Blood Safety: Resolution - November 1998

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

SIXTH MEETING

Tuesday, November 24, 1998

8:39 a.m.

Omni Shoreham Hotel

2500 Calvert Street, N.W.

Washington, D.C. 20008

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

Members

Arthur Caplan, Ph.D.

Stephen D. Nightingale, M.D., Executive Secretary

Janice K. Albrecht, Ph.D.

Larry Allen

James P. AuBuchon, M.D.

Michael P. Busch, M.D., Ph.D.

Ronald Gilcher, M.D.

Edward D. Gomperts, M.D.

Fernando Guerra, M.D.

Paul F. Haas, Ph.D.

William Hoots, M.D.

Carolyn D. Jones, J.D., M.P.H.

Dana Kuhn, Ph.D.

Tricia O'Connor

John Penner, M.D.

Jane A. Piliavin, Ph.D.

Eugene R. Schiff, M.D.

Marian Gray Secundy, Ph.D.

John Walsh

Consultants

Richard J. Davey, M.D.

Kristine A. Moore, M.D., M.P.H.

Ex Officio Members

Mary E. Chamberland, M.D.

David Feigal, M.D.

Paul R. McCurdy, M.D.

Capt. Bruce Rutherford, MSC, USN

David Snyder, R.Ph., D.D.S.

Also Present:

Jay Epstein, M.D., FDA

Eric Goosby, M.D., DHHS

Lawrence McMurtry, Deputy Executive Secretary

C O N T E N T S

AGENDA ITEM PAGE

Roll Call, Conflict of Interest Announcement 3

Welcome from the Chairman 9

Centers for Disease Control 16

Food and Drug Administration 56

Interorganizational Task Force on HCV Lookback 87

Blood Recipient Organizations 100

American Liver Foundation 115

Lunch 150

Committee Discussion 151

Motions 178

Adjournment 268

P R O C E E D I N G S

DR. NIGHTINGALE: It is one minute after 8:00 in the morning. Good morning. I'm Dr. Stephen Nightingale, the Executive Secretary of the Advisory Committee on Blood Safety and Availability and welcome to our Sixth Meeting.

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

In particular, as specified in Title XVIII of the US Code at Chapter 208(b)(2), a Special Government Employee--which all voting Committee members are--may participate in a matter of general applicability even if they are presently employed or have the prospect of being employed by an entity that might be affected by a decision of the Committee, provided that the matter will not have a special or distinct effect on the employee or the employer, other than as a part of the class. The example given in 5 CFR 2640.203, which implements Title XVIII of the US Code, is as follows:

A chemist employed by a major pharmaceutical company has been appointed to serve on an advisory committee established to develop recommendations for new standards for AIDS vaccine trials involving human subjects. Even though the chemist's employer is in the process of developing an experimental AIDS vaccine and therefore will be affected by the new standards, the chemist may participate in formulating the advisory committee's recommendations. The chemist's employer will be affected by the new standards only as part of the class of all pharmaceutical companies and other research entities that are attempting to develop an AIDS vaccine.

Committee members have been given a copy of this section of the Code. Additional copies are available at the desk.

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

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

Finally, I will make every effort to see that the transcript and the summary of this meeting and the final draft of any recommendations will be posted on our Web site by the close of business Monday, November 30th. The Web address is www.hhs.gov/partner/Blood Safety.

Now, would the Chairman and members please signify their attendance when I call their names? Dr. Caplan?

CHAIRMAN CAPLAN: Here.

DR. NIGHTINGALE: Dr. Albrecht?

DR. ALBRECHT: Present.

DR. NIGHTINGALE: Mr. Allen?

MR. ALLEN: Present.

DR. NIGHTINGALE: Dr. AuBuchon?

DR. AuBUCHON: Present.

DR. NIGHTINGALE: Dr. Busch? Dr. Busch?

[No response.]

DR. NIGHTINGALE: Dr. Chamberland?

DR. CHAMBERLAND: Present.

DR. NIGHTINGALE: Dr. Davey?

DR. DAVEY: Yes.

DR. NIGHTINGALE: Dr. Feigal?

DR. FEIGAL: Yes.

DR. NIGHTINGALE: Dr. Gilcher?

DR. GILCHER: Yes.

DR. NIGHTINGALE: Dr. Gomperts?

DR. GOMPERTS: Yes.

DR. NIGHTINGALE: Dr. Goosby?

DR. GOOSBY: Yes.

DR. NIGHTINGALE: Dr. Guerra?

DR. GUERRA: Here.

DR. NIGHTINGALE: I know that Dr. Haas is unable to make the meeting. We hope all goes well with him and his family.

Dr. Hoots?

DR. HOOTS: Here.

DR. NIGHTINGALE: Ms. Jones? Ms. Jones?

[No response.]

DR. NIGHTINGALE: Dr. Kuhn?

DR. KUHN: Present.

DR. NIGHTINGALE: Dr. McCurdy?

DR. McCURDY: Here.

DR. NIGHTINGALE: Dr. Moore?

DR. MOORE: Here.

DR. NIGHTINGALE: Ms. O'Connor?

MS. O'CONNOR: Here.

DR. NIGHTINGALE: Dr. Penner?

DR. PENNER: Here.

DR. NIGHTINGALE: Dr. Piliavin?

DR. PILIAVIN: Piliavin.

DR. NIGHTINGALE: Piliavin. I apologize once again.

Captain Rutherford?

CAPTAIN RUTHERFORD: Here.

DR. NIGHTINGALE: Dr. Schiff?

DR. SCHIFF: Here.

DR. NIGHTINGALE: Dr. Secundy?

DR. SECUNDY: Here.

DR. NIGHTINGALE: Dr. Snyder?

DR. SNYDER: Here.

DR. NIGHTINGALE: Mr. Walsh?

MR. WALSH: Here.

DR. NIGHTINGALE: Thank you. We'd note that Dr. Busch is present at the meeting. Also present is Dr. Epstein, the Director of the Office of Blood Research and Review of FDA. Dr. Epstein?

DR. EPSTEIN: Here.

DR. NIGHTINGALE: Thank you. The agenda for today's meeting is the Seventh Report of the House Committee on Government Reform and Oversight titled "Hepatitis C: Silent Epidemic, Mute Public Health Response." Dr. Caplan, the Chairman of the Advisory Committee, will preside.

Dr. Caplan?

CHAIRMAN CAPLAN: Well, we have a busy day this morning. I want to remind the Committee that we've really been asked by the Surgeon General to take a look at this Seventh Report of the House Committee on Government Reform and Oversight from October 15th. We've sent it to the Committee, I think, at least four times, in my memory of mails that have come. So I hope that the message was clear to pay attention to this.

I want to just look at three findings and three recommendations in brief. You know, when we've met in the past, we've had to scramble to the slides and the overheads, concocting language as we drive toward consensus on certain matters pertaining to blood safety and availabilty. But in this case, we've got something to respond to by the end of the day. It doesn't limit us, but there are some things we're supposed to say something about.

The findings of this report were as follows: The Federal response to the hepatitis C epidemic has lacked focus and energy. Secondly, the proposed HCV lookback is too limited. Third, private organizations with some Federal assistance have taken the lead in HCV public education efforts. I can say that if you read the report, that was said with a critical edge to it, that private organizations should not be taking the lead on this. And there are a series of recommendations, and I'm inside the report on page 2 of it, just to remind you again.

The Secretary of HHS should take the lead in coordinating the Federal public health response to the hepatitis C epidemic, including implementation of a research plan. The Department of Defense should test recruits, active-duty personnel, and those about to be discharged for hepatitis C infection. The Department of Veterans Affairs should conduct additional studies of the prevalence of hepatitis C in veterans' populations. The hepatitis C lookback plan should be expanded, and the Federal education campaign for HCV infection should be launched immediately.

What this report wound up concluding, arguing, was that they were not convinced that the Government was making the public health response to the hepatitis C epidemic that was required, and so we've been asked to think about, listen to testimony today on those matters, and then to reaffirm or add or come back and change what we've been told by that particular subcommittee of the House about this particular problem.

I want to just note something else that caught my eye. I collected a couple of things since our last meeting. Some of them, again, Dr. Nightingale, Mac, did a great job getting materials out to you. Some of you know there were articles in the New England Journal last week on combination therapy for hepatitis C. While far from a cure, they were optimistic. I'm not going to go through those articles or the editorial ran, but things are moving fast in the area of intervention for hepatitis C. That means, I think personally, that the ante is raised about the importance of lookback. The ante is raised about the importance of public education campaigns.

I have a friend who has hepatitis C, and he's been trying very hard to get access to different forms of therapy, combination therapies. He believes that the right response for him with his infection is to try and clear the virus from his body. And I asked him if he felt that this Government and our country was doing what we should to respond to hepatitis C epidemic, and he said no, because every day he meets people who didn't realize that they might be infected.

That is not a good situation. So it is, I think, our mandate to the American people to make sure that if this problem is out there and if there are steps they can take, either through the cessation of drinking, watching what they do with ibuprofen, getting themselves vaccinated against other forms of hepatitis, not sharing razors, or moving towards some of these emerging interventions, we have to make sure that people are aware of what they need to be aware of, that medical and health communities are able to answer questions and inform them.

So that's how I see our task, as against that backdrop of saying, well, if there are steps that can be taken to reduce infection, if there are steps that might be taken to reduce the burden of the disease, if, as other statistics show, we've got 4 million people infected and an explosion in the number of people getting liver transplants due to this particular virus, we have to make sure we're doing all that we can do in terms of a response, both public and private, to hepatitis C.

I'd just mention one last comment, and then we'll go to the first witness.

This is a statement from the American Association for the Study of Liver Diseases. They had a meeting in Chicago and thoughtfully sent me a statement about one of the things they are bothered about. And they reported at that meeting about the challenge of hepatitis C, what it was doing in terms of cost and burden to the American people. But this statement caught my eye.

The main reason for the drastic increase in severe hepatitis C-related liver disease--that means leading to transplant, leading to death--is that 90 percent of people with chronic hepatitis C don't know they have it.

Well, that's not an acceptable situation. If that's what the problem is, then we've got to make sure we are vigilant in pushing to make sure that that number is much smaller.

So I'll stop there. That's our charge. We want to be mindful of the fact that by the end of the day we have to say something about this report and what we want to tell the Surgeon General and, through indirection, the other Federal agencies here and even Congress. I suspect we might even say if we want them to spend some more money, we might say they should spend some more money. What the heck? It's not ours. Well, indirectly. It's so far distant.

So we can move now to the first witness, having reminded you why we're here and what we're trying to do. I think we're going to hear from CDC first?

DR. NIGHTINGALE: Hear from CDC.

CHAIRMAN CAPLAN: I don't know who we've got from CDC. Oh, Dr. Alter?

DR. ALTER: Thank you. Good morning. I'm Miriam Alter from the Hepatitis Branch of the Centers for Disease Control and Prevention in Atlanta, and you should all have a hard copy--most of you should have a hard copy of the presentation. There may be one or two of you who do not because we may not have brought enough copies. But if that's the case, I'll be showing the exact same information on the slides, and we will get you a hard copy if you need it.

As the first presentation today, we would like to review the guiding principles which underlie the recommendations made by this Committee last year.

Identifying transfusion recipients at potential risk for HCV infection can be accomplished with two approaches: targeted lookback, which is the direct notification of prior recipients of donors who later tested positive for HCV, and how we define positive may, in fact, be the major crux of all the issues we're dealing with; and general lookback, which includes public notification through broad education campaigns about the need to be tested, as well as education of health care professionals to routinely ascertain transfusion histories of their patients and test those with such a history.

Targeted lookback for transfusion recipients at potential risk for HCV infection has several advantages. It focuses on a specific group known to be at risk. It reaches persons unaware they were transfused. And it is perceived as proactive.

This approach also has several disadvantages. Many notifications may be based on false positive results because supplemental or confirmatory testing is not available on donors who tested repeat reactive for the anti-HCV. This approach will not reach recipients from donors testing falsely negative unless sensitive tests or donors who were never tested because they donated before testing was available. Records might not be available as far back as 1988, which is the current time frame for the lookback. Many individuals are untraceable, and based on limited evaluation, there has been a poor response on the part of recipients to programs such as this in the past as well as in other locations.

General lookback or notification for transfusion recipients at potential risk for HCV infection also has several advantages. It is not dependent on donor status or record availability, and it reaches at-risk persons who would not otherwise be identified--that is, recipients who receive blood from donors who tested falsely negative on the less sensitive test or who received blood from potentially infected donors before testing was available.

The disadvantages of this approach is it might not reach some individuals who are unaware they were transfused, it is perceived as not proactive, and there is no substantial data on its effectiveness.

In order to maximize the advantages and minimize the disadvantages of notifying transfusion recipients at potential risk for HCV infections, the Committee made its current recommendations for identifying these individuals, which includes a combination of both approaches:

Direct notification of prior recipients of donors who later tested confirmed positive by multiantigen assays, which were widely implemented by July 1992. In the guidance provided by FDA, this is further clarified, and, in fact, it will include a small number of recipients who received blood from donors who had repeat reactive antibody tests that were not confirmed in order to include the entire time period that encompasses multiantigen testing.

The current recommendation also provides for general notification of all persons transfused before July 1992.

By using both of these--this slide illustrates the components of this comprehensive strategy using both approaches. Now, if we start--actually, Jean, can I borrow your...

If we start here in 1998, for donors who have donated previously and come back to be tested--and have come back to be tested after multiantigen tests were widely implemented, which is from July 1992 forward, lookback will be triggered for their recipients if they donated previously, those previous donations--if they donated previously, back to 1988 or as far as--or as far back as records are available.

So keep in mind that if a donor who is--let's say a donor donated in 1992 and was negative on the first generation--first-version screening test, this donor then comes back to donate again in June of 1996 and is now found to be positive on both the multiantigen screening and supplemental assays, lookback will be triggered for the prior donations from that individual. This individual might have donated not only back in 1992, but perhaps back in 1989 as well.

So that the time period actually refers to when the donor is tested, not when the recipient was transfused. So that the targeted lookback refers to prior transfusion recipients of donors who donated previously and came back to be tested with a multiantigen assay.

General lookback will encompass all individuals transfused prior to 1992, which will include recipients of donors, of repeat donors who tested repeat reactive but unconfirmed on the first version of the assay. So you'll notice that, in fact, there is considerable overlap between the two approaches.

In discussing the public health issues of these approaches, we are not considering costs or any other measures of outcome other than the immediate impact of the notification on the recipient. This slide shows the estimated number of transfusion recipients for notification using the time period specified in the recommendation made by this Committee last year.

We have updated the numbers based on our understanding of the availability of supplemental or confirmatory results on a small percentage of donors testing repeat reactive on the first version assay. Although the absolute numbers may have changed from previous versions, the magnitude of the relationship between each category has not.

Now, let's look at the column labeled single antigen. Single antigen testing was first introduced in May of 1990 and spanned about a two-year time frame. The total number of recipients for notification based on repeat donors who tested repeat reactive for anti-HCV by the single antigen assay has been reduced by about 30 percent from the previous estimate because we have recently been informed that about 30 percent of these were tested by RIBA, and those results are available, and about 25 percent of those are expected to be positive--are estimated to be positive by RIBA, and that's why--and that reflects this number of those who have been tested by RIBA and found to be positive as well as those who have not been tested.

So of the 500,000-plus recipients estimated that will require notification based on single antigen testing, about a third will be recipients of true positive donors. This includes donors who were tested by RIBA and found positive, plus the estimated number of RIBA positive donors among those not tested. So a true positive donor for the purposes of this presentation is defined as someone whose antibody is a true positive.

The percentage of individuals who receive a false notification--that is, their donor was not infected with HCV and their antibody was not a true positive--is about 68 percent, or over 300,000. Now, of all those notified, we expect, based on survival rates for persons transfused five to ten years ago, about 10 percent of these individuals will be alive. We will miss through a targeted lookback about 43,000 individuals because their donors tested falsely negative on this assay.

Now, if we look at the second version--I'm sorry. If we look at the second time period, which is after multiantigen testing was widely implemented, we find that a little over 300,000 recipients will be triggered for notification. Of these, because most have RIBA testing results, 90 percent of the notifications will be based on a true positive donor and only 10 percent on a false positive.

Again, based on survival rates for individuals transfused in the past, about 18 percent of these are expected to be alive, and because the sensitivity of these tests were greater, only about 10,000 individuals would be missed through a direct notification.

Based on these calculations, we can summarize the consequences of performing targeted lookback for all recipients since screening was implemented in 1990 based on their anti-HCV screening results, without regard for whether or not confirmatory testing was done--that is, if confirmatory testing is done, the notification would be based on that. If confirmatory testing was not done, then the notification would be based on the screening test results.

The estimated target population, which is a combination of the two groups I showed you on the previous slide, is about 850,000. An average of 53 percent of these notifications would be made to recipients at potential risk--that is, their donors were truly anti-HCV positive. This ranges from a low of 32 percent for recipients of donors tested by single antigen assays to a high of 90 percent for recipients of donors tested by multiantigen assays.

Now, as we stated previously, this approach fulfills the right to know. It provides the opportunity for the individual to determine their infection status and to obtain, if they're positive, follow-up or evaluation for clinical disease and possible treatment, recognizing that most, or 80 to 90 percent of these individuals, are already deceased from other causes.

On the other hand, 47 percent of these notifications will be made to recipients not at risk. Only 10 percent would be falsely notified using multiantigen assays, but as many as 68 percent would be falsely notified if we based notification on single antigen testing.

These false notifications would be made to as many as 400,000 individuals or their families, and certainly the right to know is an underlying principle of this program. But this principle also demands that the information provided have a high level of diagnostic certainty so that this activity does not generate more harm than good.

Providing false information might be detrimental and will certainly require additional counseling for reassurance. Furthermore, an additional 50,000 recipients at risk would not be notified through this approach because their donors tested falsely negative.

As I said before, these estimates have been revised based on the availability of supplemental or confirmatory testing of a small proportion of version 1.0 donors, information that was not known a year ago.

Keeping with the guiding principles of trying to notify as many recipients as possible who received blood from a true positive donor, we can estimate the number of transfusion recipients for notification based only on donor testing status without regard specifically for the time frame in which the donor was tested, not when the recipient was transfused.

If we look at the number of notified recipients--the number of recipients who will be triggered for lookback based on donors tested by the single antigen screening assay with no supplemental or RIBA testing, then we have about 480,000-plus recipients, of whom about 25 percent are estimated to have received a donation from a donor who later tested truly positive. Seventy-five percent did not receive a unit from a donor who was infected. Again, the rest of the calculations remain the same as previously.

If we base targeted lookback on both single and multiantigen-tested donors who were also tested by RIBA, then about 360,000 recipients would be notified directly, of whom 91 percent received blood from a donor who later tested truly positive, and only 9 percent would be notified when they were--would be notified but had received blood from a donor whose test result was later--was actually a false positive.

Thus, we believe that by modifying slightly the original recommendation that this Committee made for identifying transfusion recipients at risk for HCV infection will retain the spirit of the original recommendation, maximize the direct notification of individuals at risk, and minimize the number of false notifications. This would include targeted notification based on supplemental testing results without regard for time period, including all of the provisions that are currently included in the FDA guidance.

General notification for all persons transfused before July 1992, and this would accomplish reducing the false notifications from a potential high of 400,000 to a low of 32,000, and minimizes the number of recipients missed due to donors testing falsely negative.

This approach differs very little from the previous one, except to take advantage of all the supplemental or confirmatory testing that's available, thereby minimizing the number of false notifications; so that recipients transfused from donors who later came back to be tested and tested positive using either single or multiantigen screening assays, plus the results of supplemental assays, would be directly notified. This would include all recipients of multiantigen-tested donors as well as about 30 percent--as well as a small proportion of recipients from donors who came back during first version testing.

In addition, we again go even further with general lookback to include all recipients tested before--who received blood before July of 1992.

Now, in order to encourage individuals with a history of transfusion to be tested, as well as to ensure that these individuals receive the right follow-up, our major focus in terms of education has been the health care professional because they need to be able to adequately address the patient's needs. Education of the health care professional started well before the Committee's recommendations for lookback for transfusion recipients.

In March of 1996, the NIH issued a consensus statement on the management of hepatitis C. In November 1997, the CDC, in collaboration with the Hepatitis Foundation International, broadcast an interactive, live teleconference by satellite on diagnosis, clinical management, and prevention of hepatitis C, targeting primary care physicians, which was broadcast to more than 2,000 downlink sites.

Then in January 1998, Secretary Shalala agreed with the recommendations of this Committee calling for lookback--two approaches, targeted and general--to identify recipients of HCV-infected blood.

In February of 1998, a Hepatitis Summit was sponsored by the American Digestive Health Foundation and focused on providing health education messages to minorities as well as information to health care professionals on hepatitis C.

In March of 1998, and revised in September of 1998, the FDA issued guidance for industry for both quarantine of units found to be positive for anti-HCV as well as notification of blood collection--as well as notification in order to carry out directed or targeted lookback.

In April of 1998, the CDC convened a meeting of representatives from the American Red Cross, America's Blood Centers, the American Association of Blood Banks, and the Council of State and Territorial Epidemiologists to discuss implementation issues for lookback and coordination of efforts.

The American Association of Blood Banks formed its Interorganizational Task Force on HCV Lookback to coordinate efforts nationwide, and the CDC updated its Web site in order to include current information on this effort as well as information in general about hepatitis C.

Between June and September 1998, educational materials and screening guidelines were mailed to more than 250,000 physicians and other health care professionals, including members of the American Academy of Family Practitioners, the American Academy of Pediatrics, the American College of Physicians, the American College of Obstetricians and Gynecologists, and the American College of Surgeons.

A similar mailing was made when the recommendations for prevention and control of HCV infection and HCV-related chronic disease was published in an MMWR in October of 1998. These guidelines, a copy of which should have been--either you received by mail from us or was provided to you by Steve Nightingale, includes guidelines for preventing transmission of HCV, identification, counseling, and testing of persons at risk, including transfusion recipients, and providing appropriate medical evaluation and management.

Between October 1998 and January of next year, we will be distributing education materials to transfusion services, including a brochure or pamphlet for transfusion recipients specifically which is entitled "Get Tested for Hepatitis C," and you have a copy of it that I provided to you this morning.

These educational materials include letters that CDC has worked with the AABB Interorganizational Task Force on that transfusion services can use to notify both patients and physicians, which explains the risks involved, why they're being notified, what they can do about it, and where they can get tested.

Early next year, we will be finalizing the protocol to evaluate the effectiveness of our lookback activities, and we'll also be providing software to transfusion services to assist in targeted lookback.

By March of 1999, CDC's public advertising campaign will be launched to notify the public about the need for testing of transfusion recipients for hepatitis C. We will also have established a Web-based training site for health care professionals on HCV prevention, including testing of transfusion recipients. And by the middle of next year, we hope to begin evaluation of the effectiveness of these lookback efforts.

As promised, in the January 1998 memo from Secretary Shalala, we have gone forward in collaboration with the Agency for Health Care Policy Research and FDA with the development of a plan to evaluate the effectiveness of both the targeted and general lookback efforts. The objectives of this plan are to evaluate the effectiveness of both approaches for identifying persons infected with HCV, encouraging persons found positive to obtain appropriate medical follow-up, and its effectiveness for promoting healthy lifestyles and behaviors among those found to be infected, such as decreasing or eliminating alcohol consumption. In addition, we will collect cost data in terms of dollars and personnel resources so that we can evaluate the cost-effectiveness of these programs.

This evaluation plan includes two national surveys, one of blood collection establishments and the other of transfusion services, to collect the basic information about all of the donors who are triggering lookback as well as the recipients who are eligible for notification. It will also include follow-up studies of a sample of transfusion recipients presumed to have been notified and/or who have obtained HCV testing to determine the outcome and impact of the notification process on the transfusion recipient, including those who test negative; and for the general notification efforts will include a survey and study of private and public health care services to determine the extent of HCV testing of persons with transfusion history.

As a result of this evaluation, we will determine if our efforts need to be expanded in order to more--to identify a larger number of transfusion recipients who may be at risk of HCV infection.

We believe that, with a slight modification, the recommendations that this Committee made represent good public health practice and minimize the negative impact on individuals who are not at risk of acquiring this infection. We also believe and feel have demonstrated that the Department of Health and Human Services has actively gone forward with a variety of programs to achieve this important--to achieve a successful outcome to this important public health program.

Thank you.

CHAIRMAN CAPLAN: Thank you, Miriam.

First, let's take some time for questions. I wanted to lead off with just one question about the public health campaign that you've undertaken for physicians and health care professionals, which I've been following very closely and I think is great.

I noticed an editorial in the British medical journal, The Lancet, although I've seen these around, too, and I just wanted to get your opinion about the public health campaign. Basically what it said is how much money would be needed to do a thorough public health campaign. The current CDC budget for HCV is about $10 million. It's far too little. It's far smaller than the amount to do the job than the CDC asked Congress for, which you'll recall we had some discussion here about it being more than a $48 million level. It's only a portion of what the American Liver Foundation has told us might be necessary for a campaign.

What I'm asking is, as we get the materials out, begin the education campaign, are the resources there, in your opinion, to really push the materials that are being developed aggressively, adequately, to the health care community? Can we get the message out given what the commitment is?

DR. ALTER: I think given--do you want to, Kris--

DR. MOORE: Go ahead, but I have a comment on that, too. Go ahead.

DR. ALTER: Although Hal Margolis might want to add to this, I think we have actually very widely disseminated this information. In terms of the education of health care professional, I don't know how much more we could saturate the market with our current materials. What I think would be important is resources to evaluate whether or not what we have done is effective and whether or not we need to do something additional.

DR. MOORE: As someone who works in a state health department, I think CDC has really done an excellent job in trying to get information out; but I also think that there's this conception that if you put out an MMWR article, people read it, people absorb it, people learn that information. And having worked with community--

CHAIRMAN CAPLAN: Is that not true?

DR. MOORE: Well, I'm beginning to believe it's probably not fully true, with work in this area but also in a number of other areas related to immunizations, and take pneumococcal vaccination, for example, where we're doing a number of other kinds of projects, or GBS guidelines. I mean, there are so many different levels where this has been demonstrated over and over again.

But I really think there is a very strong need to have people at the state level that can really help to push this information. For example, in Minnesota, because we've been interested in this, we've done four or five provider conferences. We've met with the Association for Practitioners in Infection Control several times. We've sent information to all the hospitals in the state. We've worked with the blood banks, and we've done a lot of other steps that I think if you really want providers to change practice, you have to have somebody at the local level at them, you know, just kind of putting the messages out over and over again.

And I would really advocate for resources to CDC so that they could then put some categorical funding out to states. I just think without those resources, it just doesn't happen to the level that we would like to see. And I know that this is something that's been discussed at CDC, and the resources just simply haven't been there. I'd strongly advocate for that.

DR. ALTER: You're absolutely right, Kris, and the resources that Dr. Caplan referred to were part of the CDC's overall nationwide campaign--excuse me, nationwide plan for HCV prevention and control, which includes not only primary prevention activities but the identification of everyone at risk, of which, as we all understand, the transfusion recipients are very important, but as small component of that. So Kris' comment is well taken and extremely important.

In terms of some of the broader issues, however, the resources--we have actually dedicated--I think had sufficient resources to deal with both the--at least the educational programs directed at the health care professional and will have for the public. But we need to direct some of those efforts at a very local level in order to get the message across.

DR. EPSTEIN: Miriam, I have a technical questions. When you looked at EIA 1.0 RIBA tested to develop the numbers for recipients, were you including indeterminate results of RIBA 2?

DR. ALTER: For the purposes of these estimates, I didn't. I assumed an overall rate of positivity of about 25 percent, recognizing that RIBA 2.0 indeterminates might be included in there. I looked at some of the--Steve Kleinman's publication, looked at the percentage who were indeterminate in that group, and I imagine since that was a relatively--it's only 40,000 or so donors, you know, that the range of indeterminates probably varies widely. But I didn't include them because it was a little too difficult to estimate.

DR. EPSTEIN: But it would drive the numbers up?

DR. ALTER: The number who would get notified, yes, it would, and it would drive the number of false notifications up as well. But the magnitude of the relationships, again, would remain the same, and I think that that's--in principle, the principle here are the number of individuals who would be falsely notified, and since we have an approach to deal with that, the numbers could change tomorrow of next week, but the magnitude would remain the same.

DR. PENNER: With respect to the first-generation hepatitis C antigen testing, that was the 1990 to 1992--the 1990 to '92 assays?

DR. ALTER: That's correct.

DR. PENNER: If I'm reading this correctly, you're saying that you'll have to notify 54,000 live recipients, to let about a third of them know that they were truly exposed to the live virus?

DR. ALTER: No. The number of notifications that would have to be made is over 500,000.

DR. PENNER: However, 54,000 of those are alive, you're saying?

DR. ALTER: Expected to be alive, right. But a lot of them, they won't know that at the time that they send out the notification.

DR. PENNER: So it's really 54,000 that you're concerned about who--

DR. ALTER: No, because--I'm sorry.

DR. PENNER: About two-thirds of those which would be receiving false positive testing.

DR. ALTER: You could look at it that way. On the other hand, keep in mind their families receive these notifications as well.

DR. PENNER: And so the agency is saying that you prefer to make the decisions for them so they don't get upset by this?

DR. ALTER: No--

DR. PENNER: And those individuals who happen to have been--really received the live virus would not be notified in this way.

DR. ALTER: We feel that it's just as important for people not to receive false notification as it is for people to receive notifications based on a high level of certainty. And since these individual--since we're using two approaches of notification--it isn't that we're not notifying people. It's that we're using two different approaches. And everyone who was transfused before July of 1992 will be encouraged to be tested through very aggressive public education campaigns. The fact that they won't receive a specific letter of notification will need to be evaluated to determine whether or not we need to go further with efforts to get individuals tested.

DR. PENNER: We already heard from an expert that spoke at this Committee that direct notification by mail would be much more effective than a general announcement to the public.

DR. ALTER: If I remember correctly, it was a marketing individual who spoke and who did an excellent job at presenting that. And, yes, this--that might be a slight overstatement of what he said, and you know what? To be quite honest, I don't think we know what the impact of these two approaches is going to be. I think in the next presentation you're going to see some examples of other notification programs and the responses to them. And I think that our plans for evaluation will help us answer that.

DR. PENNER: There's one other issue, though. Many patients do not know that they've been transfused, including those who are in prenatal situations or at least newborns, as well as a number of patients who have undergone surgical procedures. They're completely unaware that they've ever received any blood transfusion. What about those individuals?

DR. ALTER: Well, as I mentioned early on, there are advantages and disadvantages to each approach, and neither of them is perfect. And, yes, you can miss some of the individuals who are not aware that they were transfused.

I think in some studies of HIV it was estimated it's about 12 percent of those transfused. However--and some of them, you're right, will be missed.

However, you know, to somewhat alleviate that number, we will be encouraging--we will be--part of our messages will be risk factors for transfusion so that people will be made aware that they could have had a transfusion, they should find out about it, as well as the same types of messages to physicians when they're looking at their patients' histories. Neither of these approaches is perfect. We feel that the combination of the two maximizes the advantages of both of them and minimizes the disadvantages of both of them.

DR. PENNER: The disadvantage is being frightened by the fact you received the letter and it may not--

DR. ALTER: And you're not at risk.

DR. PENNER: And you're not at risk.

DR. ALTER: That's correct.

DR. PENNER: And despite the fact the British and the Canadians have already gone through this and have accepted the fact that the first-generation testing was worthwhile notifying the individual recipients?

DR. ALTER: You're going to hear some of those results, I think in Dr. Mied's presentation.

CHAIRMAN CAPLAN: We're going to take two more comments. We'll do one from Marian, and then I think I have one pressing question that I was holding in reserve, and then we've got to get to the FDA testimony, but the themes will stay here.

DR. SECUNDY: I want to try to bring this down to the level of the most simplistic. As I heard you--

CHAIRMAN CAPLAN: Hit that mike a little.

DR. SECUNDY: You indicated that at some point in time--and I guess I need to know what time period would be involved--that you would look at your results using these approaches and make a determination of whether or not they had worked sufficiently or if you were going to need to step up efforts.

I've got one comment and a question related to that. It would appear to me, from what I'm understanding, that with the exception of some minor incremental changes, we've been at this for two years, and we have looked at those results, and it seems to be somewhat mixed in terms of a sense of whether or not any of that has worked.

But the question that I have is: What time frame are you suggesting for this approach to be used and at what point will you evaluate and what criteria are you using to determine whether or not it has worked? And then, finally, what do you anticipate might be involved in stepping up efforts?

DR. ALTER: Okay. Everything that's been done in the last two years has led up to the notification process, whichever approach is involved, because the education had to be laid as groundwork before we could aggressively pursue testing of individuals at risk. That's number one.

As provided for in the current FDA guidance, transfusion--notification of transfusion services of recipients who need to be notified must begin by March of '99. Some of this has begun already, as I imagine you'll hear from some of the other speakers today.

However, the bulk of the notification will begin in March of next year, and it is an ongoing process. Given the hundreds of thousands of people involved, it will take time to complete notification of everyone. In the same month, we will begin our public education campaign.

We will need to give both the public education campaign, as well as the notification process, time to settle in, time for people to hear the message or receive the message in the mail and take some action. So I would think that in terms of evaluation, we wouldn't begin to really look at it until, let's say, the end of '99. In other words, we'd have to implement the procedures to look at it at the time the notification--both the public and direction notification begins, and then at the end of the year or the beginning of 2000, we might have sufficient data to take a preliminary look at it.

DR. SECUNDY: Well, what will you--

DR. ALTER: Okay. What will we be measuring? We will be specifically measuring the proportion of recipients identified who are ultimately tested, the proportion of those tested who are identified as positive, the reasons persons do not receive notifications, and the reasons persons, upon being notified, do not get tested. That will be some of the basic information upon which we will initially evaluate both approaches.

We will compare them and see if we think one has had a substantial impact over the other based just on the differences in the percentage of individuals we can estimate got tested using both approaches.

CHAIRMAN CAPLAN: Dr. Alter, let me--I said I was going to take one more question, but you're hitting an area that's got Dr. AuBuchon and myself ready to ask a question. I'm going to ask you to be as succinct as possible because we've got to get over to the FDA testimony. But, quickly, just two quick questions from me, and then Jim, and then we'll let you out of there. You've been up there a while.

Do you think it's possible to send out a notification to these 54,000 people, risking--

DR. ALTER: It's not 54--

CHAIRMAN CAPLAN: --false notification of many people to find them that won't frighten people? In other words, is the issue as we look at this gap of the single antigen testing, can we avoid a panic? Can we avoid undue distress? Is there a way to reach out to that 'tweener group as we try to do a lookback without unduly frightening them, saying you've got a problem, perhaps, but you'd better come in, or there's a reason for concern? Is the issue really--

DR. ALTER: Some individuals are going to get letters like that because there is a certain percentage of individuals who received blood from donors who came back to be tested by multiantigen assays where the donor was not confirmed, and they're included in the guidance issued by FDA, and that's fine. You know, it does represent a small percentage, and we have constructed what we think are reasonable letters to these individuals explaining what this means.

But you're talking about doing that to 400,000 people or their families, and although I can't predict what an individual's reactions will be, I can tell you anecdotally--well, I'd rather not. The Canadians have some experience with this, but I--

CHAIRMAN CAPLAN: The reason I ask--

DR. ALTER: I don't--you know, it's just our opinion on whether that letter frightens you or not.

CHAIRMAN CAPLAN: The reason I ask this, in part, is I'm sitting at an institution that has ties to many outfits that are proposing to do general population screening for breast cancer, gene testing for depression, and they're saying we're going to look at entire ethnic groups or X, Y, and Z, and they're not hesitating because the yield will be tiny, much less than what we're talking about here. They are trying to be careful how they market, let's say, genetic testing, looking for probability and risk factors.

So I'm a little--you don't have to answer this. I'm just watching sort of--

DR. ALTER: But keep in mind that we're not notifying one group in favor of another.

CHAIRMAN CAPLAN: I understand that.

DR. ALTER: I think that's a very important principle. We're notifying everyone, but in different ways. And I don't know that there's really an answer for your question.

CHAIRMAN CAPLAN: Back-of-the-envelope calculation, if there's 50,000 people out there in, again, this 'tweener group who might be benefited by a direct notification, perhaps might be found as opposed to a general lookback, general notification, public education campaign, if we figure that there's $100,000 per head on a liver transplant and--I don't know--a tenth of them convert to liver failure and maybe 30 to 40 percent of them could have been helped by available or emerging therapies, that's a pretty good chunk of change on the therapy end, forgetting the education campaign and so on. So if I just do a quick back-of-the-envelope, I come out with a question that says: Isn't it cost-effective to find some percentage of those 50,000 if we are now moving toward a position where we could prevent morbidity and mortality?

DR. ALTER: Dr. Caplan, I appreciate that perspective. I think, however, that we've been criticized in the past for even the perception that we might be considering cost as an issue here. And since cost--if you want to look at cost-effectiveness, you would also have to look at the resources required to notify the over 500,000 people or, you know, the almost 500,000 people that would result in the 50,000 alive getting testing. Okay? Of which only a small percentage of them would actually get tested. So it's not that you're identifying 50,000 people who are alive. Then you have to take into account how many of them can be found, how many of them will respond to the test--to the call to be tested, and all of that. And we did not go into those calculations because we did not feel that that should be a part of this particular decision.

CHAIRMAN CAPLAN: Jim, you're going to get the last question.

DR. AuBUCHON: A comment, Mr. Chairman. I just wanted to take this opportunity to publicly thank the Centers for Disease Control and Prevention, and particularly Dr. Alter, for their efforts and for her efforts in making information available to the blood banking community and making materials available for us to use in this notification process.

As a physician in a transfusion service who's deeply embroiled at the moment in conducting these notifications, I greatly appreciate having this information available, Miriam, and I thank you and the CDC for all of the efforts, because without this information, blood bankers who are not hepatologists, who are not counselors, who are not public health experts, would not have the information that we need to conduct this in the most thorough manner possible and to have the greatest possible outcome.

Thank you.

DR. ALTER: Thank you, Jim.

CHAIRMAN CAPLAN: Thanks, Dr. Alter.

We're going to watch the time carefully because we do have--I know that many on the Committee want to ask questions, and I'm going to ask people to try and keep their prepared remarks succinct so that they leave time for questions. Otherwise, Steve will be breaking off various appendages of mine in unseemly fashion here if we go way off schedule.

So let's try and keep our prepared formal presentation as brief as possible because I know the Committee wants to put questions. Who do we have? Dr. Mied?

DR. NIGHTINGALE: Yes.

CHAIRMAN CAPLAN: From the FDA.

DR. MIED: Thank you, Dr. Caplan.

I am Paul Mied from the Division of Transfusion Transmitted Diseases in the Office of Blood in the Center for Biologics Evaluation and Research, or CBER. I'm going to summarize the actions taken by FDA to implement HCV lookback following the statement of a Department position by Dr. Shalala in January 1998, and I'll focus especially on the sequence of events that led to the change from the March guidance to the September guidance:

On September 23, 1998, FDA issued a Revised Guidance for Industry Document on HCV lookback. The FDA recommendations contained in this revised guidance document--and I think you'll find this in Tab E--are provided to enable quarantine and disposition of units from prior collections from donors with repeatedly reactive screening tests for anti-HCV. Additionally, FDA recommends that consignees of certain blood and blood component units collected since January 1, 1988, which were anti-HCV negative or untested, be notified when donors subsequently test repeatedly reactive for anti-HCV in a licensed multiantigen screening test and reactive in a licensed or investigational supplemental test. This notification would enable recipients to be informed that they had been transfused with units that may have contained HCV so that they may obtain further medical counseling. This document was provided on the CBER home page for comment and implementation on September 23rd and published in the Federal Register with a notice of availability on October 21st. Additionally, this guidance document was mailed to all blood establishments on November 20, 1998.

Now, since the comment period never really closes on guidance documents, comments on the revised guidance will be evaluated by FDA as they are received and changes made as warranted.

The September 23rd revised guidance document replaced the March 20, 1998, Guidance for Industry supplemental testing and the notification of consignees of donor test results for anti-HCV, which had undergone major revision by FDA in response to comments received from the industry and the public during the 60-day comment period following its issuance in March.

Now, as a result of these significant changes in the guidance, FDA made known its intention to reissue comprehensive guidance on HCV lookback at a public meeting of the Blood Products Advisory Committee in June 1998, and these significant changes encompass several major issues.

First of all, due to difficulties surrounding the availability of the investigational RIBA 3 supplemental test, the blood banking community requested that the time frame to complete prospective notification of consignees be lengthened from within 30 days to within 45 days following the donor's repeatedly reactive screening test.

Secondly, since the retrospective lookback is expected to involve an estimated 500,000 components and difficult lookback situations may be anticipated for some blood establishments, the blood organizations requested an extension of the time period to complete the retrospective lookback from within 18 months to within two years from the date of the original guidance. The revised guidance states that consignee notifications should be completed within 18 months of the date of publication of this guidance or by March 23, 2000, thus providing a full two years from the date of the original guidance as requested.

The time frame to complete recipient notification by transfusion services has been clarified. Due to the large number of notifications which are anticipated, industry requested that transfusion services be given a year to carry out notifications of recipients identified in the retrospective review of records rather than eight weeks, as provided for prospective notifications.

In the revised guidance, FDA recommends that prospective notifications be completed within a maximum of 12 weeks and that retrospective notifications be completed within one year of the date on which the hospital or transfusion service received notification from the blood establishment.

The use of an EIA 3.0 test following an indeterminate RIBA 2 test result is another significant change.

Now, due to difficulties surrounding the availability of investigational RIBA 3 kits, the blood banking community suggested, for RIBA 2 indeterminates, that the lookback be waived if an EIA 3.0 test is performed and the result is negative. Data has been obtained to confirm the validity of this approach, and so the revised guidance document permits the use of the EIA 3.0 to resolve RIBA 2 indeterminates if the original screen had been performed with an EIA 2.0.

Now, I'd like to emphasize that the revised guidance document was ready for CBER clearance when these changes were completed in July. However, additional comments and suggestions for changes were received belatedly. These includes the recommendation that FDA, in accordance with good guidance practices, incorporate the previous recommendations on product retrieval from the July 1996 memo to blood establishments. Thus, the revised guidance document supersedes that memo. This major revision, which brought the agency's recommendations regarding the two parts of lookback--product retrieval and recipient notification--into one comprehensive guidance document necessitated a major rewrite of the guidance document in August.

Now, other change which were made following the June BPAC meeting included the extension of the time frame for beginning notification of consignees. The March guidance recommended that notification of consignees following the retrospective review of records should begin within six months of publication of the guidance, that is, by September 20, 1998. The revised guidance states that blood establishments should begin notification of consignees as soon as feasible and no later than six months from the date of issuance of this guidance, that is, the revised guidance, or by March 23, 1999.

Now, I'll address the need for this extension in just a moment.

The revised guidance document includes specific recommendations on labeling of products released from quarantine for consistency with existing regulations on product labeling. Flow chart diagrams were also provided to assist industry in implementing the complex set of procedures which are specified in the recommendations.

To permit easier, more rapid notification of the recipient, the blood organizations requested that establishments be permitted the option of notifying the patient directly as an alternative to notifying the patient's physician of record that the patient was transfused with a unit that potentially contained HCV. The revised guidance states that when the patient is notified directly, the physician should be informed concurrently.

Now, in addition, during this time, June through July, we were quite heavily involved in the process of drafting a proposed rule on HCV lookback, and the bureaucratic process of reconciling the proposed rule with the revised guidance document and getting it cleared through general counsel was a major accomplishment during this time period.

The March 20th guidance was withdrawn on September 8th by a notice on the CBER Web site. The revised guidance was issued on September 23rd, 15 days later. FDA withdrew the September--excuse me. FDA withdrew the March 20th guidance so that blood establishments would not be compelled to implement the previous outdated guidance which recommended that notification start by September 20, 1998. And I should point out that the blood industry was aware that this action did not signal discontinuation of the lookback initiative.

The reasons we extended the implementation deadline for consignee notifications to start were, first of all, that the wholesale changes we had made in the guidance required time to implement and that such an extension was necessary to allow time for the physician education to be completed. The six-month period from the date of issuance of the revised guidance for blood establishments to begin notification of consignees was provided to more closely coincide with the rollout program for physician education, ensuring that counseling messages would be available for use in notification of recipients.

Indeed, now that the MMWR recommendations for prevention and control of HCV infection and HCV-related chronic disease, which contains guidelines on counseling and treatment, was issued on October 16, 1998, some of the larger and independent blood banks are beginning to notify consignees.

So you can see that the first nine months of this year has been a period of intense, basically non-stop effort at FDA in the implementation of HCV lookback, with the development of the initial guidance document, the revised guidance document, and rulemaking on HCV lookback. And FDA's role in HCV lookback implementation is going to continue.

Here's an outline of FDA's plan with the time frame for accomplishing each part of that plan.

Now that the revised guidance document has been published, we will continue to establish policy by guidance by responding to comments on the revised guidance document and conducting inspectional surveillance of lookback activities. We're also going to be assisting other DHHS components in evaluating the effectiveness of the public outreach and the targeted lookback programs.

FDA is also committed to establishing requirements for HCV lookback through the rulemaking process. As I mentioned, a draft proposed rule is awaiting DHHS and OMB clearance. FDA will respond to public comments on the proposed rule, issue a final rule, and conduct oversight of implementation of HCV lookback procedures by the industry.

Now, with respect to implementation of HCV lookback by the industry, the time frames for the retrospective lookback and the revised guidance document issued on September 23, 1998, are as follows:

Blood establishments should begin notification of consignees as soon as feasible and within six months from the date of issuance of the revised guidance, that is, by March 23, 1999.

Blood establishments should complete all notifications of consignees within 18 months of the date of issuance of the revised guidance, that is, by March 23, 2000.

A transfusion service should begin notification of the recipient when notified by the blood establishment and should complete all notifications of recipients within one year following receipt of notification from the blood establishment, that is, by March 23, 2001, for the last of the notifications received.

I'm going to shift gears a little bit and share with you some of the operational experience with HCV lookback driven by EIA 2.0 and 3.0, that is, what people are doing now and how effective it's been.

According to AABB, now that the MMWR has been issued, some of the larger and independent blood banks are just beginning to notify consignees. The American Red Cross is preparing to begin notifying consignees. I should point out that some of the smaller blood banks actually had started to notify consignees before the MMWR was issued. Some blood establishments are doing the lookback and the notifications in stages: first, the RIBA 2 positives, then RIBA 2 indeterminates, with additional testing as needed.

At the AABB meeting earlier this month, Dr. Mindy Goldman presented the experience of the Province of Quebec with HCV lookback. They initiated targeted lookback in March 1995. Out of 1.75 million donations collected from March 1990 to March 1997, they identified 561 repeat donors who were anti-HCV positive. Their prior donations totaled 3,197 components. The information they received from the consignees on 2,329 of these components was that, for many of the components, the patient had died or was not traceable, but that 355 recipients, or 11 percent, were located and were tested for anti-HCV. Of these, 217, or 61 percent, were positive, and of those, 103, or 47 percent, learned of their infection for the first time.

Surprisingly, 114, a little more than half, already had been tested and knew they were positive. However, in the preceding six months, there had been a lot of publicity and special education efforts in Canada about hepatitis C and blood transfusion. So one lesson here is that public outreach messages do work.

Also, they found more cases than expected. The yield rate after three and a half years of the lookback effort was 355, or 11 percent, of the target population that was tested.

Contrast this with the experience of the blood center of southeastern Wisconsin as presented at the AABB meeting by Drs. Becker and McFarland. They initiated lookback in August 1997 on 304 RIBA 2 positive donations, which were traceable to 34 repeat donors, with prior donations made after January 1987 which were not discarded; 319 products from prior collections were identified that required notification. Information was obtained on 120 of those components, leading the tracing and notification of 9 recipients, of whom 5, or 56 percent, tested positive. A comparable percentage to that in the Canadian study.

However, the yield rate of 2.8 percent of tracing living recipients who were willing to be tested was about one-fourth of the 11 percent found in the Canadian study.

Now, there currently are evaluations underway to determine the utility of first-generation EIA lookback, going back to EIA 1.0 in the targeted lookback effort. The military and some private sector blood banks have indicated they are considering doing lookback on EIA 1.0 repeatedly reactive donors.

Now, there's divided opinion over whether attempting to locate and recall EIA 1.0 repeatedly reactive donors is appropriate. Most feel if you have a sample, do a RIBA to determine whether to notify. I'd like to emphasize that while there are no outcome data available yet from any of these efforts.

I'm going to just be summarizing the limited information that we've been able to obtain so far. You will see, though, that lookback based on EIA 1.0 is being approached in a variety of different ways.

The military's experience is that many of their donors are first-time donors, with no prior donations to go back and look for, so the number of lookbacks they have to do is considerably lower compared to the civilian population. They are doing lookback based on unconfirmed 1.0 repeatedly reactives. They have no supplemental test results.

Now, the services have been given the option to do additional testing if they want to, that is, RIBA 2 or RIBA 3 with the Red Cross or EIA 3.0 if they want to, but none of them have taken that option because they don't have frozen samples back that far, and it's difficult to call donors back in for additional testing. Most of their facilities have begun the retrospective review of records.

The American Red Cross presently intends to do lookback for EIA 1.0 repeatedly reactives, but only for those with supplemental test results, investigational RIBA 2. Their projections are that, because of extending the lookback to first-generation EIA, the number of repeat donors to do lookback on will increase from 28,000 to 37,000, an increase of about a third; the number of components will increase from 242,000 to 320,000, an increase of about a third; and the number of recipients to be traced and notified will increase from 50,000 to 60,000.

Blood Systems, Inc., of Scottsdale, Arizona, is doing lookback for all unconfirmed EIA 1.0 repeatedly reactives. They no longer have stored samples, but they're searching records and they're sending out letters to consignees covering 14,000 donations.

The Community Blood Center in Kansas City, Missouri, has stored samples for their EIA 1.0 repeatedly reactives, and they are preparing to do consignee notifications based on EIA 2.0 and RIBA 2 results on those stored samples. Extending the lookback to first-generation EIA has nearly doubled the volume of their lookback effort.

If we would attempt to answer the question of what should be the scope of lookback for HCV, we may be able to draw on the experience from the Canadian and the Wisconsin studies I've cited and from previous lookback efforts. One option that we might discuss would be a lookback effort of contacting and testing all transfusion recipients.

In the general lookback effort for HIV in the San Francisco area, the number of persons who could be recontacted after 6 to 12 months was very low, and only 4.4 percent of the 17,331 persons notified by individual letter who were transfused during the risk period prior to screening for HIV actually sought testing.

Now, shortly after anti-HCV kits were licensed in 1990, one blood center initiated a pilot study of general HCV lookback, a transfusion recipient education program about hepatitis C. Following the widely publicized, large-scale targeted community education and notification campaign, a very small proportion, only an estimated 1 to 5 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 a supplement test.

Therefore, based on these two studies, targeted and general efforts to notify all transfusion recipients have limitations similar to targeted lookback based on donor testing.

I think I'll stop there and take any questions you might have.

CHAIRMAN CAPLAN: Thanks, Dr. Mied.

Let's open the floor up for questions, comments?

MS. O'CONNOR: With the two studies you cited here, were there any general education efforts that went along with that?

DR. MIED: I think there certainly was in the Zuck study, the HCV study. There was a widespread community education and notification campaign. The first study is Dr. Busch's study. Maybe he can comment on the scope of the education that was--

DR. BUSCH: Right. These are two different formats. The first study involved particularly UCSF, but also several other regions in the Bay area. The hospitals searched their transfusion records and sent letters, individual letters, to all patients who they had information they had been transfused in the prior risk period. And you see that only about 5 percent of those letters ended up triggering recipients to come in and get tested.

The second study did not include specific letters to recipients. It was exclusively a large general public education campaign approach with free testing available.

DR. PENNER: No combined?

DR. BUSCH: Right. There was no--to my knowledge, in the states there's no experience where--I mean, there was--in addition at the same time San Francisco sent letters. That was coincident with when CDC put out their broad recommendation that transfused recipients should be tested for HIV.

CHAIRMAN CAPLAN: Yes?

DR. GOMPERTS: This is a question for Dr. Mied as well as Dr. Alter. To what extent has the procedure for testing been evaluated as a barrier to this overall public health campaign?

DR. MIED: The procedure for testing?

DR. GOMPERTS: Yes. Where is testing being done?

DR. MIED: Where is testing--testing is being done by the blood establishments, or oftentimes they will send samples out and receive back the results.

Are you talking about the donors or the recipients?

DR. GOMPERTS: I'm talking about recipients.

DR. ALTER: My understanding is that the American Red Cross and many--I know that the American Red Cross plans to, in their letter to the recipient, offer testing to them at whatever each local area sets up as a testing site, free of charge. That's my understanding. And other blood centers I think will be varying their approaches, but in the letter of notification it will tell the recipient where they can be tested and under, you know, what conditions.

So I don't think that testing, at least for the targeted recipient, is--is an issue that will be very clearly stated in their notification letter. In terms of general notification, these individuals will be told to go to their regular source of medical care for such testing.

DR. GOMPERTS: Do you see this as a barrier?

DR. ALTER: For people who lack any source of medical care, it could be. It will be important that our current programs, such as Medicare and Medicaid, cover this testing.

DR. GOMPERTS: Can I just ask one additional question? Any possibility, any thoughts from a point of view of opening up the HIV testing centers to HCV?

DR. ALTER: In terms of our overall plan for testing people at high risk for HCV, which would include transfusion recipients, we have taken a variety of approaches for testing, including the use of HIV counseling and testing sites, to provide HCV follow-up as well. I don't know that those are the best places for people with a history of transfusion to seek testing. In fact, they might not--they might be discouraged from seeking testing if that were the designated place, and one of the areas that we're working on with state and local health departments is to establish testing places in which people who fall outside, you know, high-risk groups for HIV would be comfortable to be tested, and that's part of the plan that we submitted last April to the Department.

CHAIRMAN CAPLAN: Dr. AuBuchon?

DR. AuBUCHON: I would just note, without comment that to my knowledge the last statement from Health Care Financing Administration was that they had not yet decided whether or not to require the Medicare carriers to pay for HCV testing subsequent to notification as part of targeted lookback.

A question. Can you give us an update on the status of the licensure, potential licensure of RIBA 3.0? This supplemental test would correspond to the most sensitive EIA testing that's available and the one that is generally used blood-collecting agencies but for which there is not a corresponding licensed supplemental test.

DR. MIED: I wish I could give you an update. Unfortunately, I'm not able to do that. We would like to see the test get licensed. We recognize the benefits of having it out there, and we hope that licensure can be accomplished soon.

DR. BUSCH: Paul, just one clarification and then one issue. The clarification, you reported for Blood Systems, Incorporated, that they were triggering lookback on all first-gen repeat reactives, and I know for a fact that is not correct. Their program is similar to the Red Cross' proposed program, triggering lookback on first-gen repeat reactives for which confirmatory data was available and which were confirmed positive. And that began approximately a year and a half into screening. So they have confirmatory data beginning basically when the Chiron (ph) reference lab opened in July of, I believe, '91.

DR. MIED: I don't know how many samples they do have prior confirmatory results for. The impression I got was that it was a very small proportion of the total number of the 1.0 repeat reactives, and that when they changed their facility, many of the samples they had that they could now go back and retest were not stored properly, and they had to discard them all. So I think you're correct, but it's probably a small proportion of the total repeat reactives from 1.0 that they have.

DR. BUSCH: If they have confirmatory, again. So the only program that's actually proposed to trigger lookback on repeat reactives in the absence of confirmatory data is the military program.

The other point is extending the first gen--for those samples for which one has confirmation on first gen, extending it to indeterminates I don't think is warranted. And the numbers that result are dramatically increased. You nearly double the number of notifications that would be triggered if you include RIBA 2 indeterminates. And I think we know, similar to the policies that are currently approved by FDA, if you have a better confirmatory assay, such as the third-gen RIBA for second-gen reactives, you're not requiring notification of indeterminates. And I would think that same policy could and should apply here. If we have first-gen repeat reactives and we have second-generation RIBA, among the second-generation RIBA indeterminates only a very small fraction would be confirmed positive. I think that's a group that there's a very, very low probability of true infection.

DR. MIED: But you're absolutely right, Mike. Point well taken. There's quite a difference in doing it on positives versus positives and indeterminates.

CHAIRMAN CAPLAN: Let me try a different line of questioning to you about speed of lookback and implementation of policy. Let's see. What are we in? We're at the end of November. I think the Committee was hoping at one point that lookback would have started. I remember a lot of discussion here of not worrying too much about the pre-'92 group in the hope that we'd be underway. And I understand, Dr. Mied, that the revisions and reactions and input from other sources led to the revised rule and rulemaking as well.

I guess what troubles me a little bit is, as I look out there and see some lookback campaigns, some are going to be launched in a different direction, and some are out there by private companies, which are now able to directly market things they think might be efficacious, and you can see a certain kind of education campaign. I've seen some advertising copy and some ads that have me worried that the American people will find out that if they're breathing and have blood they ought to go out and have a hepatitis C test. I would rather hear that message coming from government agencies, authoritative sources, physicians, health care professionals. So that leads me to be nervous about speed.

The question that I have for you is: Can we be assured, given that we're in November, that we are going to start in March, that the timetable will be firm, that we're not going to see ourselves set back further? I mean, the context here is not simply one of letting people know about their risks, about ways to reduce morbidity or harm and infectivity, but also that as you look on the therapy side, the ante goes up and messages are going to start to be coming out from many sources, some of which may--how can I put this?--have a spin on that message.

So what I'm looking for is some assurance that we were here once before and we're not looking back yet, and I know we're getting ready to look back again. I saw the slide. I understood what the story was. But I'd like to have some assurance that we won't be sitting here in April wondering what's up.

DR. MIED: Dr. Caplan, I think that the good news is that many small blood establishments have begun their notification process, and no doubt some of them have completed their notifications. The larger and independent blood establishments or blood organizations are notifying consignees now, and I think that our recommendations state that you don't have to wait until March, that blood establishments should begin notification of consignees as soon as feasible, and for many blood establishments, that's now.

In fact, it has been feasible for them to notify, and they have done so, but that they complete all notifications by March 23, 1999, and that's a firm date, that they begin notifying by that time. So that's a firm date, and certainly the counseling materials are out there. CDC has done a wonderful job in getting those out, and now that they're widely available, you know, I think that that can proceed and that date is easily accomplishable.

CHAIRMAN CAPLAN: David, I see your--

DR. FEIGAL: I just wanted to comment that I think as soon as this Committee made its recommendations, even before Secretary Shalala made her statement, we're aware of the fact that the blood centers were beginning to identify the products that needed to be traced. And one of the things that's difficult to appreciate in terms of the magnitude of this is the amount of it that's invisible before the letter goes out.

You saw some of the trees that start with the millions of units, and then whittle it down to the number of recipients, and then expand back up to the number of components. So I think it's that first part that is well under way.

Some of the comments will adjust some of that, but I think the industry knew that there were certain people that were going to be part of the lookback no matter what. We're arguing about some of the margins. And I think that process is well under way.

DR. SECUNDY: The congressional report made comments about the failure--the lack of a monitoring or enforcement mechanism for FDA relative to the industry and the lookback. Can you speak to that issue relative to what you have presented? How are you going to know that it's being done? What processes exist formally or informally?

DR. MIED: We have inspectional surveillance of blood establishments. Now that the revised guidance is out there with its firm dates by which they need to begin notification and complete notification, our inspectional surveillance activity of blood establishments will see that that, in fact, is accomplished.

Once the regulation is out there, then we will conduct surveillance to see that the regulation is complied with, not just the guidance. So we have that oversight now with the guidance by inspections, and we will have it with the rule when it is published.

DR. GUERRA: A couple of comments. I think, you know, as we have seen in our own community and in other communities around at least the State of Texas, the initial efforts are certainly underway with any number of the blood centers that have initiated that in their communities and I think are being very good about trying to be appropriate in the way they have taken the information to the recipients of those units where they have identified individuals that have been positive.

The greater concern for us has been that there is certainly some lag in reporting to us, at least from a public health standpoint where we're trying to maintain some surveillance in the community, and the other is that we are getting now an increased number of calls from the people that are worried because they have had some contact with those that have been found to have received a blood transfusion from somebody that's hepatitis C positive.

So I think that somehow we have to bring those two systems together of public health at the local and state level and the blood center industry.

CHAIRMAN CAPLAN: All right. Thank you, Dr. Mied.

Let's go right into our next presentation. This is the Interorganizational Task Force on HCV Lookback. It's the AABB, America's Blood Centers, ARC. I'm not sure who actually is doing the presentation on this one. All right.

xx DR. TRIULZI: Thank you, Dr. Caplan. Good morning.

My name is Dr. Darrell Triulzi, and I am an associate professor of pathology and medicine at the University of Pittsburgh and medical director of a large multi-hospital transfusion service in Pittsburgh that supports the largest liver transplant program in the nation.

Since our transfusion service does account for two-thirds of all the blood transfused in Pittsburgh, I have abundant experience in the lookback process for HIV, HTLV, and CJD, and it is anticipated that our transfusion service alone will receive a list of more than 3,000 components implicated in the HCV lookback in its current form.

From this background, as one in the trenches, I'm speaking to you this morning on behalf of the AABB Interagency Task Force on HCV Lookback, and I'm thankful to have the opportunity to speak to you on this important issue.

Following the recommendation of this Committee to conduct targeted lookback for recipients of prior components from donors determined by testing after May of '92 to be HCV antibody positive, the AABB formed an interagency work force to coordinate efforts with the health care community. This task force is comprised of representatives from the American Association of Blood Banks, America's Blood Centers, the American Red Cross, and has liaisons with the FDA, CDC, and HCFA. The task force represents all facets of blood banking, including blood collection centers and also hospital transfusion services.

This task force has taken a very active role in seeing that HCV lookback is effectively implemented and that state-of-the-art information about HCV is immediately available not only to blood banks and transfusion services, but also to physicians and patients.

The Advisory Committee has received updates from Dr. Jim AuBuchon, who is a member of your Committee, and has also been provided with a copy of a letter from the AABB to Representative Shays which discussed some of the task force activities in detail.

Targeted lookback is a massive endeavor. The time and effort required by the entire health care community should not be underestimated. In the Canadian HCV lookback experience, they reported two hours of physician time and 12 hours of technologist time were necessary to identify the recipient of each blood component. Three years into the process in the Canadian experience, they are only one-third of the way to completion of their HCV notification effort.

There have been several key developments in the HCV lookback effort in the United States. First, the CDC, with input from the blood banking and transfusion medicine community, has developed sample letters for both patients and physicians and a patient brochure to be used nationwide in the HCV lookback program. Second, on September 23rd, the FDA issued a revised comprehensive guidance document. And, finally, recipients obviously cannot be notified in a vacuum, and we have worked diligently to provide education and counseling materials for notifying the physician and the recipient.

The task force developed a physician script for use by the notifying physician and also the CDC published an MMWR on recommendations for prevention and control of hepatitis C on October 16th. These educational materials were provided to all AABB members.

HCFA has not yet published guidance for hospitals, and we remain concerned that the hospital community is not aware of the significant resources needed to conduct HCV lookback. Further, HCFA has not acted to ensure reimbursement for testing of Medicare recipients. A specific recommendation from this Committee may be helpful in accomplishing those actions.

Since the publication of the draft FDA guidance document, blood-collecting agencies have been working diligently to identify involved donors and work toward notification of hospitals. We appreciate the FDA's understanding of the importance of coordinating the patient notification effort from hospitals and physicians with public and physician education about the importance of this effort.

We estimate that the approximately 300,000 components are subject to lookback investigation in the current form of guidance document. Records for many of these units have been identified, and consignee letters are now going out. Now that all the educational pieces have been provided, including the recent MMWR, we anticipate that hospital notification of individuals will proceed at a rapid pace.

We support the concept of recipient notification and the extension of previous recommendations to include donations from donors found to be repeat reactive with the 1.0 HCV test who have been subsequently confirmed with RIBA 2.0. New information indicates that there are some blood banks that do, in fact, have such confirmatory test records, and this extension will provide useful information to some individuals.

On the basis of information presented to this Committee, including the problems associated with false positive tests, lack of sensitivity, and the Canadian experience with HCV lookback, we believe that the most effective way of notifying recipients with repeat reactive HCV 1.10 and confirmatory test has not been done is the general notification plan presented by the CDC.

However, if lookback is extended to HCV 1.0, the Committee should understand it would be impossible to accomplish the targeted notification of an additional 536,000 individuals within the current time frames and that, in fact, it would be years.

At the same time, we support the CDC evaluation of the effectiveness of targeted and general notification and stand ready to assist in these efforts.

In closing, I would ask that the Committee consider the following five points to increase the effectiveness of HCV lookback:

One, that if the Committee elects to recommend HCV lookback to 1.0, that adequate time be allowed to perform this task;

That there be licensure of the confirmatory test, meaning RIBA 3.0, to resolve donor status in regard to infectivity, so that way we may minimize unnecessary notification of recipients;

Three, that there be assistance from the Social Security locator service to find patients so that we may, indeed, in the shortest time frame possible get notification to those individuals;

Four, that there be assistance from the state government, such as Bureau of Vital Statistics, in sharing information on patient vital status, such as whether they are alive or dead, so that we don't need to unnecessarily notify families;

And, five, that there be coverage of testing costs by HCFA for Medicare and Medicaid patients.

Thank you for the opportunity to speak today. The Interagency Task Force remains committed to the public health effort embodied in the HCV targeted lookback and general education campaigns.

CHAIRMAN CAPLAN: Thank you. That was a paradigm of succinct presentation.

DR. PENNER: Since there's a reliance on the Canadian data, as I recall, the Canadians did not use the--or apply ALT elimination of donors prior to their lookback, and this I think would eliminate a lot of the repeat donors that would be applying. So I don't know that their data really is applicable here.

DR. TRIULZI: Okay.

DR. BUSCH: Just to respond to that, it, in fact, goes the other direction; i.e., that in the States where we introduced anti-core and ALT, that resulted in deferral of a large number of infected donors who would have presented and been found in triggered lookback. So the Canadian program, in fact, would have a much higher yield because they didn't defer those doors. They were detected in the context of first-generation and second-generation screening.

DR. PENNER: What I'm proposing, though, is that many of those ALT donors that would have been repeat donors are now excluded, so, therefore, you have a population of more single donors who are first-time donors.

CAPTAIN RUTHERFORD: Concerning changing the law to allow us to go to the Social Security Administration, I know that the DOD has tried unsuccessfully, wants to have the law changed to allow us to do that. For those of you who do not know, there is a law written using the Social Security Administration and the IRS to allow the state health departments and the District of Columbia and commonwealths to go to the Social Security Administration. Well, if your state health department does not sign the MOU, then you are blocked from going to the Social Security Administration.

So the law is really written to allow us to do that, but it neuters us if you do not sign the agreement from the local health department. So I think it's an outstanding idea. If we are really sincere on trying to locate recipients, then this is one way to do it.

CHAIRMAN CAPLAN: We've flagged an issue here that is near and dear to my heart. Remember the recent debate, too, that took place when Congress mandated the identifier number be put forward, and I don't think the American people understand the public health consequences of not being able to trace through public records identifier numbers that face--that challenge people who want to do this kind of lookback or other similar sorts of public health interventions. So maybe the Committee will be able to speak on that in the discussion period later.

I think it's quite possible to protect privacy without sacrificing public health, but I don't think we've made a good case about that, and these kinds of things are obstacles. So I understood what you were asking for about help in that area.

DR. TRIULZI: Can I just make a comment? That's especially true, because going back to 1.0, you're talking about donations between '90 and '92 and may extend back into the '80s when people have moved two and three times, and their vital status and their location may be unknown.

DR. AuBUCHON: Dr. Penner's comments about the inapplicability of the Canadian experience may be true, but in a different direction related to being able to find recipients. In the Canadian health care system and also in Finland, where they have reported a similar experience with HCV lookback, they have universal health care; they know where their recipients are; they know where their patients are; and they provide them free testing and free follow-up service. So any concerns about insurability would not deter someone from getting tested. Therefore, the issue of establishing some system to identify patients over time is extremely important. Unfortunately, it did not begin 15 years ago in such a way that it would allow us better probability of finding recipients we're looking for in HCV targeted lookback.

DR. GILCHER: Darrell, have you considered recalling the HCV 1.0 donors and retesting them and then with a 3.0 test? That's what we intend to do, and that actually will eliminate a lot of the false positives that we first found.

DR. TRIULZI: Right. Did everybody hear the question? It was about recalling the donors who were tested with 1.0.

The blood center that provides us with blood recalled the donors from the 1992, the 2.0, on. About 20 percent was the response, the ability to recall donors. So 80 percent, you could not get them back. I suspect that number of 20 percent would be even lower for people who donated between 1990 and '92.

The other problem is that RIBA 3 is not widely available to all blood centers in this country, and I think that's a problem. It's not a licensed test, and there are availability issues, and that's one of the reasons why we bring that up to the Committee, that at least having the 3.0 would allow us to resolve as many of these donors as possible.

DR. GILCHER: My comment is not RIBA 3. My comment is EIA 3.0.

DR. TRIULZI: That would be widely available. EIA 3.0 could be used to the same intent.

CHAIRMAN CAPLAN: All right. Why don't we push on? Maybe the thing to do at this point is to take a break. We can go to the recipient blood group organizations, COTT, Hemophilia, IDF and so on, after the break. We can also hear from the American Liver Foundation at that point.

So let's break for 15 minutes and reassemble pretty promptly at about 10:15.

[Recess.]

CHAIRMAN CAPLAN: We are going to hear next from representatives of some of the blood recipient organizations; following them the American Liver Foundation, Alan Brownstein.

Terry, why don't you launch us?

MR. RICE: Good morning. My name is Terry Rice, and I'm a member of the Board of Directors at the Committee of Ten Thousand.

I had a few overheads for us to enjoy today which would have made my presentation a little longer, but they ended up in Manhattan somewhere yesterday, and I haven't gotten them back yet. So I put together a little bit of what I could recollect my presentation was, and I'll present it to you today. It'll be shorter, so it's probably better for everybody.

First, I'd like to thank the Blood Safety and Availability Committee for inviting us to speak today on the subject concerning HCV lookback. We are pleased that the Federal Government and the blood banking industry are finally taking the initiative and moving to notify those exposed to hepatitis C through blood transfusions.

The history of HIV and HCV is one of regulatory failure and industry inaction, an explosive combination that resulted in the devastating AIDS epidemic in the hemophilia community, as well as the HCV infection of potentially hundreds of thousands of American citizens, a history that is in large part preventable and avoidable. It is from this perspective that we address the proposed lookback initiative.

Prior to the availability of early inactivated factor concentrates and improved donor screening techniques, virtually all persons with hemophilia were infected with the hepatitis C virus. While today we may view this as some historical matter of fact, it still gives me pause to reflect that this reality emerged within the world's best medical care delivery system and regulatory structure. Believe it or not, there was a time when the medical community and the regulatory structure considered it normal or acceptable for persons with hemophilia to be infected with non-A/non-B hepatitis and for the industry to ship knowingly lot after lot of adulterated product. Simply put, there may not be another community more devastated by hepatitis C than the hemophilia community.

Suffice it to say we've experienced the emotional and physical suffering which accompanies chronic HCV infection, as well as a sense of abandonment from those responsible to warn and inform.

Recently, CDC estimates indicate that some 4 million Americans are now infected with HCV, and this number is growing. HHS has estimated that the yearly total society cost of hepatitis C approximates $600 million. Since an estimated one million of these infections are considered a result of blood and blood product transfusions, it would be reasonable to rationalize that society is bearing some $150 million in negative externalities from the production processes of these products. That's not a bad subsidy for industry. Society seems to have made a substantial down payment on whatever it may cost to carry out a humane and ethical lookback initiative.

One might ask why are we here. Why is hepatitis C lookback important? At the core of a free society is the right to self-determination. Americans have a right to know critical medical information that can substantially impact the quality of life as well as one's longevity. It is commensurate with an individual's right to informed consent. Treatment options are available to persons infected with HCV. Many of these therapies work best if intervention occurs in the early stages of disease.

Changes in lifestyle, such as eliminating alcohol intake, can have a positive effect on an infected person's well-being and disease progression. Americans should be informed if they are at risk so that they might seek diagnosis and treatment options. One would hope that we would try to reach as many people at risk as possible through the most effective method of communication--direct notification.

The scope of the current lookback is too limited. Proponents of this plan want to begin notification with the introduction of the second-generation HCV antibody test in 1992. This test was not only more sensitive than its predecessor, but had an increased specificity. It also coincided with an available confirmatory test to eliminate more false positives. While supporters advocate saving these dollars by limiting this lookback, we would be leaving out a number of Americans who might benefit from this notification.

We support at the Committee of Ten Thousand extending the lookback cutoff date to 1990 with the availability of the first-generation HCV antibody screening test, as other countries who have already carried out their HCV lookback initiatives have done. It is estimated that if we do carry this HCV lookback back to 1990 and the first-generation test, an additional 700,000 persons might be identifiable as potentially at risk. Although there will be a number of reductions in that number based on mortality and perhaps only 10 percent of these individuals still being alive today, still there may be as many as 50,000 to 70,000 individuals who can benefit from this additional public health lookback and information for their own personal health.

Essentially, if the current lookback proceeds with the 1992 cutoff date, we will limit our availability to notifying approximately 300,000 of the one million potentially infected Americans. To coin a phrase, if it's good enough to screen with, it's good enough to look back for.

Another troubling exclusion is that users of blood products which were made from donors who were infected with HCV have not been included in this lookback. Although I am troubled by this, I am not surprised. The hemophilia community is still waiting for an HIV lookback to be carried out by industry, as we would presume is required by law. This statute was ignored with respect to blood products users although it was carried out with respect to whole blood recipients who had a lookback conducted in the late '80s.

But in the lookback, users of plasma products, such as hemophilic factor, we're being expressly exempted. Decisionmakers have explained that this exemption was based on good economic cost/benefit considerations. Since all persons with hemophilia typically have good medical care, they would already be advised that it's time to be tested, and there may not be a serious benefit in identifying those individuals.

I think that from our perspective it just seems that every time there is a lookback, persons with hemophilia are excluded. Is it just because we happen to have such a breadth of infection that we all just assume that we should be tested? But we think that there is a pattern that's developing, and we hope that every time there is a lookback that we're not expressly exempted from that particular initiative.

Let's not be naive. We feel that industry is--although I'm sure that the leaders in industry want to do the right, moral, and ethical thing and are probably committed to notifying as many persons as possible, we have to realize that in most cases the decisionmaking is led by legal advice. And that legal advice is going to in most cases try to restrict the potential exposure and legal liability that notification processes can create for organizations.

Therefore, we believe that the leadership for this entire initiative must rest with and be carried out by the HHS since we believe that leaving it to industry to take it upon themselves to conduct this would not be in the best public interest.

Lastly, I'd like to thank the Committee and the Secretary for taking the time to address this issue. Special thanks should be given to Chairman Shays of the Human Resources Subcommittee for continuing to make this issue a forefront issue, and I'm sure that there are going to be many lives not only preserved but enhanced by his efforts and the efforts of the members of that committee.

Finally, we strongly support the seven recommendations as published by the Government Reform and Oversight Committee.

Thank you.

CHAIRMAN CAPLAN: Jan, do you want to go next?

MS. HAMILTON: Good morning. Thank you for inviting us once again. My name is Jan Hamilton. I'm Executive Director of the Hemophilia Federation of America. I'd like to thank the Chairman and Dr. Nightingale and everyone for allowing us this opportunity.

If Hollywood were having a casting call for a new superhero to portray the watchman for safety in the blood industry, they might look no farther than Congressman Christopher Shays. Congressman Shays has kept his finger on the pulse of the blood products industry for quite some time now and usually points out shortcomings of government and industry in this field with startling clarity and accuracy.

Congressman Shays has once again sounded the trumpet for concern and, yes, even alarm in the shortcomings regarding the silent epidemic of hepatitis C infection posing a threat to the public health in our country. However, it has seemed to fall on deaf ears in some of our Federal public health arenas.

The Centers for Disease Control and Prevention sources tell us that HCV has now spread to an estimated 4 million Americans. Eighty-five percent of those infected develop chronic liver disease, and about 10 to 20 percent develop cirrhosis of the liver within about 20 years after the onset of infection, to say nothing of those who convert to cancer. Deaths from hepatitis C are amounting to be 8,000 and 10,000 per year in the United States and within a decade or so should triple, without more effective programs for prevention and treatment.

In July of 1995, after an almost two-year study, the Institute of Medicine released a comprehensive report entitled "HIV and the Blood Supply: An Analysis of Crisis Decisionmaking." This report doesn't address problems of hepatitis in our population, but it does address with great detail and clarity what needed to be done to prevent another health crisis like the one with which we have become all too familiar in regards to HIV.

Some of the recommendations that you will find in this comprehensive report are: establishment by the Public Health Service of a Blood Safety Council with a Blood Safety Director, and we know that's been done; a call for other Federal agencies to understand, support, and respond to CDC's responsibility to serve as the nation's early-warning system for threats to the health of the public. Is anyone listening? The FDA should periodically review important decisions made when uncertain about the value of key decision variables. Who is reviewing these HCV decisions?

In response to lookback, the IOM determined that earlier action on lookback in regards to HIV might have reduced secondary transmission of HIV. We have to ask if we're falling into the same trap here.

When issues instructions to regulated entities, the FDA should specify clearly whether it is demanding specific compliance with legal requirements or merely providing advice for careful consideration. The FDA should tell its advisory committees what it expects from them and should independently evaluate their agendas and their performance. The FDA should develop reliable sources of the information it needs to make decisions about the blood supply. The FDA should have its own capacity to analyze this information and predict the effects of regulatory decisions, and an expert panel should be created to inform the providers of care and the public about the risks associated with blood and blood products, about alternatives to using them, and about treatments that have the support of the scientific record. And this is all from the IOM report recommendations.

It is true that only 25 percent of hepatitis C transmissions occur through the blood supply. However, attention to these could and would spill over to other areas of concern, and the educational component can certainly apply to all.

Additionally, infection in 40 percent of the cases cannot be attributed to a known risk factor which alerts us to the fact that there could be another road to transmission of HCV of which we are unaware. What is it? Where are these dangers? And why isn't more being done to find these answers?

Of the some 4 million Americans now infected with HCV, as previously stated, 85 percent develop chronic liver diseases and between 10 and 20 percent of those develop cirrhosis of the liver and up to 10,000 a year will die from this so-called silent epidemic. Most of those who have been infected are unaware of their infection. While there is no vaccine against hepatitis C, there are effectiveness treatments of which patients should be made aware. Of course, they must know to be tested for HCV first in order to avail themselves of treatment.

A look at the time line of discussion and decisions, or lack thereof, on the part of our government agencies is frightening at best. In 1996, Congressman Shays' committee recommended HHS take steps to notify 300,000 or more Americans known to have been infected with HCV through blood before 1990. To date, this has not been done. More than two years have passed, and the numbers have skyrocketed, and now we're told we're up to a million.

On seven occasions between October 31, 1989, and December 16, 1994, BPAC considered whether patients receiving HCV-infected units of blood or blood products should be notified. Even though treatment options were available, BPAC chose on each occasion not to act.

October 12, 1995, Donna Shalala committed that HCV lookback notification would be the first issue considered by this new committee. This issue was reviewed and discussed two years later, in April and August of 1997. At the August meeting, the Committee recommended lookback on patients testing positive on second generation screening, though some Committee members wanted more.

There was a steady line of Committee and agency discussion leading to a statement on March 5th by Surgeon General David Satcher, who announced an HCV lookback and education plan and stated his intention to reach "effectively as many people at risk as we can."

March 20, 1998, the FDA responded with publication of a guidance to industry in the Federal Register recommending that blood banks identify past donors of blood who tested positive for HCV on the 1992 second generation test and notify hospital blood banks and transfusion services that they should notify either at-risk patients or their doctors by September 20, 1998, more meetings and more workshops on plans for education and implementation of lookback procedures, and then on September 8, 1998, FDA withdrew the March 20, 1998, guidance for industry and didn't say anything about another guidance being issued.

The very next day, September 9, 1998, at a hearing of Congressman Shays' committee, both Acting FDA Commissioner Michael Friedman and Jay Epstein gave answers to questions posed by the Congressman regarding the lookback campaign and at no time indicated that the lookback had been withdrawn the day before.

Blood collection organizations were notified by FDA of the impending withdrawal by telephone on August 28, 1998. However, consumer groups were not notified in advance, and no written notices were sent by the FDA to blood banking organizations and no written records kept of these exchanges.

While on September 23, 1998, FDA issued a revised guidance for industry, current good manufacturing practice for blood and blood components, the guidance suggests but does not require that individuals who receive potentially HCV-infected blood and blood products should be notified by March 23, 2000.

Of the almost 1.2 million persons who have received potentially HCV-infected blood or blood products, only 25 percent would be directly informed with the lookback program instituted by HHS. Why? Because HHS has decided the first generation test had a high false positive rate, even though the sensitivity rate was 84 to 89 percent, while the second generation test was 92 to 95 percent.

Estimates are that only 22 percent received units from an individual with a false positive test. This doesn't seem to be a number significant enough to leave this at-risk group uninformed.

The CDC has developed a comprehensive, nationally focused plan for prevention and control of HCV infection entitled "A Prevention and Control Plan for Hepatitis C Virus Infection," referred to earlier today. Components include counseling and testing, professional and public education, surveillance, epidemiology and laboratory investigation and evaluation. The plan was submitted to HHS on April 14, 1998, but was not discussed by HHS's Blood Safety Committee due to HHS' refusal to commit requested funds to this CDC program; and since HHS didn't include the plan in its budget, Congress was never given the opportunity to review it.

I would like to refer once again to the Institute of Medicine report, "An Analysis of Crisis Decisionmaking." This prestigious panel stated that management of a public health risk requires an evolving process of decisionmaking under uncertainty. It includes interpretive judgment in the presence of scientific uncertainty and disagreement about values. Public health officials must characterize and estimate the magnitude of the risk which involves considering both the likelihood that infection might occur in various circumstances and the costs and benefits associated with each of the possible uncertain outcomes. They must also communicate with the public about the risk and strategies for reducing it.

We at the Hemophilia Federation of America highly recommend reviewing the pages of the Institute of Medicine report. Learn from the mistakes of the past. Help us to protect our citizens from additional risks.

The powers that be need to build energy, obtain focus, expand the lookback to a more realistic depth, and increase the educational components several-fold. Take advantage of all the consumer agencies that wish to be of assistance in spreading the word. If we join the hands of government, industry, and consumer advocacy organizations in providing education and utilize all the resources that are available, the silence can be removed from this epidemic.

Thank you for listening to our concerns.

CHAIRMAN CAPLAN: Thank you. Let's hold on to questions until we get all the presentations. Then we'll come back to the Committee.

Let's see. Don? Don Colburn is up next.

MR. COLBURN: Good morning, everyone. My name is Don Colburn. I'm a volunteer for the National Hemophilia Foundation, and I'm pleased to be here before you again.

I wish I was here on a little bit better of a topic, though, because as I reviewed the material for this meeting and we looked at our concerns, we have a number of issues that everyone thinks the hemophilia community is all wrapped tightly and secure and everything is okay.

We have approximately 25 to 30 percent of people with hemophilia who are not seen by our hemophilia treatment centers. They are outside that wrapped system. These folks may not know--they're usually mild folks with hemophilia or von Willebrand's disease. If we take a look at those folks who have been treated with a plasma product or whole blood product at that point, you're talking about a large number of people.

There is a real concern we have when we listen to things that were said this morning. I cannot believe that it actually takes 14 hours of a tech and a doctor's time to discover whether or not someone has actually become a recipient of a transfusion product. I guess my world of computerization is a little bit better.

There's also some other concerns that we have, too. I guess the economic concerns I've heard expressed here, I can understand it, I can agree with. But it strikes me that it might be a fair task, easier, just to notify everyone who's received a transfusion and let them be notified that they need to have a test for hepatitis C.

Now, one of the biggest challenges we have in the United States is the collection of blood. There are seminars held constantly on how to increase donors. What a better way to educate the public and let them know that they may have been infected and at the same time, when they do come in for their test, they can be told about the importance of blood.

We have opportunities here that we don't seize upon, and when we talk about a disease, one cannot help but go back to the early 1980s. And I guess all of you are going to have the opportunity this weekend for probably a long weekend, and I am certainly not comparing you to this group, but I would just ask you to draw your own conclusions. I might ask that you rent "The Band Played On" and watch the section where the government panel debates what they should do with HIV. It's kind of scary. We have read the same type of things for HCV.

Now, the reasons that we were given back then were a little bit different. Well, we don't know what causes AIDS. Well, we know what causes hep C. Well, we don't have any treatment for AIDS. Well, we have treatments for hep C.

You know, there are just some parallels here that I'll ask you in your wisdom to give stronger consideration to and not to give consideration to the economic concerns of those who feel that reaching out and touching past transfusion recipients is bad to do.

The other thing that I'm concerned about is I guess I feel very lucky as I approach Thanksgiving because when I was a youngster, I received a lot of whole blood transfusions, and based on the statistic I heard this morning, if you go in a hospital and have a transfusion, you have a 90 percent chance of being dead in ten years. I feel very good.

With that, I would just like to encourage the Committee to go for a more direct approach and insist upon it, that people be notified, and, you know, let's not worry about the false negatives. What better gift a person could have than to be notified you might have a viral disease and then to receive the information that you don't.

Thank you.

CHAIRMAN CAPLAN: And Miriam O'Day.

MS. O'DAY: Good morning. I'm Miriam O'Day, and I'm Vice President of the Immune Deficiency Foundation, and if you'll bear with me, I'll give the overview of the organization once again.

The primary immunodeficiency diseases are a group of nearly 80 different disorders that are intrinsic to the immune system and result in immunodeficiency. Most patients present clinically with an increased susceptibility to infection. These infections are marked by unusual severity and are generally chronic or unremitting, a point especially relevant to today's discussions since patients with primary immunodeficiency diseases may suffer severe complications from liver viral infections such as hepatitis C.

The Immune Deficiency Foundation was founded in 1980 to further education and research into the primary immunodeficiencies and thereby improve clinical care and prognosis of these patients. The foundation is comprised of over 20 chapters and represents nearly 50,000 U.S. patients. The foundation's medical advisory committee is comprised of 20 leading clinical immunologists who specialize in the care of patients with primary immunodeficiencies. Their function is to advise the foundation on its many medical programs and develop position statements on issues related to the care and treatment of this disease. It is on behalf of the IDF medical advisory committee that I'm making today's statement.

Of the nearly 50,000 U.S. patients who have primary immunodeficiency diseases, we have estimated from our survey data that some 20,000 to 30,000 currently receive IGIV antibody replacement therapy. Since the introduction of these products, these patients can look forward to a normal or near-normal life span. However, adverse events associated with the administration of IGIV have occurred and have forever changed or ended the lives of some of our patients.

Most recently, some of our patients have experienced an outbreak of hepatitis C due to the use of IGIV. In July 1994, there were 112 reported cases of hepatitis C, but this was just the first wave within this community. Because of the lack of surveillance, we do not yet know how many people were ultimately infected.

This has obviously been a tragedy for the individual patients, but it's also unfortunate that we have not learned anything about the management and natural history of hepatitis C in the vulnerable population. And as recently as October of 1998, the CDC's MMWR Volume 47 neglected to mention IGIV recipients during the period from 1993 to 1994 as high-risk individuals who should be screened for HCV, although the MMWR does mention the transmission via IGIV.

The establishment of a national registry of these cases would allow for comprehensive surveillance and, thus, we could learn about the natural history of hepatitis C within the primary immunodeficiency diseases. Physicians are currently unable to counsel their patients concerning the best treatment, relate the disease severity to immune function, give an estimate of the number of cases who have needed liver transplantation, or give any results about the outcome of this procedure and for which patients it proved the most useful.

A national registry would be the most valuable scientific resource for physicians who are dealing with the aftermath of this outbreak and for scientists who want to learn more about this common disease.

While it is presumed that transmission of hepatitis C through IGIV is no longer a threat to our patient population due to additional viral screening and viral inactivation steps, we should not fail patients who may be unaware that they have contracted this disease or to improve the management of those already diagnosed.

In summary, the IDF medical advisory committee makes the following recommendations:

Number one, the FDA, NIH, or CDC should establish a sufficient lookback and registry program to determine how many cases of hepatitis C occurred in the United States in recipients, both with and without primary immunodeficiency disease, of intravenou