertaking. It is fraught with inefficiencies.

If we do targeted look-back, at worst, blood programs will really be conducting what is an inefficient labor intensive exercise that actually masquerades as a public health measure. At best, we certainly will be able to identify a few individuals who are hepatitis-C infected, only presumably though as a result of a transfusion.

What we really need is not to pinpoint the transfusion recipient. We don't need some sort of pinpoint of light. What we really need is a floodlight, that is going to get all those individuals who are at risk of community acquired HCV out of the darkness. And certainly Dr. Margolis pointed to some of those strategies.

Thanks.

PARTICIPANT: We'll do some questions from first the commission and members, and then again go out into the audience.

PARTICIPANT: (Inaudible.)

PARTICIPANT: The question here is, is the incidence different in autologous versus donated blood due to geographic variations?

PARTICIPANT: All autologous means is that this is an individual who wanted to donate blood for himself or herself. If I could say with confidence that living in the countryside protected one from ever needing surgery, I would have moved there years ago.

PARTICIPANT: (Inaudible.)

PARTICIPANT: I don't want to sound facetious. Certainly I would concede that there are issues there which do not make a very neat comparison totally permissible.

One of the other issues is this: an autologous donor can answer yes to the question, I have had hepatitis, because certainly when those units are not used for other people, the fact that that person has had hepatitis does not preclude him or her from having his or her unit back. One is not going to get a disease from a unit of blood when you already have that disease.

PARTICIPANT: (Inaudible.)

PARTICIPANT: There certainly were other influential factors. Different questions were added, other screening was added. I just chose those points in time because they neatly coincided with when those frozen samples came to life, and also with the introduction of the first generation HCV antibody assay.

PARTICIPANT: Other questions?

PARTICIPANT: (Inaudible.)

PARTICIPANT: The question here is, would you want to be tested for hepatitis. I have to jump in on an informed consent basis here. You don't have to answer that. But would you want to be tested for hepatitis, having received blood products?

PARTICIPANT: At this rate, Dr. Gompers is going to be asking me if I believe in acupuncture. Let me just say, I am a regular blood donor. I am certainly not a regular blood donor because I'm seeking test results.

PARTICIPANT: Does that mean that you do not necessarily suggest that those of us that are using blood products should be tested, should be screened, that there are reasons for screening?

PARTICIPANT: Can you elaborate on that one a little? There are prescriptions against individuals who have been transfused. I say, there are prescriptions against individuals who have been transfused, from being blood donors for a certain period of time.

PARTICIPANT: I'm not talking about being blood donors. I'm talking about being screened for HCV.

PARTICIPANT: The question is, in your opinion, should people who are regular users of blood products be tested for HCV.

PARTICIPANT: Correct.

PARTICIPANT: My opinion in this regard is that HCV screening is something that should be considered for individuals triggered by a question, have you ever had a blood transfusion, have you ever been exposed to somebody with hepatitis-C. My consideration is not that this should be done under targeted circumstances, but this should be done under the umbrella of the sort of questions that should be added routinely to say an annual physical or to an insurance exam.

If your physician would ask you the question during an annual physical, have you been a recipient of blood derivatives, blood products or transfusion and you would answer yes, then that would be a reasonable opportunity for you to be screened. But I think under those circumstances, the broad umbrella approach, it is a little different by comparison with a recommendation that individuals who have blood products are the individuals who should now present themselves at their physician's office.

PARTICIPANT: (Inaudible.)

PARTICIPANT: No, I agree with you that there has to be a two-pronged approach to education. One of the surprising findings in those studies, which did attempt targeted look-back, was the revelation that many patients who were transfused were unaware of it. Certainly a goodly number of individuals who are transfused do know about it, and then can bring to their physician's attention the fact that that is an element of their history, if their physician forgets to ask the question.

PARTICIPANT: Your analysis of autologous donors made me recall that the recipients who are blood donors is another population. What you showed is that a half a percent approximately of donors coming in when we first started HCV screening were anti-C positive. If you look at the autologous donors, perhaps one percent is.

Dr. Margolis shows that about 1.8 percent of the general population is HCV positive. If you look at people who in the process of donating indicate that they have been transfused in the past, this is data from when we first started C screening, about three percent of people who are blood donors who had a history of prior transfusion were C positive.

(End of Tape 3, Side 2.)

-- have a much higher prevalence. But the general recipient pool is really not that much higher prevalence than the general population.

PARTICIPANT: Thanks, Mike.

PARTICIPANT: Let's go up here.

PARTICIPANT: Miriam Alter from CDC. I wanted to add some comments about the effect of different donor interventions over time on the rate of transfusion associated hepatitis-C.

In our sentinel surveillance studies in CDC, in the last 15 years, the most dramatic decline in the number of cases of acute hepatitis-C who reported a transfusion occurred actually prior to surrogate testing and right after implementation of donor screening procedures to prevent HIV infection, as well as the introduction of anti-HIV.

This may be because there are a lot of individuals who are donating who failed to acknowledge that they have been injection drug users in the past. The screening procedures that were implemented for HIV prevention actually excluded many of those individuals.

We then saw a further decrease for surrogate testing, so that by the time we got to 1990, much of the risk in transfusion associated hepatitis-C had already disappeared. I think we were at a rate of less than one percent per unit transfused.

So I think that just adds clarification to the effect of donor screening prior to anti-HCV testing.

PARTICIPANT: Let me ask one last question, the prerogative of the Chair, before we take our break. That is --

PARTICIPANT: I just wanted to follow up on what Miriam has just said. Combined with the data that we have seen, this would suggest that the people at greatest risk of acquiring hepatitis-C from a blood transfusion are the people who got transfused in the very remote past, meaning in the early 1980s, 1970s, even 1960s.

I think while Merlon didn't address it, our ability to find records in a targeted look-back fashion on those people is virtually non-existent. Until recently, hospitals were only saving records I think for about five years in most jurisdictions, transfusion records, that is. I think since HIV look-back took place in the early '90s, hospitals are holding their records for longer.

But I think it would be very unlikely that you could trace a recipient who received his transfusion prior to 1985, trace an actual unit to a specific recipient. Yet, that is where the highest yield would be.

PARTICIPANT: That is exactly what I was going to ask. I was going to ask, aside from moving and marriage and other demographic factors, what really is possible in terms of look-back, just by record keeping, pre -- I was going to say 1990, but --

PARTICIPANT: I think Steve Kleiman hits the nail on the head. That really is a very mixed bag, in terms of what the efficacy is, once one gets back to the '70s and early '80s.

PARTICIPANT: What I would like to do is let us break until about ten past four, and then we will go to the public comment period, and I will see you back at ten past four.

(Brief recess.)

PARTICIPANT: -- come back up on the podium. We are going to enter into a public comment period. I know there are three individuals who have indicated an interest in making some comments to the advisory committee. They are welcome to make a choice about where they would like to make those comments from. They are welcome to come up here to the podium and do it, they are welcome to do it from the floor microphone. I would like to limit each one of these presentations to roughly five minutes. We will have opportunity for questions, comments, if the committee would like to offer any to any of the people who are going to make public presentations.

I have Dr. Steven Kleiman from the AABB. I've got Dr. Bianco from America's Blood Centers, and I've got Glen Pierce from the National Hemophilia Foundation on my list of people. I'm going to do them in that order. As I said, you can come up here or go to the floor mike, whatever is more comfortable.

After we do that, we will then move to a discussion among the advisory committee, who are still chomping at the bit to be allowed to speak. When I told some of you during the break -- and just in equity, I will tell the rest of you, what I thought I would do is just open the floor for a period of time for people to offer some comments or remarks, either about what we have heard so far about other issues that you may want to comment on. It seems fair to let the advisory committee perhaps react to some of the things that they have heard, so I am giving you a heads-up so you can be thinking a little bit about if you want to say something to get us under way in that session before we move more to a formal agenda business. So a little open period for comment and reaction, putting a new issue on the table or a statement and so on, is what we will do after the public comment period.

PARTICIPANT: Thank you. I am chairman of the Transfusion Transmitted Diseases Committee of the American Association of Blood Banks. I am going to read their statement on HCV.

PARTICIPANT: We have those statements on the table.

PARTICIPANT: The AABB is a professional association for approximately 2200 institutions engaged in the collection and transfusion of blood and blood products. It includes American Red Cross blood service regions, independent community blood centers, hospital-based blood banks and transfusion services, and more than 8500 individuals engaged in all aspects of blood collection, processing and transfusion.

The AABB appreciates the opportunity to comment on HCV. HCV is now rarely transmitted by transfusion, because of serological screening tests which first became available in 1990. These tests identify specific antibodies to hepatitis-C virus, and as a result exclude infected donations.

The March 1997 NIH consensus conference statement on HCV concluded that the risk of transfusion related hepatitis-C is now in the range of one in 100,000 units transfused, although some believe that it may actually be five to ten times higher.

The AABB currently requires notification of any donor who tests positive for HCV, and of course, that donation is not used for transfusion. Donors with confirmed positive results are indefinitely deferred, and are no longer permitted to donate blood. Counselling and information are provided to the donor.

Such notification allows a donor to seek medical care and to make lifestyle changes, such as avoiding alcohol. The donor can also notify their contacts to be evaluated for possible infection.

There are some direct medical benefits to identifying individuals infected with HCV. As stated in the recent NIH consensus conference statement, treatment is unequivocally recommended for the group of patients with chronic hepatitis-C who are at greatest risk for progression to cirrhosis. Indication for therapy is less obvious in other groups of patients.

Because chronic HCV often is silent, notification may permit long-term medical observation and prompt treatment of clinical chronic active hepatitis, cirrhosis and hepatic cancer.

In November of 1996, the AABB published its association bulletin number 96-7, which discussed the currently available information regarding HCV look-back for recipients. Specifically discussed was whether to notify individuals who received blood components collected from a donor, whose donation was negative at the time it was released for transfusion, but whose subsequent donation tested positive for anti-HCV, what we commonly refer to as look-back.

Experience in other look-back processes, even those as compelling as HIV look-back, demonstrates that the process is a highly inefficient means of identifying affected individuals. Despite the massive effort of HIV look-back, very few individuals were actually identified and aided by the process. The AABB's review suggested that it is unlikely that targeted HCV look-back would achieve any greater success.

Although recipient notification may directly benefit some individuals, it is clear that the prevalence and frequency of transmission of HCV in the United States remains a significant public health issue that cannot be addressed by blood collection and transfusion facilities alone. Data show that at most, five percent of HCV infections are now transfusion related, and in all probability, the current number is less than three percent. Even if every potentially exposed recipient was traced, greater than 95 percent of the HCV problem would fail to be addressed by the targeted look-back approach.

AABB encourages the Public Health Service to develop an outreach plan for medical providers that will identify all patients at risk and provide testing, treatment and counselling recommendations. AABB further encourages PHS to identify a model for outreach to affected consumers who would not be in regular contact with a medical provider.

The AABB stands ready to support any PHS initiatives to benefit those individuals at risk from HCV infection, including targeted look-back if recommended. AABB would be pleased to participate in further policy development, and offers its resources to obtain additional information.

Thank you.

PARTICIPANT: Questions? If not, thank you. I'd like to have Dr. Bianco from America's Blood Centers. I believe we have your testimony.

PARTICIPANT: It is, with a couple of corrections of concordance or spelling.

I am the vice president of America's Blood Centers. America's Blood Centers or ABC is an organization that includes 72 independent community-based blood centers in the United States. ABC was formerly known as the Council of Community Blood Centers, CCBC. Together, these 72 blood centers collect over 45 percent of the blood supply in the country. Members of ABC are large and small. All are community based, not-for-profit organizations. Each center has a volunteer board of trustees made of local community leaders committed to support the blood needs of hospitals and patients in their area. All blood collected by ABC member centers comes from volunteers in the community.

ABC has a sophisticated information network. Members meet at least twice a year to share best practices in medical, technical, scientific, regulatory and business areas.

ABC organized CGMP and quality training programs to facilitate compliance with FDA requirements. Currently they have pilot programs for the introduction of ISO-9000 quality standards. ABC members also have a purchasing program and a resource sharing program.

Community blood centers have carefully followed the HCV epidemiology and questions about recipient notification and look-back since the identification of the virus and the availability of the first screening test in 1990. The question was discussed many times in public meetings without clear conclusions.

In our view, the complexity of the issue derives from two conflicting points of view. One is the public health importance of HCV infection. Many recipients of blood and blood products were infected by HCV before the availability of screening tests. However, studies published by Dr. Miriam Alter and others from CDC show that three to five percent of the U.S. population is infected with HCV; maybe those numbers are slightly different. And over 95 percent of the HCV positive individuals were infected by other means.

In addition, studies performed by Dr. Leonard Sieff and others have shown that chronic HCV infection leads to increased morbidity. Thus, HCV infection is a serious public health problem in the United States.

The other point of view relates to the perceived obligation to pass along to transfusion recipients look-back information on donors who tested negative in the past and now test positive for antibodies to HCV. Look-back is a relatively simple procedure for blood centers. Essentially, blood centers review their shipping records and notify hospitals that received previously negative units from a donor now known to be positive, implying that the donor was in a seroconversion window at the time of the negative donation.

Look-back is a major problem for hospitals. They have to identify recipients of the units, locate the records, often going back many years, identify the attending physician, and locate the recipient, who often moved somewhere else. The current experience with HIV look-back and infection that catches everybody's attention so everybody takes a serious look at it, is poor. Less than 20 percent of the recipients are located after a lot of effort.

The experience with HTLV look-back that is performed by a limited number of centers is dismal. Less than ten percent of the recipients are located.

Another disadvantage of look-back is that it depends entirely on the donor. Only repeat donors are included in look-back, and the process is only initiated when they come back to donate. Here I say first time donors, but it is actually single time donors, are not included in the process, because there is no subsequent donation. They were negative at that donation, they never came back, we don't know what happened. Thus, look-back is an inefficient method of disclosure, because it is triggered in a random fashion by a very limited number of donors and reaches a very limited number of recipients.

There were attempts made by ABC blood centers to carry out a universal look-back. For instance, the Hocksworth Blood Center in Cincinnati went to the papers and television in 1990, announcing that a test for HCV had become available, and that patients who received blood prior to availability of the test could be tested at no cost by the blood center. The public response was very small. Very few patients requested the test.

We have to realize that blood centers can effectively address public health issues of blood donors. Blood centers can and have made substantial contributions to the safety of the blood supply. However, blood centers do not have the structure or the tools to address public health issues of recipients or of the general population. The latter must be addressed by public health authorities and by health care delivery systems.

There are more effective ways to address HCV infection, including education of physicians and other health care professionals. In this context, ABC member centers support the recommendation that patients who are at risk of exposure to HCV, including recipients of blood and blood products, should be tested for HCV. ABC member centers fully support the involvement of the Public Health Service in detection and prevention of HCV. ABC also supports the involvement of private foundations such as the American Liver Foundation in the delivery of public messages about HCV.

ABC member centers are very encouraged by the constitution and by the composition of this committee, and are committed to fully support its search for information, data and its deliberations. ABC member centers are also ready to comply with recommendations made by this committee. ABC respectfully requests full consideration of these issues before issuing a final decision about HCV look-back.

Thank you.

PARTICIPANT: Thank you. Questions or comments from the commissioners? Then our final presenter in the public comment session, Dr. Glen Pierce from the National Hemophiliac Foundation.

PARTICIPANT: Thanks. I'd like to offer a consumer perspective of HCV infection. I think things have been a little bit one-sided, other than some of the nice remarks that Terry Rice has made. So what I would like to do is address some of the comments on the FDA policy that Dr. Meade presented this morning. He finished with a series of questions that the FDA feels need to be answered before one can determine whether or not look-back is worth pursuing.

Some of those questions I really think are not relevant to the discussion. I have identified four that I would like to point out.

Is HCV infection a significant medical condition? Well, from our perspective and from the perspective of somebody infected with HCV for 20 or 30 years, the answer is yes. The first case was identified in hemophilia in 1971, where someone died from liver failure, and that was where the connection was made. By the end of the 1970s, although people were generally asymptomatic, liver biopsies showed chronic persistent to chronic active hepatitis, straight through to cirrhosis, even though there was enough liver left to allow people to remain asymptomatic. From a histologic point of view, the liver was a mess, even at that point in time.

Then as we get into HIV, that really overshadowed the effects of HCV. If you wipe HIV out from the scene, HCV would have been the worst disaster possible, short of HIV, to hit this community. In fact, when I think about the number of friends and acquaintances who have passed away, liver failure from HCV infection was a primary cause of death in far more than one might imagine. So it has been a very real and a very significant disease in chronic users of blood, most of whom were infected when they were kids to young adults. That is what we are talking about here, a long period of infection.

I am happy that in the young Irish women who received Rogam once, that they have a 2.4 percent incidence to cirrhosis after 17 years. That is not the case in the hemophilia community, and I would venture to say that that may not be the case if you look at all blood transfusion recipients, most of whom are not young, healthy Irish women. So I think that would be a moot question from our point of view.

The second question: is transmission of HCV by transfusion a significant enough part of the infected population to warrant specific detection? I'm not sure what the relevance of that question is. The question wasn't asked for HIV, and yet that is a very small minority of the transfusion -- transfusion associated AIDS is a very small minority of HIV infection, but even if that is tied to HIV and you say maybe we shouldn't have done this for HIV, I think we are missing the point here.

HCV infection and transfusion recipients is an iatrogenic disease. It was caused by a medical procedure. As such, the government as well as those who are involved in distributing and administering blood and blood products have an obligation and a responsibility to those recipients, period.

Are there opportunities for intervention to warrant recipient notification? That is the third question. Well, we had an NIH consensus conference a month ago which has been made public in a variety of forms, as we heard. It appears that the FDA policy isn't taking that consensus conference into account. In addition, the FDA in '90 or '91 licensed alpha interferon for the treatment of hepatitis-C. I may have my dates wrong, but in any event, it has been out for several years as a treatment for hepatitis-C. So it seems to me like the answer to that is yes, period.

Then the final question is, does the recipient have the right to know? This is something that has come up time and time again, and it is just not clear to me why we think that those of us making decisions for the care of patients who have received infections from blood transfusions have the right to determine whether or not those patients care about the infection. Whether the patient chooses to do anything about it or not is a separate issue.

So while you say that look-back only produced five percent of patients who got tested, I'm not sure that that is the right goal, and I'm not sure that that is the right answer, because you don't know how many of those patients got the notification, figured it out that maybe this is something that affects me. Maybe they have altered their lifestyle a little, maybe they went somewhere else to get tested, or maybe they just put it away. When they are at the doctor at some point and not feeling well, they may remember that. It is up to them. They are the ones that should make the decision, not the FDA, not the Public Health Service, not the blood banks. You need to let the recipient make the decision, and not make the decision for that person.

Thank you.

PARTICIPANT: I have a question, but let me open the floor for other committee members? My question was, have you done any polling or surveying or sense of the meeting among the members of the National Hemophilia Foundation about their attitudes about their desire to know? Has there been any sort of sample or sense of the meeting or sense of the group?

PARTICIPANT: In the hemophilia community, most everyone knows they have HCV infection, because they have been followed by treatment centers, they have been treated over a long period of time, many individuals have HIV, so there is a very high overlap between those two populations.

So it has been something that, as the HCV antibody test came out, it was part of routine medical practice to get tested. Then the issue is wrestling between the patient and the physician relationship what to do about that; do you treat, do you not treat, do you wait.

So in this community -- and while I am from this community, I am really speaking for all those who don't have that option, who haven't had the option of being able to know what is going on. Those of us in hemophilia do know what is going on, and are in a much more informed position to make decisions.

PARTICIPANT: One other question for you. We heard a little bit today about financial barriers, in terms of getting tests, getting access to treatment. Could you comment on that?

PARTICIPANT: Well, alpha interferon is an approved drug for HCV, so there shouldn't be any financial barriers, other than perhaps with some HMOs that may not want to pay for treatment.

In the experience of the hemophilia docs, and you have got a couple of docs that can address that on the committee, if you are your patient's advocate, you can generally get treatment for that patient. You can get it paid for. So we are talking about approved testing and approved treatment.

PARTICIPANT: Thank you. A comment over here?

PARTICIPANT: I just would like to make a quick comment to address some of your comments, Glen. I think that the position that we at ABC -- and I hear from other people like AABB are taking, is not that recipients should not be notified. I think that a hundred percent of the people who receive blood transfusions should know that they are at risk for hepatitis-C. And they should know that risk from the beginning.

I think that a point that concerns us is to only trigger that notification through a complex process that is look-back, which is random, that reaches very few people, is inefficient. It should be bigger, it shouldn't be that small. It is bureaucratic, it is inefficient, it is small, that's all. I think we all more or less feel the same.

PARTICIPANT: A similar comment. I think the right to know issue has driven previous BPAC decisions. I think the measure of the right to know is at the end of the process, how many people actually know.

In targeted look-back, a minute proportion of those who have been transfused will wind up knowing about the infection. In a broader approach, which addresses all people who have been transfused, independent of the year they have been transfused, the final number of people who actually realize that transfusion is a risk factor and go in to be tested and find out will be much larger than a targeted look-back.

So I think it is not ignoring your right to know, it is how to get to these people in a general way. I think that is a much better approach.

PARTICIPANT: Let's do one more comment from the floor, then we'll go into some discussion with the group up here.

PARTICIPANT: Thank you. My name is Edward Burke. I am a person with hemophilia. I am a factor eight severe, so I have been a 12-year survivor of HIV.

My older brother and my younger brother are not. My sister has four children. Her second was born two months premature. She is now 19 years old and has hep-C. She has had it for 19 years. My family has been affected by the blood supply of this country since 1955.

I sit back here today. I appreciate, by the way -- thank you for giving me a chance to talk, because I'm not just another angry person with hemophilia. I am a member of the National Hemophilia Foundation. I am an executive committee member of MAN, which is man's advocacy network of the National Hemophilia Foundation. I have traveled over the entire United States, educating other persons with hemophilia and their families of their rights to know.

I would have appreciated it if someone had told us we had a choice in 1982 between factor and cryoprecipitate. You have an obligation to notify the American public. They don't know all the facts; you people have them. I will be happy to work with you in devising programs to do that. But you have to notify people, you have to give them consultation.

I see these home HIV testing programs now. It is ludicrous. If somebody goes home and takes an HIV test and finds they are positive in their own home; who is going to know how they are going to react to that?

I have met several of you people independently today, and I believe you're on the right track, and I appreciate your taking the time to do this. I would like to see the United States one time act before another country does. But unfortunately, in Canada last week, they implemented a program to notify people back to 1980 who received blood because they may have been hep-C contaminated.

So I ask you to look back and go to the look-back process and go back at least to 1980, if not back to 1975. I thank you for your time.

PARTICIPANT: Thanks. By the way, if you can supply the committee with your information about the Canada look-back, that would be of keen interest to us. I'm not sure we know about that, so we'll have to get right on top of what they decided to do.

PARTICIPANT: I'd be most happy to, sir.

PARTICIPANT: Dr. Kleiman, I was going to close down, but we'll let you speak.

PARTICIPANT: I wanted to say something about hepatitis-C look-back in Canada, because that is where I live now. There are a couple of things going on up there. One thing is that Canada is divided into provinces, and not all provinces have the same program.

There is a program in British Columbia to send letters to all transfusion recipients, a generalized look-back program from 1985 to 1990. Anybody who got a transfusion will get a letter saying that they are at some risk for hepatitis-C and should consider being tested.

Now, this of course presupposes that you have a program in place to handle these people afterwards, which they do in B.C. So it has to be a coordinated public health effort, where once the people are identified, they can go in, their physician knows what to do, the laboratory services are available, et cetera.

Now, other things in Canada, I guess I'm not as familiar with. But there are some targeted look-back programs for HCV that the Canadian Red Cross is running. I don't know how far back they go. I don't think they go back to 1980, do they?

PARTICIPANT: (Inaudible.)

PARTICIPANT: Right. I am told they do go back to trace records as far back as 1980. I don't know how well the records are kept.

Canada is a little bit different, in that they would expect a higher yield because they never instituted surrogate testing. So those donors were never removed from the situation, so that probably the levels of transmission are higher than they would have been in the U.S. during the years of 1986 to 1990.

So that is the information that I have about the Canadian experience.

PARTICIPANT: Just one quick question about that Canadian experience so far. Do you, or does anybody here that has some experience with the Canadian program have any idea what they expect this to cost?

PARTICIPANT: I don't know. Peter, do you?

PARTICIPANT: (Inaudible.)

PARTICIPANT: There were a couple of abstracts presented at the last scientific meeting of AABB about the -- with some preliminary results, I think primarily in Quebec. Those could probably be dug out by somebody.

PARTICIPANT: I think we had those in the reading packet, if I'm not mistaken. Thanks, that is very informative, and I appreciate people offering their comments from different groups and organizations.

What I wanted to do is let the committee have a chance to make a statement or comment publicly. I have a small item of business which I would like to get to before we leave here today, maybe around 5:10 or so. I'll tell you what that is.

We have in our packets some questions for the committee that came from Public Health Service and some of the agencies that hope to have our advice and options. Paul McCurdie actually had an overhead to show to you, but they took it away, not in an act of censorship, but in an act of cleanliness, probably. They are in your packets, and maybe you in the audience have seen these as well, although I can read them later. It is not so much going through the questions which are on our agenda for consideration tomorrow as, I just want to get a sense of the group before we break today of our interest and willingness to answer those questions, either by saying we would like to extend our discussion of look-back for part of tomorrow, or extend it to another meeting, or people feel given what they have heard that they are approaching a comfort level with having something to say about look-back. So that is what I am going to be asking you about, and I would like you to be thinking about that as well.

But let me do what I promised, and just open the floor to any one of the committee who would like to make a comment.

PARTICIPANT: I'd like to make a general statement. I certainly agree with everything that has been said here today, and I agree with what I said before. But I think there is another question or issue that needs to be surfaced. It is what I call public perception versus what we believe to be medical and scientific reality.

What I am saying is that the blood supply comes from the public. The public must believe that the blood supply is safe, and that those who are involved in the blood supply process are credible. I think that is a very important charge of this committee, to address that issue as well, because the public currently still has concerns about the safety of the blood supply. If we don't address it from that perspective as well, we have heard a lot of the scientific and medical evidence, which is very important, but we must deal with the issue of public perception.

Thanks.

PARTICIPANT: Jane?

PARTICIPANT: One of the things that they said at the very beginning of our discussion this morning is that one of the charges to this committee is to weigh the costs and benefit of any procedure that would be undertaken.

You have asked whether we feel ready to consider these questions. I don't believe we have yet had any information about the relative costs and benefits. We have been told that the look-back is very inefficient, and that it will be very expensive. We have not had any discussion of how efficient or how expensive these various public education campaigns are.

As a social psychologist who knows something about the persuasion process, I have serious doubts regarding the efficacy of public information campaigns. I don't feel at all qualified at this point in time to discuss the relative merits of these, until I have some information that can help me make those kinds of judgments.

PARTICIPANT: Thank you. As I was thinking of my directive when I was asked to sit on this committee, how we are supposed to bring ethical perspectives, and how it impacts consumers. I have heard much today about policy and scientific data. But there are some questions that I still need to have answered before I can make any kind of decisions.

I still would like to know what are the morbidity statistics involved in HCV, so I can ascertain the seriousness of what we have before us. I think we also need to know what the cost projection for look-back is, in order to warrant the feasibility of such a program.

I also think we need to discuss, is this going to have legal implications to do notification. I think we also need to discuss the ethical responsibility to inform persons of their HCV status. Then if we do inform them, don't they have the right to know their status in order to seek treatment, even if it is a 15 to 30 percent success rate using alpha interferon.

PARTICIPANT: There are a few of us herein the audience that went through the HIV look-back, and know what a pain it is, and how much time it took. I reflect how miserable it was in the centers while this was ongoing. So it is a chore, and it is a big problem.

The issue we have not encountered is exactly how many HCV positive confirmed, or if not confirmed, that have the other test to establish that it is positive, how many of those are present each year, what is the number. We don't have any numbers yet.

Then secondly, how many of those are first time donors and how many are ten gallon donors? So you're going to have to keep track all the way back.

Then the next issue is, how many recipients of that blood are still alive? A lot of patients don't make it through after they receive five or six units of blood or ten units, and so on. So that whittles the number down. So one is really needing to talk about specifically how many individuals are we going to have to be looking back for, and at that point, who has the responsibility? Is it the blood center, which I think most of the blood centers would prefer not to have that responsibility. But it might be that hospitals have to bear some of the responsibility as well, in trying to go back as far as possible.

But that would be one way at least of getting a grasp of this problem, which we right now have been waltzing around and really haven't gotten to.

I would make one other comment. We are talking about looking back, but we might look forward. The forward issue to me is very simple. That is, every patient who receives a unit of blood or more, when they are discharged from the hospital, have discharge planning, when the nurse comes up, hands them the brochure and tells them that within two months, they should report back and get the hepatitis-C testing done, and it will not cost them anything. At least it is putting the information into their hands and the decision up to them. I think from that time forward, it won't be a matter of having to look back.

So I think we could split it up into two issues. The look-back has not really arrived at the point where any of us are discussing anything, as far as I'm concerned.

PARTICIPANT: (Inaudible.)

PARTICIPANT: Let me offer one quick comment on this issue of doctors telling. It is just an anecdote, in my own experience, not with a committee at all, but just wearing an ethics hat.

I did get a call from a hospital near Philadelphia about the other issue that is on our plate for this meeting about CJD disease. The hospital wanted to know if they should tell people about the presence of CJD in a donor blood unit when there was no, to their knowledge, documented instance of an infection.

So the kind of situation may not just be one of poor communication or an unwillingness to be truthful; it may be a legitimate question. Are you going to make someone nervous or upset them, to what end, to what point. I'm not saying that is true in the hepatitis-C area or in what we heard this morning, but that is the kind of a question that I think we are going to be asked for advice about, just as I was asked for advice about.

So when do we tell, and is it ever a situation where the risk is so low that we don't tell, because we are not doing our patients a service that way. So that is a concrete example of wrestling with that dilemma.

PARTICIPANT: (Inaudible.)

PARTICIPANT: That is why I recognized you at all.

PARTICIPANT: I personally think that the formulation of whether or not persons at risk have a right to know is a very unfortunate characterization of the issue. So I guess I am asking, why should we assume that people have a proper and legitimate interest in facts relative to their health status.

My question to the committee would be, what is the better approach for both personal and public health? Do you go full bore and do something that will capture the whole hundred percent of people that have hepatitis-C? Or is it better from the personal and public health perspective to make a more focused effort to find the people who have transfusion transmitted disease?

My second question is, are we speaking in code? Are we really talking about the question of who should pay for this? (Inaudible.)

(End of Tape 4, Side 1.)

PARTICIPANT: Being on the public health side of the discussion as a director of a health department, there are some concerns that I would have in terms of how something like this would be structured for trying to maximize the opportunity for disseminating information to the groups at greatest risk, especially at a time when we are all going to be doing that with a number of other conditions, whether or not within the present public health system that is very much in transition with the capacity to take on another layer of responsibility that I suspect would generate a considerable amount of interest because again, there is such broad utilization of the nation's blood supply under so many different circumstances, that so many people certainly would consider themselves at risk.

Then when one mentions hepatitis, for most of the people they wouldn't be able to distinguish between the different types of hepatitis and the risk factors. So I think that it would be essential to obviously be very careful in how we structure the information and how it is that we want to try to maximize that, but at the same time recognizing that once we do, we need to be certain that we have the capacity and the infrastructure in place to respond appropriate, and to try to inform the entire community, in particular those that consider themselves at risk or at some level of risk, to inform them in a way that is reassuring to them, and that we also have as Mary was suggesting in place the resources to cover that

I think the other part of the concern relates to how populations are shifting in very significant ways because of the emergence of managed care systems. Many of the patients still don't know if their providers are -- they go to a variety of specialized services of care, there are laboratories they go to, et cetera. So I think that also has to be better defined.

Along with that is the tremendous number of uninsured that continue to rely very much on the public sector for a lot of programs and services. When we add this on as one additional layer at a time, when we are already adding layer after layer, whether it is more cases of tuberculosis in some places, whether it is a concern for other viral illnesses, hantavirus in some parts of the country, other conditions that put individuals and communities at risk, I think that we need to be sure we have the capacity to respond appropriately.

PARTICIPANT: At this stage of a long day, maybe this is partly being a slow learner. But as I looked at those questions and think about today, I'm not even sure I understand the questions very clearly. I read and I have heard data that talked about pre-1990. I hear data and discussion about 1990 to 1970, and then I think in terms of today and I like what I now call the Penner model that I just heard mentioned a few moments ago.

It seems to me that I'm not sure if we have answers to any of those questions, that the answers are the same for those three groups, period. If we are not looking at them in a much more specified way, we come up with a broad general answer which in fact is no answer.

So it seems to me we've got to be a whole lot more specific in terms of what we are looking at.

There is another thing that bothers me a lot. I understand this is the blood safety and availability committee, but it seems to me that if we say hepatitis is a public health problem, we are talking about hepatitis whether it is from blood or any other source. If we somehow get out of a meeting like this saying we'll take care of the blood component, but we're not really focusing in on the other side of it, I'm afraid that I don't want any part of this operation, because we are missing the major part of the issue.

So as we think in terms of how to get to those who have this disease, it certainly broadens our focus. But we certainly should not lose focus at the other

PARTICIPANT: Paul stole a lot of my thunder, because that exactly in one sense was what I wanted to say. I think we have been more loggers than splitters today. I think if we are really defining the issues, I think we have to be splitters a little more.

I agree with you, I think we have a real responsibility because of the very fact that people who are transfused got hepatitis-C, and hepatitis-C is a fundamental health problem in the United States. But I think in order to talk about what the recommendations should be, I think we have to be very careful that we attend the needs individually and then look at how the collective approach to each complements each other. Maybe in the best of all worlds, one approach solves everything for both agendas for this disease.

In reality, I doubt that that is going to be absolutely true. But I don't think until we really sit down and try to define these issues, including the cost benefits as a number of people have spoken to, will we be able to ascertain which component is complementary, which component is independent. I think again, if we feel strongly as a committee that it is in the public health interest to recommend something, that we recommend it regardless of whether it relates in the case of HCV to people who were transfused or not. In doing that, we are vicariously at least approaching the problem of virally transmitted disease.

So I agree strongly with what has been said. I think we need further clarification before we say yes to targeted look-back or there is a broad look-back, or there is a physician training program or there is a population information program.

PARTICIPANT: I think we need to be very careful not to be to short-sighted here. After all, where does blood come from? I think that is what we are talking about.

We have a host of donors out there, supposedly some eight billion. What happens when we flood the airways and television sets with blood deposits, hepatitis and -- remember what happened with the AIDS business? Half the donors came in at one time thinking they were going to get AIDS when they donated blood. To have to reinforce that whole issue again, bring to the fact that blood is a contagious element and therefore those centers that are collecting blood certainly must be responsible for some of this, is going to put us in a position of being very defensive again, and trying to maintain a blood supply which at times as you know is very tenuous. All you have to do is look at those requests around the holidays to get people to give blood.

PARTICIPANT: There is something that nobody is mentioning here, sort of like that old thing about an elephant in the room. One of the things about any kind of blanket -- anybody who has had a transfusion in the last X years with the assumption being made that if you have had a transfusion and it turns out that you have hepatitis-C, you got it from the transfusion.

I don't think anyone who looks at those proportions of where people got hepatitis from would assume that at least since 1986, say that is about the point when things started dipping a lot, the great majority of people who had a transfusion since 1986 and have hepatitis-C did not get it from that transfusion. But nobody was tested for hepatitis-C before they got the transfusion.

So again, speaking to these legal and responsibility issues, I think this is something we have to talk about and we have to think about. The assumption will be, if we put something in motion like this, that if you had a transfusion and you have HCV, you got HCV from the transfusion. The great majority of cases recently, that is just not true.

PARTICIPANT: I would like to reinforce what I think Dr. Kuhn has been saying, at least what I have been extrapolating from what he has been saying, and I suppose others, too.

It seems to me there are two tasks before us, one having to do with the established (inaudible) my own sense of what is the right and proper thing to do. That question has to be answered as a group, and then we will have to of course grapple with that individually in order to get to a group answer.

The second part of that however is the piece that has to do with the cost benefit analysis and what is safe and what is efficacious and what is reasonable and what is going to set a public panic. But we have to ask the right question first, and then make a determination if we have to that we may or may not do the right thing, for whatever reasons.

There are issues that I think we have yet to develop fully. This format is horrendous for this kind of discussion, as I'm sure you know. Hopefully we can correct it, and we can have a real discussion in more depth about some of the questions that are coming forth. But I certainly don't think that we are in any way prepared to address either set of questions at this point.

PARTICIPANT: I'm somewhat conflicted, as I think other people have expressed. In participating on this committee, we made a commitment to look to the charter of the committee. Clearly, there is a lot of information we have not been presented, we are unaware of. It is difficult to make a definitive decision and recommendation. But I think that this committee has to set the pace in this first session. This is obviously not the right format or procedure or process, and we have to work on that first, and we can do that off line.

But I think this committee has to make it clear that the Public Health Service has a responsibility, that the United States government has a responsibility to make certain that the information is made available to the community, to the public at large. If HCV is as prevalent as we have heard it is today, then my own community (inaudible) who we have identified only five percent of thus far across the country, is very similar to what we are talking about with HCV. It is important to know, no matter how expensive a treatment is, no matter how efficacious a treatment is, it is important to know, and it is our responsibility to make certain they know.

So at the very least, I hope we walk out of the meeting tomorrow with the ability to make a statement that this is not another BPAC, that this is not another committee that is going to reconvene in six months -- with respect to BPAC, the deck has been stacked to some extent, that this is not another committee that is going to meet in another six months. We have a lot of work to do.

There are a lot more items in the agenda that we need to address. For each of us to accept this responsibility, I just think that it is important. I wanted to express that, that it is important that we make that point clear, that we don't walk out and say we need a bunch more information, more detailed and specific information, that we want to make a statement that this is an important issue.

PARTICIPANT: One of the things that has come up repeatedly is the question of the infrastructure and how do you implement, and also the knowledge of the primary care physician. I suspect that as a first step, I know the CDC has something that is going to come maybe in a year or two to inform primary care physicians. That is really a critical element of all this. If we start with look-back and informing patients, and they go to doctors who don't really know what to do about it, we haven't really accomplished much.

So the first thing is that we get a really well informed population of primary care physicians, so that as people do come in, they will know exactly what to do.

PARTICIPANT: Well, in my role as Chair, I obviously don't want to put words in the mouth of the committee members, but I would say I sense a hesitancy over addressing these questions in the next five minutes.

The probability is, I suspect, that we can talk about this a bit tomorrow. My hunch is that we are going to be talking about, who else do we might need to hear from, when next we might want to meet. If I'm wrong about that, you can tell me that tomorrow morning.

I did want to wrap up today's session with two other thoughts. One is, what we decide or what we recommend or what we say does not have to be couched simply in terms of look-back, yes, no. It is obviously the case that we can say there are criteria to consider, or factors or aspects that ought to be part of any decision about what to do with a look-back situation or a disease that threatens the integrity of the blood supply. There may be other things known and unknown where this kind of issue will come up, so that we want to be careful in making a recommendation, and realize that it could well be generalized to other kinds of problems, and they require more than a statement just about a yes or a no, or do it or don't do it, in terms of guiding these agencies as to how they deal with the safety of the blood supply.

The other is, we have to talk a little bit about some mechanisms of practical action. As I watch the committee here, you see me chair our sessions, I am doing so far the tradition of Lenin or Stalin or something. We haven't said whether we vote on these things, whether we vote by majority, whether we would require a two-thirds majority to say something. So those procedural issues can be discussed, too, in terms of how we want to move.

But my hunch is, just my own read on what I have been listening to from members of the committee now is, it seems to me that there is a request for financial information, legal, social, psychological, comparative. Other speakers might want to be put in front of the committee. I hear a willingness to come and listen and participate in that. If that is the sense that we carry forward tomorrow, then I will do all I can to make sure that we have a chace to do that. If you are willing to be somewhat flexible with your schedules as we move towards the summer, maybe within two or three months, to make that happen then, see whether we can even schedule a meeting past that date. We may not be able to get everybody, but I think we can move forward, knowing that if most of us can be here, we will try and bring everybody up to speed on what they need to know. But it is getting the process rolling that is going to be essential, if that is the direction you all decide to take us.

My last comment is this. I think the ethics officer is gone from the meeting room, so I have to be careful about how I say this, ethicist to ethicist. But this committee when it meets always does so in public. We are chartered in a public body. While we don't necessarily have to sit in the proverbial flying wing formation here, in future we can actually look at one another; that is possible.

We do have to be public in what we do. So people have asked me, are we going to meet tonight, will we meet at other times. No, we won't do any business or have any meetings, but it does cross my mind that many people may be coming for dinner at 7 o'clock in the lobby. What they are going to talk about or who they rendezvous, I don't know, but I say that publicly, so there it is. Let the chips fall where they may.

So unless someone is desperate to offer a comment, I'm going to bring us to a close. Did you want to jump in there with one brief comment?

PARTICIPANT: Yes. This issue of HCV look-back has been debated by many, many people for four or five years now. The fact that the panel can't come to a conclusion in just one afternoon makes a lot of sense to me. It is an extraordinarily complex issue, and it is a very important decision. I urge you to -- if everybody has the time, to take the time that you need to get the right answer. I think what this committee recommends is probably going to steer policy for the whole country.

So I want to support what four or five people said, that these are -- especially if you have just heard them for the first time today, there are a lot of ramifications to these issues, and I think they really need some careful consideration.

PARTICIPANT: At this point, what I would like to do is thank everyone for agreeing to be on the committee. I really appreciate your taking the time out of your lives to come. I hope to see you all here tomorrow at 8:30 in the morning.

(Whereupon, the meeting recessed, to reconvene the following day.)